EA043556B1 - POLYCYCLIC GLUTAMINYL CYCLASE INHIBITORS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to new heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (5-oxoprolyl, pGlu*) to release ammonia and the intramolecular cyclization of N-terminal glutamate residues to pyroglutamic acid to release water.

BACKGROUND OF THE INVENTION

Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu*), releasing ammonia. QC was first isolated by Messer from the milky sap of the tropical plant Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). Corresponding enzymatic activity was discovered 24 years later in the pituitary gland of animals (Busby, W. H. J. et al., 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl Acad Sci USA 84, 3628-3632). In the case of mammalian QC, the conversion of Gln to pGlu by QC can be demonstrated for the precursors TRH and GnRH (Busby, W. H. J. et al., 1987 J Biol Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 Proc Natl Acad Sci U S A 84, 3628-3632). In addition, initial localization experiments of QC revealed its colocalization with its hypothetical catalytic products in the bovine pituitary gland, further supporting its proposed function in the synthesis of peptide hormones (Bockers, T. M. et al., 1995 J Neuroendocrinol 7, 445-453 ). In contrast, the physiological function of plant QC is less understood. In the case of the enzyme from C. papaya, a role in plant defense against pathogenic microorganisms has been suggested (El Moussaoui, A. et al., 2001 Cell Mol Life Sci 58, 556-570). Putative QCs from other plants have recently been identified through sequence comparisons (Dahl, S. W. et al., 2000 Protein Expr Purif 20, 27-36). The physiological function of these enzymes, however, is still uncertain.

Known QCs from plants and animals show strong specificity for Lglutamine at the N-terminal position of substrates, and their kinetic properties have been found to obey the Michaelis-Menten equation (Pohl, T. et al., 1991 Proc Natl Acad Sci USA 88, 10059 -10063; Consalvo, A. P. et al., 1988 Anal Biochem 175, 131-138; Gololobov, M. Y. et al., 1996 Biol Chem Hoppe Seyler 377, 395-398). Comparison of the primary QC structures from C. papaya and the highly conserved mammalian QC structures, however, did not reveal any sequence homology (Dahl, S. W. et al., 2000 Protein Expr Purif 20, 27-36). While plant QCs appear to belong to a new family of enzymes (Dahl, S.W. et al., 2000 Protein Expr Purif 20, 27-36), mammalian QCs have been found to have strong sequence homology with bacterial aminopeptidases (Bateman, R S. et al., 2001 Biochemistry 40, 11246-11250), which leads to the conclusion that QC from plants and animals have different evolutionary origins.

Recombinant human QC as well as QC activity from brain extracts have recently been shown to catalyze the cyclization of N-terminal residues of both glutaminyl and glutamate. Most surprising is the fact that cyclase-catalyzed Glu ₁ -conversion is favored by a pH of about 6.0, with Glu ₁ -conversion to pGlu derivatives occurring at an optimum pH of about 8.0. Since the formation of pGlu-Ae-linked peptides can be suppressed by inhibition of recombinant human QC and QC activity from porcine pituitary gland extracts, the QC enzyme is a target in drug development for the treatment of Alzheimer's disease.

QC inhibitors 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 2008/128986, WO 2008/128987, WO 2010/026212, WO 2011/029920,

WO 2011/107530, WO 2011/110613, WO 2011/131748 and WO 2012/123563.

EP 02011349.4 discloses polynucleotides encoding insect glutaminyl cyclase, as well as the polypeptides they encode, and their use in methods for screening agents that reduce glutaminyl cyclase activity. Such agents are suitable as pesticides.

Definitions.

The terms ki or KI and K _D are binding constants that describe the binding of the inhibitor to the enzyme and subsequent release from it. Another value is the IC ₅₀ value, which reflects the concentration of inhibitor that, at a given substrate concentration, results in 50% enzyme activity.

The term DP IV inhibitor or dipeptidyl peptidase IV inhibitor is generally known to one skilled in the art and refers to enzyme inhibitors that inhibit the catalytic activity of DP IV or DP IV-like enzymes.

DP IV activity is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV) and similar DP IV enzymes. These enzymes are post-proline (to a lesser extent post-alanine, post-serine or post-glycine) serine-degrading proteases found in various tissues of the mammalian body, including the kidney, liver and intestine, where they

- 1 043556 remove dipeptides at the N-terminus of biologically active peptides with high specificity if proline or alanine forms residues that are adjacent to the N-terminal amino acid in their sequence.

The term PEP inhibitor or prolyl endopeptidase inhibitor is generally known to one skilled in the art and refers to enzyme inhibitors that inhibit the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).

PEP activity is defined as the catalytic activity of an endoprotease that is capable of hydrolyzing post-proline bonds in peptides or proteins where proline is located at amino acid position 3 or higher, counting from the N-terminus of the peptide or protein substrate.

The term QC as used herein includes glutaminyl cyclase (QC) and QC-like enzymes. QC and QC-like enzymes have identical or similar enzymatic activities, hereinafter referred to as QC activity. In this respect, QC-like enzymes may be fundamentally different in their molecular structure from QC. Examples of QC-like enzymes are glutaminyl peptide cyclotransferase-like proteins (QPCTLs) from human (GenBank NM017659), mouse (GenBank BC058181), Macasa fascicularis (GenBank AB168255), Macasa mulatta (GenBank XMOO1110995), Canis familiaris (GenBank XM541552), Rattus norvegicus (GenBank XM001066591 ), Mus musculus (GenBank BC058181), and Bos tauras (GenBank BT026254).

The term QC activity as used herein is defined as the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu*) or N-terminal L-homoglutamine or L-β-homoglutamine residues to the cyclic pyrogomoglutamine derivative, releasing ammonia. Thus, see diagrams 1 and 2.

Scheme 1. Glutamine cyclization using QC

Scheme 2. Cyclization of L-homoglutamine using QC

The term EC as used herein includes the activity of QC and QC-like enzymes as glutamate cyclase (EC), hereinafter referred to as EC activity.

The term EC activity as used herein is defined as the intramolecular cyclization of N-terminal glutamate residues to pyroglutamic acid (pGlu*) by QC. Thus, see diagram 3.

Scheme 3. N-terminal cyclization of uncharged glutamyl peptides using QC (EC)

The term QC inhibitor glutaminyl cyclase inhibitor is generally known to one skilled in the art and refers to enzyme inhibitors that inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase (EC) activity.

QC suppression efficiency.

In light of the correlation with QC suppression, in preferred embodiments, according to the claimed method and medical use, an agent with an IC ₅₀ for QC suppression of 10 μM or less, more preferably 1 μM or less, even more preferably 0.1 μM or less is used, or 0.01 μM or less, or most preferably 0.001 μM or less. Indeed, inhibitors with Ki values in the range below micromolar, preferably nanomolar and even more preferably picomolar are contemplated. Thus, while the active agents are described herein as QC inhibitors for convenience, it will be understood that such nomenclature is not intended to limit the subject matter of the present invention to a particular mechanism of action.

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Molecular weight of QC inhibitors.

In general, QC inhibitors according to the claimed method or medical use will be small molecules, for example, with molecular weight values of 500 g/mol or less,

400 g/mol or less, preferably 350 g/mol or less, and even more preferably

300 g/mol or less, and even 250 g/mol or less.

The term subject as used herein refers to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment.

The term therapeutically effective amount as used herein means an amount of an active compound or pharmaceutical agent that produces a biological or medical response in a tissue system, animal or human, sought by a researcher, veterinarian, physician, or other clinician, that provides a reduction in the severity of symptoms of a disease or disorders to be treated.

As used herein, the term pharmaceutically acceptable includes both human and veterinary use. For example, the term pharmaceutically acceptable includes a compound acceptable in the field of veterinary medicine or a compound acceptable in the field of medicine and human health.

Throughout the specification and claims, the expression alkyl, unless specifically limited, means C ₁ . ₁₂ αalkyl group, suitably a C ₁ - ₈ alkyl group, for example C ₁ . ₆ alkyl group, for example, C ₁ _ ₄ alkyl group. Alkyl groups can be straight or branched chain. Suitable alkyl groups include, for example, methyl, ethyl, propyl (eg npropyl and isopropyl), butyl (eg n-butyl, isobutyl, sec-butyl and t-butyl), pentyl (eg n-pentyl), hexyl ( eg n-hexyl), heptyl (eg n-heptyl) and octyl (eg n-octyl). The expression alk, for example in the expressions alkoxy, haloalkyl and thioalkyl, should be interpreted in accordance with the definition of alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy), butoxy (eg, n-butoxy), pentoxy (eg, n-pentoxy), hexoxy (eg, n-hexoxy), heptoxy (eg, n-heptoxy ) and octoxy (for example, n-octoxy). Exemplary thioalkyl groups include methylthio-. Exemplary haloalkyl groups include fluoroalkyl, such as CF3.

The expression alkylene denotes a chain of the formula -(CH ₂ ) _n -, where n is an integer, for example 1-5, unless specifically limited.

The expression cycloalkyl, unless specifically limited, means a C ₃ - ₁₀ cycloalkyl group (ie 3-10 carbon atoms in the ring), more suitably C ₃ . ₈ cycloalkyl group, for example, C _{3 6} cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The most suitable number of carbon atoms in the ring is between three and six.

The expression heterocyclyl, unless specifically limited, refers to a carbocyclyl group where one or more (e.g., 1, 2, or 3) ring atoms are replaced by heteroatoms selected from N, S, and O. A specific example of a heterocyclyl group is a cycloalkyl group (e.g., cyclopentyl or more particularly cyclohexyl), wherein one or more (for example, 1, 2 or 3, especially 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O. Illustrative heterocyclyl groups containing one heteroatom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two heteroatoms include morpholine, piperazine, dioxolane and dioxane. A further specific example of a heterocyclyl group is a cycloalkenyl group (e.g., a cyclohexenyl group) wherein one or more (e.g., 1, 2, or 3, especially 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S, and A. An example of such a group is dihydropyranyl (for example, 3,4-dihydro-2Hpyran-2-yl-).

The expression _{aryl, unless specifically limited, means a C6_12 aryl group, suitably a C6_10 aryl group ,} more suitably _{a C6_8} aryl group. An aryl group will contain at least one aromatic ring (eg, one, two or three rings). An example of a typical aryl group with one aromatic ring is phenyl. An example of a typical aryl group with two aromatic rings is naphthyl.

The expression heteroaryl, unless specifically limited, means an aryl moiety wherein one or more (e.g., 1, 2, 3, or 4, suitably 1, 2, or 3) ring atoms are replaced by heteroatoms selected from N, S, and O, or also a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3 or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O. Illustrative monocyclic heteroaryl groups having one heteroatom , include five-membered rings (eg, pyrrole, furan, thiophene) and six-membered rings (eg, pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include five-membered rings (e.g., pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-1-yl, imidazol-2-yl, imidazol-4-yl), six-membered 3 043556 rings (for example, 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 (eg, indol-6-yl), benzofuran, benzothiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline, and purine.

The expression -alkylaryl, unless specifically limited, means an aryl moiety that is attached via an alkylene moiety, for example a C1_ ₄ alkylene moiety.

The expression -alkylheteroaryl, unless specifically limited, means a heteroaryl moiety that is attached via an alkylene moiety, for example a _C1-4 alkylene moiety.

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

The term amino refers to the -NH ₂ group.

If benzimidazolyl is shown as benzimidazol-5-yl, which is presented as such, one skilled in the art will understand that benzimidazol-6-yl, which is presented as is an equivalent structure. As used herein, the two forms of benzimidazolyl are encompassed by the term benzimidazol-5-yl.

Stereoisomers.

All possible stereoisomers of the claimed compounds are included in the present invention.

If the compounds of the present invention have at least one chiral center, they may suitably exist as enantiomers. If compounds possess two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Preparation and isolation of stereoisomers.

If the methods for preparing the compounds of the present invention provide a mixture of stereoisomers, such isomers can be separated using conventional techniques such as preparative chromatography. The compounds can be obtained in racemic form, or the individual enantiomers can be obtained either by enantiospecific synthesis or by resolution. Compounds, for example, can be separated into their enantiomer components using standard techniques, such as forming diastereomeric pairs by forming a salt 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 reduction of the free base. Compounds can also be separated by formation of diastereomeric esters or amides followed by chromatographic separation and removal of chiral auxiliaries. Alternatively, compounds can be separated using a chiral HPLC column.

Pharmaceutically acceptable salts.

In light of the close relationship between free compounds and compounds in the form of their salts or solvates, whenever a compound is mentioned in this context, the corresponding salt, solvate or polymorph is also provided, provided that this is possible or appropriate in the circumstances.

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

Suitable salts in accordance with the present invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example, p-toluenesulfonic, benzenesulfonic, naphthalene sulfonic or naphthalene disulfonic), salicylic, glutaric, gluconic, tricarballyl, cinnamic, substituted cinnamic (for example, hair dryer il-, methyl -, methoxy- or halogenated cinnamic acid, including 4methyl- and 4-methoxycinnamic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (for example, 1- or 3-hydroxy-2-naphthoic acid), naphthalene acrylic acid (for example, naphthalene-2-acrylic acid) , benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzene acrylic (for example, 1,4-benzenediacrylic), isethionic acids, perchloric, propionic, glycolic, hydroxyethanesulfonic, pamic, cyclohexanesulfamic, salicylic, saccharic and trifluoroacetic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexylamine and N-methyl-Dglucamine.

All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be within the scope of the present invention.

Polymorphic crystalline forms.

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 (ie, 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, can also be obtained in the form of their hydrates, or they include other solvents used for their crystallization.

Prodrugs.

The present invention further includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of compounds that are readily converted in vivo into the desired therapeutically active compound. Thus, in such cases of the treatment methods of the present invention, the term administration will cover the treatment of various disorders described by prodrug variants of one or more of the claimed compounds, but which are converted to the said compound in vivo upon administration to a subject. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Drugs, ed. H. Bundgaard, Elsevier, 1985.

Protective groups.

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 in question. This can be achieved through traditional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, incorporated herein by reference in its entirety. The protecting groups can be removed at a suitable subsequent stage using methods known in the art.

As used herein, the term composition is intended to include a product containing the claimed compound in therapeutically effective amounts, as well as any product that is formed, directly or indirectly, from combinations of the claimed compounds.

Carriers and additives for herbal formulations.

Thus, in the case of liquid oral preparations such as, for example, suspensions, tinctures and solutions, suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; in the case of solid preparations for oral administration, such as, for example, powders, capsules, gelatin capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like.

Carriers that can be added to the mixture include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavoring agents, sweeteners, preservatives, coating agents, disintegrants, dyes and coloring agents.

Soluble polymers as targetable drug carriers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide polylysine substituted with a palmitoyl moiety. In addition, the compounds of the present invention can be coupled with a class of biodegradable polymers useful for achieving controlled drug release, for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymer hydrogels .

Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as gum acacia, 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, and the like.

Description of the invention

According to the present invention there is provided a compound of formula (I) selected from the group consisting of compounds of formulas (IIa), (IIIa), (IVa), (Va) and (XVa)

where Z is selected from CH and N;

X ₁ is selected from methyl, N, O, S;

n is 1 or 2;

Y 1-Y4 and Y ₆ , Y ₇ and Y ₁₀ are independently selected from CH and N;

Y 5 represents C;

Y ₈ and Y ₉ are independently selected from C and N;

R ₅ is selected from halogen, C _1-12 alkyl and O-C _1-12 alkyl and

R6 is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl;

where X1 is selected from methyl, N, O, S;

n is 1 or 2;

Y 1-Y4 and Y ₆ , Y7 and Y ₁₀ are independently selected from CH and N;

Y ₅ represents C;

Y ₈ and Y ₉ are independently selected from C and N;

R ₅ is selected from halogen, C _1-12 alkyl and O-C _1-12 alkyl and

R6 is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl;

where Z is selected from CH and N;

o equals 0 or 1;

p equals 0 or 1;

Y 1-Y4 and Y ₆ , Y ₇ and Y ₁₀ are independently selected from CH and N;

Y 5 represents C;

Y ₈ and Y ₉ are independently selected from C and N;

R ₅ is selected from halogen, C _1-12 alkyl, O-C _1-12 alkyl and O-phenyl and

R6 is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl;

where o equals 0 or 1;

p equals 0 or 1;

Y 1-Y4 and Y ₆ , Y ₇ and Y ₁₀ are independently selected from CH and N;

Y ₅ represents C;

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Y ₈ and Y ₉ are independently selected from C and N;

R5 is selected from halogen, C _1-12 alkyl, O-C _1-12 alkyl and O-phenyl; And

R ₆ is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl; And

where Y ₁ -Y ₄ and Y ₆ , Y7 and Y ₁₀ are independently selected from CH and N;

Y 5 represents C;

Y ₈ and Y ₉ are independently selected from C and N;

Y4 is optionally substituted with C _1-12 alkyl or halogen;

R5 is selected from halogen, C _1-12 alkyl, O-C _1-12 alkyl, O-phenyl and O-C _3-10 cycloalkyl and

R ₆ is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl.

In a preferred embodiment, the compound of formula (I) is a compound selected from the following:

5-[3-({4'-fluoro-[1,1'-biphenyl]-2-yl}amino)propyl]-1,3,4-thiadiazol-2-amine;

5-{[2-({4'-fluoro-[1,G-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-M-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,G-biphenyl]-2-amine;

',4'-dimethoxy-M-[3 -(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1 '-biphenyl]-2-amine;

5-[4-({4'-fluoro-[1,G-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;

M-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-2-amine;

M-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-methoxyphenyl)pyridin-4-amine;

M-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(3,4-dimethoxyphenyl)pyridin-4-amine;

M-[4-(5-amino-1,3,4-thiadiazol-2-yl)phenyl]-3-(4-fluorophenyl)pyridin-2-amine;

K-[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-M-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,G-biphenyl]-2-amine;

N-|2-(4-mcτocycnyl)φcnyl|-4-(4-mctil-4H-1.2.4-τpiazol-3-yl)anilinl

2-(4-methoxyphenyl)-M-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine;

2-(4-fluorophenyl)-M-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine;

4-(4-methyl-4H-1,2,4-triazol-3-yl)-M-[2-(4-phenoxyphenyl)phenyl]aniline;

3-(3,4-dimethoxyphenyl)-M-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine;

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N-[(1H-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1, G-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;

M-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline;

M-(1H-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline;

M-(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 and

N-(1H-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline;

or a pharmaceutically acceptable salt or solvate thereof, including all tautomers and stereoisomers.

Methods of synthesis.

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

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 Synthesis Method B.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthesis Method C.

In a further preferred embodiment, the compounds of formula (I) of 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 Synthesis Method E.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthetic Method F.

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) of the present invention are prepared according to Synthesis Method H.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthetic Method I.

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In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthesis Method K.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to the synthesis method L.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to the synthesis method M.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to the synthesis method N.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to the synthesis method O.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthesis Method P.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthesis Method Q.

In a further preferred embodiment, the compounds of formula (I) of the present invention are prepared according to Synthetic Method R.

Routes of therapeutic use.

Physiological substrates of QC (EC) in mammals are, for example, amyloid beta peptides (3-40), (3-42), (11-40 and (11-42), ABri, ADan, gastrin, neurotensin, FPP, CCL 2, CCL 7, CCL 8, CCL 16, CCL 18, fractalkine, orexin A, [Gln ³ ]-glucagon(3-29), [Gln^-substance P(5-11) and QYNAD peptide. For more details, see in Table 1. The compounds and/or combinations of the present invention and pharmaceutical compositions containing at least one QC inhibitor (EC) are useful for the treatment of conditions that can be treated by modulating QC activity.

Table 1

Amino acid sequences of physiologically active peptides with an N-terminal glutamine residue that tend to cyclize to form the final pGlu

Peptide Amino acid sequence Function Abeta(l-42) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-TyrGlu-Val-His-His-Gln-Lys-Leu-Val-Phe-PheAla-Glu-Asp-Val-Gly-Ser-Asn- Lys-Gly-Ala-IleIle-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Plays a role in neurodegeneration, such as Alzheimer's disease, familial British dementia, familial Danish dementia, Down syndrome Abeta(l-40) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-TyrGlu-Val-His-His-Gln-Lys-Leu-Val-Phe-PheAla-Glu-Asp-Val-Gly-Ser-Asn- Lys-Gly-Ala-Ile- Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val Plays a role in neurodegeneration, such as Alzheimer's disease, familial British dementia, familial Danish dementia, Down syndrome Abeta(3-42) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-ValHis-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-GluAsp-Val-Gly-Ser-Asn-Lys-Gly- Ala-Ile-Ile-GlyLeu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Plays a role in neurodegeneration, such as Alzheimer's disease, familial British dementia, familial Danish dementia, Down syndrome Abeta(3-40) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-ValHis-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-GluAsp-Val-Gly-Ser-Asn-Lys-Gly- Ala-Ile-Ile-GlyLeu-Met-Val-Gly-Gly-Val-Val Plays a role in neurodegeneration, such as Alzheimer's disease, familial British dementia, familial Danish dementia, Down syndrome

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Abeta(ll-42) Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe- Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile- Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Plays a role in neurodegeneration, such as Alzheimer's disease, familial British dementia, familial Danish dementia, Down syndrome Abeta(ll-40) Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe- Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile- Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val Plays a role in neurodegeneration, such as Alzheimer's disease, familial British dementia, familial Danish dementia, Down syndrome AB ri EASNCFA IRFENKFAV ETLIC SRTVKKNIIEEN Pyroglutamate form plays a role in familial British dementia ADan EASNCFA IRFENKFAV ETLIC FNLFLNSQEKHY Pyroglutamate form plays a role in familial Danish dementia Gastrin 17 Swiss-Prot: P01350 QGPWL EEEEEAYGWM DF (amide) Gastrin stimulates the production and secretion of hydrochloric acid in the gastric mucosa and the secretion of its digestive enzymes pancreas. It also stimulates smooth contraction muscles and increases blood circulation and water secretion in the stomach and intestines. Neurotensin Swiss-Prot: P30990 QLYENKPRRP YIL Neurotensin plays an endocrine or paracrine role in the regulation of fat metabolism. It causes contraction of smooth muscles. FPP QEP amide Thyrotropin-releasing hormone (TRH)-related tripeptide is found in seminal plasma. Recent in vitro and in vivo data have demonstrated that FPP plays an important role in the regulation of sperm fertility. TRH Swiss-Prot: P20396 QHP amide TRH functions as a regulator of TSH biosynthesis in the anterior pituitary gland and as a neurotransmitter/neuromodulator in the central and peripheral nervous system. GnRH Swiss-Prot: P01148 QHWSYGLRP(G) amide Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones. CCL16 (small inducible cytokine A16) Swiss-Prot: 015467 QPKVPEW VNTPSTCCLK YYEKVLPRRL WGYRKALNC HLPAIIFVTK RNREVCTNPN DDWVQEYIKD PNLPLLPTRN LSTVKIITAK NGQPQLLNSQ Demonstrates chemotactic activity against lymphocytes and monocytes, but not neutrophils. Also demonstrates strong myelosuppressive activity, suppresses the proliferation of myeloid progenitor cells. Recombinant SCYA16 demonstrates chemotactic activity in against monocytes and THP1 monocytes, but not against resting lymphocytes and neutrophils. Induces calcium flux in THP-1 cells that have been desensitized by prior expression of RANTES. CCL8 (small inducible cytokine A8) Swiss-Prot: P80075 QPDSVSI PITCCFNVIN RKIPIQRLES YTRITNIQCP KEAVIFKTKR GKEVCADPKE RWVRDSMKHL DQIFQNLKP A chemotactic factor that attracts monocytes, lymphocytes, basophils and eosinophils. May play a role in neoplasia and host inflammatory responses. This protein can bind heparin. CCL2 (MCP-1, small inducible cytokine A2) Swiss-Prot: P13500 QPDAINA PVTCCYNFTN RKISVQRLAS YRRITSSKCP KEAVIFKTIV AKEICADPKQ KWVQDSMDHL DKQTQTPKT A chemotactic factor that attracts monocytes and basophils, but not neutrophils or eosinophils. Increases antitumor activity monocytes Involved in the pathogenesis of diseases characterized by monocyte infiltrates such as psoriasis, rheumatoid arthritis or atherosclerosis. May be involved in the recruitment of monocytes to the arterial wall during the pathological process of atherosclerosis. Binds to CCR2 and CCR4. CCL18 (small inducible cytokine A18) Swiss-Prot: P55774 QVGTNKELC CLVYTSWQIP QKFIVDYSET SPQCPKPGVI LLTKRGRQIC ADPNKKWVQK YISDLKLNA A chemotactic factor that attracts lymphocytes, but not monocytes or granulocytes. May be involved in the migration of B cells to B cell follicles in lymph nodes. Attracts intact T lymphocytes towards dendritic cells and activated macrophages in lymph nodes, has chemotactic activity in against naive T cells, CD4+ and CD8+ T cells and thus may play a role in both humoral and cell-mediated immune answers. Fractalkine (neurotactin) Swiss-Prot: P78423 QHHGVT KCNITCSKMT SKIPVALLIH YQQNQASCGK RAIILETRQH RLFCADPKEQ WVKDAMQHLD RQAAAALTRNG GTFEKQIGEV KPRTTPAAGG MDESVVLEPE ATGESSSLEP TPSSQEAQRA LGTSPELPTG VTGSSGTRLP PTPKAQDGGP VGTELFRVPP VSTAATWQSS APHQPGPSLW AEAKTSEAPS TQDPSTQAST ASSPAPEENA PSEGQRVWGQ GQSPRPENSL EREEMGPVPA HTDAFQDWGP GSMAHVSWP VSSEGTPSRE PVASGSWTPK AEEPIHATMD PQRLGVLITP VPDAQAATRR QAVGLLAFLG LLFCLGVAMF TYQSLQGCPR KMAGEMAEGL RYIPRSCGSN SYVLVPV The soluble form is chemotactic against T cells and monocytes, but not against neutrophils. The membrane-bound form promotes the adhesion of these leukocytes to endothelial cells. May play a role in the regulation of leukocyte adhesion and migration processes on the endothelium, binds to CX3CR1. CCL7 (small inducible cytokine A7) Swiss-Prot: P80098 QPVGINT STTCCYRFIN KKIPKQRLES YRRTTSSHCP REAVIFKTKL DKEICADPTQ KWVQDFMKHL DKKTQTPKL A chemotactic factor that attracts monocytes and eosinophils, but not neutrophils. Increases antitumor activity monocytes Also induces release of gelatinase B. This protein can bind to heparin. Binds to CCR1, CCR2 and CCR3.

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Orexin A (hypocretin1) Swiss-Prot 043612 QPLPDCCRQK TCSCRLYELL HGAGNHAAGILTL Neuropeptide that plays significant role in regulating food intake and the sleep-wake cycle, possibly by coordination of a complex of behavioral and physiological responses data complementary homeostatic functions. It also plays a broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and regulation of body fluids. Orexin-A binds to both OX1R and OX2R with high affinity. Substance P RPKPQQFFGLM Belongs to the tachykinins. Tachykinins are active peptides that excite neurons, induce behavioral responses, are potent vasodilators and secretagogues, and cause contraction (directly or indirectly) of many smooth muscles. QYNAD Gln-Tyr-Asn-Ala-Asp Acts on voltage-sensitive sodium channels.

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

β-Amyloid peptides with a pyroglutamic acid residue at positions 3, 11 and/or 22 have been described to be more cytotoxic and hydrophobic than amyloid β-peptides 140(42/43) (Saido T.C. 2000 Medical Hypotheses 54(3): 427-429).

Numerous N-terminal variants, such as Abeta(3-40), Abeta(3-42), Abeta(11-40) and Abeta(11-42), can be produced by the enzyme β-secretase, an enzyme that cleaves the precursor protein β-site amyloid (BACE) at various sites (Huse J.T. et al., 2002 J. Biol. Chem. 277 (18): 16278-16284), and/or by processing by aminopeptidase or dipeptidyl aminopeptidase from full-length Abeta( 1-40) and Abeta(1-42). In all cases, the cyclization of the resulting N-terminal glutamic acid residues is catalyzed by QC.

Transepithelial transducer cells, particularly the gastrin (G) cell, coordinate the secretion of gastric acid when food enters the stomach. Recent work has shown that several active products are formed from the gastrin precursor, and there are several control points in gastrin biosynthesis. Biosynthetic precursors and intermediates (progastrin and Gly-gastrins) are putative growth factors; their products, amidated gastrins, control the proliferation of epithelial cells, the differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and the expression of genes associated with histamine synthesis and storage in ECL cells, as well as acid secretion, providing potent stimulation. Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which in turn suppress the functioning of parietal cells but stimulate the growth of superficial epithelial cells. Plasma gastrin concentrations are elevated in subjects with Helicobacter pylori, which is known to have an increased risk of duodenal ulcers and gastric cancer (Dockray, G.J. 1999 J Physiol 15 315-324).

The peptide hormone gastrin, released from antral G cells, is known to stimulate the synthesis and release of histamine from ECL cells in the acid-producing mucosa via CCK-2 receptors. Mobilized histamine induces acid secretion by binding to H(2) receptors located on parietal cells. Recent research suggests that gastrin, both in its fully amidated and less processed forms (progastrin and glycine-supplemented gastrin), is also a growth factor for the gastrointestinal tract. It was found that the main trophic effect of amidated gastrin is in the acid-producing gastric mucosa, in which it causes an increase in the proliferation of gastric stem cells and ECL cells, which leads to an increase in the mass of parietal and ECL cells. On the other hand, the primary trophic target of less processed gastrin (eg gastrin supplemented with glycine) appears to be the colonic mucosa (Koh, T. J. and Chen, D. 2000 Regul Pept 9337-44).

Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be dysregulated in this disorder. Clinical studies that measured cerebrospinal fluid (CSF) NT concentrations found a subgroup of patients with schizophrenia with reduced CSF NT concentrations who experienced recovery when treated with an effective antipsychotic drug. There is also a large body of evidence consistent with the involvement of NT systems in the mechanism of action of antipsychotic drugs. The behavioral and biochemical effects of centrally administered NT are remarkably similar to those of systemically administered antipsychotic drugs.

- 11 043556 drugs, and antipsychotic drugs increase neurotransmission involving NT. This correlation of data leads to the hypothesis that NT functions as an endogenous antipsychotic agent. Moreover, typical and atypical antipsychotic drugs differentially alter neurotransmission involving the NT in the nigrostriatal and mesolimbic dopamine terminal regions, and such effects are predictive of side effect susceptibility and efficacy, respectively (Binder, E. B. et al., 2001 Biol Psychiatry 50 856-872).

Fertilization promoting peptide (FPP), a tripeptide related to thyrotropin-releasing hormone (TRH), is found in seminal plasma. Recent in vitro and in vivo data have demonstrated that FPP plays an important role in the regulation of sperm fertility. In particular, FPP initially stimulates the inclusion of infertile (incompetent) sperm and ensures their faster transformation into fertile ones, then ensures the arrest of competence, as a result of which the sperm do not undergo spontaneous loss of acrosome and, therefore, do not lose the ability to fertilize. Such responses are mimicked and actually enhanced by adenosine, which is known to control the adenylyl cyclase (AC)/cAMP signal transduction pathway. It has been shown that both FPP and adenosine stimulate the production of cAMP in incompetent cells, but suppress it in competent cells, while FPP receptors somehow interact with adenosine receptors and G proteins to achieve regulation of AS. Such events negatively influence the tyrosine phosphorylation state of various proteins, some of which are important upon initial incorporation, others likely involved in the acrosome response itself. Calcitonin and angiotensin II, also found in seminal plasma, have similar effects in vitro on failing sperm and may enhance responses to FPP. Such molecules have similar effects in vivo, providing effects on fertility by stimulating and then maintaining fertilizing potential. Either reduced availability of FPP, adenosine, calcitonin and angiotensin II or defects in their receptors contribute to male infertility (Fraser, L.R. and Adeoya-Osiguwa, S.A. 2001 Vitam Horm 63, 1-28).

CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and fractalkine play important roles in pathophysiological conditions such as suppression of myeloid progenitor cell proliferation, neoplasia, host inflammatory responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertension, liver fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodeling, heart failure, arteriopathy after organ transplantation and vein graft rejection.

A number of studies have highlighted, in particular, the very important role of MCP-1 for the development of atherosclerosis (Gu, L., et al. (1998) Mol. Cell 2, 275-281; Gosling, I., 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 graft rejection (Saiura, A., et al. (2004) Arterioscler. Thromb. Vasc. Biol. 24, 1886-1890). In addition, MCP-1 may also play a role in preeclampsia (Katabuchi, H., et al. (2003) Med Electron Microsc. 36, 253-262), as a paracrine factor in tumor development (Ohta, M., et al. (2003) Int. J Oncol. 22, 773-778; Li, S., et al. (2005) J Exp. Med 202, 617-624), for neuropathic pain (White, F. A., et al. (2005) ) Proc. Natl. Acad. Sci. U.S.A) and AIDS (Park, I. W., Wang, J. F., and Groopman, J. E. (2001) Blood 97, 352-358; Coll, B., et al. (2006) Cytokine 34, 51-55).

