US009181233B2

(12) United States Patent (10) Patent No.: US 9,181.233 B2 Heiser et al. (45) Date of Patent: Nov. 10, 2015

2007/0191366 A1* 8, 2007 Hoffmann et al...... 514,235.5

(54) INHIBITORS OF GLUTAMINYLCYCLASE 2008/0214620 A1* 9, 2008 Heiser et al...... 514,338 (75) Inventors: Ulrich Heiser, Halle/Saale (DE); Daniel 2010.0040575 A1 2/2010 Hoffmann et al...... 424/85.2 Ramsbeck, Halle/Saale (DE); Torsten 2010 OO69381 A1 3, 2010 Itoh Hoffmann, Halle/Saale (DE); Livia FOREIGN PATENT DOCUMENTS Boehme, Halle/Saale (DE); Hans-Ulrich Demuth, Halle/Saale (DE) EP 1375486 1, 2004 WO WO 2004/005.283 1, 2004 (73) Assignee: PROBIODRUGAG. Halle/Saale (DE) WO WO 2004/O14881 2, 2004 WO WO 2004/031177 4/2004 WO WO2005/121132 12/2005 (*) Notice: Subject to any disclaimer, the term of this WO WO 2007/OO3961 1, 2007 patent is extended or adjusted under 35 WO WO 2008/O16123 2, 2008 U.S.C. 154(b) by 224 days. WO WO 2008/042571 4/2008 WO WO2008/065141 6, 2008 (21) Appl. No.: 13/040,159 WO WO 2008.154241 12/2008 WO WO 2008,157 273 12/2008 WO WO 2009/051705 4/2009 (22) Filed: Mar. 3, 2011 WO WO 2009, 111442 9, 2009 (65) Prior Publication Data OTHER PUBLICATIONS US 2011 FO224259 A1 Sep. 15, 2011 International Application Published as WO2005/121132 on Jun. 5, 2008, abstract in English only. Related U.S. Application Data Hess et al., 1-(5-Carboxy- and 5-carbamoylindol-lyl)propane-2- ones as inhibitors of human cytosolic phospholipase A2a: (60) Provisional application No. 61/309,951, filed on Mar. Bioisosteric replacement of the carboxylic acid and carboxamide 3, 2010. moiety, Bioorganic & Medicinal Chemistry, 2007, pp. 2883-2891, vol. 15, No. 8. Sawhney et al., Benzothiazole Derivatives: Part I—Synthesis of 2-(4- (51) Int. Cl. Thiazolyl)- & 6-(4- Thiazolyl)-benzothiazoles & Their Derivatives CO7D 235/04 (2006.01) as Potential Anthelmintics, Indian J. Of Chemistry, 1970, pp. 882 A6 IK3I/4I84 (2006.01) 884, vol. 8, No. 10. CO7D 417/04 (2006.01) Registry (STN) online). Apr. 19, 2002 (search date: Nov. 28, 2014) CO7D 403/04 (2006.01) CAS No. 406.189-44-4, 1 page. CO7D 413/04 (2006.01) (52) U.S. Cl. * cited by examiner CPC ...... C07D 417/04 (2013.01); A61 K3I/4184 (2013.01); C07D 235/04 (2013.01); C07D Primary Examiner — Theodore R West 403/04 (2013.01); C07D 413/04 (2013.01) (74) Attorney, Agent, or Firm — Dentons US LLP (58) Field of Classification Search None (57) ABSTRACT See application file for complete search history. The invention relates to novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC cata (56) References Cited lyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu) under U.S. PATENT DOCUMENTS liberation of ammonia and the intramolecular cyclization of 4,746,669 A 5, 1988 Caldwell et al. N-terminal glutamate residues into pyroglutamic acid under 7,371,871 B2 * 5/2008 Schilling et al...... 548,346.1 liberation of water. 7,732,162 B2 * 6/2010 Hoffman et al...... 435/18 2006/0293334 A1* 12/2006 Fuji et al...... 514,249 17 Claims, No Drawings US 9, 181,233 B2 1. 2 INHIBITORS OF GLUTAMINYL. CYCLASE pronounced sequence homology to bacterial aminopepti dases (Bateman, R. C. et al. 2001 Biochemistry 40, 11246 CROSS-REFERENCE TO RELATED 11250), leading to the conclusion that the QCs from plants APPLICATIONS and animals have different evolutionary origins. Recently, it was shown that recombinant human QC as well This application claims priority to U.S. Provisional Appli as QC-activity from brain extracts catalyze both, the N-ter cation Ser. No. 61/309,951, filed on Mar. 3, 2010, which is minal glutaminyl as well as glutamate cyclization. Most strik incorporated herein by reference in its entirety. ing is the finding, that cyclase-catalyzed Glu-conversion is favored around pH 6.0 while Gln-conversion to pGlu-deriva MATERIAL INCORPORATED-BY-REFERENCE 10 tives occurs with a pH-optimum of around 8.0. Since the formation of pClu-AB-related peptides can be suppressed by The Sequence Listing, which is a part of the present dis inhibition of recombinant human QC and QC-activity from closure, includes a computer readable form comprising pig pituitary extracts, the enzyme QC is a target in drug nucleotide and/or amino acid sequences of the present inven tion. The Subject matter of the Sequence Listing is incorpo 15 development for treatment of Alzheimer's disease. Inhibitors of QC are described in WO 2004/098625, WO rated herein by reference in its entirety. 2004/098591, WO 2005/039548, WO 2005/075436, WO FIELD OF THE INVENTION 2008/055945, WO 2008/055947, WO 2008/055950 and WO2008/0651.41. The invention relates to novel heterocyclic derivatives as EP 02011 349.4 discloses polynucleotides encoding insect inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC cata glutaminyl cyclase, as well as polypeptides encoded thereby lyzes the intramolecular cyclization of N-terminal glutamine and their use in methods of Screening for agents that reduce residues into pyroglutamic acid (5-oxo-prolyl, pGlu) under glutaminyl cyclase activity. Such agents are useful as pesti liberation of ammonia and the intramolecular cyclization of cides. N-terminal glutamate residues into pyroglutamic acid under 25 liberation of water. DEFINITIONS BACKGROUND OF THE INVENTION The terms “k, or “K” and “K” are binding constants, which describe the binding of an inhibitor to and the subse Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the 30 quent release from an enzyme. Another measure is the “ICso intramolecular cyclization of N-terminal glutamine residues value, which reflects the inhibitor concentration, which at a into pyroglutamic acid (pGlu) liberating ammonia. A QC given substrate concentration results in 50% enzyme activity. was first isolated by Messer from the latex of the tropical plant The term “DP IV-inhibitor” or “dipeptidyl peptidase IV Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). inhibitor' is generally known to a person skilled in the art and 24 years later, a corresponding enzymatic activity was dis 35 means enzyme inhibitors, which inhibit the catalytic activity covered in animal pituitary (Busby, W. H. J. etal. 1987J Biol of DP IV or DPIV-like enzymes. Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 “DP IV-activity” is defined as the catalytic activity of Proc Natl AcadSci USA 84,3628-3632). For the mammalian dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. QC, the conversion of Gln into pGlu by QC could be shown These enzymes are post-proline (to a lesser extent post-ala for the precursors of TRH and GnRH (Busby, W. H. J. et al. 40 nine, post-serine or post-glycine) cleaving serine proteases 1987J Biol Chem 262,8532-8536; Fischer, W. H. and Spiess, found in various tissues of the body of a mammal including J. 1987 Proc Natl AcadSci USA 84,3628-3632). In addition, kidney, liver, and intestine, where they remove dipeptides initial localization experiments of QC revealed a co-localiza from the N-terminus of biologically active peptides with a tion with its putative products of catalysis in bovine pituitary, high specificity when proline oralanine form the residues that further improving the Suggested function in peptide hormone 45 are adjacent to the N-terminal amino acid in their sequence. synthesis (Bockers, T. M. et al. 1995 J Neuroendocrinol 7, The term “PEP-inhibitor” or “prolyl endopeptidase inhibi 445-453). In contrast, the physiological function of the plant tor” is generally known to a person skilled in the art and QC is less clear. In the case of the enzyme from C. papaya, a means enzyme inhibitors, which inhibit the catalytic activity role in the plant defense against pathogenic microorganisms of prolyl endopeptidase (PEP prolyl oligopeptidase, POP). was suggested (El Moussaoui, A. etal. 2001 Cell Mol LifeSci 50 “PEP-activity” is defined as the catalytic activity of an 58, 556-570). Putative QCs from other plants were identified endoprotease that is capable to hydrolyze post proline bonds by sequence comparisons recently (Dahl, S. W. et al. 2000 in peptides or proteins where the proline is in amino acid Protein Expr Purif 20, 27-36). The physiological function of position 3 or higher counted from the N-terminus of a peptide these enzymes, however, is still ambiguous. or protein Substrate. The QCs known from plants and animals show a strict 55 The term “QC as used herein comprises glutaminyl specificity for L-Glutamine in the N-terminal position of the cyclase (QC) and QC-like enzymes. QC and QC-like substrates and their kinetic behavior was found to obey the enzymes have identical or similar enzymatic activity, further Michaelis-Menten equation (Pohl, T. et al. 1991 Proc Natl defined as QC activity. In this regard, QC-like enzymes can Acad Sci USA 88, 10059-10063: Consalvo, A. P. et al. 1988 fundamentally differ in their molecular structure from QC. Anal Biochem 175, 131-138; Gololobov, M.Y. et al. 1996 60 Examples of QC-like enzymes are the glutaminyl-peptide Biol Chem Hoppe Seyler 377,395-398). A comparison of the cyclotransferase-like proteins (QPCTLs) from human (Gen primary structures of the QCs from C. papaya and that of the Bank NM 017659), mouse (GenBank BC058181), Macaca highly conserved QC from mammals, however, did not reveal fascicularis (GenBank AB168255), Macaca mulatta (Gen any sequence homology (Dahl, S.W. et al. 2000 Protein Expr Bank XM 001110995), Purif 20, 27-36). Whereas the plant QCs appear to belong to 65 Canis familiaris (GenBank XM 541552), Rattus norvegi a new enzyme family (Dahl, S. W. et al. 2000 Protein Expr cus (GenBank XM 001066591), Mus musculus (GenBank Purif 20, 27-36), the mammalian QCs were found to have a BC058181) and Bos taurus (GenBank BTO26254). US 9, 181,233 B2 3 4 The term “QC activity” as used herein is defined as preferably of 1 uMorless, even more preferably of 0.1 uMor intramolecular cyclization of N-terminal glutamine residues less or 0.01 uM or less, or most preferably 0.001 uM or less. into pyroglutamic acid (p.Glu) or of N-terminal L-homo- Indeed, inhibitors with K values in the lower micromolar, glutamine or L-B-homoglutamine to a cyclic pyro-homo- preferably the nanomolar and even more preferably the pico glutamine derivative under liberation of ammonia. Seethere- 5 molar range are contemplated. Thus, while the active agents fore schemes 1 and 2. are described herein, for convenience, as “QC inhibitors, it will be understood that Such nomenclature is not intending to limit the subject of the invention to a particular mechanism of Scheme 1: Cyclization of glutamine by QC action. peptide peptide " Molecular Weight of QC Inhibitors h In general, the QC inhibitors of the subject method or NH, HN O medical use will be small molecules, e.g., with molecular HN weights of 500 g/mole or less, 400 g/mole or less, preferably O of 350 g/mole or less, and even more preferably of 300 g/mole QC NH or less and even of 250 g/mole or less. The term “subject' as used herein, refers to an animal, preferably a mammal, most preferably a human, who has O NH2 O been the object of treatment, observation or experiment. The term “therapeutically effective amount” as used herein, means that amount of active compound or pharma ceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a Scheme 2: Cyclization of L-homoglutamine by QC researcher, Veterinarian, medical doctor or other clinician, peptide as which includes alleviation of the symptoms of the disease or peptide disorder being treated. As used herein, the term “pharmaceutically acceptable' HN NH HN O embraces both human and veterinary use: For example the O term “pharmaceutically acceptable' embraces a veterinarily so acceptable compound or a compound acceptable in human medicine and health care. N Throughout the description and the claims the expression N “alkyl, unless specifically limited, denotes a C- alkyl O group, Suitably a Cls alkyl group, e.g. Calkyl group, e.g. C. alkyl group. Alkyl groups may be straight chain or NH2 35 branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyland isopropyl), butyl (e.g. n-butyl, The term “EC as used herein comprises the activity of QC iso-butyl, sec-butyl and tert-butyl), pentyl (e.g. n-pentyl), and QC-like enzymes as glutamate cyclase (EC), further hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl) and octyl (e.g. defined as EC activity. 40 n-octyl). The expression “alk', for example in the expressions The term “EC activity” as used herein is defined as “alkoxy”, “haloalkyl and “thioalkyl should be interpreted intramolecular cyclization of N-terminal glutamate residues in accordance with the definition of “alkyl. Exemplary into pyroglutamic acid (p.Glu) by QC. See therefore scheme alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-pro 3. poxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hex