MCP-1 levels are elevated in the CSF of patients with AD and patients demonstrating mild cognitive impairment (MCI) (Galimberti, D., et al. (2006) Arch. Neurol. 63, 538-543). In addition, MCP-1 is characterized by increased levels in the serum of patients with MCI and early AD (Clerici, K, et al., (2006) Neurobiol. Aging 27, 1763-1768).

Several cytotoxic T-lymphocyte peptide vaccines against hepatitis B, human immunodeficiency virus, and melanoma have recently 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 analogue of the immunodominant peptide of the Melan-A/MART-1 antigen with glutamic acid at the N-terminus. It has been described that the amino and gamma-carboxyl groups of glutamic acid residues, as well as the amino and gamma-carboxamide groups of glutamine residues, readily condense to form pyroglutamine derivatives. To overcome this stability problem, several peptides of pharmaceutical interest have been developed with pyroglutamic acid instead of glutamine or glutamic acid at the N-terminus without loss of pharmacological properties. Unfortunately, compared to ELA, the pyroglutamic acid derivative (PyrELA) as well as the N-terminal acetyl-capped derivative (AcELA) failed to induce cytotoxic T lymphocyte (CTL) activity. Despite the obvious minor modifications introduced into PyrELA and

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AcELA, these two derivatives, appear to have less affinity than ELA for specific MHC class I. Therefore, in order to maintain full ELA activity, the formation of PyrELA must be avoided (Beck A. et al., 2001, J Pept Res 57(6):528-38.).

Orexin A is a neuropeptide that plays a significant role in the regulation of food intake and the sleep-wake cycle, possibly by coordinating a complex of behavioral and physiological responses to these complementary homeostatic functions. It also plays a role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance, and regulation of body fluids.

Recently, increased levels, compared with healthy individuals, of the pentapeptide QYNAD were identified in the cerebrospinal fluid (CSF) of patients suffering from multiple sclerosis or Guillain-Barré syndrome (Brinkmeier H. et al., 2000, Nature Medicine 6, 808-811). There is much controversy in the literature regarding the mechanism of action of the pentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially regarding the effectiveness of its interaction with and blockade of sodium channels, which leads to increased axonal dysfunction, which is implicated in inflammatory autoimmune diseases of the central nervous system. systems. But recently it could be demonstrated that it is not QYNAD, but its cyclized, pyroglutamate form, pEYNAD, that is the active form that blocks sodium channels, leading to increased axonal dysfunction. Sodium channels are expressed at high densities on myelinated axons and play an essential role in the transmission of action potentials along axons in the mammalian brain and spinal cord. Thus, they have been suggested to be involved in several aspects of the pathophysiology of inflammatory autoimmune diseases, especially multiple sclerosis, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

In addition, QYNAD is a substrate of the enzyme glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in the mammalian brain, especially in the human brain. Glutaminyl cyclase efficiently catalyzes the formation of pEYNAD from its precursor QYNAD.

Accordingly, the present invention provides the use of compounds of formula (I) for the preparation of a medicament intended for the prevention, or reduction of severity, or treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, familial British dementia, familial Danish dementia, neurodegeneration in Down syndrome, Huntington's disease, Kennedy's disease, peptic ulcer disease, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zollinger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, host inflammatory responses, cancer, malignant metastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, disorders of humoral and cell-mediated immune responses, processes of adhesion and migration of leukocytes into the endothelium, consumption disorders food, sleep-wake cycle disorders, dysregulation of energy metabolism homeostasis, autonomic dysfunction, hormonal imbalance or dysregulation of body fluids, multiple sclerosis, Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

In addition, by administering a compound of the present invention to a mammal, it may be possible to stimulate the proliferation of myeloid progenitor cells.

In addition, administration of a QC inhibitor according to the present invention can lead to suppression of male infertility.

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

The present invention also provides a method of treating the above diseases, comprising administering a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.

Most preferably, said method and corresponding routes of administration are provided for the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, familial British dementia, familial Danish dementia, neurodegeneration in Down syndrome, Parkinson's disease and Huntington's chorea, which includes the administration of a therapeutically active an amount of at least one compound of formula (I) to a mammal, preferably a human.

Even more preferably, the present invention provides a treatment method and corresponding routes of application for the treatment of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.

Pharmaceutical combinations.

In a preferred embodiment, the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor,

- 13 043556 optionally in combination with at least one other agent selected from the group consisting of nootropic drugs, neuroprotectors, antiparkinsonian drugs, inhibitors of amyloid protein deposition, inhibitors of beta-amyloid synthesis, antidepressants, anxiolytic drugs, antipsychotic drugs and drugs drugs against multiple sclerosis.

Most preferably, said QC inhibitor is a compound of formula (I) of the present invention.

More specifically, the aforementioned other agent is selected from the group consisting of beta-amyloid antibodies, vaccines, cysteine protease inhibitors, PEP inhibitors, LiCl, acetylcholinesterase (AChE) inhibitors, PIMT enhancers, beta-secretase inhibitors, gamma-secretase inhibitors, aminopeptidase inhibitors , preferably dipeptidyl peptidase inhibitors, most preferably DP IV inhibitors; neutral endopeptidase inhibitors, phosphodiesterase-4 (PDE-4) inhibitors, TNF-alpha inhibitors, M1 muscarinic receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents, MCP-1 antagonists, or agent selected from the group consisting of Antegren (natalizumab), Neurelan (fampridine-SR), Campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin4), matrix metalloproteinase inhibitors (e.g. BB 76163), interferon-tau (trophoblastin) and SAIK-MS.

In addition, the other agent may be, for example, an anti-anxiety drug or an antidepressant selected from the group consisting of:

(a) benzodiazepines, e.g. alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, fludiazepam, loflazepate, lorazepam, mataqualone, oxazepam, prazepam, tranxene, (b) selective serotonin reuptake inhibitors (SSRIs), e.g. citalopram, flu oxetine , fluvoxamine, escitalopram, sertraline, paroxetine, (c) tricyclic antidepressants, e.g. amitriptyline, clomipramine, desipramine, doxepin, imipramine, (d) monoamine oxidase inhibitors (MAOIs), (e) azapyrones, e.g. buspirone, tandopsiron, (f) serotonin-norepinephrine reuptake inhibitors (SNRIs), eg venlafaxine, duloxetine, (g) mirtazapine, (h) norepinephrine reuptake inhibitors (NRIs), eg reboxetine, (i) bupropion, (j) nefazodone, (k) beta -blockers, (l) NPY receptor ligands: NPY agonists or antagonists.

In a further embodiment, the other agent may be, for example, an anti-multiple sclerosis drug selected from the group consisting of dihydroorotate dehydrogenase inhibitors, e.g. SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. HMR1715, MNA-279 ), autoimmune suppressive agent, e.g., laquinimod, paclitaxel, antibodies, e.g., AGT-1, granulocyte-monocyte colony-stimulating factor (GM-CSF) monoclonal antibody, Nogo receptor modulators, ABT-874, alemtuzumab (Campath), anti-OX40 antibody , CNTO-1275, DN-1921, natalizumab (syn. AN-100226, Antegren, VLA-4 Mab), daclizumab (syn. Zenepax, Ro-34-7375, SMART to Tas), J-695, priliximab (syn. centara, CEN-000029, SM-T412), MRA, Dantes, antibodies to IL-12, peptide nucleic acid (PNA) drugs, for example, reticulose, interferon-alpha, for example, alphaferon, human interferon alpha (syn. omniferon, leukoferon-alpha), interferon-beta, e.g. fron, interferon-beta-1a-like avonex, betron (Rebif), interferon-beta analogues, interferon-beta-transferrin fusion protein, recombinant interferon-beta-1b-like betaserone, interferon-tau, peptides such as AT-008, AnergiX.MS, immunokine (alpha-immunokine-NNSO3), cyclic peptides such as KaKZD-7349, therapeutic enzymes such as soluble CD8 (sCD8), plasmid encoding specific multiple sclerosis autoantigen, and a plasmid encoding a cytokine, for example, BHT-3009; TNF-alpha inhibitor, e.g. BLX-1002, thalidomide, SH-636, TNF antagonists, e.g. solimastat, lenercept (syn. RO-45-2081, tenefuz), onercept (sTNFR1), CC-1069, TNF-alpha, e.g., etanercept (syn. enbrel, TNR-001), CD28 antagonists such as abatacept, Lck tyrosine kinase inhibitors, cathepsin K inhibitors, neuron-targeting taurine transporter membrane protein analogues, and the plant-derived calpain leupeptin inhibitor such as Neurodura, chemokine receptor-1 (CCR1) antagonist, e.g. BC-471, CCR2 antagonists, AMPA receptor antagonists, e.g. ER-167288-01 and ER-099487, E-2007, talampanel, potassium channel blockers, e.g. fampridine, small molecule tosyl antagonists -proline-phenylalanine in the interaction of VLA-4/VCAM, for example, TVS-3342, molecular inhibitors of cell adhesion, for example TVS-772, antisense oligonucleotides, for example, EN-101, immunoglobulin free light chain (IgLC) binding antagonists with mast cell receptors, for example, F-991, apoptosis-inducing antigens, for example, MS alogen, alpha-2 adrenergic receptor agonist, for example, tizanidine (syn. zanaflex, ternelin, sirdalvo, sirdalud, myonidin), copolymer of L-tyrosine, L-lysine, L-glutamic acid and L-alanine, for example, glatiramer acetate (syn. Copaxone, COP-1, copolymer-1), topoisomerase II modulators, for example , mitoxantrone hydrochloride, adenosine deaminase inhibitor, for example, cladribine (syn. Leystatin, Milinax, RWJ-26251), interleukin-10, for example, ilodecakin (syn. Tenovil, Sch-52000, CSIF), interleukin-12 antagonists, for example, lysophylline ( syn. CT1501R, LSF, lysophylline), ethanamine, for example SRI-62-834 (syn. CRC-8605, NSC-614383), immunomodulators, for example, SAIK-MS, PNU-156804, alpha-fetoprotein peptide (AFP), IPDS , retinoid receptor agonists, e.g. adapalene (syn. Differin, CD-271), TGF-beta, e.g. GDF-1 (growth and differentiation factor 1), TGF-beta-2, e.g. BetaKine, MMP inhibitors, e.g. glycomed, phosphodiesterase 4 (PDE4) inhibitors, for example, RPR-122818, purine nucleoside phosphorylase inhibitors, for example, 9-(3-pyridylmethyl)-9-deazaguanine, peldesine (syn. BCX-34, TO-200), alpha-4/beta-1 integrin antagonists, e.g. ISIS-104278, alpha-4 antisense integrin (CD49d), e.g. ISIS-17044, ISIS-27104, cytokinin-inducing agents, e.g. nucleosides , ICN-17261, cytokine inhibitors, heat shock protein vaccines, e.g. HSPPC-96, neuregulin growth factors, e.g. GGF-2 (syn. neuregulin, glial growth factor 2), cathepsin S inhibitors, bropyrimine analogues , for example, PNU-56169, PNU-63693, monocyte chemoattractant protein 1 inhibitors, for example, benzimidazoles like MCP-1 inhibitors, LKS-1456, PD-064036, PD-064126, PD-084486, PD-172084, PD-172386.

Additionally, the present invention provides pharmaceutical compositions, for example, for parenteral, enteral or oral administration, containing at least one QC inhibitor, optionally in combination with at least one of the other agents mentioned above.

These combinations provide, in particular, an advantageous effect. Thus, such combinations have been shown to be effective and useful for the treatment of the above-mentioned diseases. Accordingly, the present invention provides a method for treating such conditions.

The method includes either co-administration of at least one QC inhibitor and at least one of the other agents, or their sequential administration.

Co-administration involves administering a formulation that contains at least one QC inhibitor and at least one of the other agents, or essentially simultaneous administration of separate formulations of each agent.

Antibodies to beta-amyloid and compositions containing them are described, for example, in

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 2003/045128 WO 2003/040183 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 2000/072880 WO 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, WO 1989/006242.

Anti-amyloid beta antibodies may be selected, for example, from polyclonal, monoclonal, chimeric or humanized antibodies. In addition, these antibodies may be applicable for the development of active and passive immunotherapies, i.e. vaccines and monoclonal antibodies.

Suitable examples of anti-amyloid beta antibodies include ACU-5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (Pfizer Inc)); Ablynx/Boehringer Ingelheim nanobody therapeutics; Intellect Neurosciences/IBL amyloid-beta-specific humanized monoclonal antibodies; m266, m266.2 (Eli Lilly &Co.); AAB-02 (Elan); bapineizumab (Elan); BAN-2401 (Bioarctic Neuroscience AB); ABP-102 (Abiogen Pharma SpA); BA27, BC-05 (Takeda); R-1450 (Roche); ESBA-212 (ESBATech AG); AZD-3102 (AstraZeneca) and amyloid beta antibodies Mindset BioPharmaceuticals Inc.

Particularly preferred are antibodies that recognize the N-terminus of the Ab peptide. A suitable antibody that recognizes the Ae-N-terminus is, for example, Acl-24 (AC Immune SA).

- 15 043556

Monoclonal antibodies to amyloid beta peptide are disclosed in WO 2007/068412, WO/2008/156621 and WO/2010/012004. Corresponding chimeric and humanized antibodies are disclosed in WO

2008/011348 and WO/2008/060364. A vaccine composition for the treatment of amyloid-associated disease is 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.

Suitable vaccines for the treatment of amyloid-associated disease are, for example, Affitopes AD-01 and AD-02 (GlaxoSmithKline), ACC-01 and ACC-02 (Elan/Wyeth), CAD-106 (Novartis/Cytos Biotechnology).

Suitable cysteine protease inhibitors are cathepsin B inhibitors. Cathepsin B inhibitors 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 2002/021509, WO 1998/046559,

WO 1996/021655.

Examples of suitable PIMT enhancers are

10-aminoaliphatyldibenz[b,1]oxepines described in WO 98/15647 and WO 03/057204 respectively. Also useful in accordance with the present invention are the PIMT activity modulators described in WO 2004/039773.

Beta-secretase inhibitors 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, WO03/059346, WO2006/099352, WO2006/078576, WO2006/060109, WO2006/057983,

WO2006/057945, WO2006/055434, WO2006/044497, WO2006/034296, WO2006/034277, WO2006/029850,

WO2006/026204, WO2006/014944, WO2006/014762, WO2006/002004, US 7109217, WO2005/113484, WO2005/103043, WO2005/103020, WO2005/065195, WO2005/051914, WO2005/044830, WO2005/032471, WO2005/018545 , WO2005/004803, WO2005/004802, WO2004/062625, WO2004/043916, WO2004/013098, WO03/099202, WO03/043987, WO03/039454, US 6562783, WO02 /098849 and WO02/096897.

Suitable examples of beta-secretase inhibitors for the purpose of the present invention are WY-25105 (Wyeth); posyphene, (+)-phenserine (TorreyPines/NIH); LSN-2434074, LY-2070275, LY2070273, LY-2070102 (Eli Lilly &Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU38773, PNU-90530 (Elan/Pfizer); KMI-370, KMI-358, kmi-008 (Kyoto University); OM-99-2, OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca/Astex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 (De Novo Pharmaceuticals Ltd.), and CT-21166 (CoMentis Inc.).

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 7122675, US 7030239, US 6992081, US 6982264, WO2005/097768, WO2005/028440, WO2004/101562, US 6756511, US 6683091, WO03/066592, WO03/014075, WO03/013527, WO02/36555, WO01/53255, US 7109217, US 7101895, US 7049296, US 7034182, US 6984626, WO2005/040126, WO2005/030731, WO2005/014553, US 689095 6, EP 1334085, EP 1263774, WO2004/101538, WO2004/ WO03/091278 , US 6649196, US 6448229, WO01/77144 and WO01/66564.

Suitable gamma secretase inhibitors for the purpose of the present invention are

GSI953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, L-852631, L-852646 (Merck & Co. Inc.); LY-450139, LY-411575, AN-37124 (Eli Lilly &Co.); BMS-299897, BMS-433796 (BristolMyers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); NGX-555 (TorreyPines Therapeutics Inc.) and semagacestat (Eli Lilly).

- 16 043556

DP IV inhibitors and compositions containing such inhibitors are described, for example, in US6011155;

US6107317; US6110949; US6124305; US6172081; WO99/61431, WO99/67278, WO99/67279, DE19834591, WO97/40832, WO95/15309, WO98/19998, WO00/07617, WO99/38501, WO99/46272, WO99/38501, WO 01/68603, WO01/40180, WO01/81337, WO01/81304, WO01/55105, WO02/02560, WO01/34594, WO02/38541, WO02/083128, WO03/072556, WO03/002593, WO03/000250, WO03/000 180, WO03/000181, EP1258476, WO03/002553, WO03/002531, WO03/002530, WO03/004496, WO03/004498, WO03/024942, WO03/024965, WO03/033524, WO03/035057, WO03/035067, WO 03/037327, WO03/040174, WO03/ 045977, WO03/055881, WO03/057144, WO03/057666, WO03/068748, WO03/068757, WO03/082817, WO03/101449, WO03/101958, WO03/104229, WO03/7 4500, WO2004/007446, WO2004/007468, WO2004/018467, WO2004/018468, WO2004/018469, WO2004/026822, WO2004/032836, WO2004/033455, WO2004/037169, WO2004/041795, WO2004/043 940, WO2004/048352, WO2004/050022, WO2004/052850, WO2004/ 058266, WO2004/064778, WO2004/069162, WO2004/071454, WO2004/076433, WO2004/076434, WO2004/087053, WO2004/089362, WO2004/099185, WO 2004/103276, WO2004/103993, WO2004/108730, WO2004/110436, WO2004/111041, WO2004/112701, WO2005/000846, WO2005/000848, WO2005/011581, WO2005/016911, WO2005/023762, WO2005/025554, WO2005/026 148, WO2005/030751, WO2005/033106, WO2005/037828, WO2005/ 040095, WO2005/044195, WO2005/047297, WO2005/051950, WO2005/056003, WO2005/056013, WO2005/058849, WO2005/075426, WO2005/082348, WO 2005/085246, WO2005/087235, WO2005/095339, WO2005/095343, WO2005/095381, WO2005/108382, WO2005/113510, WO2005/116014, WO2005/116029, WO2005/118555, WO2005/120494, WO2005/121089, WO2005/121 131, WO2005/123685, WO2006/995613; 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.

Suitable DP IV inhibitors for the purpose of the present invention are, for example, sitagliptin, des-fluoro-sitagliptin (Merck & Co. Inc.); vildagliptin, DPP-728, SDZ-272-070 (Novartis); AVT-279, AVT-341 (Abbott Laboratories); dengliptin, TA-6666 (Glaxo SmithKline plc); SYR-322 (Takeda San Diego Inc.); talabostat (Point Therapeutics Inc.); Ro-0730699, R-1499, R-1438 (Roche Holding AG); FE999011 (Ferring Pharmaceuticals); TS-021 (Taisho Pharmaceutical Co. Ltd.); GRC-8200 (Glenmark Pharmaceuticals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi Pharma Corp.); DP-893, CP-867534-01 (Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co. Ltd.); PHX-1149 (Phenomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.); PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 (ActivX Biosciences Inc.); sulfostine (Zaidan Hojin); KR-62436 (Korea Chemical Technology Research Institute); P32/98 (Probiodrag AG); BI-A, BI-B (Boehringer Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. Ltd.) and NNC72-2138 (Novo Nordisk A/S).

Other preferred DP IV inhibitors are:

(i) dipeptide-like compounds disclosed in WO 99/61431, for example N-valylprolyl, Obenzoylhydroxylamine, alanylpyrrolidine, isoleucyl thiazolidine such as L-alloisoleucyl thiazolidine, L-threoisoleucyl pyrrolidine and salts thereof, especially fumaric salts, and L alloisoleucyl pyrrolidine and salts thereof;

(ii) peptide structures disclosed in WO 03/002593, for example tripeptides;

(iii) peptidyl ketones disclosed in WO 03/033524;

(vi) substituted amino ketones disclosed in WO 03/040174;

(v) topical DP IV inhibitors disclosed in WO 01/14318;

(vi) prodrugs of 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.

Suitable beta-amyloid synthesis inhibitors for the purpose of the present invention are, for example, bisnorcimserine (Axonyx Inc.); (R)-flurbiprofen (MCP-7869; Flurizan) (Myriad Genetics); nitroflurbiprofen (NicOx); BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466 (BTG plc), RQ00000009 (RaQualia Pharma Inc).

Suitable inhibitors of amyloid protein deposition for the purpose of the present invention are, for example, SP-233 (Samaritan Pharmaceuticals); AZD-103 (Ellipsis Neurotherapeutics Inc.); AAB-001 (bapineizumab), AAB-002, ACC-001 (Elan Corp plc); Colostrinin (ReGen Therapeutics plc); tramiprosate (Neurochem); AdPEDI-(amyloid-beta1-6)11) (Vaxin Inc.); 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 Inc.); m266 (Eli Lilly &Co.); EGb761 (Dr. Willmar Schwabe GmbH); SPI-014 (Satori Pharmaceuticals Inc.); ALS-633, ALS-499 (Advanced Life Sciences Inc.); AGT-160 (ArmaGen Technologies Inc.); TAK-070 (Takeda Pharmaceutical Co. Ltd.); CHF5022, CHF-5074, CHF-5096 and CHF-5105 (Chiesi Farmaceutici SpA.), SEN-1176 and SEN-1329 (Senexis Ltd.), AGT-160 (ArmaGen Technologies), davunetide (Allon Therapeutics), ELND-005 (Elan Corp/Transition Therapeutics) and nilvadipine (Archer Pharmaceuticals).

Suitable PDE-4 inhibitors for the purpose of the present invention are, for example, doxophylline (Instituto Biologico Chemioterapica ABC SpA.); idudilast, tipelukast, ibudilast eye drops (Kyorin Pharmaceutical Co. Ltd.); theophylline (Elan Corp.); cilomilast (GlaxoSmithKline plc); ato

- 17 043556 peak (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659, CP-220629, PDE 4d BHN inhibitor (Pfizer Inc.); arophylline, LAS-37779 (Almirall Prodesfarma SA.); roflumilast, hydroxypumafentrin (Altana AG), tetomilast (Otska Pharmaceutical Co. Ltd.); tipelukast, ibudilast (Kyorin Pharmaceutical), CC10004 (Celgene Corp.); HT-0712, IPL-4088 (Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 (Memory Pharmaceuticals Corp.); oglemilast, GRC-4039 (Glenmark Pharmaceuticals Ltd.); AWD-12-281, ELB353, ELB-526 (Elbion AG); EHT-0202 (ExonHit Therapeutics SA.); ND-1251 (Neuro3d SA.); 4AZA-PDE4 (4 AZA Bioscience NV); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottapharm SpA.); GP-0203, NCS-613 (Centre National de la Recherche Scientifique); KF-19514 (Kyowa Hakko Kogyo Co. Ltd.); ONO-6126 (Ono Pharmaceutical Co. Ltd.); OS-0217 (Dainippon Pharmaceutical Co. Ltd.); IBFB-130011, IBFB-150007, IBFB-130020, IBFB-140301 (IBFB Pharma GmbH); IC-485 (ICOS Corp.); RBx-14016 and RBx-11082 (Ranbaxy Laboratories Ltd.). The preferred PDE-4 inhibitor is rolipram.

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.

Suitable MAO inhibitors for the purpose of the present invention are, for example, Linezolid (Pharmacia Corp.); RWJ-416457 (R.W. Johnson Pharmaceutical Research Institute); budipine (Altana AG); GPX-325 (BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indandol (Chiesi Farmaceutici SpA.); moclobemide (Roche Holding AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370 (Burroughs Wellcome Co.); CX-157 (Krenitsky Pharmaceuticals Inc.); deoxypeganine (HF Arzneimittelforschung GmbH & Co. KG); bifemelan (Mitsubishi-Tokyo Pharmaceuticals Inc.); RS-1636 (Sankyo Co. Ltd.); ezupron (BASF AG); rasagiline (Teva Pharmaceutical Industries Ltd.); ladostigil (Hebrew University of Jerusalem); safinamide (Pfizer), NW-1048 (Newron Pharmaceuticals SpA.), EVT-302 (Evotec).

Suitable histamine H3 antagonists for the purpose of the present invention are, for example, ABT-239, ABT-834 (Abbott Laboratories); 3874-H1 (Aventis Pharma); UCL-2173 (Free University of Berlin), UCL-1470 (BioProjet, Societe Civile de Recherche); DWP-302 (Daewoong Pharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); cipralisant, GT-2203 (Gliatech Inc.); 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 A/S) and Sch79687 (Schering-Plough).

PEP inhibitors and compositions containing such inhibitors are described, for example, in

JP 01042465,

JP 03031298, JP 04208299, WO 00/71144, US 5,847,155; JP 09040693, JP 10077300, JP 05331072,

JP 05015314, WO 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP 01068396, EP 0709373,

US 5965556, US 5756763, US 6121311, JP 63264454, JP 64000069, JP 63162672, EP 0268190, EP 0277588,

EP0275482, US 4977180, US 5091406, US 4983624, US 5112847, US 5100904, US 5254550, US 5262431,

US 5340832, US 4956380, EP 0303434, JP 03056486, JP 01143897, JP 1226880, EP 0280956, US 4857537,

EP 0461677, EP 0345428, JP 02275858, US 5506256, JP 06192298, EP 0618193, JP 03255080, EP 0468469,

US 5118811, JP 05025125, WO 9313065, JP 05201970, WO 9412474, EP 0670309, EP 0451547, JP 06339390,

US 5073549, US 4999349, EP 0268281, US 4743616, EP 0232849, EP 0224272, JP 62114978, JP 62114957,

US 4757083, US 4810721, US 5198458, US 4826870, EP 0201742, EP 0201741, US 4873342, EP 0172458, JP 61037764, EP 0201743, US 4772587, EP 037 2484, US 5028604, WO 91/18877, JP 04009367, JP 04235162, US 5407950, Wo 95/01352, JP 01250370, JP 02207070, US 5221752, EP 0468339, JP 04211648, Wo 99/46272, Wo 2006/058720 and PST/EP/061428.

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

Other suitable compounds that can be used in accordance with the present invention in combination with QC inhibitors are NPY, an NPY mimetic, or an NPY agonist, or an antagonist or ligand of NPY receptors.

Preferred according to the present invention are NPY receptor antagonists.

Suitable NPY receptor ligands or antagonists are the 3a,4,5,9b-tetrahydro-1H-benz[e]indol-2-ylamine-derived compounds disclosed in WO 00/68197.

NPY receptor antagonists that may be mentioned include those disclosed in European patent applications EP 0614911, EP 0747357, EP 0747356 and EP 0747378; 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 97/19682,

WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420;

WO 00/30674, US Patent Nos. 5552411, 5663192 and 5567714; 6114336, Japanese patent applications JP 09157253; international patent applications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; US Patent No. 5328899; German patent application DE 3939797; European Patent Applications EP 355794 and EP 355793 and Japanese Patent Applications JP 06116284

- 18 043556 and JP 07267988. Preferred NPY antagonists include those compounds that are 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 that may be mentioned include those disclosed in European patent applications EP

0614911, EP 0747357, EP 0747356 and EP 0747378; 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 97/19682, WO 97/25041, WO 97/34843, WO 97/46250,

WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; US Patent 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 compounds specifically disclosed in these patent documents.

Particularly preferred compounds include amino acid-based NPY antagonists. Amino acid-based compounds that may be mentioned include those disclosed in international patent applications 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, for example, BIBP3226 and especially (R)-1H(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]argininamide (Example 4 of the international patent application WO 99/15498).

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

Suitable M1 receptor antagonists for the purpose of the present invention are, for example, CDD-0102 (Cognitive Pharmaceuticals); cevimeline (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics); sabcomelin (GlaxoSmithKline); alvameline (H Lundbeck A/S); LY-593093 (Eli Lilly &Co.); VRTX-3 (Vertex Pharmaceuticals Inc.); WAY-132983 (Wyeth), CI-101 7/(PD151832) (Pfizer Inc.), and MCD-386 (Mitridion Inc.).

Acetylcholinesterase inhibitors and compositions containing such inhibitors are described, for example, in

WO2006/071274, WO2006/070394, WO2006/040688, WO2005/092009, WO2005/079789, WO2005/039580,

WO2005/027975, WO2004/084884, WO2004/037234, WO2004/032929, WO03/101458, WO03/091220,

WO03/082820, WO03/020289, WO02/32412, WO01/85145, WO01/78728, WO01/66096, WO00/02549,

WO01/00215, WO00/15205, WO00/23057, WO00/33840, WO00/30446, WO00/23057, WO00/15205,

WO00/09483, WO00/07600, WO00/02549, WO99/47131, WO99/07359, WO98/30243, WO97/38993, WO97/13754, WO94/29255, WO94/20476, WO94/19356, W O93/03034 and WO92/ 19238.

Suitable acetylcholinesterase inhibitors for the purpose of the present invention are, for example, donepezil (Eisai Co. Ltd.); rivastigmine (Novartis AG); (-)-phenserine (TorreyPines Therapeutics); ladostigil (Hebrew University of Jerusalem); Huperzine A (Mayo Foundation); galantamine (Johnson &Johnson); memokin (Universita di Bologna); SP-004 (Samaritan Pharmaceuticals Inc.); BGC-201259 (Sankyo Co. Ltd.); physostigmine (Forest Laboratories Inc.); NP-0361 (Neuropharma SA); ZT-1 (Debiopharm); tacrine (Warner-Lambert Co.); metrifonate (Bayer Corp.), INM-176 (Whanln), huperzine A (NeuroHitech/Xel Pharmaceutical), mimopezil (Debiopharm), and dimebon (Medivation/Pfizer).

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, WO2004/009062,

WO03/010159, WO02/072542, WO02/34718, WO01/98262, WO01/94321, WO01/92204, WO01/81295,

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, 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.

Suitable NMDA receptor antagonists for the purpose of the present invention are, for example, memantine (Merz & Co. GmbH); topiramate (Johnson &Johnson); AVP-923 (Neurodex) (Neurological Research Center); EN-3231 (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dexanabiol (HU-211; Sinnabidol; PA-50211) (Pharmos); EpiCept NP-1 (Dalhousie University); indandol (V-3381; CNP-3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA129) (Wyeth); RGH-896 (Gedeon Richter Ltd.); Traxoprodil (CP-101606), Bezonprodil (PD-196860, CI-1041) (Pfizer Inc.); CGX-1007 (Cognetix Inc.); delucemine (NPS-1506) (NPS Pharmaceuticals Inc.); EVT-101 (Roche Holding AG); acamprosate (Synchroneuron LLC); CR-3991, CR-2249, CR-3394 (Rottapharm SpA.); AV-101 (4-Cl-kynurenine (4-Cl-KYN)), 7-chlorokynurenic acid (7-Cl-KYNA) (VistaGen); NPS-1407 (NPS Pharmaceuticals Inc.); YT1006 (Yaupon Therapeutics Inc.); ED-1812 (Sosei R&D Ltd.); hyamntane (N-2(adamantly)hexamethyleneimine hydrochloride) (RAMS); lanceycemin (AR-R-15896) (AstraZeneca); EVT-102, Ro-25-6981 and Ro63-1908 (Hoffmann-La Roche AG/Evotec), neramexane (Merz).

- 19 043556

In addition, the present invention relates to combination therapies useful for the treatment of atherosclerosis, restenosis or arthritis, administration of a QC inhibitor in combination with another therapeutic agent selected from the group consisting of angiotensin converting enzyme (ACE) inhibitors; angiotensin II receptor blockers; diuretics; calcium channel blockers (CCBs); beta blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; compounds that increase high density lipoprotein (HDL) levels; renin inhibitors; IL-6 inhibitors; anti-inflammatory corticosteroids; antiproliferative agents; nitric oxide donors; extracellular matrix synthesis inhibitors; inhibitors of signal transduction involving growth factors or cytokines; MCP-1 antagonists and tyrosine kinase inhibitors, providing preferential or synergistic therapeutic effects when compared with each component of monotherapy separately.

Angiotensin II receptor blockers are those active agents that bind to the AT ₁ receptor subtype of the angiotensin II receptor, but do not lead to activation of the receptor. As a consequence of blockade of the AT ₁ receptor, such antagonists, for example, can be used as antihypertensive agents.

Suitable angiotensin II receptor blockers that can be used in combination according to the present invention include AT ₁ receptor antagonists having different structural features, preferably those with non-peptide structures. For example, mention may be made of compounds which are selected from the group consisting of valsartan (EP 443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP 403159), irbesartan (EP 454511), olmesartan (EP 503785), tazosartan (EP 539086), telmisartan (EP 522314), compounds with the designation E-4177 of the formula:

compounds designated SC-52458 with the following formula:

and compounds with the designation compound ZD-8731 of the formula:

or in each case a pharmaceutically acceptable salt thereof.

Preferred AT ₁ receptor antagonists are those that have been approved and reached the market, with the most preferred being valsartan or a pharmaceutically acceptable salt thereof.

Interfering with the enzymatic breakdown of angiotensin to angiotensin II by ACE inhibitors represents a successful option for blood pressure regulation and thus also makes available a therapeutic option for the treatment of hypertension.

A suitable ACE inhibitor to be used in the combination of the present invention is, for example, a compound selected from the group consisting of alacepril, benazepril, benazeprilate; captopril, ceronapril, cilazapril, delapril, enalapril, enoprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or in each case a pharmaceutically acceptable salt thereof.

Preferred ACE inhibitors are those that have been marketed, with benazepril and enalapril being the most preferred.

The diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide and chlorthalidone. The most preferred diuretic is hydrochlorothiazide. The diuretic further comprises a potassium-sparing diuretic such as amiloride or triametherin or a pharmaceutically acceptable salt thereof.

The class of SSVs essentially includes dihydropyridines (DHPs) and non-DHP agents such as diltiazem-type and verapamil-type SSVs.

The SSV useful in said combination is preferably a member of DHP selected from the group consisting of amlodipine, felodipine, riosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine and nivaldipine, and preferably is a representative non-DHP agent selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil and in each case a pharmaceutically acceptable salt thereof. Everyone is like that

SERs are therapeutically useful, for example, as antihypertensive agents, drugs against angina pectoris or arrhythmia.

Preferred SERs include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and verapamil or, for example, depending on the particular SER, a pharmaceutically acceptable salt thereof. Particularly preferred DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially besylate. Particularly preferred exemplary non-DHP agents are verapamil or a pharmaceutically acceptable salt thereof, especially the hydrochloride.

Beta blockers suitable for use in the present invention include beta adrenergic blocking agents (beta blockers) that compete with epinephrine for beta adrenergic receptors and antagonize the action of epinephrine. Preferably, beta blockers are selective for the beta adrenergic receptor over alpha adrenergic receptors and therefore do not have a significant alpha blocking effect. Suitable beta blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvediol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol. If the beta blocker is an acid or base or is otherwise capable of forming pharmaceutically acceptable salts or prodrugs, such forms are considered to be covered herein, and it is known that the compounds can be administered in free form or in the form of a pharmaceutically acceptable salt or prodrug, such as physiologically hydrolyzable and acceptable ester. For example, metoprolol is suitably administered as its tartrate salt, propranolol is suitably administered as its hydrochloride salt, etc.

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

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

HMG-Co-A reductase inhibitors (also called beta-hydroxy-betamethylglutaryl coenzyme A reductase inhibitors or statins) are active drugs that can be used to lower blood lipid levels, including cholesterol.

The class of HMG-Co-A reductase inhibitors includes compounds with differing structural features. For example, mention may be made of compounds that are selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case a pharmaceutically acceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those that have been marketed, with the most preferred being atorvastatin, pitavastatin or simvastatin or a pharmaceutically acceptable salt thereof.

HDL-increasing compounds include, but are not limited to, cholesteryl ester transfer protein (CETP) inhibitors. Examples of CETP inhibitors include JTT7O5, disclosed in Example 26 of US Pat. No. 6,426,365, published July 30, 2002, and pharmaceutically acceptable salts thereof.

Suppression of interleukin 6-mediated inflammation can be achieved indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion or through direct inhibition of signal transduction pathways involving interleukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, interleukin-6 antisense oligonucleotide (ASON), gp130 protein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, serine/threonine kinase inhibitors/antibodies, mitogen-activated protein kinase (MAP) inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, nuclear factor kappa inhibitors B (NFκB)/antibodies, I B kinase inhibitors (IKK)/antibodies, activator protein 1 (AP-1) inhibitors/antibodies, STAT transcription factor inhibitors/antibodies, altered IL-6, partial peptides of IL-6 or receptor IL-6, or SOCS (suppressors of cytokine signaling) protein, PPAR gamma and/or PPAR beta/delta activators/ligands or a functional fragment thereof.

A suitable anti-inflammatory corticosteroid is dexamethasone.

Suitable antiproliferative agents include cladribine, rapamycin, vincristine and taxol.

A suitable inhibitor of extracellular matrix synthesis is halofuginone.

A suitable inhibitor of growth factor or cytokine signaling is, for example, the Ras inhibitor R115777.

A suitable tyrosine kinase inhibitor is tyrphostin.

- 21 043556

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.

MCP-1 antagonists, for example, can be selected from anti-MCP-1 antibodies, preferably monoclonal or humanized monoclonal antibodies, MCP-1 expression inhibitors, CCR2 antagonists, TNF-alpha inhibitors, VCAM-1 gene expression inhibitors and anti-C5a monoclonal antibodies.

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.

Suitable MCP-1 antagonists are, for example, C-243 (Telik Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG); CC-11006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067, AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, PRS-211092 (Pharmos Corp.); monoclonal antibodies to C5a, such as neutrazomab (G2 Therapies Ltd.); AZD-6942 (AstraZeneca plc); 2mercaptoimidazoles (Johnson &Johnson); TEI-E00526, TEI-6122 (Deltagen); RS-504393 (Roche Holding AG); SB-282241, SB-380732, ADR-7 (Glaxo SmithKline); monoclonal antibodies to MCP-1 (Johnson & Johnson).

Combinations of QC inhibitors with MCP-1 antagonists may be useful for the treatment of inflammatory diseases in general, including neurodegenerative diseases.

Combinations of QC inhibitors with MCP-1 antagonists are preferred for the treatment of Alzheimer's disease.

Most preferably, the QC inhibitor is combined with one or more compounds selected from the following group: PF-4360365, m266, bapineizumab, R-1450, Posiphen, (+)-phenserine, MK0752, LY-450139, E-2012, (R)- flurbiprofen, AZD-103, AAV-001 (bapineizumab), tramiprosate, EGb-761, TAK-070, doxophylline, theophylline, cilomilast, tofimilast, roflumilast, tetomilast, tipelukast, ibudilast, NT-0712, MEM-1414, olemilast, linezolid , budipine, isocarboxazid, phenelzine, tranylcypromine, indantadol, moclobemide, rasagiline, ladostigil, safinamide, AVT-239, AVT-834, GSK-189254A, ciproxifan, JNJ-17216498, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro -benzothiazole, Z-321, ONO-1603, JTP-4819, S17092, BIBP3226; (R)-N2-(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]argininamide, cevimeline, sabcomelin, (PD-151832), donepezil, rivastigmine, (-)-phenserine, ladostigil, galantamine, tacrine, metrifonate, memantine, topiramate, AVP-923, EN-3231, neramexan, valsartan, benazepril, enalapril, hydrochlorothiazide, amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil, amlodipine, acebu tolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, rindolol, propranolol, sotalol, timolol, PLAVIX® (clopidogrel bisulfate), PLETAL® (cilostazol), aspirin, ZETIA® (ezetimibe) and KT6-971, statins, atorvastatin, pitavastatin or simvastatin; dexamethasone, cladribine, rapamycin, vincristine, taxol, aliskiren, C-243, ABN-912, SSR-150106, MLN-1202 and betaferon.

In particular, the following combinations are considered:

a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with atorvastatin for the treatment and/or prevention of atherosclerosis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with an immunosuppressive agent, preferably rapamycin, to prevent and/or treat restenosis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of the examples 1-1323, in combination with immunosuppressive agents, preferably paclitaxel, for the prevention and/or treatment of restenosis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with inhibitors AChE, preferably donepezil, for the prevention and/or treatment of Alzheimer's disease, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with interferons, preferably Aronex, for the prevention and /or treatment of multiple sclerosis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with interferons, preferably betaferon, for the prevention and/or treatment of multiple sclerosis, a QC inhibitor , preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with interferons, preferably Rebif, for the prevention and/or treatment of multiple sclerosis,

- 22 043556 a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with Copaxone for the prevention and/or treatment of multiple sclerosis, a QC inhibitor, preferably a QC inhibitor of formula (I ), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with dexamethasone to prevent and/or treat restenosis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1 -1323, in combination with dexamethasone for the prevention and/or treatment of atherosclerosis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with dexamethasone for the prevention and/or treatment rheumatoid arthritis, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of restenosis, where the inhibitor HMG-Co-A reductase selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of atherosclerosis, where the HMG-Co-A reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with HMG-Co-A reductase inhibitors, for the prevention and/or treatment of rheumatoid arthritis, wherein the HMG-Co-A inhibitor -reductase selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with antibodies to amyloid-beta for the prevention and/or treatment of mild cognitive impairment, wherein the anti-amyloid-beta antibody is Acl-24, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with anti-amyloid-beta antibodies for the prevention and/or treatment of Alzheimer's disease, wherein the anti-amyloid-beta antibody is Acl-24, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of the examples 1-1323, in combination with anti-amyloid-beta antibodies for the prevention and/or treatment of neurodegeneration in Down syndrome, wherein the anti-amyloid-beta antibody is Acl-24, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor , selected from any of Examples 1-1323, in combination with beta-secretase inhibitors 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 QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with beta-secretase inhibitors for the prevention and/or treatment of Alzheimer's disease, wherein the beta-secretase inhibitor is selected from WY-25105, GW840736X and CTS-21166, a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of Examples 1-1323, in combination with beta-secretase inhibitors for the prevention and/or treatment of neurodegeneration in Down syndrome, wherein the beta inhibitor -secretase 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 of Examples 1-1323, in combination with gamma secretase inhibitors for the prevention and/or treating mild cognitive impairment, wherein the gamma 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 of Examples 1- 1323, in combination with gamma secretase inhibitors for the prevention and/or treatment of Alzheimer's disease, wherein the gamma 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 of Examples 1-1323, in combination with gamma secretase inhibitors for the prevention and/or treatment of neurodegeneration in Down syndrome, wherein the gamma secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124.

- 23 043556

This combination therapy is particularly suitable for AD, FAD, FDD and neurodegeneration in Down syndrome, as well as atherosclerosis, rheumatoid arthritis, restenosis and pancreatitis.

Such combination therapies may result in a better therapeutic effect (less proliferation as well as less inflammation, stimulation of proliferation) than would occur with the agent alone.

Regarding the specific combination of QC inhibitors and additional compounds, reference is made in particular to WO 2004/098625 in this regard, which is incorporated herein by reference.

Pharmaceutical compositions.

To prepare the pharmaceutical compositions of the present invention, at least one compound of formula (I), optionally in combination with at least one of the other agents mentioned above, can be used as the active ingredient(s). The active ingredient(s) are intimately mixed with a pharmaceutical carrier in accordance with conventional pharmaceutical formulation techniques, which carrier may take a number of different forms depending on the form of preparation required for administration, for example, oral or parenteral, such as intramuscular. When preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, in the case of liquid oral preparations such as, for example, suspensions, tinctures and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; in the case of solid preparations for oral administration, such as, for example, powders, capsules, gelatin capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Due to their ease of administration, tablets and capsules represent the most advantageous unit dosage form for oral administration, in which case solid pharmaceutical carriers are obviously used. If necessary, the tablets can be sugar-coated or enteric-coated by standard techniques. In the case of parenteral administration, the carrier will generally contain sterile water, however other ingredients may be included, for example, for purposes such as to facilitate dissolution or for preservation.

It is also possible to prepare injectable suspensions, in which case suitable liquid carriers, suspending agents and the like can be used. Pharmaceutical compositions herein will contain, per dosage unit, eg, tablet, capsule, powder, injection, teaspoon, etc., the amount of active ingredient(s) necessary to deliver an effective dose as described above. Pharmaceutical compositions herein will contain, per dosage unit, for example, tablet, capsule, powder, injection, suppository, teaspoon, etc., from about 0.03 mg to 100 mg/kg (preferably 0.1-30 mg /kg) and can be provided at a dosage of approximately 0.1-300 mg/kg per day (preferably 1-50 mg/kg per day) of each active ingredient or combination thereof. Dosages, however, may vary depending on the requirements of the patients, the severity of the condition being treated and the compound used. Either daily dosing or post-periodic dosing may be used.

Preferably, such compositions are presented in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions for parenteral use, metered-dose aerosol or liquid sprays, drops, ampoules, syringe-tube devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for weekly or monthly administration; for example, an insoluble salt of the active compound, such as a 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, for example, traditional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or resins, and other pharmaceutical diluents, for example water, to form the composition into a solid dosage form containing a uniform mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. When such compositions are specified before they are formulated into a dosage form, it is intended that the active ingredient is uniformly dispersed in the composition, whereby the composition can be readily divided into equally effective dosage forms such as tablets, pills and capsules. This composition, before being converted into a solid dosage form, is then divided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of each active ingredient or combination thereof of the present invention.

Tablets or pills of the compositions of the present invention may be coated or otherwise mixed to provide a dosage form providing the benefit of a sustained release. For example, a tablet or pill may contain an internal drug and an external dose component, the latter being in the form of a coating around the former. The two components may be separated by an enteric layer, which serves to inhibit disintegration in the stomach and allow the internal component to pass intact into the duodenum or delay its release. A variety of materials can be used in the case of such enteric layers or coatings, and such materials include a number of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

These liquid forms in which the compositions of the present invention may be formulated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil. butter or peanut butter, and tinctures and similar pharmaceutical carrier vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, gum acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical composition may contain from about 0.01 mg to 100 mg, preferably from about 5 to 50 mg of each compound, and can be formulated in any form suitable for the selected route of administration. Carriers include essential and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweeteners, preservatives, coloring agents and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, drops, capsules (each of which includes immediate-release, time-release and sustained-release formulations), granules, powders and liquid forms such as solutions , syrups, tinctures, emulsions and suspensions. Forms suitable for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three or four times each day. In addition, the compounds of the present invention can be administered in intranasal form through topical application of suitable intranasal vehicles or through transdermal skin patches, which are well known to those skilled in the art. When administered in the form of a transdermal delivery system, dosing will, of course, be continuous rather than intermittent in the dosing pattern.

For example, for oral administration in the form of a tablet or capsule, the active drug component may be combined with a non-toxic pharmaceutically acceptable inert oral carrier such as ethanol, glycerin, water and the like. Moreover, if desired or necessary, suitable binding agents; lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as gum acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, chloride sodium, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Liquid forms in suitable flavored suspending or dispersing agents such as synthetic and natural gums, eg tragacanth, gum acacia, methylcellulose, etc. For parenteral administration, sterile suspensions and solutions are required. Isotonic preparations, which generally contain suitable preservatives, are used if intravenous administration is necessary.

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

The compounds or combinations of the present invention can also be delivered using monoclonal antibodies as separate carriers to which the compound molecules are attached. The compounds of the present invention can also be combined with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxyoxide polylysine substituted with a palmitoyl moiety. In addition, the compounds of the present invention can be coupled with a class of biodegradable polymers useful for achieving controlled drug release, for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymer hydrogels .

The compounds or combinations of the present invention can be administered in any of the above compositions and in accordance with dosage schedules established in the prior art, whenever treatment of these disorders is required.

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The daily dosage of the products can vary widely from 0.01 to 1,000 mg per mammal per day. For oral administration, the compositions are preferably presented 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 milligrams of each active ingredient, or combinations thereof, for symptomatic dose adjustment in the patient being treated. An effective amount of drug is typically provided at a dose level of from about 0.1 mg/kg to about 300 mg/kg body weight per day. Preferably, the range is from about 1 to about 50 mg/kg body weight per day. The compounds or combinations can be administered in a 1 to 4 times daily regimen.

Optimal dosages to be administered can be readily determined by one skilled in the art and will vary depending on the particular compound used, the route of administration, the strength of the drug, the route of administration and the severity of the disease state. In addition, factors associated with the particular patient being treated, including the patient's age, weight, diet, and timing of administration, will result in the need for dosage adjustments.

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 of the other agents mentioned above, and a pharmaceutically acceptable carrier.

The compositions are preferably presented in unit dosage form in an amount suitable for the respective daily dosage.

Suitable dosages, including especially unit dosages, of the compounds of the present invention include known dosages, including unit doses of such compounds as described or referred to in the literature, such as the British Pharmacopoeia and the United States Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.) , Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see 31st ed., p. 341, and the pages cited therein) or the above publications.

Examples

In a further embodiment, the present invention provides compounds of formulas (IIa) and (IIb), where X1, n, Z, Y1, Y ₂ , Y 3, Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , _{Y 9} , Y ₁₀ , R ₅ and R ₆ are as defined in Examples 1-265

(Pa) (Пь).

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Conn. Xi η Ζ γ. Υ, Uz γ ₄ Υ, γ ₆ Υ, Ys γ ₉ Υ10 Rs R6 1 CH ₂ 1 sn CH sn sn sn With sn sn sn sn sn n N 2 dn ₂ 1 Ν CH sn sn sn With sn sn sn sn sn n N 3 S 1 Ν CH sn sn sn With sn sn sn sn sn n Η 4 dn ₂ 1 sn sn sn sn sn With Ν sn sn sn sn n n 5 dn ₂ 1 Ν sn sn sn sn With Ν sn sn sn sn n n 6 S 1 Ν sn sn sn sn With Ν sn sn sn sn n n 7 dn ₂ 1 sn sn sn sn sn With sn Ν sn sn sn n n 8 dn ₂ 1 Ν sn sn sn sn With sn Ν sn sn sn n n 9 S 1 Ν sn sn sn sn With sn Ν sn sn sn n n 10 dn ₂ 1 sn sn sn sn sn With Ν sn sn sn Ν n n eleven dn ₂ 1 Ν sn sn sn sn With Ν sn sn sn Ν n n 12 S 1 Ν sn sn sn sn With Ν sn sn sn Ν n n 13 dn ₂ 1 sn sn sn sn sn With Ν Ν sn sn sn n n 14 dn ₂ 1 Ν sn sn sn sn With Ν Ν sn sn sn n n 15 S 1 Ν sn sn sn sn With Ν Ν sn sn sn n n 16 dn ₂ 1 sn sn sn sn sn With sn Ν sn Ν sn n Absent 17 dn ₂ 1 Ν sn sn sn sn With sn Ν sn Ν sn n 18 S 1 Ν sn sn sn sn With sn Ν sn Ν sn n 19 dn ₂ 1 sn sn sn sn sn With sn sn N sn Ν Absent n 20 dn ₂ 1 Ν sn sn sn sn With sn sn N sn Ν n 21 S 1 Ν sn sn sn sn With sn sn N sn Ν n 22 1 With sn sn sn sn n n 23 dn ₂ 1 sn sn sn sn sn With sn sn N sn sn Absent n 24 dn ₂ 1 Ν sn sn sn sn With sn sn N sn sn n 25 S 1 Ν sn sn sn sn With sn sn N sn sn n 26 dn ₂ 1 sn Ν sn sn sn With sn sn sn sn sn N n 27 dn ₂ 1 Ν Ν sn sn sn With sn sn sn sn sn N n 28 S 1 Ν Ν sn sn sn With sn sn sn sn sn N n 29 dn ₂ 1 sn Ν sn sn sn With Ν sn sn sn sn N n thirty dn ₂ 1 Ν Ν sn sn sn With Ν sn sn sn sn N n 31 S 1 Ν Ν sn sn sn With Ν sn sn sn sn N n 32 dn ₂ 1 sn Ν sn sn sn With sn Ν sn sn sn N n 33 dn ₂ 1 Ν Ν sn sn sn With sn Ν sn sn sn n n 34 S 1 Ν Ν sn sn sn With sn Ν sn sn sn n n 35 dn ₂ 1 CH Ν sn sn sn With Ν sn sn sn Ν n n 36 dn ₂ 1 Ν Ν sn sn sn With Ν sn sn sn Ν n n 37 S 1 Ν Ν sn sn sn With Ν sn sn sn Ν n n 38 dn ₂ 1 CH Ν sn sn sn With sn sn N sn Ν Absent n 39 dn ₂ 1 Ν Ν sn sn sn With sn sn N sn Ν n 40 S 1 Ν Ν sn sn sn With sn sn N sn Ν n 41 dn ₂ 1 CH Ν sn sn sn With Ν sn sn sn sn N n 42 dn ₂ 1 Ν Ν sn sn sn With Ν sn sn sn sn N n 43 S 1 Ν Ν sn sn sn With Ν sn sn sn sn N n 44 dn ₂ 1 CH Ν Ν sn sn With sn sn N sn Ν Absent n 45 dn ₂ 1 Ν Ν Ν sn sn With sn sn N sn Ν n 46 S 1 Ν Ν Ν sn sn With sn sn N sn Ν n 47 dn ₂ 1 CH Ν Ν sn sn With sn sn sn sn sn N n 48 dn ₂ 1 Ν Ν Ν sn sn With sn sn sn sn sn N n 49 S 1 Ν Ν Ν sn sn With sn sn sn sn sn N n 50 dn ₂ 1 CH sn Ν sn sn With sn sn sn sn sn N n 51 dn ₂ 1 Ν CH Ν sn sn With sn sn sn sn sn n n 52 S 1 Ν sn Ν sn sn With sn sn sn sn sn n n 53 dn ₂ 1 CH sn Ν sn sn With Ν sn sn sn sn n n 54 dn ₂ 1 Ν sn Ν sn sn With Ν sn sn sn sn n n 55 S 1 Ν sn Ν sn sn With Ν sn sn sn sn n n 56 dn ₂ 1 CH sn Ν sn sn With sn Ν sn sn sn n n 57 dn ₂ 1 Ν sn Ν sn sn With sn Ν sn sn sn n n 58 S 1 Ν sn Ν sn sn With sn Ν sn sn sn n n 59 dn ₂ 1 CH sn Ν sn sn With sn Ν sn Ν sn n Absent 60 dn ₂ 1 Ν sn Ν sn sn With sn Ν sn Ν sn n 61 S 1 Ν sn Ν sn sn With sn Ν sn Ν sn n 62 dn ₂ 1 CH sn Ν sn sn With Ν sn sn Ν sn n N 63 dn ₂ 1 Ν sn Ν sn sn With Ν sn sn Ν sn n N 64 S 1 Ν sn Ν sn sn With Ν sn sn Ν sn n Η 65 dn ₂ 1 CH sn Ν sn sn With sn sn N sn Ν Absent N 66 dn ₂ 1 Ν sn Ν sn sn With sn sn N sn Ν N 67 S 1 Ν sn Ν sn sn With sn sn N sn Ν N 68 dn ₂ 1 CH sn Ν sn sn With sn sn N sn sn Absent n 69 dn ₂ 1 Ν sn Ν sn sn With sn sn N sn sn n 70 S 1 Ν sn Ν sn sn With sn sn N sn sn n 71 dn ₂ 1 CH Ν sn Ν sn With sn sn sn sn sn N n 72 dn ₂ 1 Ν Ν sn Ν sn With sn sn sn sn sn N n 73 S 1 Ν Ν sn Ν sn With sn sn sn sn sn N n 74 dn ₂ 1 CH Ν sn Ν sn With Ν sn sn sn sn N n 75 dn ₂ 1 Ν Ν sn Ν sn With Ν sn sn sn sn N n

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76 S 1 N N sn N sn With N sn sn sn sn n N 77 dn ₂ 1 sn N sn N sn With sn N sn sn sn n N 78 dn ₂ 1 N N sn N sn With sn N sn sn sn n N 79 s 1 N N sn N sn With sn N sn sn sn n N 80 dn ₂ 1 sn CH N CH N With sn sn sn sn sn n N 81 dn ₂ 1 N CH N CH N With sn sn sn sn sn n N 82 S 1 N CH N CH N With sn sn sn sn sn n N 83 dn ₂ 1 sn sn sn N N With sn sn sn sn sn n N 84 dn ₂ 1 N sn sn N N With sn sn sn sn sn n N 85 S 1 N sn sn N N With sn sn sn sn sn n N 86 dn ₂ 1 sn sn sn CH N With sn sn sn sn sn n N 87 dn ₂ 1 N sn sn CH N With sn sn sn sn sn n N 88 S 1 N sn sn CH N With sn sn sn sn sn n N 89 dn ₂ 1 sn sn sn sn N With sn sn N sn sn Absent N 90 dn ₂ 1 N sn sn sn N With sn sn N sn sn N 91 S 1 N sn sn sn N With sn sn N sn sn N 92 dn ₂ 1 sn sn sn sn sn With sn sn sn sn sn F N 93 dn ₂ 1 N sn sn sn sn With sn sn sn sn sn F N 94 S 1 N sn sn sn sn With sn sn sn sn sn F N 95 dn ₂ 1 sn sn sn sn sn With N sn sn sn sn F N 96 dn ₂ 1 N sn sn sn sn With N sn sn sn sn F N 97 S 1 N sn sn sn sn With N sn sn sn sn F N 98 dn ₂ 1 sn sn sn sn sn With sn N sn sn sn F N 99 dn ₂ 1 N sn sn sn sn With sn N sn sn sn F N 100 S 1 N sn sn sn sn With sn N sn sn sn F N 101 dn ₂ 1 sn sn sn sn sn With N sn sn sn N F n 102 dn ₂ 1 N sn sn sn sn With N sn sn sn N F N 103 S 1 N sn sn sn sn With N sn sn sn N F N 104 dn ₂ 1 sn sn sn sn sn With N N sn sn sn F n 105 dn ₂ 1 N sn sn sn sn With N N sn sn sn F N 106 S 1 N sn sn sn sn With N N sn sn sn F N 107 dn ₂ 1 sn sn sn sn sn With sn N sn N sn F Absent 108 dn ₂ 1 N sn sn sn sn With sn N sn N sn F 109 S 1 N sn sn sn sn With sn N sn N sn F BY dn ₂ 1 sn sn sn sn sn With sn sn N sn N Absent 111 dn ₂ 1 N sn sn sn sn With sn sn N sn N 112 S 1 N sn sn sn sn With sn sn N sn N 113 dn ₂ 1 CH sn sn sn sn With sn sn N sn sn Absent N 114 dn ₂ 1 N sn sn sn sn With sn sn N sn sn N 115 S 1 N sn sn sn sn With sn sn N sn sn N 116 dn ₂ 1 CH N sn sn sn With sn sn CH sn sn F N 117 dn ₂ 1 N N sn sn sn With sn sn sn sn sn F N 118 S 1 N N sn sn sn With sn sn sn sn sn F N 119 dn ₂ 1 CH N sn sn sn With N sn sn sn sn F N 120 dn ₂ 1 N N sn sn sn With N sn sn sn sn F N 121 S 1 N N sn sn sn With N sn sn sn sn F N 122 dn ₂ 1 CH N sn sn sn With sn N sn sn sn F N 123 dn ₂ 1 N N sn sn sn With sn N sn sn sn F N 124 S 1 N N sn sn sn With sn N sn sn sn F N 125 dn ₂ 1 CH N sn sn sn With N sn sn sn N F N 126 dn ₂ 1 N N sn sn sn With N sn sn sn N F N 127 S 1 N N sn sn sn With N sn sn sn N F N 128 dn ₂ 1 CH N sn sn sn With sn sn N sn N Absent n 129 dn ₂ 1 N N sn sn sn With sn sn N sn N n 130 S 1 N N sn sn sn With sn sn N sn N n 131 dn ₂ 1 CH N N sn sn With sn sn CH sn sn F n 132 dn ₂ 1 N N N sn sn With sn sn sn sn sn F n 133 S 1 N N N sn sn With sn sn sn sn sn F n 134 dn ₂ 1 CH N N sn sn With sn sn N sn N Absent n 135 dn ₂ 1 N N N sn sn With sn sn N sn N n 136 S 1 N N N sn sn With sn sn N sn N n 137 dn ₂ 1 CH CH N sn sn With sn sn CH sn sn F n 138 dn ₂ 1 N CH N sn sn With sn sn sn sn sn F n 139 S 1 N CH N sn sn With sn sn sn sn sn F n 140 dn ₂ 1 CH CH N sn sn With N sn sn sn sn F n 141 dn ₂ 1 N CH N sn sn With N sn sn sn sn F n 142 S 1 N CH N sn sn With N sn sn sn sn F n 143 dn ₂ 1 CH sn N sn sn With sn N sn sn sn F n 144 dn ₂ 1 N sn N sn sn With sn N sn sn sn F n 145 S 1 N sn N sn sn With sn N sn sn sn F n 146 dn ₂ 1 CH sn N sn sn With sn N sn N sn F Absent 147 dn ₂ 1 N sn N sn sn With sn N sn N sn F 148 S 1 N sn N sn sn With sn N sn N sn F 149 dn ₂ 1 CH sn N sn sn With N sn sn N sn F Absent 150 dn ₂ 1 N sn N sn sn With N sn sn N sn F 151 S 1 N sn N sn sn With N sn sn N sn F

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152 CH ₂ 1 sn CH N sn sn With sn sn N sn N Absent N 153 dn ₂ 1 N sn N sn sn With sn sn N sn N N 154 S 1 N sn N sn sn With sn sn N sn N N 155 dn ₂ 1 sn N CH N sn With sn sn sn sn sn F N 156 dn ₂ 1 N N sn N sn With sn sn sn sn sn F N 157 S 1 N N sn N sn With sn sn sn sn sn F N 158 dn ₂ 1 sn N sn N sn With N sn sn sn sn F N 159 dn ₂ 1 N N sn N sn With N sn sn sn sn F N 160 S 1 N N sn N sn With N sn sn sn sn F N 161 dn ₂ 1 sn N sn N sn With sn N sn sn sn F N 162 dn ₂ 1 N N sn N sn With sn N sn sn sn F N 163 S 1 N N sn N sn With sn N sn sn sn F N 164 dn ₂ 1 sn CH N sn N With sn sn sn sn sn F N 165 dn ₂ 1 N sn N sn N With sn sn sn sn sn F N 166 S 1 N sn N sn N With sn sn sn sn sn F N 167 dn ₂ 1 sn sn CH N N With sn sn sn sn sn F N 168 dn ₂ 1 N sn sn N N With sn sn sn sn sn F N 169 S 1 N sn sn N N With sn sn sn sn sn F N 170 dn ₂ 1 sn sn sn CH N With sn sn sn sn sn F N 171 dn ₂ 1 N sn sn sn N With sn sn sn sn sn F N 172 S 1 N sn sn sn N With sn sn sn sn sn F N 173 dn ₂ 1 sn sn sn sn N With sn N sn sn sn F n 174 dn ₂ 1 N sn sn sn N With sn N sn sn sn F n 175 S 1 N sn sn sn N With sn N sn sn sn F n 176 dn ₂ 1 sn sn sn sn sn With sn sn sn sn sn Ome Ome 177 dn ₂ 1 N sn sn sn sn With sn sn sn sn sn compulsory medical insurance compulsory medical insurance 178 S 1 N sn sn sn sn With sn sn sn sn sn Ome Ome 179 dn ₂ 1 sn sn sn sn sn With N sn sn sn sn Ome Ome 180 dn ₂ 1 N sn sn sn sn With N sn sn sn sn compulsory medical insurance compulsory medical insurance 181 S 1 N sn sn sn sn With N sn sn sn sn Ome Ome 182 dn ₂ 1 sn sn sn sn sn With sn N sn sn sn Ome Ome 183 dn ₂ 1 N sn sn sn sn With sn N sn sn sn Ome Ome 184 S 1 N sn sn sn sn With sn N sn sn sn Ome Ome 185 dn ₂ 1 sn sn sn sn sn With N sn sn sn N Ome Ome 186 dn ₂ 1 N sn sn sn sn With N sn sn sn N Ome Ome 187 S 1 N sn sn sn sn With N sn sn sn N compulsory medical insurance compulsory medical insurance 188 dn ₂ 1 CH sn sn sn sn With N N sn sn sn Ome Ome 189 dn ₂ 1 N sn sn sn sn With N N sn sn sn Ome Ome 190 S 1 N sn sn sn sn With N N sn sn sn Ome Ome 191 dn ₂ 1 CH sn sn sn sn With sn N sn N sn Ome Absent 192 dn ₂ 1 N sn sn sn sn With sn N sn N sn Ome 193 S 1 N sn sn sn sn With sn N sn N sn Ome 194 dn ₂ 1 CH sn sn sn sn With sn sn N sn N Absent Ome 195 dn ₂ 1 N sn sn sn sn With sn sn N sn N Ome 196 S 1 N sn sn sn sn With sn sn N sn N Ome 197 dn ₂ 1 CH sn sn sn sn With sn sn N sn sn Absent Ome 198 dn ₂ 1 N sn sn sn sn With sn sn N sn sn Ome 199 S 1 N sn sn sn sn With sn sn N sn sn Ome 200 dn ₂ 1 CH N sn sn sn With sn sn sn sn sn Ome Ome 201 dn ₂ 1 N N sn sn sn With sn sn sn sn sn Ome Ome 202 S 1 N N sn sn sn With sn sn sn sn sn Ome Ome 203 dn ₂ 1 CH N sn sn sn With N sn sn sn sn Ome Ome 204 dn ₂ 1 N N sn sn sn With N sn sn sn sn Ome Ome 205 S 1 N N sn sn sn With N sn sn sn sn compulsory medical insurance compulsory medical insurance 206 dn ₂ 1 CH N sn sn sn With sn N sn sn sn Ome Ome 207 dn ₂ 1 N N sn sn sn With sn N sn sn sn Ome Ome 208 S 1 N N sn sn sn With sn N sn sn sn Ome Ome 209 dn ₂ 1 CH N sn sn sn With N sn sn sn N Ome Ome 210 dn ₂ 1 N N sn sn sn With N sn sn sn N Ome Ome 211 S 1 N N sn sn sn With N sn sn sn N compulsory medical insurance compulsory medical insurance 212 dn ₂ 1 CH N sn sn sn With sn sn N sn N Absent Ome 213 dn ₂ 1 N N sn sn sn With sn sn N sn N Ome 214 S 1 N N sn sn sn With sn sn N sn N compulsory medical insurance 215 dn ₂ 1 CH N sn sn sn With N sn sn sn sn Ome Ome 216 dn ₂ 1 N N sn sn sn With N sn sn sn sn Ome Ome 217 S 1 N N sn sn sn With N sn sn sn sn compulsory medical insurance compulsory medical insurance 218 dn ₂ 1 CH N N sn sn With sn sn N sn N Absent Ome 219 dn ₂ 1 N N N sn sn With sn sn N sn N Ome 220 S 1 N N N sn sn With sn sn N sn N Ome 221 dn ₂ 1 CH N N sn sn With sn sn sn sn sn Ome Ome 222 dn ₂ 1 N N N sn sn With sn sn sn sn sn Ome Ome 223 S 1 N N N sn sn With sn sn sn sn sn Ome Ome 224 dn ₂ 1 CH CH N sn sn With sn sn sn sn sn Ome Ome 225 dn ₂ 1 N CH N sn sn With sn sn sn sn sn Ome Ome 226 S 1 N sn N sn sn With sn sn sn sn sn Ome Ome 227 dn ₂ 1 CH sn N sn sn With N sn sn sn sn Ome Ome

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228 CH ₂ 1 N CH N sn sn With N sn sn sn sn Ome Ome 229 S 1 N CH N sn sn With N sn sn sn sn Ome Ome 230 dn ₂ 1 sn sn N sn sn With sn N sn sn sn Ome Ome 231 dn ₂ 1 N sn N sn sn With sn N sn sn sn Ome Ome 232 S 1 N sn N sn sn With sn N sn sn sn compulsory medical insurance compulsory medical insurance 233 dn ₂ 1 sn sn N sn sn With sn N sn N sn Ome Absent 234 dn ₂ 1 N sn N sn sn With sn N sn N sn Ome 235 S 1 N sn N sn sn With sn N sn N sn compulsory medical insurance 236 dn ₂ 1 sn sn N sn sn With N CH sn N sn Ome Ome 237 dn ₂ 1 N sn N sn sn With N CH sn N sn Ome Ome 238 S 1 N sn N sn sn With N CH sn N sn Ome Ome 239 dn ₂ 1 sn sn N sn sn With sn CH N CH N Absent Ome 240 dn ₂ 1 N sn N sn sn With sn CH N sn N Ome 241 S 1 N sn N sn sn With sn CH N sn N Ome 242 dn ₂ 1 sn sn N sn sn With sn CH N sn sn Absent Ome 243 dn ₂ 1 N sn N sn sn With sn CH N sn sn Ome 244 S 1 N sn N sn sn With sn CH N sn sn Ome 245 dn ₂ 1 CH N sn N sn With sn CH sn sn sn Ome Ome 246 dn ₂ 1 N N sn N sn With sn sn sn sn sn Ome Ome 247 S 1 N N sn N sn With sn CH sn sn sn Ome Ome 248 dn ₂ 1 CH N sn N sn With N CH sn sn sn Ome Ome 249 dn ₂ 1 N N sn N sn With N CH sn sn sn Ome Ome 250 S 1 N N sn N sn With N CH sn sn sn Ome Ome 251 dn ₂ 1 CH N sn N sn With sn N sn sn sn Ome Ome 252 dn ₂ 1 N N sn N sn With sn N sn sn sn Ome Ome 253 S 1 N N sn N sn With sn N sn sn sn Ome Ome 254 dn ₂ 1 CH sn N sn N With sn CH sn sn sn Ome Ome 255 dn ₂ 1 N sn N sn N With sn CH sn sn sn Ome Ome 256 S 1 N sn N sn N With sn sn sn sn sn Ome Ome 257 dn ₂ 1 CH sn sn N N With sn sn sn sn sn Ome Ome 258 dn ₂ 1 N sn sn N N With sn sn sn sn sn Ome Ome 259 S 1 N sn sn N N With sn sn sn sn sn Ome Ome 260 dn ₂ 1 CH sn sn sn N With sn sn sn sn sn Ome Ome 261 dn ₂ 1 N sn sn sn N With sn sn sn sn sn Ome Ome 262 S 1 N sn sn sn N With sn sn sn sn sn Ome Ome 263 dn ₂ 1 CH sn sn sn N With sn sn N sn sn Absent Ome 264 dn ₂ 1 N sn sn sn N With sn sn N sn sn Ome 265 S 1 N sn sn sn N With sn sn N sn sn Ome

In a further embodiment, the present invention provides compounds of formulas (IIIa) and (IIIb), where X1, n, Y1, Y2, Y ₃ , Y 4, Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , _{Y 10} , R ₅ and R ₆ are as defined in Examples 266-443

(Sha) (Шь).