Scheme 3: N-terminal cyclization of uncharged glutamyl peptides by QC (EC) pie pils pils pils NH NH HN HO HN H e HN O 2 O 3 O (~5.0 < pH < 7.0) 2 O ) (~7.0 < pH < 8.0) QC/EC GE) QC/EC NH2 NH

O O O OH H2N Oe O O

The term “QC-inhibitor”“glutaminyl cyclase inhibitor” is oxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy generally known to a person skilled in the art and means (e.g. n-octoxy). Exemplary thioalkyl groups include meth enzyme inhibitors, which inhibit the catalytic activity of ylthio-. Exemplary haloalkyl groups include fluoroalkyl e.g. glutaminyl cyclase (QC) or its glutamylcyclase (EC) activity. CF. Potency of QC Inhibition The expression “alkenyl', unless specifically limited, In light of the correlation with QC inhibition, in preferred 65 denotes a C- alkenyl group, Suitably a C- alkenyl group, embodiments, the Subject method and medical use utilize an e.g. a Calkenyl group, which contains at least one double agent with an ICs for QC inhibition of 10 uM or less, more bond at any desired location and which does not contain any US 9, 181,233 B2 5 6 triple bonds. Alkenyl groups may be straight chain or 4, Suitably 1, 2 or 3) ring atoms are replaced by heteroatoms branched. Exemplary alkenyl groups including one double selected from N, S and O, or else a 5-membered aromatic ring bond include propenyl and butenyl. Exemplary alkenyl containing one or more (e.g. 1, 2, 3, or 4, Suitably 1, 2 or 3) groups including two double bonds include pentadienyl, e.g. ring atoms selected from N, S and O. Exemplary monocyclic (1E.3E)-pentadienyl. heteroaryl groups having one heteroatom include: five mem The expression “alkynyl', unless specifically limited, bered rings (e.g. pyrrole, furan, thiophene); and six mem denotes a C- alkynyl group, Suitably a C- alkynyl group. bered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl e.g. a C- alkynyl group, which contains at least one triple and pyridin-4-yl). Exemplary monocyclic heteroaryl groups bond at any desired location and may or may not also contain having two heteroatoms include: five membered rings (e.g. one or more double bonds. Alkynyl groups may be straight 10 pyrazole, oxazole, isoxazole, thiazole, isothiazole, imida chain or branched. Exemplary alkynyl groups include propy Zole, such as imidazol-1-yl, imidazol-2-ylimidazol-4-yl); six nyl and butynyl. membered rings (e.g. pyridazine, pyrimidine, pyrazine). The expression “alkylene' denotes a chain of formula Exemplary monocyclic heteroaryl groups having three het —(CH), wherein n is an integer e.g. 2-5, unless specifi eroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exem cally limited. 15 plary monocyclic heteroaryl groups having four heteroatoms The expression “cycloalkyl, unless specifically limited, include tetrazole. Exemplary bicyclic heteroaryl groups denotes a Co cycloalkyl group (i.e. 3 to 10 ring carbon include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, atoms), more Suitably a C-8 cycloalkyl group, e.g. a C quinoline, isoquinoline, indazole, benzimidazole, benzthiaz cycloalkyl group. Exemplary cycloalkyl groups include ole, quinazoline and purine. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep The expression "-alkylaryl', unless specifically limited, tyl and cyclooctyl. A most Suitable number of ring carbon denotes an aryl residue which is connected via an alkylene atoms is three to six. moiety e.g. a Calkylene moiety. The expression “cycloalkenyl', unless specifically limited, The expression "-alkylheteroaryl', unless specifically lim denotes a Cso cycloalkenyl group (i.e. 5 to 10 ring carbon ited, denotes a heteroaryl residue which is connected via an atoms), more Suitably a Css cycloalkenyl group e.g. a Cs 25 cycloalkenyl group. Exemplary cycloalkenyl groups include alkylene moiety e.g. a Calkylene moiety. cyclopropenyl, cyclohexenyl, cycloheptenyl and cycloocte The term “halogen' or “halo' comprises fluorine (F), chlo nyl. A most suitable number of ring carbonatoms is five to six. rine (Cl) and bromine (Br). The expression “carbocyclyl, unless specifically limited, The term “amino” refers to the group —NH. denotes any ring system in which all the ring atoms are carbon 30 The term “phenyl substituted by phenyl refers to biphe and which contains between three and twelve ring carbon nyl. atoms, suitably between three and ten carbonatoms and more The term “uvvu ' denotes a single bond where the stere suitably between three and eight carbon atoms. Carbocyclyl ochemistry is not defined. groups may be saturated or partially unsaturated, but do not When benzimidazolyl is shown as benzimidazol-5-yl, include aromatic rings. Examples of carbocyclyl groups 35 include monocyclic, bicyclic, and tricyclic ring systems, in which is represented as: particular monocyclic and bicyclic ring systems. Other car bocylcyl groups include bridged ring systems (e.g. bicyclo 2.2.1]heptenyl). A specific example of a carbocyclyl group is B a cycloalkyl group. A further example of a carbocyclyl group 40 is a cycloalkenyl group. R 14 -CO N. The expression "heterocyclyl', unless specifically limited, N-N2, refers to a carbocyclyl group wherein 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 45 the person skilled in the art will appreciate that benzimidazol cycloalkyl group (e.g. cyclopentyl or more particularly cyclo 6-yl, which is represented as: hexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O. Exemplary heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and pip 50 eridine, and exemplary heterocyclyl groups containing two R 14 hetero atoms include morpholine, piperazine, dioxolane and KorN ex 15 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, particularly 1 or 2, especially 1) ring 55 is an equivalent structure. As employed herein, the two forms atoms are replaced by heteroatoms selected from N, S and O. of benzimidazolyl are covered by the term “benzimidazol-5- An example of Such a group is dihydropyranyl (e.g. 3,4- y1”. dihydro-2H-pyran-2-yl-). The expression “aryl', unless specifically limited, denotes Stereoisomers: a C-2 aryl group, Suitably a Coo aryl group, more Suitably 60 All possible stereoisomers of the claimed compounds are a Cls aryl group. Aryl groups will contain at least one aro included in the present invention. matic ring (e.g. one, two or three rings). An example of a Where the compounds according to this invention have at typical aryl group with one aromatic ring is phenyl. An least one chiral center, they may accordingly exist as enanti example of a typical aryl group with two aromatic rings is omers. Where the compounds possess two or more chiral naphthyl. 65 centers, they may additionally exist as diastereomers. It is to The expression "heteroaryl', unless specifically limited, be understood that all such isomers and mixtures thereof are denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or encompassed within the scope of the present invention. US 9, 181,233 B2 7 8 Preparation and Isolation of Stereoisomers: to be encompassed within the scope of this invention. The Where the processes for the preparation of the compounds compounds, including their salts, can also be obtained in the according to the invention give rise to a mixture of stereoiso form of their hydrates, or include other solvents used for their mers, these isomers may be separated by conventional tech crystallization. niques such as preparative chromatography. The compounds Prodrugs: may be prepared in racemic form, or individual enantiomers The present invention further includes within its scope may be prepared either by enantiospecific synthesis or by prodrugs of the compounds of this invention. In general. Such resolution. The compounds may, for example, be resolved prodrugs will be functional derivatives of the compounds into their components enantiomers by standard techniques, which are readily convertible in vivo into the desired thera Such as the formation of diastereomeric pairs by Salt forma 10 tion with an optically active acid, Such as (-)-di-p-toluoyl-d- peutically active compound. Thus, in these cases, the methods tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed of treatment of the present invention, the term “administer by fractional crystallization and regeneration of the free base. ing shall encompass the treatment of the various disorders The compounds may also be resolved by formation of dias described with prodrug versions of one or more of the claimed tereomeric esters or amides, followed by chromatographic 15 compounds, but which converts to the above specified com separation and removal of the chiral auxiliary. Alternatively, pound in vivo after administration to the subject. Conven the compounds may be resolved using a chiral HPLC column. tional procedures for the selection and preparation of suitable Pharmaceutically Acceptable Salts: prodrug derivatives are described, for example, in “Design of In view of the close relationship between the free com Prodrugs’, ed. H. Bundgaard, Elsevier, 1985. pounds and the compounds in the form of their salts or Sol Protective Groups: Vates, whenever a compound is referred to in this context, a During any of the processes for preparation of the com corresponding salt, Solvate or polymorph is also intended, pounds of the present invention, it may be necessary and/or provided such is possible or appropriate under the circum desirable to protect sensitive or reactive groups on any of the Stances. molecules concerned. This may be achieved by means of Salts and solvates of the compounds of formula (I) and 25 conventional protecting groups, such as those described in physiologically functional derivatives thereof which are suit Protective Groups in Organic Chemistry, ed. J. F. W. able for use in medicine are those wherein the counter-ion or McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. associated solvent is pharmaceutically acceptable. However, Wuts, Protective Groups in Organic Synthesis, John Wiley & salts and Solvates having non-pharmaceutically acceptable Sons, 1991, fully incorporated herein by reference. The pro counter-ions or associated Solvents are within the scope of the 30 tecting groups may be removed at a convenient Subsequent present invention, for example, for use as intermediates in the stage using methods known from the art. preparation of other compounds and their pharmaceutically As used herein, the term “composition” is intended to acceptable salts and Solvates. encompass a product