Conn. Xi η Υ, Υ, Υ, Υ ₄ Υ, Ub Υ, γ ₈ Υ, Yw Rs Rs 266 dn ₂ 1 sn sn sn sn With sn sn sn sn sn n n 267 S 1 sn sn sn sn With sn sn sn sn sn n n 268 n. 1 sn sn sn sn With Ν sn sn sn sn n n 269 S 1 sn sn sn sn With Ν sn sn sn sn n n 270 n. 1 sn sn sn sn With sn Ν sn sn sn n n 271 S 1 sn sn sn sn With sn Ν sn sn sn n n 272 dn ₂ 1 sn sn sn sn With Ν sn sn sn N n n 273 S 1 sn sn sn sn With Ν sn sn sn N n n 274 n. 1 sn sn sn sn With Ν Ν sn sn sn n n 275 S 1 sn sn sn sn With Ν Ν sn sn sn n n 276 dn ₂ 1 sn sn sn sn With sn Ν sn Ν sn n Absent 277 S 1 sn sn sn sn With sn Ν sn Ν sn n 278 n. 1 sn sn sn sn With sn sn Ν sn N Absent n 279 S 1 sn sn sn sn With sn sn Ν sn N n 280 n. 1 sn sn sn sn With sn sn Ν sn sn Absent n 281 S 1 sn sn sn sn With sn sn Ν sn sn n 282 n. 1 Ν sn sn sn With sn sn sn sn sn Η n 283 S 1 Ν sn sn sn With sn sn sn sn sn n n 284 n. 1 Ν sn sn sn With Ν sn sn sn sn n n 285 S 1 Ν sn sn sn With Ν sn sn sn sn n n 286 n. 1 Ν sn sn sn With sn Ν sn sn sn n n 287 n. 1 Ν sn sn sn With sn Ν sn sn sn n n

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288 S 1 N CH CH CH c CH N CH CH CH H H 289 CH, 1 N CH CH CH c N CH CH CH N H H 290 S 1 N CH CH CH c N CH CH CH N H H 291 CH, 1 N CH CH CH c CH CH N CH N Absent H 292 S 1 N CH CH CH c CH CH N CH N H 293 CH, 1 N CH CH CH c N CH CH CH CH H H 294 s 1 N CH CH CH c N CH CH CH CH H H 295 CH, 1 N N CH CH c CH CH N CH N Absent H 296 CH, 1 N N CH CH c CH CH N CH N H 297 s 1 N N CH CH c CH CH N CH N H 298 CH, 1 N N CH CH c CH CH CH CH CH H H 299 s 1 N N CH CH c CH CH CH CH CH H H 300 CH, 1 CH N CH CH c CH CH CH CH CH H H 301 s 1 CH N CH CH c CH CH CH CH CH H H 302 CH, 1 CH N CH CH c N CH CH CH CH H H 303 s 1 CH N CH CH c N CH CH CH CH H H 304 CH, 1 CH N CH CH c CH N CH CH CH H H 305 s 1 CH N CH CH c CH N CH CH CH H H 306 CH ₂ 1 CH N CH CH c CH N CH N CH H Absent 307 s 1 CH N CH CH c CH N CH N CH H 308 CH, 1 CH N CH CH c N CH CH N CH H H 309 s 1 CH N CH CH c N CH CH N CH H H 310 CH ₂ 1 CH N CH CH c CH CH N CH N Absent H 311 s 1 CH N CH CH c CH CH N CH N H 312 CH, 1 CH N CH CH c CH CH N CH CH Absent H 313 s 1 CH N CH CH c CH CH N CH CH H 314 CH, 1 N CH N CH c CH CH CH CH CH Η H 315 s 1 N CH N CH c CH CH CH CH CH Η H 316 CH, 1 N CH N CH c N CH CH CH CH Η H 317 s 1 N CH N CH c N CH CH CH CH Η H 318 CH, 1 N CH N CH c CH N CH CH CH Η H 319 s 1 N CH N CH c CH N CH CH CH Η H 320 CH, 1 CH N CH N c CH CH CH CH CH Η H 321 s 1 CH N CH N c CH CH CH CH CH Η H 322 CH, 1 CH CH N N c CH CH CH CH CH Η H 323 s 1 CH CH N N c CH CH CH CH CH Η H 324 CH, 1 CH CH CH N c CH CH CH CH CH Η H 325 s 1 CH CH CH N c CH CH CH CH CH Η H 326 CH, 1 CH CH CH N c CH CH N CH CH Absent H 327 s 1 CH CH CH N c CH CH N CH CH H 328 CH, 1 CH CH CH CH c CH CH CH CH CH F H 329 s 1 CH CH CH CH c CH CH CH CH CH F H 330 CH, 1 CH CH CH CH c N CH CH CH CH F H 331 s 1 CH CH CH CH c N CH CH CH CH F H 332 CH, 1 CH CH CH CH c CH N CH CH CH F H 333 s 1 CH CH CH CH c CH N CH CH CH F H 334 CH, 1 CH CH CH CH c N CH CH CH N F H 335 s 1 CH CH CH CH c N CH CH CH N F H 336 CH, 1 CH CH CH CH c N N CH CH CH F H 337 s 1 CH CH CH CH c N N CH CH CH F H 338 CH, 1 CH CH CH CH c CH N CH N CH F Absent 339 s 1 CH CH CH CH c CH N CH N CH F 340 CH, 1 CH CH CH CH c CH CH N CH N Absent 341 s 1 CH CH CH CH c CH CH N CH N 342 CH, 1 CH CH CH CH c CH CH N CH CH Absent H 343 s 1 CH CH CH CH c CH CH N CH CH H 344 CH, 1 N CH CH CH c CH CH CH CH CH F H 345 s 1 N CH CH CH c CH CH CH CH CH F H 346 CH, 1 N CH CH CH c N CH CH CH CH F H 347 s 1 N CH CH CH c N CH CH CH CH F H 348 CH ₂ 1 N CH CH CH c CH N CH CH CH F H 349 s 1 N CH CH CH c CH N CH CH CH F H 350 CH, 1 N CH CH CH c N CH CH CH N F H 351 s 1 N CH CH CH c N CH CH CH N F H 352 CH, 1 N CH CH CH c CH CH N CH N Absent H 353 s 1 N CH CH CH c CH CH N CH N H 354 CH, 1 N N CH CH c CH CH CH CH CH F H 355 s 1 N N CH CH c CH CH CH CH CH F H 356 CH, 1 N N CH CH c CH CH N CH N Absent H 357 s 1 N N CH CH c CH CH N CH N H 358 CH, 1 CH N CH CH c CH CH CH CH CH F H 359 s 1 CH N CH CH c CH CH CH CH CH F H

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360 dn ₂ 1 CH N CH CH c N CH CH CH CH F H 361 s 1 CH N CH CH c N CH CH CH CH F H 362 dn ₂ 1 CH N CH CH c CH N CH CH CH F H 363 s 1 CH N CH CH c CH N CH CH CH F H 364 CH, 1 CH N CH CH c CH N CH N CH F Absent 365 s 1 CH N CH CH c CH N CH N CH F 366 CH ₂ 1 CH N CH CH c N CH CH N CH F Absent 367 s 1 CH N CH CH c N CH CH N CH F 368 CH ₂ 1 CH N CH CH c CH CH N CH N Absent Η 369 s 1 CH N CH CH c CH CH N CH N Η 370 CH ₂ 1 N CH N CH c CH CH CH CH CH F Η 371 s 1 N CH N CH c CH CH CH CH CH F Η 372 CH, 1 N CH N CH c N CH CH CH CH F Η 373 s 1 N CH N CH c N CH CH CH CH F Η 374 CH ₂ 1 N CH N CH c CH N CH CH CH F Η 375 s 1 N CH N CH c CH N CH CH CH F Η 376 CH ₂ 1 CH N CH N c CH CH CH CH CH F Η 377 s 1 CH N CH N c CH CH CH CH CH F Η 378 CH ₂ 1 CH CH N N c CH CH CH CH CH F Η 379 s 1 CH CH N N c CH CH CH CH CH F Η 380 CH ₂ 1 CH CH CH N c CH CH CH CH CH F Η 381 s 1 CH CH CH N c CH CH CH CH CH F Η 382 CH ₂ 1 CH CH CH N c CH N CH CH CH F Η 383 s 1 CH CH CH N c CH N CH CH CH F Η 384 CH ₂ 1 CH CH CH CH c CH CH CH CH CH Ome Ome 385 s 1 CH CH CH CH c CH CH CH CH CH Ome Ome 386 CH, 1 CH CH CH CH c N CH CH CH CH Ome Ome 387 s 1 CH CH CH CH c N CH CH CH CH Ome Ome 388 CH ₂ 1 CH CH CH CH c CH N CH CH CH Ome Ome 389 s 1 CH CH CH CH c CH N CH CH CH Ome OMe 390 CH ₂ 1 CH CH CH CH c N CH CH CH N OMe OMe 391 s 1 CH CH CH CH c N CH CH CH N OMe OMe 392 CH, 1 CH CH CH CH c N N CH CH CH OMe OMe 393 s 1 CH CH CH CH c N N CH CH CH OMe OMe 394 CH, 1 CH CH CH CH c CH N CH N CH OMe Absent 395 s 1 CH CH CH CH c CH N CH N CH OMe 396 CH, 1 CH CH CH CH c CH CH N CH N Absent OMe 397 s 1 CH CH CH CH c CH CH N CH N OMe 398 CH, 1 CH CH CH CH c CH CH N CH CH Absent Ome 399 s 1 CH CH CH CH c CH CH N CH CH Ome 400 CH, 1 N CH CH CH c CH CH CH CH CH Ome Ome 401 s 1 N CH CH CH c CH CH CH CH CH Ome Ome 402 CH, 1 N CH CH CH c N CH CH CH CH OMe Ome 403 s 1 N CH CH CH c N CH CH CH CH OMe OMe 404 CH, 1 N CH CH CH c CH N CH CH CH Ome OMe 405 s 1 N CH CH CH c CH N CH CH CH OMe OMe 406 CH, 1 N CH CH CH c N CH CH CH N Ome Ome 407 s 1 N CH CH CH c N CH CH CH N Ome Ome 408 CH, 1 N CH CH CH c CH CH N CH N Absent Ome 409 s 1 N CH CH CH c CH CH N CH N Ome 410 CH, 1 N CH CH CH c N CH CH CH CH OMe OMe 411 s 1 N CH CH CH c N CH CH CH CH OMe OMe 412 CH, 1 N N CH CH c CH CH N CH N Absent Ome 413 s 1 N N CH CH c CH CH N CH N Ome 414 CH ₂ 1 N N CH CH c CH CH CH CH CH OMe Ome 415 s 1 N N CH CH c CH CH CH CH CH OMe OMe 416 CH, 1 CH N CH CH c CH CH CH CH CH OMe OMe 417 s 1 CH N CH CH c CH CH CH CH CH Ome Ome 418 CH ₂ 1 CH N CH CH c N CH CH CH CH Ome Ome 419 s 1 CH N CH CH c N CH CH CH CH Ome Ome 420 CH, 1 CH N CH CH c CH N CH CH CH Ome Ome 421 s 1 CH N CH CH c CH N CH CH CH Ome Ome 422 CH, 1 CH N CH CH c CH N CH N CH Ome Absent 423 s 1 CH N CH CH c CH N CH N CH Ome 424 CH, 1 CH N CH CH c N CH CH N CH OMe Ome 425 s 1 CH N CH CH c N CH CH N CH OMe Ome 426 CH, 1 CH N CH CH c CH CH N CH N Absent OMe 427 s 1 CH N CH CH c CH CH N CH N OMe 428 CH, 1 CH N CH CH c CH CH N CH CH Absent OMe 429 s 1 CH N CH CH c CH CH N CH CH OMe 430 CH, 1 N CH N CH c CH CH CH CH CH OMe OMe 431 s 1 N CH N CH c CH CH CH CH CH OMe OMe

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In a further embodiment, the present invention provides compounds of formulas (IVa) and (IVb), where X1, o, Z, Y1, Y ₂ , Y 3, Y ₄ , Y ₅ , Y ₆ , _Y7 , Y ₈ , Y ₉ , Y ₁₀ , R ₅ and R ₆ are as defined in Examples 444-795

Rs Re

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496 0 CH CH N CH N c CH CH CH CH CH H H 497 0 N CH N CH N c CH CH CH CH CH H H 498 0 CH CH CH N N c CH CH CH CH CH H H 499 0 N CH CH N N c CH CH CH CH CH H H 500 0 CH CH CH CH N c CH CH CH CH CH H H 501 0 N CH CH CH N c CH CH CH CH CH H H 502 0 CH CH CH CH N c CH CH N CH CH Absent H 503 0 N CH CH CH N c CH CH N CH CH H 504 0 CH CH CH CH CH c CH CH CH CH CH F H 505 0 N CH CH CH CH c CH CH CH CH CH F H 506 0 CH CH CH CH CH c N CH CH CH CH F H 507 0 N CH CH CH CH c N CH CH CH CH F H 508 0 CH CH CH CH CH c CH N CH CH CH F H 509 0 N CH CH CH CH c CH N CH CH CH F H 510 0 CH CH CH CH CH c N CH CH CH N F H 511 0 N CH CH CH CH c N CH CH CH N F H 512 0 CH CH CH CH CH c N N CH CH CH F H 513 0 N CH CH CH CH c N N CH CH CH F H 514 0 CH CH CH CH CH c CH N CH N CH F Absent 515 0 N CH CH CH CH c CH N CH N CH F 516 0 CH CH CH CH CH c CH CH N CH N Absent 517 0 N CH CH CH CH c CH CH N CH N 518 0 CH CH CH CH CH c CH CH N CH CH Absent H 519 0 N CH CH CH CH c CH CH N CH CH H 520 0 CH N CH CH CH c CH CH CH CH CH F H 521 0 N N CH CH CH c CH CH CH CH CH F H 522 0 CH N CH CH CH c N CH CH CH CH F H 523 0 N N CH CH CH c N CH CH CH CH F H 524 0 CH N CH CH CH c CH N CH CH CH F H 525 0 N N CH CH CH c CH N CH CH CH F H 526 0 CH N CH CH CH c N CH CH CH N F H 527 0 N N CH CH CH c N CH CH CH N F H 528 0 CH N CH CH CH c CH CH N CH N Absent H 529 0 N N CH CH CH c CH CH N CH N H 530 0 CH N N CH CH c CH CH CH CH CH F H 531 0 N N N CH CH c CH CH CH CH CH F H 532 0 CH N N CH CH c CH CH N CH N Absent H 533 0 N N N CH CH c CH CH N CH N H 534 0 CH CH N CH CH c CH CH CH CH CH F H 535 0 N CH N CH CH c CH CH CH CH CH F H 536 0 CH CH N CH CH c N CH CH CH CH F H 537 0 N CH N CH CH c N CH CH CH CH F H 538 0 CH CH N CH CH c CH N CH CH CH F H 539 0 N CH N CH CH c CH N CH CH CH F H 540 0 CH CH N CH CH c CH N CH N CH F Absent 541 0 N CH N CH CH c CH N CH N CH F 542 0 CH CH N CH CH c N CH CH N CH F Absent 543 0 N CH N CH CH c N CH CH N CH F 544 0 CH CH N CH CH c CH CH N CH N Absent Η 545 0 N CH N CH CH c CH CH N CH N Η 546 0 CH N CH N CH c CH CH CH CH CH F Η 547 0 N N CH N CH c CH CH CH CH CH F Η 548 0 CH N CH N CH c N CH CH CH CH F Η 549 0 N N CH N CH c N CH CH CH CH F Η 550 0 CH N CH N CH c CH N CH CH CH F Η 551 0 N N CH N CH c CH N CH CH CH F Η 552 0 CH CH N CH N c CH CH CH CH CH F Η 553 0 N CH N CH N c CH CH CH CH CH F Η 554 0 CH CH CH N N c CH CH CH CH CH F Η 555 0 N CH CH N N c CH CH CH CH CH F Η 556 0 CH CH CH CH N c CH CH CH CH CH F Η 557 0 N CH CH CH N c CH CH CH CH CH F Η 558 0 CH CH CH CH N c CH N CH CH CH F Η 559 0 N CH CH CH N c CH N CH CH CH F Η 560 0 CH CH CH CH CH c CH CH CH CH CH Ome Ome 561 0 N CH CH CH CH c CH CH CH CH CH Ome Ome 562 0 CH CH CH CH CH c N CH CH CH CH OMc OMc 563 0 N CH CH CH CH c N CH CH CH CH Ome Ome 564 0 CH CH CH CH CH c CH N CH CH CH Ome Ome 565 0 N CH CH CH CH c CH N CH CH CH Ome Ome 566 0 CH CH CH CH CH c N CH CH CH N Ome Ome 567 0 N CH CH CH CH c N CH CH CH N OMc OMc 568 0 CH CH CH CH CH c N N CH CH CH Ome OMe 569 0 N CH CH CH CH c N N CH CH CH Ome OMe 570 0 CH CH CH CH CH c CH N CH N CH Ome Absent 571 0 N CH CH CH CH c CH N CH N CH OMe 572 0 CH CH CH CH CH c CH CH N CH N Absent OMc 573 0 N CH CH CH CH c CH CH N CH N Ome 574 0 CH CH CH CH CH c CH CH N CH CH Absent Ome 575 0 N CH CH CH CH c CH CH N CH CH OMe 576 0 CH N CH CH CH c CH CH CH CH CH OMe Ome 577 0 N N CH CH CH c CH CH CH CH CH OMe OMe 578 0 CH N CH CH CH c N CH CH CH CH Ome OMe 579 0 N N CH CH CH c N CH CH CH CH OMe OMe

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580 0 CH Ν CH CH CH With CH Ν CH CH CH Ome Ome 581 0 Ν Ν CH CH CH With CH Ν CH CH CH Ome Ome 582 0 CH Ν CH CH CH With Ν CH CH CH Ν compulsory medical insurance compulsory medical insurance 583 0 Ν Ν CH CH CH With Ν CH CH CH Ν Ome Ome 584 0 CH Ν CH CH CH C CH CH Ν CH Ν Absent Ome 585 0 Ν Ν CH CH CH With CH CH Ν CH Ν Ome 586 0 CH Ν CH CH CH C Ν CH CH CH CH Ome Ome 587 0 Ν Ν CH CH CH With Ν CH CH CH CH compulsory medical insurance compulsory medical insurance 588 0 CH Ν Ν CH CH With CH CH Ν CH Ν Absent Ome 589 0 Ν Ν Ν CH CH With CH CH Ν CH Ν Ome 590 0 CH Ν Ν CH CH C CH CH CH CH CH Ome Ome 591 0 Ν Ν Ν CH CH With CH CH CH CH CH Ome Ome 592 0 CH CH Ν CH CH With CH CH CH CH CH compulsory medical insurance compulsory medical insurance 593 0 Ν CH Ν CH CH With CH CH CH CH CH Ome Ome 594 0 CH CH Ν CH CH With Ν CH CH CH CH Ome Ome 595 0 Ν CH Ν CH CH C Ν CH CH CH CH Ome Ome 596 0 CH CH Ν CH CH With CH Ν CH CH CH Ome Ome 597 0 Ν CH Ν CH CH With CH Ν CH CH CH Ome Ome 598 0 CH CH Ν CH CH With CH Ν CH Ν CH Ome Absent 599 0 Ν CH Ν CH CH With CH Ν CH Ν CH Ome 600 0 CH CH Ν CH CH With Ν CH CH Ν CH Ome Ome 601 0 Ν CH Ν CH CH With Ν CH CH Ν CH Ome Ome 602 0 CH CH Ν CH CH With CH CH Ν CH Ν Absent Ome 603 0 Ν CH Ν CH CH With CH CH Ν CH Ν Ome 604 0 CH CH Ν CH CH With CH CH Ν CH CH Absent compulsory medical insurance 605 0 Ν CH Ν CH CH With CH CH Ν CH CH Ome 606 0 CH Ν CH Ν CH C CH CH CH CH CH Ome Ome 607 0 Ν Ν CH Ν CH With CH CH CH CH CH Ome Ome 608 0 CH Ν CH Ν CH With Ν CH CH CH CH Ome Ome 609 0 Ν Ν CH Ν CH With Ν CH CH CH CH compulsory medical insurance compulsory medical insurance 610 0 CH Ν CH Ν CH With CH Ν CH CH CH Ome Ome 611 0 Ν Ν CH Ν CH C CH Ν CH CH CH Ome Ome 612 0 CH CH Ν CH Ν With CH CH CH CH CH Ome Ome 613 0 Ν CH Ν CH Ν C CH CH CH CH CH Ome Ome 614 0 CH CH CH Ν Ν With CH CH CH CH CH compulsory medical insurance compulsory medical insurance 615 0 Ν CH CH Ν Ν With CH CH CH CH CH Ome Ome 616 0 CH CH CH CH Ν With CH CH CH CH CH Ome Ome 617 0 Ν CH CH CH Ν With CH CH CH CH CH Ome Ome 618 0 CH CH CH CH Ν With CH CH Ν CH CH Absent Ome 619 0 Ν CH CH CH Ν With CH CH Ν CH CH Ome 620 1 CH CH CH CH CH With CH CH CH CH CH N N 621 1 Ν CH CH CH CH With CH CH CH CH CH N N 622 1 CH CH CH CH CH With Ν CH CH CH CH N N 623 1 Ν CH CH CH CH With Ν CH CH CH CH N N 624 1 CH CH CH CH CH With CH Ν CH CH CH N N 625 1 Ν CH CH CH CH With CH Ν CH CH CH N N 626 1 CH CH CH CH CH C Ν CH CH CH Ν N N 627 1 Ν CH CH CH CH With Ν CH CH CH Ν N N 628 1 CH CH CH CH CH C Ν Ν CH CH CH N N 629 1 Ν CH CH CH CH With Ν Ν CH CH CH N N 630 1 CH CH CH CH CH With CH Ν CH Ν CH N Absent 631 1 Ν CH CH CH CH With CH Ν CH Ν CH N 632 1 CH CH CH CH CH C CH CH Ν CH Ν Absent N 633 1 Ν CH CH CH CH With CH CH Ν CH Ν N 634 1 CH CH CH CH CH With CH CH Ν CH CH Absent N 635 1 Ν CH CH CH CH With CH CH Ν CH CH N 636 1 CH Ν CH CH CH With CH CH CH CH CH N N 637 1 Ν Ν CH CH CH C CH CH CH CH CH N N 638 1 CH Ν CH CH CH With Ν CH CH CH CH N N 639 1 Ν Ν CH CH CH With Ν CH CH CH CH N N 640 1 CH Ν CH CH CH With CH Ν CH CH CH N N 641 1 Ν Ν CH CH CH With CH Ν CH CH CH N N 642 1 CH Ν CH CH CH With Ν CH CH CH Ν N N 643 1 Ν Ν CH CH CH With Ν CH CH CH Ν N N 644 1 CH Ν CH CH CH With CH CH Ν CH Ν Absent N 645 1 Ν Ν CH CH CH With CH CH Ν CH Ν N 646 1 CH Ν CH CH CH With Ν CH CH CH CH N N 647 1 Ν Ν CH CH CH With Ν CH CH CH CH N N 648 1 CH Ν Ν CH CH C CH CH Ν CH Ν Absent N 649 1 Ν Ν Ν CH CH With CH CH Ν CH Ν N 650 1 CH Ν Ν CH CH With CH CH CH CH CH N N 651 1 Ν Ν Ν CH CH With CH CH CH CH CH N N 652 1 CH CH Ν CH CH With CH CH CH CH CH N N 653 1 Ν CH Ν CH CH C CH CH CH CH CH N N 654 1 CH CH Ν CH CH With Ν CH CH CH CH N N 655 1 Ν CH Ν CH CH C Ν CH CH CH CH N N 656 1 CH CH Ν CH CH With CH Ν CH CH CH N N 657 1 Ν CH Ν CH CH With CH Ν CH CH CH N n 658 1 CH CH Ν CH CH With CH Ν CH Ν CH N Absent 659 1 Ν CH Ν CH CH With CH Ν CH Ν CH N 660 1 CH CH Ν CH CH With Ν CH CH Ν CH N Η 661 1 Ν CH Ν CH CH With Ν CH CH Ν CH N Η 662 1 CH CH Ν CH CH With CH CH Ν CH Ν Absent Η 663 1 Ν CH Ν CH CH With CH CH Ν CH Ν N

- 35 043556

664 1 CH CH N CH CH c CH CH N CH CH Absent H 665 1 N CH N CH CH c CH CH N CH CH H 666 1 CH N CH N CH c CH CH CH CH CH H H 667 1 N N CH N CH c CH CH CH CH CH H H 668 1 CH N CH N CH c N CH CH CH CH H H 669 1 N N CH N CH c N CH CH CH CH H H 670 1 CH N CH N CH c CH N CH CH CH H H 671 1 N N CH N CH c CH N CH CH CH H H 672 1 CH CH N CH N c CH CH CH CH CH H H 673 1 N CH N CH N c CH CH CH CH CH H H 674 1 CH CH CH N N c CH CH CH CH CH H H 675 1 N CH CH N N c CH CH CH CH CH H H 676 1 CH CH CH CH N c CH CH CH CH CH H H 677 1 N CH CH CH N c CH CH CH CH CH H H 678 1 CH CH CH CH N c CH CH N CH CH Absent H 679 1 N CH CH CH N c CH CH N CH CH H 680 1 CH CH CH CH CH c CH CH CH CH CH F H 681 1 N CH CH CH CH c CH CH CH CH CH F H 682 1 CH CH CH CH CH c N CH CH CH CH F H 683 1 N CH CH CH CH c N CH CH CH CH F H 684 1 CH CH CH CH CH c CH N CH CH CH F H 685 1 N CH CH CH CH c CH N CH CH CH F H 686 1 CH CH CH CH CH c N CH CH CH N F H 687 1 N CH CH CH CH c N CH CH CH N F H 688 1 CH CH CH CH CH c N N CH CH CH F H 689 1 N CH CH CH CH c N N CH CH CH F H 690 1 CH CH CH CH CH c CH N CH N CH F Absent 691 1 N CH CH CH CH c CH N CH N CH F 692 1 CH CH CH CH CH c CH CH N CH N Absent 693 1 N CH CH CH CH c CH CH N CH N 694 1 CH CH CH CH CH c CH CH N CH CH Absent H 695 1 N CH CH CH CH c CH CH N CH CH H 696 1 CH N CH CH CH c CH CH CH CH CH F H 697 1 N N CH CH CH c CH CH CH CH CH F H 698 1 CH N CH CH CH c N CH CH CH CH F H 699 1 N N CH CH CH c N CH CH CH CH F H 700 1 CH N CH CH CH c CH N CH CH CH F H 701 1 N N CH CH CH c CH N CH CH CH F H 702 1 CH N CH CH CH c N CH CH CH N F H 703 1 N N CH CH CH c N CH CH CH N F H 704 1 CH N CH CH CH c CH CH N CH N Absent H 705 1 N N CH CH CH c CH CH N CH N H 706 1 CH N N CH CH c CH CH CH CH CH F H 707 1 N N N CH CH c CH CH CH CH CH F H 708 1 CH N N CH CH c CH CH N CH N Absent H 709 1 N N N CH CH c CH CH N CH N H 710 1 CH CH N CH CH c CH CH CH CH CH F H 711 1 N CH N CH CH c CH CH CH CH CH F H 712 1 CH CH N CH CH c N CH CH CH CH F H 713 1 N CH N CH CH c N CH CH CH CH F H 714 1 CH CH N CH CH c CH N CH CH CH F H 715 1 N CH N CH CH c CH N CH CH CH F H 716 1 CH CH N CH CH c CH N CH N CH F Absent 717 1 N CH N CH CH c CH N CH N CH F 718 1 CH CH N CH CH c N CH CH N CH F Absent 719 1 N CH N CH CH c N CH CH N CH F 720 1 CH CH N CH CH c CH CH N N Absent Η 721 1 N CH N CH CH c CH CH N N Η 722 1 CH N CH N CH c CH CH CH CH CH F Η 723 1 N N CH N CH c CH CH CH CH CH F Η 724 1 CH N CH N CH c N CH CH CH CH F Η 725 1 N N CH N CH c N CH CH CH CH F Η 726 1 CH N CH N CH c CH N CH CH CH F Η 727 1 N N CH N CH c CH N CH CH CH F Η 728 1 CH CH N CH N c CH CH CH CH CH F Η 729 1 N CH N CH N c CH CH CH CH CH F Η 730 1 CH CH CH N N c CH CH CH CH CH F Η 731 1 N CH CH N N c CH CH CH CH CH F Η 732 1 CH CH CH CH N c CH CH CH CH CH F Η 733 1 N CH CH CH N c CH CH CH CH CH F Η 734 1 CH CH CH CH N c CH N CH CH CH F Η 735 1 N CH CH CH N c CH N CH CH CH F Η 736 1 CH CH CH CH CH c CH CH CH CH CH Ome Ome 737 1 N CH CH CH CH c CH CH CH CH CH Ome Ome 738 1 CH CH CH CH CH c N CH CH CH CH Ome Ome 739 1 N CH CH CH CH c N CH CH CH CH Ome Ome 740 1 CH CH CH CH CH c CH N CH CH CH Ome Ome 741 1 N CH CH CH CH c CH N CH CH CH Ome Ome 742 1 CH CH CH CH CH c N CH CH CH N Ome Ome 743 1 N CH CH CH CH c N CH CH CH N Ome Ome 744 1 CH CH CH CH CH c N N CH CH CH OMe Ome 745 1 N CH CH CH CH c N N CH CH CH OMe OMe 746 1 CH CH CH CH CH c CH N CH N CH OMe Absent 747 1 N CH CH CH CH c CH N CH N CH Ome

- 36 043556

748 1 sn CH sn sn sn With sn sn N sn N Absent Ome 749 1 N CH sn sn sn With sn sn N sn N Ome 750 1 sn sn sn sn sn With sn sn N sn sn Absent compulsory medical insurance 751 1 N sn sn sn sn With sn sn N sn sn Ome 752 1 sn N sn sn sn With sn sn CH sn sn Ome Ome 753 1 N N sn sn sn With sn sn sn sn sn Ome Ome 754 1 sn N sn sn sn With N sn sn sn sn Ome Ome 755 1 N N sn sn sn With N sn sn sn sn compulsory medical insurance compulsory medical insurance 756 1 sn N sn sn sn With sn N sn sn sn Ome Ome 757 1 N N sn sn sn With sn N sn sn sn Ome Ome 758 1 sn N sn sn sn With N sn sn sn N Ome Ome 759 1 N N sn sn sn With N sn sn sn N Ome Ome 760 1 CH N sn sn sn With sn sn N sn N Absent compulsory medical insurance 761 1 N N sn sn sn With sn sn N sn N Ome 762 1 CH N sn sn sn With N sn CH sn sn Ome Ome 763 1 N N sn sn sn With N sn sn sn sn Ome Ome 764 1 CH N N sn sn With sn sn N sn N Absent Ome 765 1 N N N sn sn With sn sn N sn N Ome 766 1 CH N N sn sn With sn sn CH sn sn Ome Ome 767 1 N N N sn sn With sn sn sn sn sn Ome Ome 768 1 CH sn N sn sn With sn sn sn sn sn Ome Ome 769 1 N sn N sn sn With sn sn sn sn sn Ome Ome 770 1 CH sn N sn sn With N sn sn sn sn Ome Ome 771 1 N sn N sn sn With N sn sn sn sn Ome Ome 772 1 CH sn N sn sn With sn N sn sn sn compulsory medical insurance compulsory medical insurance 773 1 N sn N sn sn With sn N sn sn sn Ome Ome 774 1 CH sn N sn sn With sn N sn N sn Ome Absent 775 1 N sn N sn sn With sn N sn N sn Ome 776 1 CH sn N sn sn With N sn sn N sn Ome Ome 777 1 N sn N sn sn With N sn sn N sn compulsory medical insurance compulsory medical insurance 778 1 CH sn N sn sn With sn sn N sn N Absent Ome 779 1 N sn N sn sn With sn sn N sn N Ome 780 1 CH sn N sn sn With sn sn N sn sn Absent Ome 781 1 N sn N sn sn With sn sn N sn sn Ome 782 1 CH N CH N sn With sn sn CH sn sn compulsory medical insurance compulsory medical insurance 783 1 N N CH N sn With sn sn CH sn sn Ome Ome 784 1 CH N CH N sn With N sn sn sn sn Ome Ome 785 1 N N CH N sn With N sn sn sn sn Ome Ome 786 1 CH N CH N sn With sn N sn sn sn Ome Ome 787 1 N N sn N sn With sn N sn sn sn Ome Ome 788 1 CH CH N sn N With sn sn sn sn sn Ome Ome 789 1 N sn N sn N With sn sn sn sn sn Ome Ome 790 1 CH sn CH N N With sn sn sn sn sn Ome Ome 791 1 N sn sn N N With sn sn sn sn sn compulsory medical insurance compulsory medical insurance 792 1 CH sn sn sn N With sn sn sn sn sn Ome Ome 793 1 N sn sn sn N With sn sn sn sn sn Ome Ome 794 1 CH sn sn sn N With sn sn N sn sn Absent Ome 795 1 N sn sn sn N With sn sn N sn sn Ome

In a further embodiment, the present invention provides compounds of formulas (IVa) and (IVb), where X1, o, Z, Y1, Y ₂ , Y 3, Y ₄ , Y ₅ , Y ₆ , _Y7 , Y ₈ , Y ₉ , Y ₁₀ , R5 and R ₆ are as defined in Examples 1289-1296

In both formula (IVa) and formula (IVb) o equals 0

Conn. R Z Y, Y2 Y, Υ4 Y _s Yes Y ₇ Ys Υ9 Υ10 R5 Re 1289 0 N CH sn sn sn With CH sn sn sn sn Ome N 1290 0 N N sn sn sn With sn sn sn sn sn Ome n 1291 0 N CH sn Ν sn With sn sn sn sn sn Ome n 1292 0 N CH sn Ν sn With sn sn sn sn sn Ome Ome 1293 0 N N sn sn Ν With sn sn sn sn sn F N 1294 0 N CH sn sn sn With sn sn sn sn sn O-Phenyl N 1295 0 N sn sn sn sn With sn sn sn sn sn Propoxy N 1296 0 N sn sn sn sn With sn sn sn sn sn Propan-2-yloxy N

In a further embodiment, the present invention provides compounds of formulas (Va) and (Vb), where o, Y1, _Y2 , _Y3 , _Y4 , _Y5 , _Y6 , _Y7 , _Y8 , _Y9 , _Y10 , R ₅ and R ₆ are as defined in Examples 796-971

In both formula (Va) and formula (Vb), o equals 0.

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Conn. R γ. γ ₂ Υ, Υ, γ ₅ γ ₆ Υ, Ys γ ₉ ¥yu Rs Re 796 0 sn sn sn sn With sn sn sn sn sn n N 797 0 sn sn sn sn With Ν sn sn sn sn n N 798 0 sn sn sn sn With sn Ν sn sn sn n N 799 0 sn sn sn sn With Ν sn sn sn N n N 800 0 sn sn sn sn With Ν Ν sn sn sn n N 801 0 sn sn sn sn With sn Ν sn N sn n Absent 802 0 sn sn sn sn With sn sn N sn N Absent N 803 0 sn sn sn sn With sn sn N sn sn Absent N 804 0 N sn sn sn With sn sn CH sn sn N N 805 0 N sn sn sn With Ν sn sn sn sn N N 806 0 N sn sn sn With sn Ν sn sn sn N N 807 0 N sn sn sn With Ν sn sn sn N N N 808 0 N sn sn sn With sn sn N sn N Absent N 809 0 N sn sn sn With Ν sn CH sn CH N N 810 0 N Ν sn sn With sn sn N sn N Absent N 811 0 N Ν sn sn With sn sn CH sn CH N N 812 0 sn Ν sn sn With sn sn sn sn sn N N 813 0 sn Ν sn sn With Ν sn sn sn sn N N 814 0 sn Ν sn sn With sn Ν sn sn sn N N 815 0 sn Ν sn sn With sn Ν sn N sn N Absent 816 0 sn Ν sn sn With Ν sn sn N sn N N 817 0 sn Ν sn sn With sn sn N sn N Absent N 818 0 sn Ν sn sn With sn sn N sn sn Absent N 819 0 N sn Ν sn With sn sn sn sn sn N N 820 0 N sn Ν sn With Ν sn sn sn sn N N 821 0 N sn Ν sn With sn Ν sn sn sn N N 822 0 sn Ν sn N With sn sn sn sn sn N N 823 0 sn CH Ν N With sn sn sn sn sn N N 824 0 sn CH sn N With sn sn sn sn sn N N 825 0 sn sn sn N With sn sn N sn sn Absent N 826 0 sn sn sn sn With sn sn sn sn sn F N 827 0 sn sn sn sn With Ν sn sn sn sn F N 828 0 sn sn sn sn With sn Ν sn sn sn F N 829 0 sn sn sn sn With Ν sn sn sn N F N 830 0 sn sn sn sn With Ν Ν sn sn sn F N 831 0 sn sn sn sn With sn Ν sn N sn F Absent 832 0 sn sn sn sn With sn sn N sn N Absent 833 0 sn sn sn sn With sn sn N sn sn Absent N 834 0 N sn sn sn With sn sn sn sn sn F N 835 0 N sn sn sn With Ν sn sn sn sn F N 836 0 N sn sn sn With sn Ν sn sn sn F N 837 0 N sn sn sn With Ν sn sn sn N F N 838 0 N sn sn sn With sn sn N sn N Absent N 839 0 N Ν sn sn With sn sn sn sn sn F N 840 0 N Ν sn sn With sn sn N sn N Absent N 841 0 CH Ν sn sn With sn sn CH sn CH F N 842 0 CH Ν sn sn With Ν sn CH sn CH F N 843 0 sn Ν sn sn With sn Ν sn sn sn F N 844 0 sn Ν sn sn With sn Ν sn N sn F Absent 845 0 sn Ν sn sn With Ν sn sn N sn F Absent 846 0 sn Ν sn sn With sn sn N sn N Absent N 847 0 N sn Ν sn With sn sn sn sn sn F N 848 0 N sn Ν sn With Ν sn sn sn sn F N 849 0 N sn Ν sn With sn Ν sn sn sn F N 850 0 sn Ν sn N With sn sn sn sn sn F N 851 0 sn CH Ν N With sn sn sn sn sn F N 852 0 sn sn sn N With sn sn sn sn sn F N 853 0 sn sn sn N With sn Ν sn sn sn F N 854 0 sn sn sn sn With sn sn sn sn sn Ome Ome 855 0 sn sn sn sn With Ν sn sn sn sn Ome Ome 856 0 sn sn sn sn With sn Ν sn sn sn Ome Ome 857 0 sn sn sn sn With Ν CH sn sn N Ome Ome 858 0 sn sn sn sn With Ν Ν sn sn sn Ome Ome 859 0 sn sn sn sn With sn Ν sn N sn Ome Absent 860 0 sn sn sn sn With sn CH N sn N Absent Ome 861 0 sn sn sn sn With sn CH N sn sn Absent Ome 862 0 N sn sn sn With sn CH sn sn sn Ome Ome 863 0 N sn sn sn With Ν sn sn sn sn compulsory medical insurance compulsory medical insurance

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864 0 N CH CH CH C CH N CH CH CH OMe Ome 865 0 N CH CH CH c N CH CH CH N Ome OMe 866 0 N CH CH CH c CH CH N CH N Absent OMe 867 0 N CH CH CH c N CH CH CH CH Ome Ome 868 0 N N CH CH c CH CH N CH N Absent Ome 869 0 N N CH CH c CH CH CH CH CH Ome OMe 870 0 CH N CH CH c CH CH CH CH CH OMe OMe 871 0 CH N CH CH c N CH CH CH CH Ome Ome 872 0 CH N CH CH c CH N CH CH CH Ome Ome 873 0 CH N CH CH c CH N CH N CH OMe Absent 874 0 CH N CH CH c N CH CH N CH OMe OMe 875 0 CH N CH CH c CH CH N CH N Absent OMe 876 0 CH N CH CH c CH CH N CH CH Absent OMe 877 0 N CH N CH c CH CH CH CH CH OMe OMe 878 0 N CH N CH c N CH CH CH CH OMe OMe 879 0 N CH N CH c CH N CH CH CH OMe OMe 880 0 CH N CH N c CH CH CH CH CH Ome OMe 881 0 CH CH N N c CH CH CH CH CH OMe Ome 882 0 CH CH CH N c CH CH CH CH CH OMe OMe 883 0 CH CH CH N c CH CH N CH CH Absent OMe 884 1 CH CH CH CH c CH CH CH CH CH H H 885 1 CH CH CH CH c N CH CH CH CH H H 886 1 CH CH CH CH c CH N CH CH CH H H 887 1 CH CH CH CH c N CH CH CH N H H 888 1 CH CH CH CH c N N CH CH CH H H 889 1 CH CH CH CH c CH N CH N CH H Absent 890 1 CH CH CH CH c CH CH N CH N Absent H 891 1 CH CH CH CH c CH CH N CH CH Absent H 892 1 N CH CH CH c CH CH CH CH CH Η H 893 1 N CH CH CH c N CH CH CH CH Η H 894 1 N CH CH CH c CH N CH CH CH Η H 895 1 N CH CH CH c N CH CH CH N Η H 896 1 N CH CH CH c CH CH N CH N Absent H 897 1 N CH CH CH c N CH CH CH CH Η H 898 1 N N CH CH c CH CH N CH N Absent H 899 1 N N CH CH c CH CH CH CH CH Η H 900 1 CH N CH CH c CH CH CH CH CH Η H 901 1 CH N CH CH c N CH CH CH CH Η H 902 1 CH N CH CH c CH N CH CH CH Η H 903 1 CH N CH CH c CH N CH N CH Η Absent 904 1 CH N CH CH c N CH CH N CH Η H 905 1 CH N CH CH c CH CH N CH N Absent H 906 1 CH N CH CH c CH CH N CH CH Absent H 907 1 N CH N CH c CH CH CH CH CH Η H 908 1 N CH N CH c N CH CH CH CH Η H 909 1 N CH N CH c CH N CH CH CH Η H 910 1 CH N CH N c CH CH CH CH CH Η H 911 1 CH CH N N c CH CH CH CH CH Η H 912 1 CH CH CH N c CH CH CH CH CH Η H 913 1 CH CH CH N c CH CH N CH CH Absent H 914 1 CH CH CH CH c CH CH CH CH CH F H 915 1 CH CH CH CH c N CH CH CH CH F H 916 1 CH CH CH CH c CH N CH CH CH F H 917 1 CH CH CH CH c N CH CH CH N F H 918 1 CH CH CH CH c N N CH CH CH F H 919 1 CH CH CH CH c CH N CH N F Absent 920 1 CH CH CH CH c CH CH N CH N Absent 921 1 CH CH CH CH c CH CH N CH CH Absent H 922 1 N CH CH CH c CH CH CH CH CH F H 923 1 N CH CH CH c N CH CH CH CH F H 924 1 N CH CH CH c CH N CH CH CH F H 925 1 N CH CH CH c N CH CH CH N F H 926 1 N CH CH CH c CH CH N CH N Absent H 927 1 N N CH CH c CH CH CH CH CH F H 928 1 N N CH CH c CH CH N CH N Absent H 929 1 CH N CH CH c CH CH CH CH CH F H 930 1 CH N CH CH c N CH CH CH CH F H 931 1 CH N CH CH c CH N CH CH CH F H 932 1 CH N CH CH c CH N CH N CH F Absent 933 1 CH N CH CH c N CH CH N CH F Absent 934 1 CH N CH CH c CH CH N CH N Absent Η 935 1 N CH N CH c CH CH CH CH CH F Η 936 1 N CH N CH c N CH CH CH CH F Η 937 1 N CH N CH c CH N CH CH CH F Η 938 1 CH N CH N c CH CH CH CH CH F Η 939 1 CH CH N N c CH CH CH CH CH F Η 940 1 CH CH CH N c CH CH CH CH CH F Η 941 1 CH CH CH N c CH N CH CH CH F Η 942 1 CH CH CH CH c CH CH CH CH CH OMe OMe

- 39 043556

In a further embodiment, the present invention provides compounds of formulas (Va) and (Vb), where o, Y1, Y ₂ , Y ₃ , Y ₄ , Y _{5, Y 6 ,} Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , R ₅ and R ₆ are defined in examples 1297-1300

As in formula (Va),

In a further embodiment, the present invention provides compounds of formula (VI) wherein X _b n, Z, R ₅ and R ₆ are as defined in Examples 972-977 h ₂ n

R ₆ (VI).

R ₅

Conn. Xi Z η r ₅ R ₆ 972 CH ₂ sn 1 F H 973 dn ₂ N 1 F H 974 S N 1 F H 975 dn ₂ CH 1 Ome Ome 976 dn ₂ N 1 Ome Ome 977 S N 1 OMe Ome

In a further embodiment, the present invention provides compounds of formula (VII) wherein X _, n, Z, R ₂ , R ₅ and R ₆ are as defined in Examples 978-54

Conn. Xi z n r ₂ r ₅ R ₆ 978 CH ₂ CH 1 Me F H 979 CH ₂ N 1 Me F H

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In a further embodiment, the present invention provides compounds of formula (VIII) wherein X1, n, R5 and R6 are as defined in Examples 990-993

980 S N 1 Me F N 981 dn ₂ sn 1 Me Ome Ome 982 dn ₂ N 1 Me Ome Ome 983 S N 1 Me Ome Ome 984 dn ₂ CH 1 Cyclopropyl F N 985 dn ₂ N 1 Cyclopropyl F N 986 S N 1 Cyclopropyl F N 987 dn ₂ CH 1 Cyclopropyl Ome Ome 988 dn ₂ N 1 Cyclopropyl Ome Ome 989 S N 1 Cyclopropyl Ome Ome

r ₅ (VIII).

Conn. X1 η R5 R6 990 CH ₂ 1 F N 991 S 1 F N 992 dn ₂ 1 Ome Ome 993 S 1 Ome Ome

In a further embodiment, the present invention provides compounds of formula (IX) wherein X1, n, R2, _R5 and R6 are as defined in Examples 994-1001

r ₅ (IX).

Conn. X1 η r ₂ r ₅ R6 994 CH ₂ 1 Me F Η 995 S 1 Me F Η 996 dn ₂ 1 Me Ome Ome 997 S 1 Me Ome Ome 998 dn ₂ 1 Cyclopropyl F Η 999 S 1 Cyclopropyl F Η 1000 dn ₂ 1 Cyclopropyl Ome Ome 1001 S 1 Cyclopropyl Ome Ome

In a further embodiment, the present invention provides compounds of formula (X) wherein o, R5 and R6 are as defined in Examples 1002-1005

r ₅ o equals 0.

(X).

Conn. R r ₅ R ₆ 1002 0 F Η 1003 0 Ome Ome 1004 1 F Η 1005 1 Ome Ome

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

r ₅ (Xi), o equals 0.

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In a further embodiment, the present invention provides compounds of formulas (XIIa) and (XIIb), where Z, Y1, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y7, Y ₈ , Y ₉ , Y ₁₀ , R ₅ and R ₆ are as defined in Examples 1014-1189

Conn. R r ₂ r ₅ R ₆ 1006 0 Me F Η 1007 0 Me Ome Ome 1008 0 Cyclopropyl F Η 1009 0 Cyclopropyl Ome Ome 1010 1 Me F Η 1011 1 Me Ome Ome 1012 1 Cyclopropyl F Η 1013 1 Cyclopropyl Ome Ome

(XIIa) (ХПь).

Conn. Ζ Y, _Y2 Y ₃ Y ₄ Y _s Y ₆ Y ₇ Y ₈ Y ₉ Yio R ₅ Re 1014 CH CH CH CH CH c CH CH CH CH CH H Η 1015 N CH CH CH CH c CH CH CH CH CH H Η 1016 CH CH CH CH CH c N CH CH CH CH H Η 1017 N CH CH CH CH c N CH CH CH CH H Η 1018 CH CH CH CH CH c CH N CH CH CH H Η 1019 N CH CH CH CH c CH N CH CH CH H Η 1020 CH CH CH CH CH c N CH CH CH N H Η 1021 N CH CH CH CH c N CH CH CH N H Η 1022 CH CH CH CH CH c N N CH CH CH H Η 1023 N CH CH CH CH c N N CH CH CH H Η 1024 CH CH CH CH CH c CH N CH N CH H Absent 1025 N CH CH CH CH c CH N CH N CH H 1026 CH CH CH CH CH c CH CH N CH N Absent Η 1027 N CH CH CH CH c CH CH N CH N Η 1028 CH CH CH CH CH c CH CH N CH CH Absent Η 1029 N CH CH CH CH c CH CH N CH CH Η 1030 CH N CH CH CH c CH CH CH CH CH Η Η 1031 N N CH CH CH c CH CH CH CH CH Η Η 1032 CH N CH CH CH c N CH CH CH CH Η Η 1033 N N CH CH CH c N CH CH CH CH Η Η 1034 CH N CH CH CH c CH N CH CH CH Η Η 1035 N N CH CH CH c CH N CH CH CH Η Η 1036 CH N CH CH CH c N CH CH CH N Η Η 1037 N N CH CH CH c N CH CH CH N Η Η 1038 CH N CH CH CH c CH CH N CH N Absent Η 1039 N N CH CH CH c CH CH N CH N Η 1040 CH N CH CH CH c N CH CH CH CH Η Η 1041 N N CH CH CH c N CH CH CH CH Η Η 1042 CH N N CH CH c CH CH N CH N Absent Η 1043 N N N CH CH c CH CH N CH N Η 1044 CH N N CH CH c CH CH CH CH CH Η Η 1045 N N N CH CH c CH CH CH CH CH Η Η 1046 CH CH N CH CH c CH CH CH CH CH Η Η 1047 N CH N CH CH c CH CH CH CH CH Η Η 1048 CH CH N CH CH c N CH CH CH CH Η Η 1049 N CH N CH CH c N CH CH CH CH Η Η 1050 CH CH N CH CH c CH N CH CH CH Η Η 1051 N CH N CH CH c CH N CH CH CH Η Η 1052 CH CH N CH CH c CH N CH N CH Η Absent 1053 N CH N CH CH c CH N CH N CH Η 1054 CH CH N CH CH c N CH CH N CH Η Η 1055 N CH N CH CH c N CH CH N CH Η Η 1056 CH CH N CH CH c CH CH N CH N Absent Η 1057 N CH N CH CH c CH CH N CH N Η 1058 CH CH N CH CH c CH CH N CH CH Absent Η 1059 N CH N CH CH c CH CH N CH CH Η 1060 CH N CH N CH c CH CH CH CH CH Η Η 1061 N N CH N CH c CH CH CH CH CH Η Η 1062 CH N CH N CH c N CH CH CH CH Η Η 1063 N N CH N CH c N CH CH CH CH Η Η 1064 CH N CH N CH c CH N CH CH CH Η Η 1065 N N CH N CH c CH N CH CH CH Η Η 1066 CH CH N CH N c CH CH CH CH CH Η Η 1067 N CH N CH N c CH CH CH CH CH Η Η 1068 CH CH CH N N c CH CH CH CH CH Η Η 1069 N CH CH N N c CH CH CH CH CH Η Η 1070 CH CH CH CH N c CH CH CH CH CH Η Η 1071 N CH CH CH N c CH CH CH CH CH Η Η 1072 CH CH CH CH N c CH CH N CH CH Absent Η 1073 N CH CH CH N c CH CH N CH CH Η 1074 CH CH CH CH CH c CH CH CH CH CH F Η

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1075 N CH CH CH CH c CH CH CH CH CH F H 1076 CH CH CH CH CH c N CH CH CH CH F H 1077 N CH CH CH CH c N CH CH CH CH F H 1078 CH CH CH CH CH c CH N CH CH CH F H 1079 N CH CH CH CH c CH N CH CH CH F H 1080 CH CH CH CH CH c N CH CH CH N F H 1081 N CH CH CH CH c N CH CH CH N F H 1082 CH CH CH CH CH c N N CH CH CH F H 1083 N CH CH CH CH c N N CH CH CH F H 1084 CH CH CH CH CH c CH N CH N CH F Absent 1085 N CH CH CH CH c CH N CH N CH F 1086 CH CH CH CH CH c CH CH N CH N Absent 1087 N CH CH CH CH c CH CH N CH N 1088 CH CH CH CH CH c CH CH N CH CH Absent H 1089 N CH CH CH CH c CH CH N CH CH H 1090 CH N CH CH CH c CH CH CH CH CH F H 1091 N N CH CH CH c CH CH CH CH CH F H 1092 CH N CH CH CH c N CH CH CH CH F H 1093 N N CH CH CH c N CH CH CH CH F H 1094 CH N CH CH CH c CH N CH CH CH F H 1095 N N CH CH CH c CH N CH CH CH F H 1096 CH N CH CH CH c N CH CH CH N F H 1097 N N CH CH CH c N CH CH CH N F H 1098 CH N CH CH CH c CH CH N CH N Absent H 1099 N N CH CH CH c CH CH N CH N H 1100 CH N N CH CH c CH CH CH CH CH F H 1101 N N N CH CH c CH CH CH CH CH F H 1102 CH N N CH CH c CH CH N CH N Absent H 1103 N N N CH CH c CH CH N CH N H 1104 CH CH N CH CH c CH CH CH CH CH F H 1105 N CH N CH CH c CH CH CH CH CH F H 1106 CH CH N CH CH c N CH CH CH CH F H 1107 N CH N CH CH c N CH CH CH CH F H 1108 CH CH N CH CH c CH N CH CH CH F H 1109 N CH N CH CH c CH N CH CH CH F H 1110 CH CH N CH CH c CH N CH N CH F Absent 1111 N CH N CH CH c CH N CH N CH F 1112 CH CH N CH CH c N CH CH N CH F Absent 1113 N CH N CH CH c N CH CH N CH F 1114 CH CH N CH CH c CH CH N CH N Absent Η 1115 N CH N CH CH c CH CH N CH N Η 1116 CH N CH N CH c CH CH CH CH CH F Η 1117 N N CH N CH c CH CH CH CH CH F Η 1118 CH N CH N CH c N CH CH CH CH F Η 1119 N N CH N CH c N CH CH CH CH F Η 1120 CH N CH N CH c CH N CH CH CH F Η 1121 N N CH N CH c CH N CH CH CH F Η 1122 CH CH N CH N c CH CH CH CH CH F Η 1123 N CH N CH N c CH CH CH CH CH F Η 1124 CH CH CH N N c CH CH CH CH CH F Η 1125 N CH CH N N c CH CH CH CH CH F Η 1126 CH CH CH CH N c CH CH CH CH CH F Η 1127 N CH CH CH N c CH CH CH CH CH F Η 1128 CH CH CH CH N c CH N CH CH CH F Η 1129 N CH CH CH N c CH N CH CH CH F Η ISO CH CH CH CH CH c CH CH CH CH CH OMe OMe 1131 N CH CH CH CH c CH CH CH CH CH OMe Ome 1132 CH CH CH CH CH c N CH CH CH CH Ome OMe 1133 N CH CH CH CH c N CH CH CH CH Ome OMe 1134 CH CH CH CH CH c CH N CH CH CH OMe OMe 1135 N CH CH CH CH c CH N CH CH CH OMe Ome 1136 CH CH CH CH CH c N CH CH CH N OMe OMe 1137 N CH CH CH CH c N CH CH CH N OMe Ome 1138 CH CH CH CH CH c N N CH CH CH Ome Ome 1139 N CH CH CH CH c N N CH CH CH Ome Ome 1140 CH CH CH CH CH c CH N CH N CH Ome Absent 1141 N CH CH CH CH c CH N CH N CH Ome 1142 CH CH CH CH CH c CH CH N CH N Absent Ome 1143 N CH CH CH CH c CH CH N CH N Ome 1144 CH CH CH CH CH c CH CH N CH CH Absent Ome 1145 N CH CH CH CH c CH CH N CH CH Ome 1146 CH N CH CH CH c CH CH CH CH CH Ome Ome 1147 N N CH CH CH c CH CH CH CH CH OMe OMe 1148 CH N CH CH CH c N CH CH CH CH Ome Ome 1149 N N CH CH CH c N CH CH CH CH Ome OMe 1150 CH N CH CH CH c CH N CH CH CH Ome Ome 1151 N N CH CH CH c CH N CH CH CH Ome Ome 1152 CH N CH CH CH c N CH CH CH N Ome OMe 1153 N N CH CH CH c N CH CH CH N OMe OMe 1154 CH N CH CH CH c CH CH N CH N Absent OMe 1155 N N CH CH CH c CH CH N CH N Ome 1156 CH N CH CH CH c N CH CH CH CH OMe OMe 1157 N N CH CH CH c N CH CH CH CH Ome Ome 1158 CH N N CH CH c CH CH N CH N Absent Ome

- 43 043556

1159 N N N CH CH WITH CH CH N CH N Ome 1160 CH N N CH CH With CH CH CH CH CH Ome Ome 1161 N N N CH CH With CH CH CH CH CH Ome Ome 1162 CH CH N CH CH With CH CH CH CH CH Ome Ome 1163 N CH N CH CH With CH CH CH CH CH Ome Ome 1164 CH CH N CH CH With N CH CH CH CH Ome Ome 1165 N CH N CH CH With N CH CH CH CH Ome Ome 1166 CH CH N CH CH With CH N CH CH CH Ome Ome 1167 N CH N CH CH With CH N CH CH CH Ome Ome 1168 CH CH N CH CH With CH N CH N CH Ome Absent 1169 N CH N CH CH With CH N CH N CH Ome 1170 CH CH N CH CH With N CH CH N CH Ome Ome 1171 N CH N CH CH With N CH CH N CH Ome Ome 1172 CH CH N CH CH With CH CH N CH N Absent Ome 1173 N CH N CH CH With CH CH N CH N Ome 1174 CH CH N CH CH WITH CH CH N CH CH Absent Ome 1175 N CH N CH CH With CH CH N CH CH Ome 1176 CH N CH N CH With CH CH CH CH CH Ome Ome 1177 N N CH N CH With CH CH CH CH CH Ome Ome 1178 CH N CH N CH With N CH CH CH CH Ome Ome 1179 N N CH N CH With N CH CH CH CH Ome Ome 1180 CH N CH N CH With CH N CH CH CH Ome Ome 1181 N N CH N CH With CH N CH CH CH Ome Ome 1182 CH CH N CH N With CH CH CH CH CH Ome Ome 1183 N CH N CH N With CH CH CH CH CH Ome Ome 1184 CH CH CH N N With CH CH CH CH CH Ome Ome 1185 N CH CH N N With CH CH CH CH CH Ome Ome 1186 CH CH CH CH N With CH CH CH CH CH Ome Ome 1187 N CH CH CH N With CH CH CH CH CH Ome Ome 1188 CH CH CH CH N With CH CH N CH CH Absent Ome 1189 N CH CH CH N With CH CH N CH CH Ome

In a further embodiment, the present invention provides compounds of formula (XIII) wherein Z, R ₅ and R ₆ are as defined in Examples 1190-1193

(XIII).

Conn. Z r ₅ R ₆ 1190 CH F n 1191 N F n 1192 CH Ome Ome 1193 N Ome Ome

In a further embodiment, the present invention provides compounds of formula (XIV) wherein R ₅ and R ₆ are as defined in Examples 1194-1195

(XIV).

Conn. r ₅ R ₆ 1194 F N 1195 Ome Ome

In a further embodiment, the present invention provides compounds of formulas (XVa) and (XVb), wherein Y1, Y ₂ , Y ₃ , Y ₄ , Y 5, Y ₆ , Y ₇ , _Y8 , Y ₉ , Y ₁₀ , R ₅ and R ₆ are as defined in Examples 1196-1282

(Tj ^th I ^th ^Y^X \ 1 N^ ^R 5 And Η (XVa) Y^ ² ^ [1 ^γ 3 Dx /-Vo /Re ^Y ' ΐ 7 Y ₇ R ₅ (XVb).