comprising the claimed compounds in Suitable salts according to the invention include those the therapeutically effective amounts, as well as any product formed with both organic and inorganic acids or bases. Phar 35 which results, directly or indirectly, from combinations of the maceutically acceptable acid addition salts include those claimed compounds. formed from hydrochloric, hydrobromic, sulfuric, nitric, cit Carriers and Additives for Galenic Formulations: ric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroace Thus, for liquid oral preparations, such as for example, tic, triphenylacetic, Sulfamic, Sulfanilic, succinic, oxalic, Suspensions, elixirs and Solutions, Suitable carriers and addi fumaric, maleic, malic, mandelic, glutamic, aspartic, oxalo 40 tives may advantageously include water, glycols, oils, alco acetic, methanesulfonic, ethanesulfonic, arylsulfonic (for hols, flavoring agents, preservatives, coloring agents and the example p-toluenesulfonic, benzenesulfonic, naphthalene like; for Solid oral preparations such as, for example, pow Sulfonic or naphthalenedisulfonic), Salicylic, glutaric, glu ders, capsules, gelcaps and tablets, Suitable carriers and addi conic, tricarballylic, cinnamic, Substituted cinnamic (for tives include starches, Sugars, diluents, granulating agents, example, phenyl, methyl, methoxy or halo Substituted cin 45 lubricants, binders, disintegrating agents and the like. namic, including 4-methyl and 4-methoxycinnamic acid), Carriers, which can be added to the mixture, include nec ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1 essary and inert pharmaceutical excipients, including, but not or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example limited to, Suitable binders, Suspending agents, lubricants, naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or flavorants, Sweeteners, preservatives, coatings, disintegrating 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, ben 50 agents, dyes and coloring agents. Zeneacrylic (for example 1,4-benzenediacrylic), isethionic Soluble polymers as targetable drug carriers can include acids, perchloric, propionic, glycolic, hydroxyethane polyvinylpyrrolidone, pyran copolymer, polyhydroxypropy Sulfonic, pamoic, cyclohexanesulfamic, Salicylic, saccharinic lmethacrylamidephenol, polyhydroxyethylaspartamide-phe and trifluoroacetic acid. Pharmaceutically acceptable base nol, or polyethyleneoxidepolyllysine substituted with palmi salts include ammonium salts, alkali metal salts such as those 55 toyl residue. Furthermore, the compounds of the present of sodium and potassium, alkaline earth metal salts such as invention may be coupled to a class of biodegradable poly those of calcium and magnesium and salts with organic bases mers useful in achieving controlled release of a drug, for Such as dicyclohexylamine and N-methyl-D-glucamine. example, polyactic acid, polyepsilon caprolactone, polyhy All pharmaceutically acceptable acid addition salt forms of droxybutyeric acid, polyorthoesters, polyacetals, polydihy the compounds of the present invention are intended to be 60 dropyrians, polycyanoacrylates and cross-linked or amphip embraced by the scope of this invention. athic block copolymers of hydrogels. Polymorph Crystal Forms: Suitable binders include, without limitation, starch, gela Furthermore, some of the crystalline forms of the com tin, natural Sugars such as glucose or betalactose, corn Sweet pounds may exist as polymorphs and as Such are intended to eners, natural and synthetic gums such as acacia, tragacanth be included in the present invention. In addition, some of the 65 or sodium oleate, Sodium Stearate, magnesium Stearate, compounds may form solvates with water (i.e. hydrates) or Sodium benzoate, Sodium acetate, sodium chloride and the common organic solvents, and Such solvates are also intended like. US 9, 181,233 B2 10 Disintegrators include, without limitation, starch, methyl and in which any of aforesaid carbocyclyl and heterocy cellulose, agar, bentonite, Xanthan gum and the like. clyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen and SUMMARY OF THE INVENTION Calkoxy. 5 with the proviso that the compound of formula (I) is a com According to the invention there is provided a compound of pound other than: formula (I): 6-(5-(2,3-dimethoxyphenethyl)-1,3,4-thiadiazol-2-yl)H- imidazol-2-alpyridine; 6-(5-(4-(methylthio)phenethyl)-1,3,4-thiadiazol-2-yl)H- Y (I) 10 imidazol-2-alpyridine; or R11 Nx 6-(5-(2-chloro-3-methoxyphenethyl)-1,3,4-thiadiazol-2-yl) H-imidazol-2-alpyridine. or a pharmaceutically acceptable salt, Solvate or polymorph Other objects and features will be in part apparent and in thereof, including all tautomers and stereoisomers thereof part pointed out hereinafter. wherein: 15 R" represents aheteroaryl group optionally substituted by one or more groups selected from Calkyl, Calkenyl, DETAILED DESCRIPTION OF THE INVENTION C2-alkynyl, Chaloalkyl, —Cathioalkyl, —SOC-alkyl, —SOC alkyl, Calkoxy-, According to one particular aspect of the invention which —O—C-scycloalkyl, C-scycloalkyl, -SOCscy may be mentioned there is provided a compound of formula cloalkyl, -SOC cycloalkyl, Calkenyloxy-, Calky (I): nyloxy-, —C(O)Calkyl, —C(O)OC-alkyl, Calkoxy-Calkyl-, nitro, halogen, cyano. —C(O)OH, —NHC alkyl, —N(Calkyl)(Calkyl), —C(O) 2 (I) N(Calkyl)(Calkyl). - C(O)NH2, - C(O) 25 NH(Calkyl) and —C(O)NH(Cocycloalkyl); 1n 1 and in which any of aforesaid carbocyclyl groups may optionally be substituted by one or more groups selected or a pharmaceutically acceptable salt, Solvate or polymorph from C. alkyl, Oxo, halogen and Calkoxy, thereof, including all tautomers and stereoisomers thereof Y represents a 5 membered heteroaryl group selected from 30 wherein: triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, triazol-one R" represents aheteroaryl group optionally substituted by one or triazol-thione: or more groups selected from Calkyl, Calkenyl, X represents a linker selected from —(CH), R. Calkynyl, Chaloalkyl, —C-thioalkyl, (CH), S R, (CH2). O R or (CH2). SOC-alkyl, —SOC alkyl, Cigalkoxy-, SO, R: 35 —O—C-scycloalkyl, C-scycloalkyl, -SOC-scy m represents an integer selected from 1 to 4: cloalkyl, -SOC-cycloalkyl, Calkenyloxy-, Calky in represents an integer selected from 1 or 2; nyloxy-, —C(O)Calkyl, —C(O)OC-alkyl, p represents an integer selected from 0 to 2; Calkoxy-Calkyl-, nitro, halogen, cyano, hydroxyl, R represents aryl, heteroaryl, carbocyclyl or heterocyclyl: —C(O)OH, -NH2, NHC alkyl, - N(Calkyl) in which any of aforesaid aryland heteroaryl groups may 40 (Calkyl). —C(O)N(Calkyl)(Calkyl). —C(O)NH2, optionally be substituted by one or more groups selected —C(O)NH(Calkyl) and —C(O)NH(Cocycloalkyl); fruit-cally Cytyl alth and in which any of aforesaid carbocyclyl groups may ethioalkyl, — 1-alkyl, -SO2C-alkyl, optionally be substituted by one or more groups selected Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, from Calkyl, Oxo, halogen and Calkoxy. —SOCscycloalkyl, -SOC-cycloalkyl, Calk- 45 1-4 s s 9. 1-4 y; enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) Y represents a 5 membered heteroaryl group selected from OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, triazol-one haloCalkyl, haloCalkoxy, cyano, hydroxyl, or triazol-thione; —C(O)CH, -NH. NHC alkyl, - N(Calkyl) X represents a linker selected from —(CH), , —(CH2)— (Calkyl). —C(O)N(Calkyl)(Calkyl), —C(O) 50 S-,-(CH2). O– or -(CH2), SO : NH, —C(O)NH(Calkyl) and —C(O)NH(Cocy m represents an integer selected from 1 to 4: cloalkyl); in represents an integer selected from 1 or 2; and in which any of aforesaid carbocyclyl and heterocyclyl p represents an integer selected from 0 to 2; groups may optionally be substituted by one or more R represents aryl, heteroaryl, carbocyclyl or heterocyclyl: groups selected from Calkyl, Oxo, halogen and 55 in which any of aforesaid aryl and heteroaryl groups may Calkoxy. optionally be substituted by one or more groups selected or R represents phenyl substituted by phenyl, phenyl substi from C-alkyl, C2-alkenyl, C2-alkynyl, Chaloalkyl, tuted by a monocyclic heteroaryl group, phenyl Substituted —Cathioalkyl, -SOC alkyl, -SOC-alkyl, by phenoxy, phenyl substituted by heterocyclyl phenyl Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, Substituted by —O—Calkyl-heterocyclyl phenyl Sub 60 —SOCscycloalkyl, -SOC-cycloalkyl, Calk stituted by benzyloxy, phenyl fused to carbocyclyl or phe enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) nyl fused to heterocyclyl, such that when Y represents OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, oxadiazolyl and X represents CH, R represents a group haloCalkyl, haloCalkoxy, cyano, hydroxyl, other than phenyl substituted by phenoxy: —C(O)CH, NH, -NHC alkyl, - N(Calkyl) in which any of aforesaid phenyl, benzyloxy and heteroaryl 65 (Calkyl). —C(O)N(Calkyl) (Calkyl). —C(O) groups may optionally be substituted by one or more NH, —C(O)NH(Calkyl) and —C(O)NH(Cocy groups selected from Calkyl, halogen and Calkoxy, cloalkyl); US 9, 181,233 B2 11 12 and in which any of aforesaid carbocyclyl and heterocyclyl Substituents selected from alkyl (e.g. Calkyl Such as Me), groups may optionally be substituted by one or more alkoxy- (e.g. Calkoxy- Such as OMe) and halogen (e.g. F). groups selected from Calkyl, Oxo, halogen and Calkoxy. Particular examples of R' heteroaryl groups include a or R represents phenyl substituted by phenyl, phenyl substi 5-membered ring containing 2 or 3 nitrogen atoms, which tuted by a monocyclic heteroaryl group, phenyl Substituted ring may optionally be substituted (e.g. in particular by one or by phenoxy, phenyl substituted by heterocyclyl phenyl two groups, such as methyl, for example: Substituted by —O—Calkyl-heterocyclyl phenyl Sub stituted by benzyloxy, phenyl fused to carbocyclyl or phe nyl fused to heterocyclyl, such that when Y represents 10 oxadiazolyl and X represents CH2, R represents a group other than phenyl substituted by phenoxy: in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one or more groups selected from Calkyl, halogen and Calkoxy, 15 and in which any of aforesaid carbocyclyl and heterocy clyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, oxo, halogen and Calkoxy. with the proviso that the compound of formula (I) is a com pound other than: 6-(5-(2,3-dimethoxyphenethyl)-1,3,4-thiadiazol-2-yl)H- Other examples of Rheteroaryl groups include a 9-mem imidazol-2-alpyridine; bered bicyclic ring containing 2 nitrogen atoms, which ring 6-(5-(4-(methylthio)phenethyl)-1,3,4-thiadiazol-2-yl)H- may optionally be substituted, for example: imidazol-2-alpyridine; or 25 6-(5-(2-chloro-3-methoxyphenethyl)-1,3,4-thiadiazol-2-yl) H-imidazol-2-alpyridine. When carbocyclyl and heterocyclyl are substituted, they are typically substituted by 1 or 2 substituents (e.g. 1 sub /S-n N stitent). Typically the substituent is methyl. More typically 30 CO- KCA carbocyclyl and heterocyclyl groups are unsubstituted. When aryland heteroaryl are substituted, they are typically substituted by 1, 2 or 3 (e.g. 1 or 2) substituents. Substituents for aryl and heteroaryl are selected from Calkyl (e.g. Y 21 N-N- methyl), Calkenyl (e.g. buten-3-yl), C-alkynyl (e.g. 35 OC-K C butyn-3-yl), Chaloalkyl (e.g. fluoromethyl, trifluorom S ethyl), —Cathioalkyl (e.g. —S-methyl), —SOC alkyl (e.g. —SOmethyl), - SOC alkyl (e.g. —SO-methyl), Calkoxy- (e.g. methoxy, ethoxy), —O—Cscycloalkyl When Y represents triazolyl, examples include: (e.g. —O-cyclopentyl), C-scycloalkyl (e.g. cyclopropyl. 