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Conn. γ, Υ2 Υ, Υ4 Y _s Y ₆ Y ₇ γ ₈ Υ9 Υ10 Rs Re 1196 CH sn sn sn With sn sn sn sn sn n N 1197 sn sn sn sn With N sn sn sn sn n N 1198 sn sn sn sn With sn Ν sn sn sn n N 1199 sn sn sn sn With N sn sn sn Ν n N 1200 sn sn sn sn With N Ν sn sn sn n N 1201 sn sn sn sn With sn Ν sn Ν sn n Absent 1202 sn sn sn sn With sn CH Ν sn Ν Absent N 1203 sn sn sn sn With sn sn Ν sn sn Absent N 1204 Ν sn sn sn With sn sn CH sn sn N N 1205 Ν sn sn sn With N sn sn sn sn N N 1206 Ν sn sn sn With sn Ν sn sn sn N N 1207 Ν sn sn sn With N CH sn sn Ν N N 1208 Ν sn sn sn With sn sn Ν sn Ν Absent N 1209 Ν sn sn sn With N sn CH sn sn N N 1210 Ν Ν sn sn With sn sn Ν sn Ν Absent N 1211 Ν Ν sn sn With sn sn CH sn CH N N 1212 CH Ν sn sn With sn sn sn sn sn N N 1213 sn Ν sn sn With N sn sn sn sn N N 1214 sn Ν sn sn With sn Ν sn sn sn N N 1215 sn Ν sn sn With sn Ν sn Ν sn N Absent 1216 sn Ν sn sn With N CH sn Ν sn N N 1217 sn Ν sn sn With sn sn Ν sn Ν Absent N 1218 sn Ν sn sn With sn sn Ν sn sn Absent N 1219 Ν CH Ν sn With sn sn CH sn sn N N 1220 Ν sn Ν sn With N sn sn sn sn N N 1221 Ν sn Ν sn With sn Ν sn sn sn N N 1222 CH Ν sn Ν With sn CH sn sn sn N N 1223 sn CH Ν Ν With sn sn sn sn sn N N 1224 sn sn sn Ν With sn sn sn sn sn N N 1225 sn sn sn Ν With sn sn Ν sn sn Absent N 1226 sn sn sn sn With sn sn sn sn sn F N 1227 sn sn sn sn With N sn sn sn sn F N 1228 sn sn sn sn With sn Ν sn sn sn F N 1229 sn sn sn sn With N sn sn sn Ν F N 1230 sn sn sn sn With N Ν sn sn sn F N 1231 sn sn sn sn With sn Ν sn Ν sn F Absent 1232 sn sn sn sn With sn CH Ν sn Ν Absent 1233 sn sn sn sn With sn sn Ν sn sn Absent N 1234 Ν sn sn sn With sn sn CH sn sn F N 1235 Ν sn sn sn With N sn sn sn sn F N 1236 Ν sn sn sn With sn Ν sn sn sn F N 1237 Ν sn sn sn With N CH sn sn Ν F N 1238 Ν sn sn sn With sn sn Ν sn Ν Absent N 1239 Ν Ν sn sn With sn sn CH sn CH F N 1240 Ν Ν sn sn With sn sn Ν sn Ν Absent N 1241 CH Ν sn sn With sn sn CH sn CH F N 1242 sn Ν sn sn With N sn sn sn sn F N 1243 sn Ν sn sn With sn Ν sn sn sn F N 1244 sn Ν sn sn With sn Ν sn Ν sn F Absent 1245 sn Ν sn sn With N CH sn Ν sn F Absent 1246 sn Ν sn sn With sn sn Ν sn Ν Absent N 1247 Ν CH Ν sn With sn sn CH sn CH F N 1248 Ν sn Ν sn With N sn sn sn sn F N

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1249 N sn N sn With sn N sn sn sn F N 1250 CH N CH N With sn sn sn sn sn F N 1251 sn CH N N With sn sn sn sn sn F N 1252 CH sn CH N With sn sn sn sn sn F N 1253 sn sn sn N With sn N sn sn sn F N 1254 sn sn sn CH With sn sn sn sn sn Ome Ome 1255 sn sn sn sn With N sn sn sn sn Ome Ome 1256 sn sn sn sn With sn N sn sn sn Ome Ome 1257 sn sn sn sn With N CH sn sn N Ome Ome 1258 sn sn sn sn With N N sn sn sn Ome Ome 1259 sn sn sn sn With sn N sn N sn Ome Absent 1260 sn sn sn sn With sn CH N sn N Absent Ome 1261 sn sn sn sn With sn sn N sn sn Absent Ome 1262 N sn sn sn With sn sn sn sn sn Ome Ome 1263 N sn sn sn With N sn sn sn sn Ome Ome 1264 N sn sn sn With sn N sn sn sn Ome Ome 1265 N sn sn sn With N CH sn sn N Ome Ome 1266 N sn sn sn With sn sn N sn N Absent Ome 1267 N sn sn sn With N sn sn sn sn Ome Ome 1268 N N sn sn With sn sn N sn N Absent Ome 1269 N N sn sn With sn sn CH sn sn Ome Ome 1270 CH N sn sn With sn sn sn sn sn Ome Ome 1271 sn N sn sn With N sn sn sn sn Ome Ome 1272 sn N sn sn With sn N sn sn sn Ome Ome 1273 sn N sn sn With sn N sn N sn Ome Absent 1274 sn N sn sn With N CH sn N sn Ome Ome 1275 sn N sn sn With sn sn N sn N Absent Ome 1276 sn N sn sn With sn sn N sn sn Absent Ome 1277 N CH N sn With sn sn CH sn sn Ome Ome 1278 N sn N sn With N sn sn sn sn Ome Ome 1279 N sn N sn With sn N sn sn sn Ome Ome 1280 CH N sn N With sn CH sn sn sn Ome Ome 1281 sn CH N N With sn sn sn sn sn Ome Ome 1282 sn sn sn N With sn sn sn sn sn Ome Ome

In a further embodiment, the present invention provides compounds of formulas (XVa) and (XVb), wherein Y1, Y2, Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , R ₅ and R ₆ are as defined in Examples 1310-1319

Conn. γ. Y, γ ₃ Υ ₄ Y ₅ γ ₆ Υ-7 γ ₈ γ ₉ Υ10 R ₅ R ₆ 1301 sn sn sn sn WITH sn sn sn sn sn Ome N 1302 sn sn sn Ν WITH sn sn sn sn sn Ome N 1303 N sn sn sn WITH sn sn sn sn sn Ome N 1304 CH sn Ν sn With sn sn sn sn sn Ome N 1305 sn N sn sn With sn sn sn sn sn Ome N 1306 N sn Ν sn With sn sn sn sn sn Ome N 1307 N sn sn Ν With sn sn sn sn sn Ome N 1308 CH sn Ν sn With sn sn sn sn sn Ome Ome 1309 N sn sn Ν With sn sn sn sn sn Ome Ome 1310 N sn sn Ν With sn sn sn sn sn F N 1311 CH sn sn sn With sn sn sn sn sn O-Phenyl N 1312 sn sn sn sn With sn sn sn sn sn O-Cyclohexyl N 1313 sn sn sn sn With sn sn sn sn sn Propyloxy N 1314 sn sn sn sn With sn sn sn sn sn Propan-2-yloxy N 1315 sn sn sn SN, substitute Me With sn sn sn sn sn Ome N 1316 sn sn sn SN, substitute Me With sn sn sn sn sn Ome Ome 1317 sn sn sn SN substitution F With sn sn sn sn sn C1 Ome 1318 sn sn sn SN substitution F With sn sn sn sn sn Ome Ome 1319 sn sn sn SN substitution F With sn sn sn sn sn F N

In a further embodiment, the present invention provides compounds of formula (XVI) wherein R ₅ and R 6 are as defined in Examples 1283-1284

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In a further embodiment, the present invention provides compounds of formula (XVII) wherein R ₂ , R 5 and R ₆ are as defined in Examples 1285-1288

Conn. R5 R6 1283 F N 1284 Ome Ome

R _s (XVII).

Conn. R2 R5 R6 1285 Me F N 1286 Me Ome Ome 1287 Cyclopropyl F Η 1288 Cyclopropyl Ome Ome

In a further embodiment, the present invention provides compounds of formula (XVIII) wherein X _, n, R5 and _R6 are as defined in Examples 1320-1323

Conn. X1 η R5 R6 1320 dn ₂ 1 F Η 1321 S 1 F Η 1322 dn ₂ 1 Ome Ome 1323 S 1 Ome Ome

In a preferred embodiment, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein said compound of formula (I) is selected from the following.

Example Compound Synthesis Example Connection name Structure Formula Mol. weight hQC Ki [mkM] pH 6 hQC K; [mkM] pH 8 93 A2 5-[3-({4'-Fluoro[1,G-biphenyl]2- yl}amino)prop yl]-1,3,4thiadiazol-2- amine h ₂ n _s Ci ₇ H ₁₇ FN ₄ S 328.40 2.6 1102 94 AZ 5-{[2-({4'-Fluoro[1, G-biphenyl] - 2- yl}amino)ethyl]sulfanyl}1,3,4-thiadiazol2-amine H ₂ NS Il _z >-s nV NH Ci ₆ H ₁₅ FN ₄ S 346.44 2.97 11.51 178 A4 5-{[2-({3',4'Dimethoxy-CD'biphenyl]-2yl}amino)ethyl]sulfanyl}1,3,4-thiadiazol2-amine h ₂ n _S T /)-s NH 0 c ₁₈ h ₂₀ n ₄ o ₂ s ₂ 388.50 1.10 0.97 328 IN 1 4'-Φτορ-Ν-[3-(4methyl-4H-1,2,4triazol-3yl)propyl][1,G-biphenyl]2-amine C1 ₈ H ₁₉ FN ₄ 310.36 1.97 2.86 384 VZ 3',4'-DimethoxyK-[3-(4-methyl4H-1,2,4triazol-3yl)propyl][1,G-biphenyl]2-amine vy —0 o— _{C20H24N4O2 _ _ _} 352.43 0.13 0.26 505 C2 5-[4-({4'-Fluoro[1,G-biphenyl]2yl}amino)phenyl]-1,3,4thiadiazol-2amine ² c ₂₀ h ₁₅ fn ₄ s 362.42 1.52 1.81 561 NW 5-(4-{[2-(3,4Dimethoxyphenyl)phenyl]amino}phenyl)-1,3,4thiadiazol-2- amine c ₂₂ h ₂₀ n ₄ o ₂ s 404.48 0.42 1.09 1289 C4 5-(4-{[2-(4- Mstoxifsnil) phenyl]amino}phenyl)-1,3,4thiadiazol-2amine ² /° _{C2iH18N4Os _ _} 374.46 1.87 1.48

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1290 C5 N-[4-(5-Amiiho1,3,4-thiadiazol2-yl)phenyl]-3(4methoxyphenyl)p yridin-2-amine ABOUT _{C20H17N5Os _ _} 375.44 4.17 4.70 1291 C6 N-[4-(5-Amhho1,3,4-thiadiazol2-yl)phenyl]-3(4methoxyphenyl)p yridin-4-amine R from ₂₀ h ₁₇ n ₅ os 375.44 7.16 4.22 1292 C7 Ν-[4-(5-Αμηηο1,3,4-thiadiazol2-yl)phenyl]-3(3,4dimethoxyphenyl)pyridin-4amine h ₂ n _s $=/ s, o— C ₇ iH ₁₉ N ₅ O ₂ s 405.47 54.69 7.46 521 C8 Ν-[4-(5-Αμηηο1,3,4-thiadiazol2-yl)phenyl]-3(4fluorophenyl)pyr idin-2-amine /A F from ₁₉ h ₁₄ fn ₅ s 363.41 2.69 4.27 1293 C9 Ν-[4-(5-Αμηηο1,3,4-thiadiazol2-yl)phenyl]-3(4fluorophenyl)pyra zin-2-amine Ν N h ₂ n _S /=. ^=/ I from ₁₈ h ₁₃ fn ₆ s 364.39 1.66 6.89 1294 CIO 5-(4-{[2-(4- Phenoxyphenyl) phenyl]amino}phenyl)-1,3,4thiadiazol-2amine from ₂₆ h ₂₀ n ₄ os 436.52 4.37 2.23 1295 Cll 5-(4-{[2-(4Propoxyphenyl)phenyl]amino}phenyl)-1,3,4thiadiazol-2amine from ₂₃ h ₂₂ n ₄ os 402.51 2.15 2.36 1296 C12 5-[4-({2-[4(Propan-2yloxy)phenyl]phenyl}amino)phen nil]-1,3,4- thiadiazol-2amine _{C23H22N4Os _ _} 402.51 1.51 3.27 826 854 1297 1298 852 1299 1300 973 974 D.I. D2 D3 D4 D5 D6 D7 E2 E3 4'-Φτορ-Ν-[4-(4methyl-4H-1,2,4lriazol-Zyl)phenyl]-[1,Hbiphenyl]-2amine 3',4'-Dimstoxy-[4-(4-methyl- 4H-1,2,4triazol-3yl)phenyl]-[1,1'biphenyl]-2amine Ν-[2-(4- Methoxyphenyl) phenyl]-4-(4methyl-4H-1,2,4triazol-3yl)aniline 2-(4- Methoxyphenyl)N-[4-(4-methyl4H-1,2,4triazol-3yl)phenyl]pyride in-3-amine 2-(4- Fgorphenyl)-I[4-(4-methyl-4H1,2,4-lriazol-Zyl)phenyl]pyride in-3-amine 4-(4-Methyl-4H1,2,4-1riazol-3yl)-M-[2-(4phenoxyphenyl)phenyl]aniline 3-(3,4Dimethoxyphenyl)-N-[4-(4methyl-4H-1,2,4triazol-Zyl)phenyl]pyride in-4-amine N-[3-(5-Amhho1,3,4-thiadiazole2 -yl)propyl]-4fluorobenzene-1sulfonamide N-{2-[(5- Amino-1,3,4thiadiazol-2yl)sulfanyl]ethyl}-4fluorobenzene-1sulfonamide F /° /° / Q nV W θ o O Ph ⁷ λ-Μ °\ /° ο ο ΗΝ-S' ^H 2N^SV Χν QF y! h ₂ n \=< F C ₂ 1H ₁₇ FN ₄ c ₂₃ h ₂₂ n ₄ o ₂ c ₂₂ h _{20 n} 4 o C ₂ iH ₁₉ N ₅ O c ₂₀ h ₁₆ fn ₅ c ₂₇ h ₂₂ n ₄ o c ₂₂ h ₂₁ n ₅ o ₂ CuH ₁₃ FN ₄ O ₂ S ₂ C ₁₀ H _n FN ₄ O ₂ S ₃ 344.38 386.45 356.42 357.40 345.37 418.48 387.43 316.37 334.41 1.44 0.44 0.99 1.70 2.69 1.33 Not defined 18.08 19.91 1.74 1.48 1.69 3.37 5.05 1.81 10.07 9.38 26.48 979 F2 5-(3-{[(4- Fluorophenyl)(met yl)oxo-X<vsulfanilidene]amino}propyl)1,3,4-thiadiazol2-amine O N=S— HzN with Va ϊν Q F Ci ₂ Hi ₅ FN ₄ os ₂ 314.40 11.41 11.70

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990 G1 4-Φτορ-Ν-[3-(4methyl-4H-1,2,4triazol-3yl)propyl]benzool-1sulfonamide ,O / ΗΝ-S=O guХ /a ^N 'N \=< F C12H15FN4 O ₂ S 298.33 991 G2 4-Φτορ-Ν-{2[(4-methyl-4H1,2,4-triazol-Zyl)sulfanyl]eth yl}benzene-1sulfonamide ⁿ <n F CnH ₁₃ FN ₄ O ₂ S ₂ 316.37 8.84 11.49 1332 G5 [(3,4Dimethoxyphenyl)sulfamoyl]({ 2-[(4-methyl-4H1,2,4-triazol-Zyl)sulfanyl]ethyl})amine c ₁₃ h ₁₉ n ₅ o ₄ s ₂ 373.45 13.63 11.76 1002 II Ν-[4-(2-Αμηηο1,3-thiazol-5yl)phenyl]-4fluorobenzene-1sulfonamide η ₂ ν-^ γ W% _f kN C ₁₅ H ₁₂ FN ₃ O2S2 349.40 2.93 2.64 1003 12 Ν-[4-(2-Αμηηο1,3-thiazol-5yl)phenyl]-3,4dimethoxybenzene l-1sulfonamide Η ^h 2 ⁿ S t γν ^N /О Ci ₇ H ₁₇ N ₃ O ₄ S ₂ 391.46 0.20 0.34 1075 L2 5-(1-{4'-Fluoro[1,G-biphenyl]2- yl}piperidin4-yl)-1,3,4thiadiazol-2- amine H ₂ N _S /=X Y , ^N A # ^N 'NW F Ci9H ₁₉ FN ₄ S 354.44 0.09 0.248 1190 Ml 5-[1-(4- Fluorobenzenesul phonyl)piperide in-4-yl]-1,3thiazol-2-amine Ci ₄ H ₁₆ FN ₃ O2S2 341.42 1.32 1.70 1191 M2 5-[1-(4- Fluorobenzenesul phonyl)piperide in-4-yl]-1,3,4thiadiazol-2amine h ₂ n, _s o >=/ Y />—( n-& ^N 'N '--/ O c ₁₃ h ₁₅ fn ₄ O2S2 342.41 1.18 1.60 1194 N1 1-(4- Fluorobenzenesulphonyl)-4-(4methyl-4H-1,2,4triazol-3yl)piperidine /--\P JI />—( N-s=o F C ₁₄ H ₁₇ FN ₄ O ₂ S 324.37 3.05 3.30 1226 01 Ν-[(1Η-1,3- Benzodiazol-5yl)methyl]-4'fluoro-[1,Hbiphenyl]-2amine 'X Λ J ^H H c ₂₀ H ₁₆ FN ₃ 317.35 5.91 5.29 1254 02 Ν-[(1Η-1,3- Benzodiazol-5yl)methyl]-3',4'dimethoxy-[1,Hbiphenyl]-2amine hE H C ₂ 2H ₂ iN ₃ O ₂ 359.42 0.12 0.27 1301 03 Ν-(1Η-1,3- Benzodiazol-5ylmethyl)-2-(4methoxyphenyl)a NILIN (1J ^H H _{C2iH19N3O _ _} 329.39 1.44 1.65 1302 04 Ν-(1Η-1,3- Benzodiazol-5ylmethyl)-2-(4methoxyphenyl)p-iridin-3-amine 1 "XY H C ₂ oH ₁₈ N ₄ 0 330.38 9.52 2.96 1303 05 Ν-(1Η-1,3- Benzodiazol-5ylmethyl)-3-(4methoxyphenyl)p-iridin-2-amine 1 // ^N NN < JL J ^H H C20H18N4O 330.38 2.74 2.41 1304 06 Ν-(1Η-1,3- Benzodiazol-5ylmethyl)-3-(4methoxyphenyl)p-iridin-4-amine 1 Qx.^ γ 1 < II J h H C20H18N4O 330.38 15.05 10.85 1305 07 Ν-(1Η-1,3- Benzodiazol-5ylmethyl)-4-(4methoxyphenyl)p-iridin-3-amine 1 °X^x\JL J ^H H _{C20H18N4O _ _} 330.38 11.14 4.24 1306 08 Ν-(1Η-1,3- Benzodiazol-5ylmethyl)-5-(4methoxyphenyl)p irimidin-4amine 1 °X^X TX (1J ^H H from ₁₉ h ₁₇ n ₅ o 331.37 Not defined 18.31

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1307 09 N-(1H-1,3- Benzodiazol-5ylmethyl)-3-(4mstoxyfsnyl)p-irazin-2-amine 1 Ao \ 1 J ⁿ Η _{C19H17N5O _ _} 331.37 1.90 2.21 1308 O10 N-(1H-1,3- Benzodiazol-5ylmethyl)-3 -(3,4dimethoxyphenyl)pyridin-4amine 1 A t X n C ₂ iH ₂₀ N ₄ O ₂ 360.40 1.63 0.88 1262 Oil N-(1H-1,3- Benzodiazol-5ylmethyl)-3 -(3,4dimethoxyphenyl)pyridin-2amine 1 D < D J ⁿ C ₂ iH ₂₀ N ₄ O ₂ 360.40 0.10 0.23 1309 012 N-(1H-1,3- Benzodiazol-5ylmethyl)-3-(3,4dimethoxyphenyl)pyrazin-2amine 1 A XA>n Η C20H19N5O2 361.39 0.13 0.42 1252 013 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-(4fluorophenyl)pyr-idin-3-amine Xd XY ⁱⁿ Η C1 ₉ H ₁₅ FN ₄ 318.34 145.4 2 21.96 1234 014 N-(1H-1,3- Benzodiazol-5ylmethyl)-3-(4fluorophenyl)pyr idin-2-amine '%\D J ^Η Η Ci ₉ H ₁₅ FN ₄ 318.34 58.79 12.28 1310 015 N-(1H-1,3- Benzodiazol-5ylmethyl)-3-(4fluorophenyl)pyra zin-2-amine Αί (jH ^Η Η from ₁₈ h ₁₄ fn ₅ 319.33 10.52 11.74 1311 016 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-(4phenoxyphenyl)a NILIN Q A i J I J Η Η C26H21N3O 391.46 4.34 2.11 1312 017 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-[4(cyclohexylox and) phenyl]aniline Q Ao < Д J ^H H _{C26H27N3O _} 397.51 2.03 4.17 1313 018 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-(4propoxyphenyl)aniline Ao\ ^1JHH from ₂₃ h ₂₃ n ₃ o 357.44 3.59 2.64 1314 019 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-[4(propan-2yloxy)phenyl]a NILIN ^JA^Ao K JI JH H from ₂₃ h ₂₃ n ₃ o 357.44 1.53 3.39 1315 020 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-(4methoxyphenyl)3-methylaniline 1 < 1 J ^H H C22H21N3O 343.42 2.38 1.64 1316 021 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-(3,4dimethoxyphenyl)-3methylaniline /4· H C23H23N3O2 373.45 0.43 0.42 1317 022 N-(1H-1,3- Benzodiazol-5ylmethyl)-2-(4chlorophenyl)-3fluoroaniline A ^Z k/ ^ZT from ₂₀ h ₁₅ cifn 351.8 4.89 6.83

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Synthesis of examples.

Synthesis method A

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 (0.25 g, 4.0 mmol) and 4-oxobutanenitrile (0.44 g, 5.3 mmol) was dissolved in dry MeOH (15 ml) and acetic acid (0.5 ml) was added. The reaction mixture was stirred for 2 hours 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 (3x20 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated, and purified by column chromatography using 10-20% ethyl acetate in hexanes as eluent to give pure title compound (0.17 g, 12%).

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 vacuo and the crude material was purified by column chromatography using 0-2% MeOH in DCM as eluent to obtain pure title compound (70 mg, 33%). LCMS method 10 (200 nm): RT=5.81 min, purity 95.2%, [M+1]=329.2, 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.46-7, 36 (m, 2H), 7.32-7.23 (m, 2H), 7.20-7.11 (m, 1H), 7.05-6.89 (m, 3H), 6.76- 6.55 (m, 2H), 4.61 (t, J=5.9 Hz, 1H), 3.10 (q, J=6.6 Hz, 2H), 2.82 (t, J=7 .5 Hz, 2H), 1.85 (p, J=7.2 Hz, 2H).

Synthesis method B

Stage 1

2-Substituted aniline (1.0 eq), sodium cyanoborohydride (1.5 eq) and tert-butyldimethylsilyloxyacetaldehyde (2.0 eq) were dissolved in dry MeOH (30.0 vol) and acetic acid (1.0 vol) was added about.). The reaction mixture was stirred for 1-2 hours 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 (3x20 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated, and used in the next step without further purification.

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Stage 2

The product from step 1 (1.0 eq.) and tetrabutylammonium fluoride trihydrate (1.05 eq.) 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 transferred to step 3.

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-5mercapto-thiadiazole (0.50 g, 3.8 mmol) and triphenylphosphine (1.18 g, 4.5 mmol) in anhydrous THF (16.0 mL), diethylene azodicarboxylate (0.66 g, 3.8 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. After this time, the solvents were removed in vacuo. The crude product was purified by column chromatography using 0-3% MeOH in DCM and further re-purified by the preparative TLC method using MeOH in DCM as eluent. Final re-purification was carried out by preparative HPLC to give pure product (40 mg, 7%). LCMS method 7 (200 nm): RT=5.81 min, purity 98.7%, [M]=346.0, 'H NMR (300 MHz, methanol^) δ 7.48-7.31 (m , 1H), 7.27-7.10 (m, 2H), 7.01 (dd, J=7.4, 1.6 Hz, 1H), 6.84-6.52 (m, 1H), 3.47 (t, J=6.6 Hz, 1H), 3.26 (t, J=6.6 Hz, 1H).

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- 5mercapto-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 overnight at room temperature. After this time, the solvents were removed in vacuo. The crude product was purified by column chromatography using 0-3% MeOH in DCM and repurified by preparative HPLC to give the pure product (80 mg, 7%). LCMS method 7 (205 nm): RT=5.27 min, purity 98.1%, [M]=386.9, 1H NMR (300 MHz, DMSO-d6) δ 7.30 (s, 1H), 7.14 (td, J=7.8, 7.3, 1.7 Hz, 1H), 7.09-6.96 (m, 2H), 6.89 (dd, J=8.2, 2 ,0 Hz, OH), 6.75-6.61 (m, 1H), 4.94 (t, J=6.0 Hz, 1H), 3.79 (d, J=1.8 Hz, 3H ), 3.38 (d, J=6.5 Hz, 1H), 3.24 (t, J=6.4 Hz, 1H).

Synthesis method C

Stage 1

To a solution of 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 for 1.5 hours at ambient temperature. After this time, NaBH ₃ CN (0.40 mg, 6.41 mmol) was added and the mixture was stirred for 1 hour. The reaction was quenched with saturated NaHCO ₃ solution. The aqueous layer was extracted with DCM (3x20 ml). The combined organic layers were dried over sodium sulfate, filtered, evaporated to give the product.

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

Methyl 4-({3',4'-dimethoxy-[1,1'-biphenyl]-2-yl}amino)butanoate (1.00 g, 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.

- 52 043556

Stage 2

To a solution of the appropriate starting material (3.04 mmol) in EtOH (30 ml) was added 50% hydrazine in H ₂ O (5.0 eq.). The reaction mixture was stirred for 18 hours at 80°C. After this time, the solvent was evaporated to obtain pure compound.

4-({4'-Fluoro-[1,1'-biphenyl]-2-yl}amino)butanhydrazide (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.

4-({3',4'-Dimethoxy-[1,1'-biphenyl]-2-yl}amino)butanhydrazide (0.97 g, 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.

Stage 3

To a solution of the appropriate starting material (2.6 mmol) in MeOH (8 ml) was added N,N-dimethylformamide dimethyl acetal (311 mg, 2.6 mmol). The reaction mixture was stirred for 1 hour at 80°C. After this time, the solvent was evaporated to obtain the desired product.

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

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

Stage 4

Rl ^R 2

MeNH ₂ 2M in THF (20 eq.) was added to a solution of the corresponding starting material in anhydrous THF (10.0 ml) under argon. The reaction mixture was cooled to 0°C and acetic acid (2 ml) was carefully added. The reaction mixture was stirred for 18 hours at 100°C. After this time, the reaction mixture 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 (3x20 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 fraction containing the title compound in pure form was concentrated to obtain the product.

4'-Fluoro-N-[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]-[1,1'-biphenyl]-2-amine (B1) (101 mg , eleven%). N'-[(1E)-(dimethylamino)methylidene]-4-({4'-fluoro-[1,1'biphenyl]-2-yl}amino)butanhydrazide (1.00 g, 2 .92 mmol). LCMS method 2 (220 nm): RT=4.78 min, purity 98.89%. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.46-7.36 (m, 2H), 7.32-7.21 (m, 2H), 7.21- 7.14 (m, 1H), 6.95 (d, J=1.7 Hz, 1H), 6.72-6.61 (m, 2H), 4.10 (q, J=5.3 Hz , 2H), 3.54 (s, 3H), 2.69 (d, J=7.5 Hz, 2H), 1.95-1.84 (m, 2H).

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]-butanhydrazide (1 .10 g, 2.86 mmol). LCMS method 8 (210 nm): RT=12.12 min, purity 99.45%. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.09-6.84 (m, 4H), 6.66 (d, J=7.9 Hz, 2H), 4 .11 (q, J=5.4 Hz, 2H), 3.79 (d, J=5.4 Hz, 3H), 3.53 (s, 3H), 3.40 (t, J=7, 0 Hz, 2H), 3.18 (d, J=5.3 Hz, 3H), 1.89-1.96 (m, 2H).

- 53 043556

Synthesis method D

Stage 1

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) was dissolved in DCM (5 ml) and acetyl chloride (0.17 g, 2.15 mmol) was added dropwise at 5°C, the reaction mixture was stirred at room temperature for 1 hour, after this time another portion of triethylamine and acetyl chloride was added at 5°C and the reaction mixture was stirred for an additional 30 minutes. The mixture was diluted with DCM (15.0 ml) and washed. sodium bicarbonate solution (20 ml), water (20 ml). The title compound was prepared as a 1:1 mixture of acetylated (UPLC (254 nm): RT=3.13 min, [M+H]=297.9) and diacetylated amine (UPLC (254 nm): RT=3, 58 min, [M+H]=338.9) (0.40 g, 60%). The resulting mixture was used in the next step without purification.

Stage 2

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]- 2amine (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 mixture was stirred overnight at 100°C. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using 0-3% MeOH in DCM as eluent to give pure product (0.24 g, 88%). UPLC (254 nm): RT=3.78 min, purity 85%, [M+H]=404.8.

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), concentrated hydrochloric acid (2.5 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml) and extracted with DCM (6x15 ml), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC to obtain pure product (40 mg, 25%). LCMS method 6 (200 nm): RT=20.57 min, purity 91.6%, [M+H] =363.14, LCMS (340 nm): RT=20.57 min, purity 99.2% , [M+H]=363.14, 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.59-7.33 (m, 7H), 7.27-7, 04 (m, 5H), 6.89-6.54 (m, 2H).

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 mixture was stirred overnight at 100°C. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using 0-3% MeOH in DCM as eluent to give pure product (0.2 g, 80%) . UPLC (254 nm): RT=3.64 min, 85% purity,

[M+N]=447.15.

-(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), concentrated hydrochloric acid (3.0 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml) and extracted with DCM (6x15 ml), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC to give the pure product (44 mg, 25%). LCMS (LCMS method 10, 200 nm), RT=5.22 min, purity 96.1%, [M+H]=405.11, 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s , 1H), 7.55-7.31 (m, 6H), 7.37-7.13 (m, 5H), 6.81-6.64 (m, 2H), 3.53 (s, 3H ), 3.50 (s, J=7.0 Hz, 3H).

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 minutes. and tris-(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol) was added. The reaction mixture was stirred at 100°C for 96 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^98:2 as eluent to give the product as a yellow solid (62.5 mg , 35.01%). UPLC (254 nm): RT=7.14 min, purity 80.9%, [M+H]=417.10.

-(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), concentrated hydrochloric acid (1.0 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x10 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with Hex/EtOAc/MeOH 70:25:5 to give the desired product as a yellow solid (19.6 mg, 35%). LCMS (LCMS method 11, 200 nm): RT=2.75 min, purity 98.9%, [M+H]=375.21. ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.74 (s, 1H), 7.50-7.43 (m, 2H), 7.40-7.28 (m, 5H), 7. 23-7.14 (m, 3H), 6.98-6.91 (m, 2H), 6.84-6.78 (m, 2H), 3.75 (s, 3H).

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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using a mixture of DCM/MeOH 1:0-95:5 as eluent to give the product as a pale yellow solid (114 mg, 93.6%). UPLC (254 nm): RT=5.35 min, purity 65%, [M+H]=418.70.

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), concentrated hydrochloric acid (1.7 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x15 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with DCM/MeOH 9:1 to give the desired product as a yellowish solid (16.4 mg, 16%). LCMS method 5 (200 im): RT=1.75 min, purity 99.3%, [M+H]=376.19. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.20 (dd, J=4.9, 1.9 Hz, 1H), 7.96 (s, 1H), 7.67-7.56 (m , 4H), 7.53 (dd, J=7.4, 1.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.25 (s, 2H), 7.10- 7.04 (m, 2H), 6.98 (dd, J=7.4, 4.9 Hz, 1H), 3.82 (s, 3H).

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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^95:5 as eluent with yielding the product as a yellow solid (75 mg, 53.6%). UPLC (310 nm): RT=3.96 min, purity 93%, [M+H]=418.95.

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), concentrated hydrochloric acid (1.12 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x15 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with DCM/MeOH 9:1. Purification was repeated by preparative TLC, eluting with DCM/MeOH 9:1 to give the desired product as an off-white solid (32.0 mg, 47%). LCMS method 3 (200 nm): RT=3.01 min, purity 99.8%, [M+H]=376.18. 1H NMR (300 MHz, DMSO-d6) δ 8.26-8.20 (m, 2H), 8.00 (s, 1H), 7.66-7.61 (m, 2H), 7.45- 7.40 (m, 2H), 7.32-7.18 (m, 5H), 7.07-7.02 (m, 2H), 3.80 (s, 3H).

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-(3,4dimethoxyphenyl)pyridin-4-amine (93 mg, 0.40 mmol), cesium carbonate (219 mg, 0.67 mmol) and XantPhos

- 56043556 (39 mg, 0.07 mmol) was 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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^95:5 as eluent with yielding the product as a pale yellow solid (49 mg, 32.7%). UPLC (310 nm): RT=4.72 min, 100% purity, [M+H]=448.15.

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-2yl]acetamide (49 mg, 0.11 mmol) in methanol (0.75 ml), concentrated hydrochloric acid (0.75 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (10 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x10 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC eluting with DCM/MeOH 95:5 to give the desired product as a light yellow solid (11 mg, 24.8%). LCMS method 3 (200 nm): RT=2.90 min, purity 99.6%, [M+H]=406.17. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.28-8.22 (m, 2H), 8.01 (s, 1H), 7.67-7.60 (m, 2H), 7.33 -7.17 (m, 5H), 7.09-6.99 (m, 3H), 3.77 (d, J=12.1 Hz, 6H).