40 cyclohexyl). —SOC-scycloalkyl (e.g. —SOcyclohexyl), —SOC-cycloalkyl (e.g. —SOcyclopropyl), Calkeny N N loxy- (e.g. —O-buten-2-yl), C-alkynyloxy- (e.g. N1 S. N%2 NN1 X —O-buten-2-yl), —C(O)Calkyl (e.g. —C(O)ethyl), N —C(O)OC-alkyl (e.g. —C(O)O-methyl), Calkoxy 45 ) - V rV Calkyl-(e.g. methoxy-ethyl-), nitro, halogen (e.g. fluoro, R1 X, H 8. d R1 chloro, bromo), cyano, hydroxyl, —C(O)OH, -NH. —NHC alkyl (e.g. —NHmethyl), —N(Calkyl) (Calkyl) (e.g. —N(methyl)), —C(O)N(Calkyl) When Y represents oxadiazolyl, examples include: (Calkyl)(e.g. —C(O)N(methyl)), —C(O)NH2. —C(O) 50 NH(Calkyl) (e.g. —C(O)NHmethyl), - C(O) NH(Cocycloalkyl) (e.g. —C(O)NHcyclopropyl). More N 8. O X. typically, Substituents will be selected from Calkyl (e.g. y1 methyl), Chaloalkyl (e.g. C-fluoroalkyl, e.g. CF). Y Calkoxy (e.g. OMe), halogen and hydroxy. 55 ) -d ) { When R' represents heteroaryl, examples include mono R R1 cyclic (e.g. 5 and 6 membered) and bicyclic (e.g. 9 and 10 membered, particularly 9 membered) heteroaryl rings, espe When Y represents thiadiazolyl, an example includes: cially rings containing nitrogen atoms (e.g. 1 or 2 nitrogen atoms). A suitable bicyclic heteroaryl ring is a 9-membered 60 heteroaryl ring containing 1 or 2 nitrogen atoms, especially a X. benzene ring fused to a 5-membered ring containing one or two nitrogen atoms (e.g. 1 H-benzoimidazolyl). Most Suit ably the point of attachment is through a benzene ring, e.g. the rS group is 1H-benzoimidazol-5-yl. Aforementioned heteroaryl 65 RI groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g. 1 or 2) US 9, 181,233 B2 13 14 When Y represents thiazolyl, examples include: yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen-3-y- and 4-fluoro-naphthalen-2-yl-). When R represents optionally substituted heteroaryl, examples include monocyclic rings (e.g. 5 or 6 membered rings) and bicyclic rings (e.g. 9 or 10 membered rings) which may optionally be substituted. Example 5 membered rings include pyrrolyl (e.g. pyrrol-2-yl) and imidazolyl (e.g. 1H-imidazol-2-yl or 1H-imidazol-4-yl), pyrazolyl (e.g. 1H-pyrazol-3-yl), furanyl (e.g. furan-2-yl), thiazolyl (e.g. 10 thiazol-2-yl), thiophenyl (e.g. thiophen-2-yl, thiophen-3-yl). Example 6 membered rings include pyridinyl (e.g. pyridin 2-yland pyridin-4-yl). Specific Substituents that may be men tioned are one or more e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. meth 15 oxy-). Example substituted 5 membered rings include 4.5- dimethyl-furan-2-yl-, 5-hydroxymethyl-furan-2-yl-, 5-me thyl-furan-2-yl- and 6-methyl-pyridin-2-yl-. An example Substituted 6-membered ring is 1-oxy-pyridin-4-yl-. Example 9 membered rings include 1H-indolyl (e.g. 1H-in dol-3-yl, 1 H-indol-5-yl), benzothiophenyl (e.g. benzob. thiophen-3-yl, particularly 2-benzobthiophen-3-yl), benzo 1,2,5-oxadiazolyl (e.g. benzo 1,2,5-oxadiazol-5-yl), benzo 1,2,5-thiadiazolyl (e.g. benzo 1,2,5-thiadiazol-5-yl, benzo 1,2,5thiadiazol-6-yl). Example 10 membered rings 25 include quinolinyl (e.g. quinolin-3-yl, quinolin-4-yl, quino lin-8-yl). Specific substituents that may be mentioned are one or more e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-). Example substituted 9-membered rings include 1-methyl-1H-indol-3- 30 y1. 2-methyl-1H-indol-3-yl, 6-methyl-1H-indol-3-yl. When R represents optionally substituted aryl, aryl may Example substituted 10 membered rings include 2-chloro typically represent phenyl. Exemplary Substituted phenyl quinolin-3-yl, 8-hydroxy-quinolin-2-yl, oxo-chromenyl (e.g. groups include 3-methylphenyl-, 2,3-dichlorophenyl-, 2,3- 4-oxo-4H-chromen-3-yl) and 6-methyl-4-oxo-4H-chromen difluorophenyl-, 2,4-dichlorophenyl-, 2,4-difluororophenyl-, 3-yl. 35 When R represents carbocyclyl, examples include 2,4-dimethoxyphenyl-, 2,4-dimethylphenyl-, 2,4-bis(trifluo cycloalkyl and cycloalkenyl. Examples of cycloalkyl include romethyl)phenyl-, 2,4,6-trifluorophenyl-, 2,4,6-trimeth cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo ylphenyl-, 2,6-dichlorophenyl-, 2,6-difluorophenyl-, 2,6- heptyl. Examples of cycloalkenyl include cyclohexenyl (e.g. dimethoxyphenyl-, 2,6-difluoro-4-(methoxy)phenyl-, cyclohex-2-enyl, cyclohex-3-enyl). Examples of substituted 2-isopropyl-6-methylphenyl-, 3-(cyclopentyloxy)-4-meth 40 carbocyclyl include 2-methyl-cyclohexyl-, 3-methyl-cyclo oxyphenyl-, 3,4,5-trimethoxyphenyl-, 3,4-dimethoxyphe hexyl-, 4-methyl-cyclohexyl-, 2-methyl-cyclohex-2-enyl, nyl-, 3,4-dichlorophenyl-, 3,4-difluorophenyl-, 3,4-dimeth 2-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl, 3-me ylphenyl-, 3,4,5-trifluorophenyl-, 3.5-bis(trifluororomethyl) thyl-cyclohex-3-enyl. phenyl-, 3,5-dimethoxyphenyl-, 2-methoxyphenyl-, When R represents heterocyclyl (which may optionally be 3-methoxyphenyl-, 4-(trifluoromethyl)phenyl-, 4-bromo-2- 45 Substituted), examples include tetrahydrofuranyl, morpholi (trifluoromethyl)phenyl-, 4-bromophenyl-, 4-chloro-3-(trif nyl, piperidinyl, 3,4-dihydro-2H-pyranyl, pyrrolidinyl, meth luoromethyl)phenyl-, 4-chlorophenyl-, 4-cyanophenyl-, yltetrahydrofuranyl- (e.g. 5-methyltetrahydrofuran-2-yl-). 4-ethoxyphenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4-isopro When R represents phenyl substituted by phenyl orphenyl pylphenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4-pro Substituted by a monocyclicheteroaryl group, in which any of poxyphenyl-, 4-butoxyphenyl-, 4-pentophenyl-, 4-isopropy 50 aforesaid phenyl and heteroaryl groups may optionally be loxyphenyl-, 4-tetrafluoroethyloxyphenyl-. Alternatively, R Substituted, typically the phenyl ring connected directly to the may represent unsubstituted phenyl-. Further exemplary Sub nitrogenatom is unsubstituted and the terminal phenyl ring or stituted phenyl groups include 2,3,4-trifluorophenyl, 2,3-dif the monocyclic heteroaryl ring is optionally Substituted by luoro-4-methylphenyl, 2-bromo-4-fluorophenyl-, 2-bromo one, two or three Substitutents (e.g. one or two, e.g. one). 5-fluorophenyl-, 2-chlorophenyl-, 2-fluorophenyl-, 2-fluoro 55 Typically the terminal phenyl or monocyclic heteroaryl group 5-(trifluoromethyl)phenyl-, 2-hydroxy-3-methoxyphenyl-, is unsubstituted. Typically the terminal phenyl or monocyclic 2-hydroxy-5-methylphenyl-, 3-chlorophenyl-, 3-fluorophe heteroaryl group Substitutes the other phenyl group at the nyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, 3-fluoro-5-(trif 4-position. luoromethyl)phenyl-, 2-fluoro-4-(trifluoromethyl)phenyl-, When R represents phenyl substituted by phenyl in which 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphe 60 any of aforesaid phenyl groups may optionally be substituted, nyl-, 4-bromo-2-fluorophenyl, 4-chloro-3-(trifluoromethyl) examples include -biphenyl-4-yl. phenyl-, 4-chloro-3-methylphenyl, 4-chlorophenyl-, 4-fluo When R represents phenyl substituted by a monocyclic rophenyl- and 4-propoxyphenyl-. heteroaryl group, in which any of aforesaid phenyl and het When R represents optionally substituted aryl and aryl eroaryl groups may optionally be substituted, examples represents naphthyl, examples include unsubstituted naph 65 include 4-(oxazol-5-yl)phenyl-. thyl (e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl) When R represents phenyl substituted by benzyloxy in as well as Substituted naphthyl (e.g. 4-methyl-naphthalen-2- which any of aforesaid phenyl and benzyloxy groups may US 9, 181,233 B2 15 16 optionally be substituted, examples include 4-benzyloxy In a fourth embodiment, R' represents phenyl-, 4-(3-methylbenzyloxy)phenyl- and 4-(4-methyl benzyloxy)phenyl-. When R represents optionally substituted phenyl fused to N P optionally Substituted carbocyclyl examples include indanyl (e.g. indan-4-yl-, 2-methyl-indan-4-yl-), indenyl and tetrali nyl. When R represents optionally substituted phenyl fused to optionally Substituted heterocyclyl, examples include benzo 10 wherein D represents a bond and R' and R' independently 1.3dioxo-4-yl- and 2,3-dihydro-benzo 1.4 dioxin-4-yl-. represent H or C-alkyl. Suitably R' represents bicyclic heteroaryl, especially Suitably R' represents 9-membered bicyclicheteroaryl. More suitably, R' represents a bicyclic heteroaryl ring system and in particular a phenyl ring fused with a 5 membered heteroaryl ring containing one 15 B or more (e.g. one or two, Suitably one, more Suitably two) nitrogen atoms or a pyridine ring fused with a 5-membered R 14 - O ). heteroaryl ring containing one or more (e.g. one or two, N-N2, suitably one, more suitably two) nitrogen atoms. When R' represents bicyclic heteroaryl, preferably the heteroaryl In one embodiment R'' represents Hand R' represents H. group does not contain Satoms. When R' represents a phenyl In another embodiment R' represents Hand R' represents ring fused to a 5-membered heteroaryl ring, preferably R' is C alkyl In a third embodiment R'' represents Calkyland linked to the core of formula (I) through the phenyl ring. R" represents H. In a fourth embodiment R' represents When R' represents a pyridine ring fused to a 5-membered 25 methyl and R' represents H. heteroaryl ring, preferably R' is linked to the core of formula Suitably B represents a bond. (I) through the pyridine ring. Suitably R' represents unsub Alternatively R' represents stituted heteroaryl. In particular, R' suitably represents 1H-benzoimidazolyl or imidazol-2-alpyridine, particularly 1H-benzoimidazolyl, especially 1H-benzoimidazol-5-yl. 30 In one embodiment R' represents