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)pyridin2-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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^99:1 as eluent with yielding the product as a yellowish solid (75 mg, 55.6%). UPLC (254 nm): RT=5.92 min, purity 96.8%, [M+H]=406.95.

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), concentrated hydrochloric acid (1.2 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x15 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with DCM/MeOH 95:5. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a yellowish solid (4.3 mg, 6.4%). LCMS method 2 (200 nm): RT=4.69 min, purity 98.9%, [M+H]=364.18. L NMR (300 MHz, methanol^) δ 8.22 (dd, J=5.0, 1.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.47 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (dd, J=7.4, 5.0 Hz, 1H).

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)pyrazin2-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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using a mixture of DCM/MeOH 1:0^97:3 as eluent to give the product as a yellowish solid (68 mg, 49.8%). UPLC (254 nm): RT=5.88 min, purity 95.5%,

[M+N]=407.05.

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), concentrated hydrochloric acid (1 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x15 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with DCM/MeOH 9:1. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a yellow solid (20.2 mg, 33.2%). LCMS method 4 (328 nm): RT=2.44 min, purity 97.0%, [M+H]=365.15. 1H NMR (300 MHz, DMSO- _d6 ) δ 8.70 (s, 1H), 8.19 (s, 2H), 7.86-7.79 (m, 2H), 7.64 (s, 4H ), 7.46-7.27 (m, 4H).

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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^98:2 as eluent with yielding the product as a yellow solid (115 mg, 71.7%). UPLC (254 nm): RT=7.96 min, purity 88.6%, [M+H]=479.15.

O H ₂ N. _s „ W ΙΛΟ ^ΝΗ Η °^о

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), concentrated hydrochloric acid (1.4 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x15 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with DCM/MeOH 8:2. Purification was repeated by preparative TLC, eluting with Hex/EtOAc/MeOH 70:25:5 to give the desired product as a yellowish solid (17.2 mg, 19.9%). LCMS method 11 (200 nm): RT=3.57 min, purity 97.5%, [M+H]=437.16. ¹ H NMR (300 MHz, methanol^) δ 7.52-7.43 (m, 2H), 7.41-7.15 (m, 8H), 7.10-7.01 (m, 1H), 6.97-6.84 (m, 4H), 6.82-6.72 (m, 2H).

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 using a stream of argon for

- 58 043556 min and tris-(dibenzylideneacetone)dipalladium(0) (33 mg, 0.04 mmol) was added. The reaction mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^97:3 as eluent with yielding the product as a yellowish solid (55.7 mg, 31.1%). UPLC (254 nm): RT=8.07 min, purity 86.8%, [M+H]=445.30.

TO

5-(4-{[2-(4-Propoxyphenyl)phenyl]amino}phenyl)-1,3,4-thiadiazol-2-amine (C11).

To a solution of K-[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), concentrated hydrochloric acid (0.84 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (10 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x10 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with Hex/EtOAc/MeOH 70:25:5. Repurification was carried out by soaking with diethyl ether to obtain the desired product as a light brown solid (11 mg, 22%). LCMS method 4 (200 nm): RT=3.67 min, purity 98.9%, [M+H]=403.19. 1H NMR (300 MHz, methanol^) δ 7.56-7.47 (m, 2H), 7.41-7.27 (m, 5H), 7.17 (td, J=7.3, 1, 5 Hz, 1H), 6.96-6.81 (m, 4H), 3.94 (t, J=6.5 Hz, 2H), 1.79 (dtd, J=13.8, 7.4 , 6.4 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H).

N-{5-[4-({2-[4-(Propan-2-yloxy)phenyl]phenyl}amino)phenyl]-1,3,4-thiadiazol-2-yl}acetamide.

N-[5-(4-Bromphenyl)-1,3,4-thiadiazol-2-yl]acetamide (100 mg, 0.34 mmol), 2-[4-(propan-2yloxy)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 mixture was stirred at 100°C for 72 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using DCM/MeOH 1:0^97:3 as eluent with yielding the product as a yellowish solid (87.4 mg, 58.6%). UPLC (254 nm): RT=7.59 min, purity 87.6%, [M+H]=445.15.

O h ₂ n. _s _ W °х

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), concentrated hydrochloric acid (1.3 ml) was added dropwise. The reaction mixture was refluxed overnight. After this time, the reaction mixture was diluted with saturated sodium bicarbonate solution (15 ml), the methanol was evaporated and extraction was carried out with ethyl acetate (2x15 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative TLC, eluting with Hex/EtOAc/MeOH 70:25:5. Re-purification was carried out by soaking with methanol to obtain the desired product as a yellow solid (7 mg, 8.8%). LCMS method 4 (200 nm): RT=3.54 min, purity 97.4%, [M+H]=403.20. 1H NMR (300 MHz, methanol-d4) δ 7.55-7.47 (m, 2H), 7.41-7.27 (m, 5H), 7.18 (td, J=7.3, 1 .5 Hz, 1H), 6.94-6.81 (m, 4H), 4.59 (dq, J=12.1, 6.1 Hz, 1H), 1.30 (d, J=6, 0 Hz, 6H).

Synthesis method E

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 eq.) in 1. Amine (1.0 eq.) was added to 4-dioxane (3.0 mL). Degas reaction mixture

- 59 043556 zated for 30 minutes. Xantphos (30 mg, 0.05 mmol) and an appropriate catalyst were then 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. Fractions containing the title compound were combined and concentrated. The product was re-purified by P-TLC using 4% MeOH in DCM as eluent.

4'-Fluoro-N[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[1,G-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), chloroform adduct and tris-(dibenzylideneacetone)dipalladium were used (0) (26 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.05 mmol). LCMS method 2 (200 nm): RT=5.54 min, purity 97.6%, [M+H]=345.15. 1H NMR (300 MHz, DMSO- _d6 ) δ 8.46 (s, 1H), 7.82 (s, 1H), 7.45-7.49 (m, 4H), 7.34-7.40 (m, 3H), 7.17-7.25 (m, 3H), 6.88 (d, J=9.0 Hz, 2H), 3.69 (s, 3H).

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), Cs ₂ CO ₃ (396 mg, 1.2 mmol), chloroform adduct and tris- (dibenzylideneacetone)diyalladium(0) (26 mg, 0.05 mmol). LCMS method 2 (200 im): RT=4.8 min, purity 98.7%, [M+H]=387.14. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=9 Hz, 2H), 7.31-7.42 (m, 3H), 7.19-7.25 (m, 1H), 6.99 (d, 2H, J=6 Hz), 6.88 (d, 2H, J=9 Hz), 3.76 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H).

/°

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 Cs ₂ CO ₃ (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 minutes. Xantphos (22 mg, 0.04 mmol) and chloroform-tris-(dibenzylideneacetone)dipalladium(0) adduct (19 mg, 0.02 mmol) were then added and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. The product was purified again 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, purity 94.03%, [M+H]=357.21. ¹ H NMR (300 MHz, methanol^) δ 8.48 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.39 (s, 1H), 7.37-7 .28 (m, 4H), 7.29-7.13 (m, 1H), 6.94 (dd, J=8.8, 3.3 Hz, 4H), 3.80 (s, 3H), 3.78(s,3H).

nRHJ^ ^nh q /°

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 Cs ₂ CO ₃ (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 minutes. Xantphos (20 mg, 0.03 mmol) and chloroform-tris-(dibenzylideneacetone)dipalladium(0) adduct (18 mg, 0.02 mmol) were then added and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. 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, purity 96.3%, [M+H]=358.22. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 8.24 (s, 1H), 7.84 ( d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.39 (dd, J=8.1, 4.7 Hz, 3H), 6.98 (t, J=9.1 Hz, 4H), 3.78 (s, 3H), 3.74 (s, 3H).

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 Cs ₂ CO ₃ (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 minutes. Xantphos (23 mg, 0.04 mmol) and chloroform-tris-(dibenzylideneacetone)dipalladium(0) adduct (20 mg, 0.02 mmol) were then added and the mixture was stirred at

- 60 043556

100°C overnight. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. Fractions containing the title compound were combined and concentrated. The product was purified again by P-TLC using 4% MeOH in DCM as eluent to give the desired product as a light orange solid (5 mg, 4%). LCMS method 1 (205 nm): RT=5.82 min, purity 99.46%, [M+H]=346.22. ¹ H NMR (300 MHz, methanol-d4) δ 8.50 (s, 1H), 8.37 (dd, J=4.7, 1.5 Hz, 1H), 7.89 (d, J=7 ,2 Hz, 1H), 7.70 (dd, J=9.1, 5.6 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.42 (dd, J =8.2, 4.7 Hz, 1H), 7.16 (t, J=8.7 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 3.78 (s , 3H).

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 Cs ₂ CO ₃ (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 minutes. Xantphos (22 mg, 0.04 mmol) and chloroform-tris-(dibenzylideneacetone)dipalladium(0) adduct (20 mg, 0.02 mmol) were then added and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-5% MeOH in DCM as eluent. 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, purity 99.51%, [M+H]=419.20. ¹ H NMR (300 MHz, methanol^) δ 8.47 (s, 1H), 7.74-7.14 (m, 11H), 7.09 (t, J=7.9 Hz, 1H), 7 .09-6.77 (m, 6H), 3.75 (s, 3H).

O o\/

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 Cs ₂ CO ₃ (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 minutes. Xantphos (18 mg, 0.03 mmol) and chloroform-tris-(dibenzylideneacetone)dipalladium(0) adduct (16 mg, 0.02 mmol) were then added and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated and purified by column chromatography using 0-10% MeOH in DCM as eluent. 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, purity 98.21%, [M+H]=388.24. 1H NMR (300 MHz, methanol^) δ 8.55 (s, 1H), 8.26-8.19 (m, 2H), 7.72-7.58 (m, 2H), 7.43-7 .25 (m, 3H), 7.09 (d, J=4.2 Hz, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H) .

Synthesis method F

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. Saturated sodium bicarbonate solution was added to the mixture and the aqueous layer was extracted three times with EA (3x80 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. Fractions containing the title compound were combined and concentrated (3.301 g, 62%). UPLC (254 nm): RT=1.91 min, purity 68%, [M-H]=223.7.

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Br

N-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide. To a solution of 5-(3-bromopropyl)-1,3,4-thiadiazol2-amine (3.3 g, 14.8 mmol) in anhydrous DCM (35 mL) under argon was added triethylamine (4.14 mL, 29. 7 mmol) and acetyl chloride (1.16 ml, 16.3 mmol). The reaction mixture was stirred for 6 hours at ambient temperature. After this time, 1 M HCl (50 ml) was added and the aqueous layer was extracted three times with DCM (3x80 ml). The combined organic layers were dried over sodium sulfate, filtered, evaporated to give pure product (3.144 g, 80%). UPLC (254 nm): RT=2.43 min, purity 89%, [M+H]=265.65.

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]acetamideα (1.0 g, 3.8 mmol) in anhydrous DMF (20.0 mL) under argon was added sodium azide (0.37 g, 5.7 mmol). The reaction mixture was stirred for 2 hours. After this time, water (10 ml) was added and the aqueous layer was extracted with DCM (3x80 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give pure product (0.6 g, 71%). UPLC (254 nm): RT=2.29 min, purity 98%, [M+H]=227.0.

I nh ₂

HN. _s

N-[5-(3-Aminopropyl)-1,3,4-thiadiazol-2-yl]acetamide.

A solution of methyl-N-[5-(3-αzidopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.6 g, 2.7 mmol) in anhydrous tetrahydrofuran (7 ml) was added dropwise to the granule suspension LAH (0.1 g, 2.8 mmol) in anhydrous THF (5 ml) under argon. The reaction mixture was stirred for 1 hour at ambient temperature. After this time, LAH (0.1 g, 2.8 mmol) was added. Stirring was continued for 2 hours. After this time, 0.2 ml of water was added, followed by the addition of 0.4 ml of 20% NaOH and 0.6 ml of water. The suspension was filtered through celite and washed with DCM/MeOH 9:1. Evaporation of the solvents gave the title compound (0.22 g, 41%). UPLC (254 nm): RT=1.17 min, purity 57%, [M-H]=201.2.

N-{5-[3-(4-Fluorobenzenesulfonamido)propyl]-1,3,4-thiαdiazol-2-yl}αcetamide.

N-[5-(3-aminopropyl)- 1,3,4-thiadiazol-2yl]acetamide (170 mg, 0.85 mmol). The reaction mixture was stirred for 18 hours at ambient temperature. After this time, the solvents were evaporated, 1 M HCl was added to the residue and the aqueous layer was extracted with DCM (3x20 ml). The combined organic layers were dried over sodium sulfate, filtered, evaporated to give the product (0.02 g, 7%). UPLC (254 nm): RT=2.56 min, purity 98%, [M+H]=358.85.

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-thiαdiazol-2-yl}αcetamide (20 mg, 0.06 mmol) was dissolved in a solution of HCl (2 ml) and MeOH (2 ml). The reaction mixture was stirred for 18 hours at 80°C. After this time, sodium bicarbonate solution was added and the aqueous layer was extracted with DCM (3x10 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 gave the desired product (3 mg, 17%). LCMS method 1 (200 nm): RT=2.56 min, purity 96.0%. [M+N]=317.15. 1H NMR (300 MHz, MeOH-d ₄ ) δ 7.87-7.94 (m, 2H), 7.29-7.39 (m, 2H), 2.86-2.97 (m, 4H) , 1.82-1.91 (m, 2H).

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Synthesis method G

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 mixture 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). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82-7.95 (m, 2H), 7.25-7.33 (m, 2H), 4.92 (t, 1H), 3.54- 3.64 (t, 2H), 3.323.44 (dt, 2H).

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-1,3,4thiadiazole (0.10 g, 0.75 mmol ), potassium carbonate (0.31 g, 2.25 mmol) was dissolved in acetonitrile (2.0 ml) and stirred at 80°C overnight. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using 0-5% MeOH in DCM as eluent to give pure product (120 mg, 48%). LCMS method 2 (200 nm): RT=4.24 min, purity 99.71%, [M+H]=334.97, ΊI NMR (300 MHz, DMSO-d ₆ ) δ 7.92 (br s , 1H), 7.80-7.90 (m, 2H), 7.37-7.47 (m, 2H), 7.30 (br s, 2H), 3.07 (m, 4H).

4-Φτορ-Ν-{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-1,2,4triazole (0.10 g, 0. 87 mmol), potassium carbonate (0.36 g, 2.61 mmol) was dissolved in acetonitrile (2.0 ml) and stirred at 80°C overnight. After this time, the reaction mixture was cooled to room temperature, filtered through celite, evaporated and purified by column chromatography using 0-5% MeOH in DCM as eluent to give pure product (200 mg, 73%). LCMS method 2 (200 nm): RT=3.79 min, purity 97.39%, [M+H]=317.05, 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 7.97 (s, 1H), 7.88-7.77 (m, 2H), 7.49-7.35 (m, 2H), 3.53 (s, 3H), 3.21 -2.99 (m, 4H).

Synthesis method H

N-[5-(3-Bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide was synthesized according to the procedure described for E2.

N-[5-(3-{[(4-Fluorophenyl)(methyl)oxo-λ-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-yl]acet amide.

To a solution of (4-fluorophenyl)(imino)methyl-λ-sulfanone (0.1 g, 0.58 mmol) in anhydrous DMSO (4 mL) under argon was added KOH (0.065 g, 1.15 mmol). The suspension was stirred for 1.5 hours at

- 63 043556 ambient temperature. After this time, a solution of K-[5-(3-bromopropyl)-1,3,4-thiadiazol-2-yl]acetamide (0.229 g, 0.87 mmol) in anhydrous DMSO was added dropwise slowly (1.5 h). (4 ml). Immediately after completion of the dropwise addition, the reaction was quenched with water (5 ml). The aqueous layer was extracted with DCM (10 ml) and then extracted 5 times with chloroform/isopropyl alcohol 3:1 (5x20 ml). The combined organic layers were dried over sodium sulfate, filtered, evaporated to give pure product (0.06 g, 29%). UPLC (254 nm): RT=2.2 min, purity 61%, [M+H]=357.2.

5-(3-{[(4-Fluorophenyl)(methyl)oxo-λ-sulfanylidene]amino}propyl)-1,3,4-thiadiazol-2-amine (F2).

N-[5-(3-{[(4-Fluorophenyl)(methyl)oxo-λ-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 for 3 hours at 80°C. After this time, sodium bicarbonate solution was added and the aqueous layer was extracted with DCM (3x10 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 gave the desired product (5 mg, 9%). LCMS (245 nm): RT=5.91 min, purity 98.88%. [M+H]=315.17, ^1H NMR (300 MHz, CDCl ₃ ) δ 7.98-7.87 (m, 2H), 7.22-7.26 (m, 2H), 5.21 (s, 2H), 3.11 (s, 2H), 2.89-3.09 (m, 2H), 1.97-2.00 (m, 2H).

Synthesis method I

Methyl 4-(4-fluorobenzenesulfonamido)butanoate.

To a solution of 3,4-dichlorobenzenesulfonyl 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 for 18 hours at ambient temperature. After this time, 1 M HCl (5 ml) was added and the aqueous layer was extracted with DCM (3x5 ml). The combined organic layers were dried over sodium sulfate, filtered, evaporated to give the product (0.605 g, 68%). UPLC (254 nm): RT=2.89 min, [M+H]=275.85.

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 H ₂ O (0.65 ml, 10.4 mmol). The reaction mixture was stirred for 1 hour at 80°C. After this time, the reaction mixture was cooled, water (20 ml) was added and the aqueous layer was extracted three times with EA (3x10 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give pure product (180 mg, 31%). UPLC (254 nm): RT=1.88 min, purity 65%, [M+H]=276.2.

K-(3-{K'-[(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,K-dimethylformamide dimethyl acetal (78 mg, 0.65 mmol). The reaction mixture was stirred for 1 hour at 80°C. After this time, the solvent was evaporated to obtain the desired product (216 mg, 100%). UPLC (254 nm): RT=1.78 min, purity 60%, [M+H]=331.3.

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4-Φτορ-Ν -[3-(4-methyl-4H-1,2,4-triazol-3-yl)propyl]benzene-1-sulfonamide (G1).

M MeNH ₂ in THF (32 ml, 3.3 mmol) was added to a solution of N-(3-{N'-[(1dimethylamino)methylidene]hydrazinecarbonyl}propyl)-4-fluorobenzene-1-sulfonamide (216 mg, 0. 63 mmol) in anhydrous THF (5.0 ml) under argon. The reaction mixture was cooled to 0°C and acetic acid (2 ml) was carefully added. The reaction mixture was stirred for 1 hour at 100°C. After this time, the reaction mixture was cooled to room temperature, water (5 ml) was added and the aqueous layer was extracted three times with EA (3x20 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. The resulting 40 mg of product was repurified by P-TLC using 4% MeOH in DCM as eluent and then repurified by preparative HPLC. The fraction containing the title compound in pure form was concentrated (3 mg, 2%). LCMS method 1 (200 nm): RT=6.17 min, purity 99.5%, [M+H]=299.2. 'H NMR (300 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.84-7.90 (m, 2H), 7.15-7.23 (m, 2H), 5.62 ( t, J=5.6 Hz, 1H), 3.64 (s, 3H), 3.12 (q, J=3.1 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H), 2.06-2.15 (m, 2H).

Synthesis method K

N-(2-Chloρethyl)sulfamoylαchloride.

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). The reaction mixture 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). 1H NMR (300 MHz, d ₆ -DMSO) δ 11.0 (bs, 1H), 3.83 (t, 2H), 3.36 (t, 2H).

Ί θ,ο ρΗ ^HN ^vJ ^Ho \ (2-Chloroethyl)[(3,4-dimethoxyphenyl)sulfamoyl]amine.

N-(2-Chloethyl)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 mixture was stirred at room temperature overnight. After this time, the reaction mixture was 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, purity 11%, [M+H]=294.95.

[(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-4H1,2,4-triazole (0.22 g, 0.74 mmol), potassium carbonate (0.31 g, 2.21 mmol) was dissolved in acetonitrile (1.7 ml) and stirred at 80°C for 3 hours. After this time, the reaction mixture was cooled to room temperature, filtered through celite , evaporated and purified by column chromatography using 0-5% MeOH in DCM as eluent to give pure product (8 mg, 3%). LCMS method 2 (200 nm): RT=3.08 min, purity 99.1%, [M+H]=374.03, 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.57 (s, 1H), 6.96-6.75 (m, 2H), 6.72-6.63 (m, 1H), 3.71 (d, J=2.7 Hz, 6H), 3.51 (s , 3H), 3.23-3.08 (m, 4H).

- 65 043556

Synthesis method L

[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 any further purification (5.4 g, 200%). UPLC (254 nm): RT=2.88 min, purity 50%, [M-2H]=293.5.

[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 any further purification (8.1 g, 200%). UPLC (254 nm): RT=2.77 min, purity 50%, [M-2H]=335.6.

N-[4-(2-Amuho-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-bromothiazole bromide (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) were degassed with a stream of argon for 20 min and the [1,G-bis(diphenylphosphino)ferrocene complex was added in one portion ]dichloropalladium(P) with dichloromethane (0.84 g, 1.2 mmol). The reaction mixture was stirred overnight at 130°C. After this time, the reaction mixture was filtered through celite, washed with DCM, water (40 ml) was added, the layers were separated and the aqueous layer was extracted three times with DCM (3x25 ml), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using methanol in DCM (0-3%) as eluent and the product containing fraction was further purified by preparative HPLC to give the pure product as a red solid (48 mg, 2%). LCMS method 1 (254 nm): RT=6.73 min, purity 99.6%, [M+H]=349.7. ^1H NMR (300 MHz, DMSO- _d6 ) δ 10.36 (s, 1H), 7.84-7.76 (m, 2H), 7.45-7.36 (m, 2H), 7. 28 (dd, J=6.6, 2.0 Hz, 3H), 7.14-6.97 (m, 4H).

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-bromothiazole bromohydrate (1.20 g, 4.6 mmol) and potassium carbonate (3, 21 g, 23.1 mmol) in 1,4dioxane (40.0 ml) and water (4.0 ml) were degassed with a stream of argon for 20 min and the [1,G-bis(diphenylphosphino)ferrocene complex was added in one portion ]dichloropalladium(P) with dichloromethane (0.51 g, 0.7 mmol). The reaction mixture was stirred overnight at 130°C. After this time, the reaction mixture was filtered through celite, washed with DCM, water (40 ml) was added, the layers were separated and the aqueous layer was extracted three times with DCM (3x25 ml), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using methanol in DCM (0-3%) as eluent and the product containing fraction was further purified by preparative HPLC to give the pure product as an orange solid (45 mg, 3%). LCMS method 2 (200 nm): RT=2.99 min, purity 99.9%, [M+H]=392.0. 1H NMR (300 MHz, DMSO- _d6 ) δ 8.16 (s, 1H), 7.34-7.22 (m, 5H), 7.13-6.95 (m, 5H), 3.79 (s, 3H), 3.76 (s, 3H).

- 66 043556

Synthesis method M

2-Bromo-4'-fluoro-1,1'-biphenyl.

A solution of 1,2-dibromobenzene (8.26 g, 35.0 mmol), 4-fluorophenylboronic 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) were degassed with a stream of argon for 20 min and tetrakis(triphenylphosphine)palladium(0) (1.00 g, 0. 9 mmol). The reaction mixture was stirred overnight at 100°C. After this time, the reaction mixture was filtered through celite, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (2x15 ml), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using hexanes as eluent to give the title product (5.50 g, 122%). UPLC (254 nm): RT=4.33 min, 91% purity, [M+H]=not observed.

I

- {4'-Fluoro-[1,1'-biphenyl]-2-yl}piperidin-4-carbonitrile.

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) were degassed under a stream of argon for 20 min and tris(dibenzylideneacetone) was added in one portion )dipalladium(0) (0.11 g, 0.12 mmol). The reaction mixture was stirred overnight at 100°C. After this time, the reaction mixture was filtered through celite, washed with ethyl acetate and evaporated. The crude product was purified by column chromatography using ethyl acetate in hexanes (0-4%) as eluent to give the title product (0.18 g, 54%). UPLC (254 nm): RT=4.25 min, purity 90%, [M+H]=281.4.

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}piperidin-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 hours. After this time, the reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution (15 ml) and extracted with DCM (3x15 ml), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The crude product was triturated with ethyl acetate (1 ml), filtered 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, 200 nm): RT=4.97 min, purity 96.7%, [M+H ]=355.2. 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.707.58 (m, 2H), 7.38-7.17 (m, 4H), 7.16-6.89 (m, 4H), 3.05 (d, J=11.8 Hz, 2H), 2.87 (ddd, J=11.5, 7.6, 3.9 Hz, 1H), 2.62 (t, J=11.3 Hz, 2H), 1.86 (d, J=12.7 Hz, 2H), 1.54 (qd, J=12.0, 3.8 Hz, 2H).

Synthesis method N

tert-Butyl 4-(2-amino-1,3-thiazol-5-yl)piperidin-1-carboxylate was synthesized in two steps according to the literature (total yield: 60%).

- 67 043556 tert-Butyl-4-(2-acetamido-1,3-thiazol-5-yl)piperidin-1-carboxylate.

To a solution of tert-butyl 4-(2-amino-1,3-thiazol-5-yl)piperidin-1-carboxylate (3.75 g, 13.23 mmol) in anhydrous DCM (35 ml) under argon was added triethylamine (3.69 ml, 26.4 mmol) and acetyl chloride (1.00 ml, 14.6 mmol). The reaction mixture was stirred for 48 hours at ambient temperature. After this time, water (50 ml) was added and the aqueous layer was extracted five times with DCM (5x80 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give pure product (4.175 g, 97%). UPLC (254 nm): RT=4.27 min, [M+H]=326.25.

N-[5-(Piperidin-4-yl)-1,3-thiazol-2-yl]acetamide.

4 M HCl in dioxane (10 ml). The reaction mixture was stirred for 18 hours. After this time, the reaction mixture was filtered, the precipitate was washed with EA (2x40 ml) and dried under reduced pressure to obtain pure product (2.752 g, 82%). UPLC (254 nm): RT=2.1 min, [M+H]=226.25.

N-{5-[1 -(4-fluorobenzenesulfonyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide.

To a solution of 3,4-dichlorobenzenesulfonyl chloride (182 mg, 0.94 mmol) in a solvent mixture of DCM (3.0 mL) and pyridine (3.0 mL) was added N-[5-(piperidin-4-yl )-1,3-thiazol-2yl]acetamide (211 mg, 0.94 mmol). The reaction mixture was stirred for 48 hours at ambient temperature. After this time, the solvents were evaporated and the crude product was transferred to the next step.

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 for 18 hours at 80°C. After this time, saturated sodium bicarbonate solution was added and the aqueous layer was extracted with DCM (3x10 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. 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, purity 95.99%, [M+H]=342.07. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.85-7.90 (m, 2H), 7.35-7.41 (m, 2H), 6.7 (s, 1H), 3.82 (d, J=12.0 Hz, 2H), 2.61-2.73 (m, 1H), 2.40-2.49 (m, 2H), 1.98-2.04 (m, 2H ), 1.60-1.75 (m, 2H).

1-(4-Fluorobenzenesulfonyl)piperidine-4-carbonitrile.

To a solution of piperidine-4-carbonitrile (500 mg, 4.54 mmol) in a solvent mixture of DCM (5.0 mL) and pyridine was added 4-fluorobenzenesulfonyl chloride (880 mg, 4.54 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was diluted with 1 M HCl (50 ml) and DCM (50 ml) and the layers were separated. The organic layer was washed twice with 1 M HCl (2x50 ml) and concentrated to give the desired product as a beige solid. 1H NMR (400 MHz, chloroform-d) δ 7.98-7.66 (m, 2H), 7.36-7.12 (m, 2H), 3.29-3.06 (m, 4H), 2.91-2.71 (m, 1H), 2.17-1.89 (m, 4H).

_H2N.s

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 tisemicarbazide (190 mg, 2.05 mmol) were dissolved in TFA (4.0 ml) and the reaction mixture was stirred for 2 h at 60°C. After this time, the solvent was concentrated and the residue was suspended in solution

- 68 043556

DCM:MeOH (4.0 ml, 95:5 v:v), and the precipitate was filtered to obtain 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, purity 97.59%, [M+H]=343.13. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.20-7.71 (m, 2H),

7.51 (t, J=8.8 Hz, 2H), 3.66 (dt, J=12.2, 3.7 Hz, 2H), 2.95 (ddd, J=11.3, 7, 5, 3.8 Hz, 1H), 2.43 (dd, J=11.8, 2.6

Hz, 2H), 2.10-1.91 (m, 2H), 1.76-1.43 (m, 2H).

Synthesis method O

tert-Butyl-4-{N'-[( 1 E)-(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-dimethylformamide dimethyl acetal (245 mg, 2.05 mmol). The reaction mixture was stirred for 18 hours at 100°C. After this time, the solvent was evaporated to obtain the desired product (601 mg, 98%).

/

L />—(N-Boc tert-Butyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate.

To a solution of tert-butyl-4-{N'-[( 1 E)-(dimethylamino)methylidene]hydrazinecarbonyl}piperidine-1 carboxylate (600 mg, 2.01 mmol) in anhydrous THF (6.0 ml) was added 2 M MeNH ₂ in THF (15 ml, 40.2 mmol) under argon. The reaction mixture was cooled to 0°C and acetic acid (2 ml) was carefully added. The reaction mixture was stirred for 18 hours at 100°C. After this time, the reaction mixture was cooled to room temperature, water (20 ml) was added and the aqueous layer was extracted three times with EA (3x50 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the crude compound (511 mg, 95%).

/

L /W NH2CI ^N 'N \—/

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)piperidin-1-carboxylate (511 mg, 1.71 mmol) in THF (5.0 mL) 4 M HCl in dioxane (6.0 ml). The reaction mixture was stirred for 18 hours. After this time, the reaction mixture was filtered, the precipitate was washed with EA (2x40 ml) and dried under reduced pressure to obtain the product (347 mg, 100%).

/

F

-(4-Fluorobenzenesulfonyl)-4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine (N1).

To a solution of 4-fluorobenzenesulfonyl 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 for 18 hours at ambient temperature. After this time, the solvent was evaporated, 1 M HCl (5 ml) was added and the aqueous layer was extracted with DCM (3x10 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, purity 96.34%, [M+H]=325.11, ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (s, 1H ), 7.77-7.90 (m, 2H), 7.20-7.28 (m, 2H), 7.78-7.83 (m, 1H), 3.62 (s, 3H), 2.60-2.86 (m, 4H), 2.02-2.15 (m, 4H).

Synthesis method P

- 69 043556 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) was 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, purity 93.2%, [M+H]=233.2.

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-bromosuccinimide (0.64 g, 3.62 mmol), dibenzoyl peroxide (22 mg , 0.1 mmol) was suspended in carbon tetrachloride (16 ml). The reaction mixture was stirred overnight at 90°C. After this time, the reaction mixture was 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, purity 80%, [M+H]=312.75.

4'-Fluoro-[1,1'-biphenyl]-2-amine.

A solution of 2-bromoaniline (1.5 g, 8.7 mmol), 4-fluorophenylboronic 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) were degassed with a stream of argon for 20 min and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.43) was added in one portion g, 0.5 mmol). The reaction mixture was stirred overnight at 100°C. After this time, the reaction mixture was filtered through celite, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (2x15 ml), 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 hexanes to give pure product (1.65 g, 100%). UPLC (254 nm): RT=3.31 min, purity 99%, [M+H]=187.9.

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-1,3benzodiazol-1-carboxylate (244 mg, 0.59 mmol) to DMF (1.0 ml) was added sodium carbonate (170 mg, 1.6 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was diluted with ethyl acetate (15.0 ml) and washed with half-saturated saline (3x20 ml). The organic layer was dried over sodium sulfate, filtered, evaporated to obtain the crude product, which was purified by column chromatography using 0-2% MeOH in DCM as eluent to obtain the desired product as an off-white solid (48 mg, 22%) . LCMS method 2 (200 nm): RT=4.13 min, purity 97.2%, [M+H]=318.25. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.62-7.43 (m, 3H), 7.32 (t, J=8.9 Hz, 2H), 7 .18 (d, J=8.2 Hz, 1H), 7.05 (ddd, J=8.5, 7.4, 1.6 Hz, 1H), 6.97 (dd, J=7.5 , 1.6 Hz, 1H), 6.70-6.44 (m, 2H), 5.32 (s, 1H), 4.40 (d, J=5.9 Hz, 2H).

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) were 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). The reaction mixture was stirred overnight at 100°C. After this time, the reaction mixture was filtered through celite, the layers were separated and the aqueous layer was extracted twice with ethyl acetate (2x15 ml), 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 hexanes as eluent to give pure product (3.2 g, 80%). UPLC (254 nm): RT=3.25 min, purity 90%, [M+H]=229.9.