R13 35 R' suitably represents H, R' suitably represents H or methyl. R" suitably represents H or methyl. In one embodiment of the invention, R' represents Hand 40 R" represents methyl. In another embodiment, R' repre sents methyl and R' represents H. In a third embodiment, wherein A represents a bond and R'', R'' and R' indepen R' represents Hand R' represents H. dently represent H or C-alkyl. Suitably A represents a bond. In a second embodiment, R' represents Alternatively R' represents 45

B R 14 -CO ) KrNeX N-N2, R17 In one embodiment R' represents Hand R7 represents H. wherein B represents a bond and R'' and R' independently In another embodiment R' represents Hand R'' represents represent H or C-alkyl. 55 Calkyl. In a third embodiment R' represents C-alkyland In a third embodiment, R' represents R7 represents H. Suitably C represents a bond. Alternatively R' represents 60 R I6 -K s-) N Nex R17

65 wherein C represents a bond and R'' and R7 independently represent H or C-alkyl. US 9, 181,233 B2 17 In one embodiment R' represents Hand R' represents H. 1,3,4-thiadiazolyl, i.e. In another embodiment R' represents H and R' represents Calkyl. In a third embodiment R' represents C-alkyland R" represents H. Suitably D represents a bond. More suitably R' represents

10 Suitably, Y represents thiazolyl. In one embodiment, Y represents thiazolyl. Such as:

15 Most suitably R' represents

N Suitably, Y represents triazol-one, such as: ( 2H-1,2,4-triazol-3-one, i.e. N H

25 Suitably, Y represents triazolyl, oxadiazolyl or thiadiaz olyl. More suitably, Y represents triazolyl orthiadiazolyl. In a further embodiment, Y is attached to R' via a carbon atom. Suitably, Y represents triazolyl, such as: 4H-1,2,4-triazolyl, i.e. 30 Suitably, Y represents triazol-thione, such as: 4H-1,2,4-triazol-3-thione, i.e. X N 35 N R rV RI X or R H ; O

1H-1,2,3-triazolyl, i.e. 40

Suitably, X represents a linker selected from —(CH2) - R2, (CH.), S R, -(CH), O R or -(CH.), 45 SO. R. More suitably, X represents a linker selected from -(CH2),(CH), R2 Ror andCH, -(CH2), SR'). S R (i.e. —CH2—R. Suitably, X represents —(CH), R. In one embodi ment, X represents —CH. R. —(CH) R' or 50 —(CH.) R. In a further embodiment, X represents —CH R or —(CH) R. In a yet further embodiment, Suitably, Y represents oxadiazolyl. In one embodiment, Y X represents —CH. R. In an alternative embodiment, X represents oxadiazolyl. Such as: represents -(CH2): R. 1,3,4-oxadiazolyl, i.e. Suitably, X represents —(CH), S R. In one embodi 55 ment, X represents —CH2—S R. Suitably, X represents -(CH2) -O-R. In one embodi ment, X represents —CH2—O R. Suitably, X represents -(CH2). SO. R. In one embodiment, X represents —CH2—SO. R. 60 Suitably, m represents an integer selected from 1 to 3. In a further embodiment, m represents an integer selected from 1 or 2. Suitably, in represents 1. Suitably, p represents an integer selected from 0 or 1. In a 65 further embodiment, p represents 1. Suitably, Y represents thiadiazolyl. In one embodiment, Y Suitably, R represents aryl, heteroaryl, carbocyclyl, het represents thiadiazolyl. Such as: erocyclyl phenyl substituted by phenoxy or phenyl fused to US 9, 181,233 B2 19 20 heterocyclyl. More suitably, R represents aryl, heteroaryl, substituted by 4-O-(CH2)-2-morpholinyl, 4-O-(CH)-3- phenyl substituted by phenoxy or phenyl fused to heterocy morpholinyl, 2-O-(CH)-2-morpholinyl or 4-O-(CH)-2- clyl. Yet more suitably, R represents optionally substituted piperazinyl. aryl or phenyl substituted by phenoxy. Still yet more suitably, In one embodiment, R represents optionally substituted R represents optionally substituted aryl. phenyl fused to optionally substituted heterocyclyl. When R In one embodiment, R represents carbocyclyl. When R represents optionally Substituted phenyl fused to optionally represents carbocyclyl, R suitably represents cyclohexyl. substituted heterocyclyl, R suitably represents benzo-1,3- In one embodiment, R represents optionally substituted dioxolanyl, 4-methoxy (benzo-1,3-dioxolanyl), 6-methoxy aryl. When R represents optionally substituted aryl, R suit (benzo-1,3-dioxolanyl), 2,2-difluoro(benzo-1,3-dioxolanyl) ably represents optionally Substituted phenyl or napthyl. 10 or benzo-1,4-dioxanyl. In a further embodiment, when R More suitably, R represents optionally substituted phenyl. represents optionally Substituted phenyl fused to optionally In one embodiment, R represents phenyl optionally sub substituted heterocyclyl, R suitably represents benzo-1,3- stituted by one or more groups selected from C alkyl (e.g. dioxolanyl. methyl), C alkoxy (e.g. methoxy or ethoxy), —C-thio One particular subset of compounds of formula (I) which alkyl (e.g. methylthio), haloCo alkyl (e.g. trifluoromethyl), 15 may be mentioned are those wherein R' represents haloCalkoxy (e.g. trifluoromethoxy) or halogen (e.g. chlo rine or fluorine). In a further embodiment, R represents phe nyl optionally Substituted by one or more groups selected N from Calkoxy (e.g. methoxy) or halogen (e.g. chlorine). ( When R represents optionally substituted phenyl, R suit N ably represents 2-methylphenyl, 4-methylphenyl, 4-trifluo H romethylphenyl, 5-trifluoromethylphenyl, 2.5-bis(trifluo romethyl), 4-methylthio(phenyl), 2-methoxyphenyl, Y represents triazolyl or thiadiazolyl. X represents 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 25 (CH2), and -(CH2), S - (i.e. —CH2—, (CH), or 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethox —CH, S ) and R represents phenyl optionally substi yphenyl, 3,4,5-trimethoxyphenyl, 4-ethoxyphenyl, 2-fluo tuted by one or more groups selected from Calkoxy (e.g. rophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophe methoxy) or halogen (e.g. chlorine) or R represents phenyl nyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, substituted by phenoxy. 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4- 30 Processes dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, According to a further aspect of the invention there is 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluo provided a process for preparing a compound of formula (I) rophenyl, 2-chloro-6-fluorophenyl, 4-trifluoromethoxyphe which comprises: nyl, 3-chloro-4-methoxyphenyl, 2-chloro-3-methoxyphenyl (a) preparing a compound of formula (I) wherein R' repre or 2-chloro-5-trifluoromethylphenyl. 35 sents 1H-benzodimidazolyl from a compound of formula In one embodiment, R represents optionally substituted heteroaryl. When R represents optionally substituted het (II): eroaryl, R suitably represents optionally substituted pyridyl. In an alternative embodiment, R represents unsubstituted (II) pyridyl, e.g. pyridin-4-yl. 40 In one embodiment, R represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being Substi tuted. When R represents phenyl substituted by phenyl, the aforesaid phenyl groups optionally being substituted, R suit ably represents phenyl substituted by 3-phenyl, phenyl sub 45 stituted by 4-phenyl, phenyl substituted by 3-(3-chlorophe ON nyl), phenyl substituted by 4-(3-chlorophenyl), phenyl NH2 substituted by 4-(3,4-dichlorophenyl) or 3-fluorophenyl sub stituted by 4-phenyl. In one embodiment, R represents optionally substituted 50 wherein X and Y are as defined above for compounds of phenyl substituted by optionally substituted phenoxy. When formula (I). Process (a) typically comprises dissolving a com R represents optionally substituted phenyl substituted by pound of formula (II) in a Suitable solvent. Such as formic acid optionally substituted phenoxy, R suitably represents phenyl and formic acid orthoethylester, followed by treatment with sodium formate and Pd/C and heating to 110°C. for 24 h. A substituted by 4-phenoxy. In one embodiment, R represents non-limiting example of the methodology of process (a) is optionally substituted phenyl substituted by optionally sub 55 stituted heterocyclyl. When R represents optionally substi described in Section F herein. tuted phenyl substituted by optionally substituted heterocy (b) preparing a compound of formula (I) wherein Y represents clyl, R suitably represents 3-chlorophenyl substituted by 1,2,4-triazolyl by reacting a compound of formula (III): 4-morpholinyl, phenyl Substituted by 4-piperazinyl Substi tuted by 4N-methyl, phenyl substituted by 4-piperazinyl sub 60 (III) stituted by 4N-phenyl, phenyl substituted by 3-piperazinyl N substituted by 4N-phenyl or 2-chlorophenyl substituted by / V 6-piperazinyl substituted by 4N-ethyl. OS2N In one embodiment, R represents optionally substituted phenyl substituted by —O Calkyl-heterocyclyl. When 65 Y R represents optionally substituted phenyl substituted by —O Calkyl-heterocyclyl, R suitably represents phenyl US 9, 181,233 B2 21 22 wherein R' is as defined above for compounds of formula (I), (f) preparing a compound of formula (I) whereinY represents with a compound of formula X NH, wherein X is as 1,3,4-thiadiazolyl by reacting a compound of formula defined above for compounds of formula (I). Process (b) (VII): typically comprises heating to 150° C. overnight. A non limiting example of the methodology of process (b) is described in Section A, Method 1 herein. (VII) (c) preparing a compound of formula (I) whereinY represents 1,2,4-triazolyl by reacting a compound of formula (IV):

10 (IV) wherein R' is as defined above for compounds of formula (I), with a compound of formula X COOH, wherein X is as 15 defined above for compounds of formula (I). Process (f) typi cally comprises reaction in the presence of acetonitrile, Lawesson’s reagent and POCl followed by heating to reflux 1N overnight. A non-limiting example of the methodology of process (f) is described in Section C, Method 3 herein. wherein R' is as defined above for compounds of formula (I), (g) preparing a compound of formula (I) wherein Y represents with a compound of formula X NH, wherein X is as 4H-1,2,4-triazolyl by reacting a compound of formula defined above for compounds of formula (I). Process (c) (VIII): typically comprises reaction in the presence of glacial acetic 25 acid followed by heating at 130-135° C. for 48 hours. A (VIII) non-limiting example of the methodology of process (c) is NH2 described in Section A, Method 2 herein. (d) preparing a compound of formula (I) wherein Y represents HN NH 1,2,4-oxadiazolyl by reacting a compound of formula (V): 30 NRI

(V) OH wherein R' is as defined above for compounds of formula (I), HN NH with a compound of formula X COOH, wherein X is as 35 defined above for compounds of formula (I). Process (g) N typically comprises reaction in the presence of DMF and RI carbonyldiimidazole followed by heating to 110° C. for 24 hours. A non-limiting example of the methodology of process wherein R' is as defined above for compounds of formula (I), 40 (g) is described in Section D herein. with a compound of formula X COOH, wherein X is as (h) preparing a compound of formula (I) wherein Y represents defined above for compounds of formula (I). Process (d) thiazolyl by reacting a compound of formula R' COON typically comprises dissolving the compound of formula with a compound of formula X CO CH, NH, X-COOH in DMF, followed by treatment with carbonyldi wherein R' and X are as defined above for compounds of imidazole and stirred at room temperature for 1 hour. The 45 formula (I). Process (h) typically comprises reaction in the compound of formula (V) is then added followed by heating presence of acetonitrile, Lawesson’s reagent, TEA and at 110° C. overnight. A non-limiting example of the method POCl, followed by heating to reflux overnight. A non ology of process (d) is described in Section B herein. limiting example of the methodology of process (h) is (e) preparing a compound of formula (I) whereinY represents described in Section Eherein. 1,3,4-thiadiazolyl from a compound of formula (VI): 50 (i) preparing a compound of formula (I) wherein Y represents 1,2,4-triazol-one or 1,2,4-triazol-thione from a compound of formula (IX): (VI)

55 (IX)