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-benzodiazol-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 overnight at 80°C. After this time, the reaction mixture was diluted with ethyl acetate (15.0 ml) and washed with half-saturated saline (3x20 ml). The organic layer was dried over sodium sulfate, filtered, evaporated to obtain the crude product, which was purified by column chromatography using 0-2% MeOH in DCM as eluent to obtain the desired product as an off-white solid (70 mg, 17%) . LCMS method 2 (205 nm): RT=3.66 min, purity 96.5%, [M+H]=360.1. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.20 (dd, J=8.3, 1 ,6 Hz, 1H), 7.12-6.87 (m, 5H), 6.61 (ddd, J=8.3, 5.9, 1.2 Hz, 2H), 5.26 (t, J=5.9 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H).

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-1,3benzodiazole-1-carboxylate (156 mg, 0.50 mmol) in DMF (1.0 ml) sodium carbonate (144 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 100:0^98:2. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as an off-white solid (35 mg, 23%). LCMS method 2 (230 nm): RT=3.90 min, purity 96.6%, [M+H]=330.24. 1H NMR (300 MHz, methanol^) δ 8.13 (s, 1H), 7.56 (d, J=5.5 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H) , 7.25 (dd, J=8.4, 1.2 Hz, 1H), 7.15-6.93 (m, 4H), 6.75-6.63 (m, 2H), 4.45 (s, 2H), 3.84 (s, 3H).

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-benzodiazol-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 overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 100:0:0^9:1:0.1. Re-purification was carried out by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0.1, to obtain the desired product as an off-white solid (10 mg, 7%). LCMS method 1 (205 nm): RT=4.66 min, purity 97.8%, [M+H]=331.27. 1H NMR (300 MHz, methanol-d ₄ ) δ 8.14 (s, 1H), 7.81 (d, J=5.7 Hz, 1H), 7.58 (t, J=3.9 Hz, 4H), 7.27 (d, J=9.6 Hz, 1H), 7.20-6.97 (m, 4H), 4.49 (s, 2H), 3.86 (s, 3H).

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-benzodiazol-1-carboxylate (202 mg, 0. 65 mmol) in DMF (1.0 ml) was added sodium carbonate (159

- 71 043556 mg, 1.50 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Re-purification was carried out by preparative TLC, eluting with DCM/MeOH/NH ₃

95:5:0^9:1:0.1 to give the desired product as a white solid (4 mg, 2.5%). LCMS method 3 (200 nm): RT=2.66 min, purity 96.3%, [M+H]=331.11. 1H NMR (300 MHz, methanol-d ₄ ) δ 8.12 (s, 1H), 7.97 (dd, J=5.2, 1.8 Hz, 1H), 7.62-7.51 (m , 2H), 7.35 (t, J=8.7 Hz, 3H), 7.25 (d, J=9.7 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H ), 6.69 (dd, J=7.2, 5.2 Hz, 1H), 4.69 (s, 2H), 3.83 (s, 3H).

I

TX i and Λ J ^H H №(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-benzodiazol-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 overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Purification was repeated by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0^9:1:0.1 to give the desired product as a white solid (12 mg, 7%). LCMS method 3 (245 nm): RT=2.36 min, purity 97.4%, [M+H]=331.25. 1H NMR (300 MHz, methanol- _d4 ) δ 8.28 (s, 1H), 8.26-8.18 (m, 2H), 7.77-7.67 (m, 2H), 7.42 -7.32 (m, 3H), 7.11 (d, J=6.7 Hz, 2H), 6.98 (d, J=7.1 Hz, 1H), 5.52 (s, 2H) , 3.87 (s, 3H).

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-benzodiazol-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 overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Re-purification was carried out by preparative HPLC to obtain the desired product as a white solid (5 mg, 4%). LCMS (LCMS method 3, 245 nm): RT=2.43 min, purity 73.7%, [M+H]=331.25. 1H NMR (300 MHz, methanol-d ₄ ) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.91 ( s, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.44 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 1H), 5.77 (s, 2H), 3.88 (s, 3H).

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-benzodiazol-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 overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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, purity 100.0%, [M+H]=332.20. 1H NMR (300 MHz, methanol-d ₄ ) δ 8.86 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.44-7.35 (m, 3H), 7.14-7.06 (m , 2H), 5.51 (s, 2H), 3.87 (s, 3H).

- 72 043556

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-benzodiazol-1-carboxylate (240 mg, 0. 77 mmol) to DMF (1.0 ml) was added sodium carbonate (221 mg, 2.09 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Purification was repeated by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0^9:1:0.1 to give the desired product as an off-white solid (5 mg, 2%). LCMS method 3 (270 nm): RT=3.04 min, purity 87.4%, [M+H]=332.24. 1H NMR (300 MHz, methanol^) δ 8.13 (s, 1H), 7.96 (d, J=2.9 Hz, 1H), 7.76 (d, J=2.9 Hz, 1H) , 7.58 (dd, J=12.8, 8.6 Hz, 4H), 7.29 (dd, J=8.3, 1.4 Hz, 1H), 7.09 (d, J=8 .8 Hz, 2H), 4.73 (s, 2H), 3.86 (s, 3H).

H

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-benzodiazol-1-carboxylate (214 mg, 0.69 mmol) to DMF (1.0 ml) was added sodium carbonate (137 mg, 1.30 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 95:5^9:1. 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 (200 nm): RT=2.8 min, purity 95.2%, [M+H]=361.16. ¹ H NMR (300 MHz, methanol^) δ 8.28 (d, J=2.2 Hz, 2H), 8.21 (dd, J=7.2, 1.9 Hz, 1H), 7.75 (s, 2H), 7.37 (dd, J=8.4, 1.5 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.07-6.94 ( m, 3H), 5.52 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H).

A < JI J ^H H

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-benzodiazol-1-carboxylate (150 mg, 0.48 mmol) to DMF (1.0 ml) was added sodium carbonate (138 mg, 1.30 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH3 95:5:0^9:1:0.1. Purification was repeated by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0^9:1:0.1 to give the desired product as an off-white solid (11 mg, 7%). LCMS method 1 (200 nm): RT=4.98 min, purity 93.2%, [M+H]=361.25. 1H NMR (300 MHz, methanol-d4) δ 8.13 (s, 1H), 7.98 (dd, J=5.2, 1.8 Hz, 1H), 7.55 (d, J=8, 7 Hz, 2H), 7.37 (dd, J=7.2, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 7.09- 6.91 (m, 3H), 6.69 (dd, J=7.2, 5.2 Hz, 1H), 4.70 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H).

I oJ·., <:11 J h H

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-benzodiazol-1-carboxylate (175 mg, 0.56 mmol) to DMF (1.0 ml) was added sodium carbonate (137 mg, 1.30 mmol). The reaction mixture was stirred overnight at 80°C. By request

- 73 043556 After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Purification was repeated by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0^9:1:0.1 to give the desired product as an off-white solid (8 mg, 5%). LCMS method 3 (200 nm): RT=2.97 min, purity 87.7%, [M+H]=362.21. 1H NMR (300 MHz, methanol-d4) δ 8.14 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H ), 7.65-7.44 (m, 2H), 7.377.20 (m, 3H), 7.09 (d, J=8.2 Hz, 1H), 4.73 (s, 2H), 3 .89 (s, 3H), 3.85 (s, 3H).

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)-1H1,3-benzodiazol-1-carboxylate (202 mg, 0.65 mmol) sodium carbonate (186 mg, 1.75 mmol) was added to DMF (1.0 mL). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Purification was repeated by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0^9:1:0.1 to give the desired product as an off-white solid (8 mg, 4%). LCMS method 1 (200 nm): RT=3.04 min, purity 96.1%, [M+H]=319.23. 1H NMR (300 MHz, 1H NMR (300 MHz) δ 8.20 (s, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.77-7.51 (m, 4H) , 7.30 (t, J=8.6 Hz, 3H), 7.23-7.01 (m, 2H), 4.53 (s, 2H).

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)-1H1,3-benzodiazol-1-carboxylate (128 mg, 0.41 mmol) sodium carbonate (118 mg, 1.12 mmol) was added to DMF (0.7 ml). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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. Re-purification was carried out by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0.1, to obtain the desired product as a white solid (7.7 mg, 4.95%). LCMS method 1 (200 nm): RT=5.04 min, purity 97.1%, [M+H]=319.23. 1H NMR (300 MHz, methanol-d4) δ 8.09 (s, 1H), 8.00 (dd, J=5.2, 1.8 Hz, 1H), 7.58-7.41 (m, 4H), 7.34 (dd, J=7.2, 1.8 Hz, 1H), 7.25-7.14 (m, 3H), 6.70 (dd, J=7.2, 5, 2 Hz, 1H), 4.69 (s, 2H).

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)-1H1,3-benzodiazol-1-carboxylate (214 mg, 0.69 mmol) sodium carbonate (137 mg, 1.30 mmol) was added to DMF (1.0 mL). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH/NH ₃ 95:5:0^9:1:0.1. Purification was repeated by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0^9:1:0.1 to give the desired product as an off-white solid (3 mg, 2%). LCMS method 1 (202 nm): RT=3.08 min, purity 95.4%, [M+H]=320.22. 1H NMR (300 MHz, methanol^) δ 8.13 (s, 1H), 8.00 (d, J=2.8 Hz, 1H), 7.79 (d, J=2.8 Hz, 1H) , 7.70 (dd, J=8.8, 5.4 Hz, 2H), 7.62-7.51 (m, 2H), 7.33-7.23 (m, 3H), 4.73 (s, 2H).

- 74 043556

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-1,3benzodiazole-1-carboxylate (132 mg, 0.42 mmol) in DMF (1.0 ml) sodium carbonate (122 mg, 1.15 mmol) was added. The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^96:4. Re-purification was carried out by preparative TLC, eluting with DCM/MeOH/NH ₃ 95:5:0.1, to obtain the desired product as a white solid (25 mg, 16.7%). LCMS method 2 (205 nm): RT=4.99 min, purity 99.6%, [M+H]=392.26. 1H NMR (300 MHz, methanol-d4) δ 8.13 (s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.47-7.33 (m, 4H), 7 .27 (dd, J=8.5, 1.5 Hz, 1H), 7.17-7.02 (m, 7H), 6.71 (ddd, J=7.8, 6.2, 1, 2 Hz, 2H), 4.48 (s, 2H).

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) sodium carbonate (119 mg, 1.12 mmol) was added to DMF (1.0 mL). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 95:5. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a white solid (4.9 mg, 3.3%). LCMS method 2 (200 nm): RT=5.17 min, purity 100%, [M+H]=398.26. 1H NMR (300 MHz, methanol^) δ 8.12 (s, 1H), 7.55 (d, J=7.9 Hz, 2H), 7.37-7.21 (m, 3H), 7, 11-6.96 (m, 4H), 6.68 (ddd, J=8.6, 5.5, 1.3 Hz, 2H), 4.44 (s, 2H), 4.34 (tt, J=8.4, 3.6 Hz, 1H), 2.06-1.75 (m, 4H), 1.66-1.28 (m, 6H).

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-1,3benzodiazole-1-carboxylate (152 mg, 0.49 mmol) in DMF (1.0 ml) sodium carbonate (140 mg, 1.32 mmol) was added. The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^98:2. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a white solid (34.4 mg, 21.9%). LCMS method 2 (200 nm): RT=4.58 min, purity 100%, [M+H]=358.25. 1H NMR (300 MHz, methanol-d4) δ 8.09 (s, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.36-7.25 (m, 2H), 7 ,20 (dd, J=8.4, 1.5 Hz, 1H), 7.10-6.89 (m, 4H), 6.66 (t, J=7.3 Hz, 2H), 4, 37 (s, 2H), 3.90 (t, J=6.5 Hz, 2H), 1.77 (dtd, J=13.8, 7.4, 6.4 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H).

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-benzodiazol-1-carboxylate (152 mg , 0.49 mmol) in DMF (1.0 ml) was added sodium carbonate (140

- 75 043556 mg, 1.32 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^99:1. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a white solid (24.3 mg, 15.5%). LCMS method 4 (200 nm): RT=2.42 min, purity 97.3%, [M+H]=358.26. ¹ H NMR (300 MHz, methanol^) δ 8.10 (s, 1H), 7.54 (d, J=7.9 Hz, 2H), 7.37-7.26 (m, 2H), 7 ,21 (dd, J=8.4, 1.5 Hz, 1H), 7.10-6.91 (m, 4H), 6.66 (t, J=7.3 Hz, 2H), 4, 57 (hept., J=12.0, 6.0 Hz, 1H), 4.39 (s, 2H), 1.31 (d, J=6.0 Hz, 6H).

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) sodium carbonate (149 mg, 1.41 mmol) was added to DMF (1.0 mL). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^97:3. Purification was repeated by preparative TLC, eluting with DCM/MeOH 9:1 to give the desired product as a white solid (40.7 mg, 25.3%). LCMS (LCMS method 4, 205 nm): RT=2.14 min, purity 98.9%, [M+H]=344.27. 1H NMR (300 MHz, DMSO-d6) δ 12.33 (d, J=11.8 Hz, 1H), 8.14 (s, 1H), 7.57-7.36 (m, 2H), 7 ,18-7.05 (m, 5H), 6.93 (t, J=7.8 Hz, 1H), 6.54-6.38 (m, 2H), 4.44 (d, J=17 .8 Hz, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.81 (s, 3H), 1.88 (s, 3H).

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) to DMF (1.0 ml) was added sodium carbonate (131 mg, 1.23 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^97:3. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a white solid (47.5 mg, 31%). LCMS (LCMS Method 4, 205 nm): RT=1.99 min, purity 97.3%, [M+H]=374.27. 1H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.14 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.10 (t, J=7.8 Hz, 2H), 6.93 (t, J=7.8 Hz, 1H), 6.79-6.71 (m, 2H), 6.47 (dd, J= 15.8, 7.8 Hz, 2H), 4.55 (s, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.79 (d, J=9.0 Hz, 6H), 1.92 (s, 3H).

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)-1H1,3-benzodiazole-1-carboxylate (156 mg, 0.50 mmol ) sodium carbonate (143 mg, 1.35 mmol) was added to DMF (1.0 mL). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^97:3. Purification was repeated by preparative TLC, eluting with DCM/MeOH 95:5 to give the desired product as a white solid (40.6 mg, 25.6%). LCMS (LCMS Method 4, 200 nm): RT=2.29 min, purity 94.2%, [M+H]=344.27. 1H NMR (300 MHz, DMSO-d6) δ 12.33 (d, J=17.3 Hz, 1H), 8.15 (d, J=4.1 Hz, 1H), 7.58 (dd, J =8.8, 7.0 Hz, 3H), 7.50-7.36 (m, 3H), 7.20-7.10 (m, 1H), 7.05 (td, J=8.3 , 6.8 Hz, 1H), 6.46-6.34 (m, 2H), 5.48 (dt, J=16.2, 6.0 Hz, 1H), 4.38 (t, J= 6.0 Hz, 2H).

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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) to DMF (1.0 ml) was added sodium carbonate (129 mg, 1.21 mmol). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^97:3. Purification was repeated by preparative TLC, eluting with DCM/MeOH 9:1 to give the desired product as a white solid (29.3 mg, 19.2%). LCMS (LCMS Method 4, 200 nm): RT=1.92 min, purity 90.1%, [M+H]=378.23. 1H NMR (300 MHz, DMSO- _d6 ) δ 12.38 (s, 1H), 8.16 (s, 1H), 7.50 (s, 2H), 7.21-6.98 (m, 3H ), 6.93-6.85 (m, 2H), 6.45-6.37 (m, 2H), 5.27 (s, 1H), 4.39 (d, J=6.0 Hz, 2H), 3.80 (d, J=7.1 Hz, 6H).

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)-1H1,3-benzodiazol-1-carboxylate (168 mg, 0.54 mmol) sodium carbonate (155 mg, 1.46 mmol) was added to DMF (1.0 mL). The reaction mixture was stirred overnight at 80°C. After this time, the reaction mixture was cooled to room temperature 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 DCM/MeOH 1:0^97:3. Purification was repeated by preparative TLC, eluting with DCM/MeOH 9:1 to give the desired product as a white solid (29.3 mg, 19.2%). LCMS (LCMS Method 4, 205 nm): RT=2.12 min, purity 96.6%, [M+H]=336.23. ^1H NMR (300 MHz, DMSO- _d6 ) δ 12.32 (s, 1H), 8.15 (s, 1H), 7.55 (s, 1H), 7.45-7.32 (m, 5H), 7.15 (s, 1H), 7.10-6.99 (m, 1H), 6.46-6.36 (m, 2H), 5.37 (s, 1H), 4.39 (d, J=6.0 Hz, 2H).

Synthesis method Q

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. 4-Fluorophenylsulfonyl chloride (0.21 g, 1.08 mmol) was then 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 the pyridine was evaporated in vacuo. The crude product was purified by column chromatography using MeOH in DCM (0-3%) as eluent.

Fractions containing the title compound were combined and concentrated (55 mg, 19%). LCMS method 1 (200 nm): RT=5.81 min, purity 93.2%, [M+ACN]=347.27. 1H NMR (300 MHz, DMSO- _d6 ) δ 8.17 (s, 1H), 8.04-7.66 (m, 2H), 7.56-7.31 (m, 4H), 7.05 (d, J=8.4 Hz, 1H), 4.10 (s, 2H).

Synthesis method R

[(1H-1,3-Benzodiazol-5-yl)methyl] [(4-fluorophenyl)(methyl)oxo-λ-sulfanylidene] amine (Q1).

(4-Fluorophenyl)(imino)methyl-λ-sulfanone (250 mg, 1.5 mmol) and potassium hydroxide (234 mg, 2.18 mmol) in DMSO (13.0 ml) were stirred at 50°C for 1 After this time, the reaction mixture was cooled to room temperature and tert-butyl 5-(bromomethyl)-1H-1,3benzodiazole-1-carboxylate (650 mg, 2.10 mmol) was added. The reaction mixture was stirred overnight and after this time water (50 ml) was added and extracted with DCM (5x30 ml). The combined organic layers were dried over sodium sulfate, filtered, evaporated to give a solution of the crude product in DMSO, which was purified by preparative HPLC to give the title compound as a colorless oil (26 mg, 5%). LCMS method 1 (200 nm): RT=5.72 min, purity 96.3%, [M+H]=304.15. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.03-7.91 (m, 2H), 7.54 (s, 1H), 7.51-7.42 ( m, 3H), 7.12 (dd, J=8.3, 1.6 Hz, 1H), 4.15 (d, J=14.4 Hz, 1H), 3.98 (d, J=14 .5 Hz, 1H), 3.25 (s, 3H).

Analytical methods of NMR.

1H NMR spectra (300 MHz) were recorded on a BRUKER FOURIER 300. Solvent was DMSO-D6 unless otherwise stated. Chemical shifts are expressed in parts per million (ppm) downfield from the tetramethylsilane signal. The splitting patterns are designated as follows: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), and br (broadband).

HPLC-MS.

LCMS method 1.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Gemini-NX 3 µm C18 (4.6x50 mm), 110 A, column number OOV-4453-EO, internal column number 002.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 14 min;

elution: gradient.

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 95 5 0.5 2.0 95 5 0.5 9.5 20 80 0.5 10.5 20 80 0.5 12.0 95 5 0.5 14.0 95 5 0.5

0.1 v/v% aqueous solution of formic acid.

Mobile phase A:

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 2.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Gemini-NX 3 µm C18 (4.6x50 mm), 110 A, column number OOV-4453-EO, internal column number 002.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 12 min;

elution: gradient.

- 78 043556

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 80 20 0.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 80 20 0.5 12.0 80 20 0.5

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 3.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Kinetex® 2.6 µm XB-S18 (4.6x50 mm), 110 A, column number OOV-4496-E0, internal column number 019.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 1.0 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 7 min;

elution: gradient.______________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 95 5 1.0 1.0 95 5 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 5 1.0 7.0 95 5 1.0

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 4.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Kinetex® 2.6 µm XB-S18 (4.6x50 mm), 110 A, column number 00B-4496-E0, internal column number 019.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 1.0 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 6 min;

elution: gradient.

- 79 043556

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 80 20 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 80 20 1.0 6.0 80 20 1.0

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 5.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Kinetex® 2.6 µm XB-S18 (4.6x50 mm), 110 A, column number OOV-4496-E0, internal column number 019.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 1.0 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 7 min;

elution: gradient.

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

HPLC method 6.

Device: HPLC-MERCK CHROMASTER with gradient pump and DAD detector.

Column: XBridge C18 3.5 µm (4.6x150 mm), Column No. 186003034, Column ID 009.

Reagents:

methanol for HPLC with purity for Ultra Gradient HPLC, Baker boric acid >99.5%, Sigma-Aldrich;

analytical grade sodium hydroxide, Eurochem BGD purified water for HPLC.

HPLC terms:

wavelength: 210.0 nm ±4.0 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 5 µl;

analysis duration: 30 min.

elution: gradient._______________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 50 50 0.5 22.0 5 95 0.5 25.0 5 95 0.5 27.0 50 50 0.5 30.0 50 50 0.5

- 80 043556

Mobile phase A.

Borate buffer c=5 mM, pH 9.6.

Preparation: 0.618 g of boric acid, placed in a 2 liter volumetric flask, was dissolved in 1.5 liters of purified water. The pH was adjusted to 9.6 using 1 M NaOH solution (6 ml). Finally, the solution was diluted to the mark using purified water.

Mobile phase B.

l MeOH with the same amount of 1 M NaOH as in phase A (3 ml).

Syringe wash solution: acetonitrile.

LCMS method 7.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Gemini-NX 3 µm Cl8 (4.6x50 mm), PO A, column number OOV-4453-EO, internal column number 002.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 12 min;

elution: gradient.______________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 60 40 0.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 60 40 0.5 12.0 60 40 0.5

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 8.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Gemini-NX 3 µm Cl8 (4.6x50 mm), PO A, column number OOV-4453-EO, internal column number 002.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 28 min;

elution: gradient.______________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 95 5 0.5 4.0 95 5 0.5 19.0 20 80 0.5 21.0 20 80 0.5 24.0 95 5 0.5 28.0 95 5 0.5

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

-81 043556

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 9.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Kinetex XB-C18 2.6 µm (4.6x50 mm), 100 A, column no. 00B-4496-E0, internal column no. 019.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 1.0 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 7 min;

elution: gradient.________________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 100 0 1.0 1.0 95 5 1.0 4.0 80 20 1.0 4.75 20 80 1.0 5.25 20 80 1.0 6.0 95 5 1.0 7.0 100 0 1.0

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 10.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Gemini-NX 3 µm C18 (4.6x50 mm), 110 A, column number OOV-4453-EO, internal column number 002.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 12 min;

elution: gradient.________________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 70 thirty 0.5 6.7 20 80 0.5 7.5 20 80 0.5 7.8 5 95 0.5 9.5 5 95 0.5 10.0 70 thirty 0.5 12.0 70 thirty 0.5

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

- 82 043556

LCMS method 11.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Kinetex® 2.6 µm XB-S18 (4.6x50 mm), 110 A, column number 00B-4496-E0, internal column number 019.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 1.0 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 6 min;

elution: gradient.__________________________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 thirty 70 1.0 3.35 20 80 1.0 3.75 20 80 1.0 3.9 5 95 1.0 4.75 5 95 1.0 5.0 thirty 70 1.0 6.0 thirty 70 1.0

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

LCMS method 12.

Instrument: Dionex Ultimate 3000 for UHPLC with DAD/MSQ Plus Thermo Scientific detector.

Column: Gemini-NX 3 µm C18 (4.6x50 mm), 110 A, column number OOV-4453-EO, internal column number 002.

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

Milli-Q qualified water for LCMS.

HPLC terms:

wavelength range: (190-340) nm ±4 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 2.0 µl;

analysis duration: 14 min;

elution: gradient.__________________________________________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.0 100 0 0.5 2.0 95 5 0.5 8.0 80 20 0.5 9.5 20 80 0.5 10.5 20 80 0.5 12.0 95 5 0.5 14.0 100 0 0.5

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Syringe wash solution: 20% MeOH.

MS Terms:

mass number range: 100-1000 mass/charge;

ionization: variable;

scanning speed: 12000 amu/s.

UPLC-MS.

Device: Shimadzu LCMS-2020 single quadrupole mass spectrometer for liquid chromatography.

Column: Acquity UPLC 1.8 µm C18 (2.1x50 mm), 100 A, Column No. 186003532, Internal Column No. Pur CC-MS001.

- 83 043556

Reagents:

formic acid >98%, Sigma-Aldrich;

acetonitrile for HPLC UV/gradient purity, Baker;

purified water for HPLC.

UPLC terms:

wavelength: 254 and 280 nm;

flow rate: 0.5 ml/min;

column temperature: 25°C;

automatic dispenser temperature: 20°C;

injection volume: 3 µl;

analysis duration: 6.0 min;

elution: gradient.___________________________

Time [min.] Mobile phase A [%] Mobile phase B [%] Flow [ml/min.] 0.01 95 5 0.5 4.00 5 95 0.5 5.00 5 95 0.5 5.20 95 5 0.5 6.00 95 5 0.5

Mobile phase A: 0.1% v/v aqueous formic acid solution.

Mobile phase B: 0.1% v/v acetonitrile formic acid solution.

Rinse solution using a syringe:

100% acetonitrile.

MS Terms:

mass number range: 50-1000 mass/charge;

ionization: variable;

scanning speed: 7500 amu/s.

Activity screening.

Glutaminyl cyclase, determination by analysis of IC ₅₀ values and calculation of Ki values.

10 mM stock solutions of the compounds were prepared in DMSO. To determine IC _50, stock solutions of compounds were subjected to serial dilution (1:3) in DMSO.

All measurements were performed using an EnSpire Perkin Elmer multimode reader using glutaminyl-7-amino-4-methylcoumarin (H-Gln-AMC) as substrate and recombinant pyroglutamyl aminopeptidase (pGAP) as an auxiliary enzyme. Reactions were performed at ambient temperature in black 96-well half-area microplates. 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 ). In 10 minutes. preincubation at ambient temperature, the enzymatic reaction was initiated by adding 50 μl of Gln-AMC-substrate/pGAP mixture in assay buffer. The final substrate concentrations were 50 and 200 μM when measured at pH 8.0 or 6.0, respectively. Fluorogenic AMC release 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 IC ₅₀ values were performed using GraphPad Prism software. _IC50 values were calculated from normalized data (QC activity without inhibitor=100%) using curvilinear regression according to a 4-parameter logistic equation.

Ki values were calculated according to the following formula:

Ki=IC50/(1+[S]/Km), where [S] reflects the substrate concentration in the assay (200 µM at pH 6.0, 50 µM at pH 8.0) and Km is the corresponding Michaelis-Menten constant (390 µM at pH 6.0, 62 µM at pH 8.0).

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 and the signals were recorded and filtered using a LeCroy 9350M digital storage oscilloscope attached to a personal computer . Samples (5 μL) were mixed with equal volumes of matrix solution. The matrix used was a DHAP/DAHC solution prepared by dissolving 30 mg 2',6'dihydroxyacetophenone (Aldrich) and 44 mg diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile/0.1% TFA in water (1/1, v/v .). A small volume (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 Unit) to ensure rapid and uniform crystallization of the sample.

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Claims (7)

For long-term testing of Glu ¹ -cyclization, Αβ-derived peptides were incubated in 100 μl of 0.1 M sodium acetate buffer, pH 5.2, or 0.1 M Bis-Tris buffer, pH 6.5, at 30°C. Peptides were used at concentrations of 0.5 mM [Av(3-11)a] or 0.15 mM [Av(3-21)a], and 0.2 U. QC was added for the entire 24 hours. For Av(3-21)a, assays included 1% DMSO. At various time points, samples were removed from the assay tube, peptides were extracted using ZipTips (Millipore) according to the manufacturer's recommendations, mixed with matrix solution (1:1 v/v), and mass spectra were recorded sequentially. Negative controls either did not contain QC or contained a heat-inactivated enzyme. For inhibitor studies, the sample composition was the same as described above, except for the addition of an inhibitory compound (5 mM or 2 mM of the test compound of the present invention). The compounds and combinations of the present invention may have the advantage that they are, for example, more effective, more selective, have fewer side effects, have better composition and stability properties, have better pharmacokinetic properties, are more bioavailable, are able to cross the blood-brain barrier and are more effective in the mammalian brain, are more compatible or effective in combination with other drugs, or are more easily synthesized than other prior art compounds. Throughout the specification and claims that follow, unless the context otherwise requires, the word contain and variants such as contains and containing are to be understood to include, but not exclude, any specified integer, step, group of integers, or groups of steps. another integer, stage, group of integers or groups of stages. All patents and patent applications mentioned in the specification of the present invention are hereby incorporated by reference in their entirety. The present invention covers all combinations of preferred and more preferred groups and embodiments of the groups mentioned above. CLAIM 1. A compound selected from the group consisting of compounds of formulas (IIa), (IIIa), (IVa), (Va) and (XVa) where Z is selected from CH and N; X1 is selected from methyl, N, O, S; n is 1 or 2; Y1-Y4 and Y ₆ , Y ₇ and Y ₁₀ are independently selected from CH and N; Y ₅ represents C; Y 8 and Y9 are independently selected from C and N; R5 is selected from halogen, C _1-12 alkyl and O-C _1-12 alkyl and R ₆ is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl; (Sha), where X1 is selected from methyl, N, O, S; n is 1 or 2; Y 1-Y4 and Y ₆ , Y ₇ and Y ₁₀ are independently selected from CH and N; Y ₅ represents C; Y ₈ and Y ₉ are independently selected from C and N; R5 is selected from halogen, C _1-12 alkyl and O-C _1-12 alkyl and R ₆ is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl; - 85 043556 where Z is selected from CH and N; o equals 0 or 1; p equals 0 or 1; Y ₁ -Y ₄ and Y ₆ , Y7 and Y ₁₀ are independently selected from CH and N; Y ₅ represents C; Y ₈ and Y ₉ are independently selected from C and N; R ₅ is selected from halogen, C _1-12 alkyl, O-C _1-12 alkyl and O-phenyl and R6 is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl; where o equals 0 or 1; p equals 0 or 1; Y ₁ -Y ₄ u Y ₆ , Y7 and Y ₁₀ are independently selected from CH and N; Y 5 represents C; Y ₈ and Y ₉ are independently selected from C and N; R ₅ is selected from halogen, C _1-12 alkyl, O-C _1-12 alkyl and O-phenyl and R6 is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl; And where Y _r Y ₄ and Y ₆ , Y7 and Y _{lo are} independently selected from CH and N; Y ₅ represents C; Y 8 and Y9 are independently selected from C and N; Y 4 is optionally substituted with C _1-12 alkyl or halogen; R ₅ is selected from halogen, C _1-12 alkyl, O-C _1-12 alkyl, O-phenyl and O-C _3-10 cycloalkyl and R6 is selected from hydrogen, C _1-12 alkyl and O-C _1-12 alkyl. 2. A compound according to claim 1, which is a compound selected from 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; - 86 043556 4'-φτορ-Ν-[4-(4-mestil-411 -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; M-[2-(4-methoxyphenyl)phenyl]-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline; 2-(4-methoxyphenyl)-I-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine; 2-(4-fluorophenyl)-I-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-3-amine; 4-(4-methyl-4H-1,2,4-triazol-3-yl)-I-[2-(4-phenoxyphenyl)phenyl]aniline; 3-(3,4-dimethoxyphenyl)-I-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]pyridin-4-amine; N-[(1Η-1,3-benzodiazol-5-yl)methyl]-4'-fluoro-[1,1'-biphenyl]-2-amine; N-[(1Η-1,3-benzodiazol-5-yl)methyl]-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)aniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)pyridin-3-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyridin-4-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-4-(4-methoxyphenyl)pyridin-3-amine; M-(1H-1,3-benzodiazol-5-ylmethyl)-5-(4-methoxyphenyl)pyrimidin-4-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(4-methoxyphenyl)pyrazin-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dime hundred xyphenyl)pyridin-4-amine; N-(1H-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dime hundred xyphenyl)pyridin-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(3,4-dime hundred xyphenyl)pyrazin-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-fluorophenyl)pyridin-3-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyridin-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-(4-fluorophenyl)pyr azin-2-amine; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-phenoxyphenyl)aniline; M-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(cyclohexyloxy)phenyl]aniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-propoxyphenyl)aniline; M-(1H-1,3-benzodiazol-5-ylmethyl)-2-[4-(propan-2-yloxy)phenyl]aniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-methoxyphenyl)-3-methylaniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-methylaniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(4-chlorophenyl)-3-fluoroaniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-3-fluoroaniline; N-(1Η-1,3-benzodiazol-5-ylmethyl)-3-fluoro-2-(4-fluorophenyl)aniline; or a pharmaceutically acceptable salt or solvate thereof, including all tautomers and stereoisomers. 3. Use of a compound according to claim 1 or 2 as a medicinal product. 4. A pharmaceutical composition containing a compound according to claim 1 or 2 in combination with one or more therapeutically acceptable diluents or carriers. 5. Use of a compound according to claim 1 or 2 in the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, familial British dementia and familial Danish dementia. 6. Use of the pharmaceutical composition according to claim 4 in the treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, familial British dementia and familial Danish dementia. 7. A method of treating or preventing a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, familial British dementia and familial Danish dementia, which includes administering to a subject an effective amount of a compound at π. 1 or 2 or the pharmaceutical composition according to claim 4. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2