60 wherein R' and X are as defined above for compounds of formula (I). Process (e) typically comprises the use of with Lawesson’s reagent and heating to reflux. A non-limiting 65 example of the methodology of process (e) is described in wherein R' and X are as defined above for compounds of Section C, Methods 1 and 2 herein. formula (I) and W represents O or S. Process (i) typically US 9, 181,233 B2 23 24 comprises the use of 5% NaCO followed by heating to Therapeutic Uses reflux for 3 hours. A non-limiting example of the methodol Physiological Substrates of QC (EC) in mammals are, e.g. ogy of process (i) is described in Section G herein. amyloid beta-peptides (3-40), (3-42), (11-40 and (11-42), () interconversion of compounds of formula (I); and ABri, ADan, Gastrin, Neurotensin, FPP, CCL 2, CCL 7, CCL (k) deprotecting a compound of formula (I) which is pro 8, CCL 16, CCL 18, Fractalkine, Orexin A, Gln-glucagon tected. (3-29), Gln)-substance P(5-11) and the peptide QYNAD. Compounds of formula (I) and intermediate compounds For further details see table 1. The compounds and/or com may also be prepared using techniques analogous to those binations according to the present invention and pharmaceu known to a skilled person, or described herein. tical compositions comprising at least one inhibitor of QC Novel intermediates are claimed as an aspect of the present 10 (EC) are useful for the treatment of conditions that can be invention. treated by modulation of QC activity. TABL E 1. Amino acid sequences of physiological active peptides with an N-terminal glutamine residue, which are prone to be cyclized to final pClu Peptide Amino acid sequence Function Abeta(1-42) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser Plays a role in Gly-Tyr-Glu-Val-His-His-Gln-Lys neurodegeneration, e.g. in Leu-Val-Phe-Phe-Ala-Glu-Asp-Val Alzheimer's Disease, Familial Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly- British Dementia, Familial Lieu-Met-Val-Gly-Gly-Val-Val-Ile-Ala Danish Dementia, Down Syndrome Abeta(1-40) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser Plays a role in Gly-Tyr-Glu-Val-His-His-Gln-Lys neurodegeneration, e.g. in Leu-Val-Phe-Phe-Ala-Glu-Asp-Val Alzheimer's Disease, Familial Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly- British Dementia, Familial Leu-Met-Val-Gly-Gly-Val-Val Danish Dementia, Down Syndrome Abeta (3-42) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr Plays a role in Glu-Val-His-His-Gln-Lys-Leu-Val neurodegeneration, e.g. in Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser Alzheimer's Disease, Familial Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met- British Dementia, Familial Wal-Gly-Gly-Val-Val-Ile-Ala Danish Dementia, Down Syndrome Abeta (3-40) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr Plays a role in Glu-Val-His-His-Gln-Lys-Leu-Val neurodegeneration, e.g. in Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser Alzheimer's Disease, Familial Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met- British Dementia, Familial Val-Gly-Gly-Val-Val Danish Dementia, Down Syndrome Abeta (11-42) Glu-Val-His-His-Gln-Lys-Leu-Val Plays a role in Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser neurodegeneration, e.g. in Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met - Alzheimer's Disease, Familial Wal-Gly-Gly-Val-Val-Ile-Ala British Dementia, Familial Danish Dementia, Down Syndrome Abeta (11- 40) Glu-Val-His-His-Gln-Lys-Leu-Val Plays a role in Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser neurodegeneration, e.g. in Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met - Alzheimer's Disease, Familial Val-Gly-Gly-Val-Val British Dementia, Familial Danish Dementia, Down Syndrome

ABri EASNCFA IRHFENKFAW ETLIC Pyroglutamated form plays a SRTWKKNIIEEN role in Familial British Dementia

ADan EASNCFA IRHFENKFAW ETLIC Pyroglutamated form plays a FNLFLNSOEKHY role in Familial Danish Dementia

Gastrin 17 OGPWL EEEEEAYGWM DF Gastrin stimulates the stomach Swiss-Prot: PO1350 (amide) mucosa to produce and secrete hydrochloric acid and the pancreas to secrete its digestive enzymes. It also stimulates Smooth muscle contraction and increases blood circulation and water secretion in the stomach and intestine. US 9, 181,233 B2 25 26 TABLE 1- Continued Amino acid sequences of physio ogical active peptides with an N-terminal glutamine residue, which are prone to be cyclized to final pClu Peptide Amino acid sequence Function Neurotensin OLYENKPRRP YIL Neurotensin plays an endocrine Swiss-Prot: P3O990 or paracrine role in the regulation of fat metabolism. It causes contraction of Smooth muscle.

FPP QEP amide A tripeptide related to thyrotrophin releasing hormone (TRH) , is found in seminal plasma. Recent evidence obtained in vitro and in vivo showed that FPP plays an important role in regulating sperm fertility.

TRH QHP amide TRH functions as a regulator of Swiss-Prot: P2O396 the biosynthesis of TSH in the anterior pituitary gland and as a neurotransmitter/ neuromodulator in the central and peripheral nervous systems.

GnRH OHWSYGL RP (G) amide Stimulates the Secretion of Swiss-Prot: PO1148 gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.

CCL16 (Small QPKVPEW VNTPSTCCLK Shows chemotactic activity for inducible cytokine YYEKWLPRRL WGYRKALNC lymphocytes and monocytes A16) HLPAIIFWTK RNREWCTNPN but not neutrophills. Also shows Swiss-Prot; 015467 DDWVOEYIKD PNLPLLPTRN potent myelosuppressive LSTWKIITAK NGOPOLLNSQ activity, suppresses proliferation of myeloid progenitor cells. Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophills. Induces a calcium flux in THP-1 cells that were desensitized by prior expression to RANTES.

CCL8 (Small QPDSVSI PITCCFNVIN Chemotactic factor that attracts inducible cytokine RKIPIORLES YTRITNIOCP monocytes, lymphocytes, A8) KEAWIFKTKR GKEWCADPKE basophills and eosinophills. May Swiss-Prot: P8 OO75 RWVRDSMKHL DOIFONLKP play a role in neoplasia and inflammatory host responses. This protein can bind heparin.

CCL2 (MCP-1, small QPDAINA PVTCCYNFTN Chemotactic factor that attracts inducible cytokine RKISWORLAS YRRITSSKCP monocytes and basophills but A2) KEAVIFKTIV AKEICADPKO not neutrophills or eosinophills. Swiss-Prot: P13500 KWVODSMDHL DKOTOTPKT Augments monocyte anti-tumor activity. Has been implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis or atherosclerosis. May be involved in the recruitment of monocytes into the arterial wall during the disease process of atherosclerosis. Binds to CCR2 and CCR4.

CCL18 (Small OVGTNKELC CLVYTSWOIP Chemotactic factor that attracts inducible cytokine OKFIVDYSET SPOCPKPGVI lymphocytes but not monocytes A18) LLTKRGROIC ADPNKKWVOK or granulocytes. May be Swiss-Prot: P55774 YISDLKLNA involved in B cell migration into B cell follicles in lymph nodes. US 9, 181,233 B2 27 28 TABLE 1 - continued Amino acid sequences of physiological active peptides with an N-terminal glutamine residue, which are prone to be cyclized to final pClu Peptide Amino acid sequence Function Attracts naive T lymphocytes toward dendritic cells and activated macrophages in lymph nodes, has chemotactic activity for naive T cells, CD4+ and CD8+ T cells and thus may play a role in both humoral and cell-mediated immunity responses.

Fractalkine QHHGVT KCNITCSKMT The soluble form is chemotactic (neurotactin) SKIPVALLIH YOONOASCGK for T cells and monocytes, but Swiss-Prot: P78423 RAIILETROH RLFCADPKEO not for neutrophills. The WWKDAMOHLD ROAAALTRNG membrane-bound form GTFEKOIGEV KPRTTPAAGG promotes adhesion of those MDESWWLEPE ATGESSSLEP leukocytes to endothelial cells. TPSSOEAQRA LGTSPELPTG May play a role in regulating WTGSSGTRLP PTPKAODGGP leukocyte adhesion and VGTELFRVPP VSTAATWOSS migration processes at the APHOPGPSLW AEAKTSEAPS endothelium binds to CX3CR1. TODPSTOAST ASSPAPEENA PSEGORVWGO GOSPRPENSL EREEMGPWPA HTDAFODWGP GSMAHWSWWP WSSEGTPSRE PWASGSWTPK AEEPIHATMD PORLGVLITP VPDAOAATRR QAVGLLAFLG LLFCLGVAMF TYQSLQGCPR KMAGEMAEGL RYIPRSCGSN SYWLWPW

CCL7 (Small QPVGINT STTCCYRFIN Chemotactic factor that attracts inducible cytokine KKIPKORLES YRRTTSSHCP monocytes and eosinophills, but A7) REAVIFKTKL DKEICADPTO not neutrophills. Augments Swiss-Prot: P80098 KWVODFMKHL DKKTOTPKL monocyte anti-tumor activity. Also induces the release of gelatinase B. This protein can bind heparin. Binds to CCR1, CCR2 and CCR3.

Orexin A (Hypocretin- QPLPDCCROK TCSCRLYELL Neuropeptide that plays a 1) HGAGNHAAGI LTL significant role in the regulation Swiss-Prot 04361.2 of food intake and sleep Wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids. Orexin-A binds to both OX1R and OX2R with a high affinity.

Substance P RPK POOFFGLM Belongs to the tachykinins. Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many Smooth muscles.

QYNAD Gln-Tyr-Asn-Ala-Asp Acts on voltage-gated sodium channels. US 9, 181,233 B2 29 30 Glutamate is found in positions 3, 11 and 22 of the amyloid Sion. This concatenation of findings led to the hypothesis that B-peptide. Among them the mutation from glutamic acid (E) NT functions as an endogenous antipsychotic. Moreover, to glutamine (Q) in position 22 (corresponding to amyloid typical and atypical antipsychotic drugs differentially alter precursor protein APP 693, Swissprot P05067) has been NT neurotransmission in nigrostriatal and mesolimbic described as the so called Dutch type cerebroarterial amyloi dopamine terminal regions, and these effects are predictive of dosis mutation. side effect liability and efficacy, respectively (Binder, E. B. et The B-amyloid peptides with a pyroglutamic acid residue al. 2001 Biol Psychiatry 50 856-872). in position 3, 11 and/or 22 have been described to be more Fertilization promoting peptide (FPP), a tripeptide related cytotoxic and hydrophobic than the amyloid 3-peptides 1-40 to thyrotrophin releasing hormone (TRH), is found in seminal (42/43) (Saido T. C. 2000 Medical Hypotheses 54(3): 427 10 429). plasma. Recent evidence obtained in vitro and in vivo showed The multiple N-terminal variations, e.g. Abeta(3-40), that FPP plays an important role in regulating sperm fertility. Abeta(3-42), Abeta(11-40) and Abeta (11-42) can be gener Specifically, FPP initially stimulates nonfertilizing (unca ated by the B-secretase enzyme B-site amyloid precursor pro pacitated) spermatozoa to “switch on and become fertile tein-cleaving enzyme (BACE) at different sites (Huse J.T. et 15 more quickly, but then arrests capacitation so that spermato al. 2002 J. Biol. Chem. 277 (18): 16278-16284), and/or by Zoa do not undergo spontaneous acrosome loss and therefore aminopeptidase or dipeptidylaminopeptidase processing do not lose fertilizing potential. These responses are mim from the full length peptides Abeta(1-40) and Abeta(1-42). In icked, and indeed augmented, by adenosine, known to regu all cases, cyclization of the then N-terminal occurring late the adenylyl cyclase (AC)/cAMP signal transduction glutamic acid residue is catalyzed by QC. pathway. Both FPP and adenosine have been shown to stimu Transepithelial transducing cells, particularly the gastrin late cAMP production in uncapacitated cells but inhibit it in (G) cell, co-ordinate gastric acid secretion with the arrival of capacitated cells, with FPP receptors somehow interacting food in the stomach. Recent work showed that multiple active with adenosine receptors and G proteins to achieve regulation products are generated from the gastrin precursor, and that of AC. These events affect the tyrosine phosphorylation state there are multiple control points in gastrin biosynthesis. Bio 25 of various proteins. Some being important in the initial synthetic precursors and intermediates (progastrin and Gly “switching on, others possibly being involved in the gastrins) are putative growth factors; their products, the ami acrosome reaction itself. Calcitonin and angiotensin II, also dated gastrins, regulate epithelial cell proliferation, the found in seminal plasma, have similar effects in vitro on differentiation of acid-producing parietal cells and histamine uncapacitated spermatozoa and can augment responses to secreting enterochromaffin-like (ECL) cells, and the expres 30 FPP. These molecules have similar effects in vivo, affecting sion of genes associated with histamine synthesis and storage fertility by stimulating and then maintaining fertilizing poten in ECL cells, as well as acutely stimulating acid secretion. tial. Either reductions in the availability of FPP, adenosine, Gastrin also stimulates the production of members of the calcitonin, and angiotensin II or defects in their receptors epidermal growth factor (EGF) family, which in turn inhibit contribute to male infertility (Fraser, L. R. and Adeoya parietal cell function but stimulate the growth of surface 35 Osiguwa, S.A. 2001 Vitam Horm 63, 1-28). CCL2 (MCP-1), epithelial cells. Plasma gastrin concentrations are elevated in CCL7, CCL8, CCL16, CCL18 and fractalkine play an impor subjects with Helicobacter pylori, who are known to have tant role in pathophysiological conditions, such as Suppres increased risk of duodenal ulcer disease and gastric cancer sion of proliferation of myeloid progenitor cells, neoplasia, (Dockray, G.J. 1999 J Physiol 15315-324). inflammatory host responses, cancer, psoriasis, rheumatoid The peptide hormone gastrin, released from antral G cells, 40 arthritis, atherosclerosis, vasculitis, humoral and cell-medi is known to stimulate the synthesis and release of histamine ated immunity responses, leukocyte adhesion and migration from ECL cells in the oxyntic mucosa via CCK-2 receptors. processes at the endothelium, inflammatory bowel disease, The mobilized histamine induces acid secretion by binding to restenosis, pulmonary fibrosis, pulmonary hypertention, liver the H(2) receptors located on parietal cells. Recent studies fibrosis, liver cirrhosis, nephrosclerosis, ventricular remodel Suggest that gastrin, in both its fully amidated and less pro 45 ing, heart failure, arteriopathy after organ transplantations cessed forms (progastrin and glycine-extended gastrin), is and failure of vein grafts. also a growth factor for the gastrointestinal tract. It has been A number of studies have underlined in particular the cru established that the major trophic effect of amidated gastrin is cial role of MCP-1 for the development of atherosclerosis for the oxyntic mucosa of stomach, where it causes increased (Gu, L., et al., (1998) Mol. Cell 2, 275-281; Gosling, J., et al., proliferation of gastric stem cells and ECL cells, resulting in 50 (1999) J. Clin. Invest 103, 773-778); rheumatoid arthritis increased parietal and ECL cell mass. On the other hand, the (Gong, J. H., et al., (1997).J. Exp. Med 186, 131-137; Ogata, major trophic target of the less processed gastrin (e.g. gly H., et al., (1997).J. Pathol. 182, 106-114); pancreatitis (Bhatia, cine-extended gastrin) appears to be the colonic mucosa M., et al., (2005) Am. J Physiol Gastrointest. Liver Physiol (Koh, T.J. and Chen, D. 2000 Regul Pept 9337–44). 288, G1259-G1265); Alzheimer's disease (Yamamoto, M., et Neurotensin (NT) is a neuropeptide implicated in the 55 al., (2005) Am. J Pathol. 166, 1475-1485); lung fibrosis pathophysiology of schizophrenia that specifically modulates (Inoshima, I., et al., (2004) Am. J Physiol Lung Cell Mol. neurotransmitter systems previously demonstrated to be mis Physiol 286, L1038-L1044); renal fibrosis (Wada, T., et al., regulated in this disorder. Clinical studies in which cere (2004).J. Am. Soc. Nephrol. 15.940-948), and graft rejection brospinal fluid (CSF) NT concentrations have been measured (Saiura, A., et al., (2004) Arterioscler: Thromb. Vasc. Biol. 24. revealed a subset of schizophrenic patients with decreased 60 1886-1890). Furthermore, MCP-1 might also play a role in CSFNT concentrations that are restored by effective antip gestosis (Katabuchi, H., et al., (2003) Med Electron Microsc. sychotic drug treatment. Considerable evidence also exists 36, 253-262), as a paracrine factor in tumor development concordant with the involvement of NT systems in the mecha (Ohta, M., et al., (2003) IntJ Oncol. 22,773-778; Li, S., et al., nism of action of antipsychotic drugs. The behavioral and (2005) J. Exp. Med 202, 617-624), neuropathic pain (White, biochemical effects of centrally administered NT remarkably 65 F. A., et al., (2005) Proc. Natl. Acad. Sci. U.S.A) and AIDS resemble those of systemically administered antipsychotic (Park, I. W., Wang, J. F., and Groopman, J. E. (2001) Blood drugs, and antipsychotic drugs increase NT neurotransmis 97, 352-358: Coll, B., et al., (2006) Cytokine 34, 51-55). US 9, 181,233 B2 31 32 MCP-1 levels are increased in CSF of AD patients and selected from the group consisting of mild cognitive impair patients showing mild cognitive impairment (MCI) (Galim ment, Alzheimer's disease, Familial British Dementia, Famil berti, D., et al., (2006) Arch. Neurol. 63,538-543). Further ial Danish Dementia, neurodegeneration in Down Syndrome, more, MCP-1 shows an increased level in serum of patients Huntington's disease, Kennedy's disease, ulcer disease, with MCI and early AD (Clerici, F., et al., (2006) Neurobiol. duodenal cancer with or w/o Helicobacter pylori infections, Aging 27, 1763-1768). colorectal cancer, Zolliger-Ellison syndrome, gastric cancer Several cytotoxic T lymphocyte peptide-based vaccines with or without Helicobacter pylori infections, pathogenic against hepatitis B, human immunodeficiency virus and psychotic conditions, Schizophrenia, infertility, neoplasia, melanoma were recently studied in clinical trials. One inter inflammatory host responses, cancer, malign metastasis, esting melanoma vaccine candidate alone or in combination 10 melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, with other tumor antigens, is the decapeptide ELA. This pancreatitis, restenosis, impaired humoral and cell-mediated peptide is a Melan-A/MART-1 antigen immunodominant immune responses, leukocyte adhesion and migration pro peptide analog, with an N-terminal glutamic acid. It has been cesses in the endothelium, impaired food intake, impaired reported that the amino group and gamma-carboxylic group sleep-wakefulness, impaired homeostatic regulation of of glutamic acids, as well as the amino group and gamma 15 energy metabolism, impaired autonomic function, impaired carboxamide group of glutamines, condense easily to form hormonal balance or impaired regulation of body fluids, mul pyroglutamic derivatives. To overcome this stability problem, tiple sclerosis, the Guillain-Barré syndrome and chronic several peptides of pharmaceutical interest have been devel inflammatory demyelinizing polyradiculoneuropathy. oped with a pyroglutamic acid instead of N-terminal Furthermore, by administration of a compound according glutamine or glutamic acid, without loss of pharmacological to the present invention to a mammal it can be possible to properties. Unfortunately compared with ELA, the pyro stimulate the proliferation of myeloid progenitor cells. glutamic acid derivative (PyrELA) and also the N-terminal In addition, the administration of a QC inhibitor according acetyl-capped derivative (AcELA) failed to elicit cytotoxic T to the present invention can lead to Suppression of male fer lymphocyte (CTL) activity. Despite the apparent minor modi tility. fications introduced in PyrELA and AchELA, these two 25 In a preferred embodiment, the present invention provides derivatives probably have lower affinity than ELA for the the use of inhibitors of QC (EC) activity in combination with specific class I major histocompatibility complex. Conse other agents, especially for the treatment of neuronal dis quently, in order to conserve full activity of ELA, the forma eases, artherosclerosis and multiple Sclerosis. tion of PyrELA must be avoided (Beck A. et al. 2001, J Pept The present invention also provides a method of treatment Res 57(6):528-38). 30 of the aforementioned diseases comprising the administration Orexin A is a neuropeptide that plays a significant role in ofatherapeutically active amount of at least one compound of the regulation of food intake and sleep-wakefulness, possibly formula (I) to a mammal, preferably a human. by coordinating the complex behavioral and physiologic Most preferably, said method and corresponding uses are responses of these complementary homeostatic functions. It for the treatment of a disease selected from the group con plays also a role in the homeostatic regulation of energy 35 sisting of mild cognitive impairment, Alzheimer's disease, metabolism, autonomic function, hormonal balance and the Familial British Dementia, Familial Danish Dementia, neu regulation of body fluids. rodegeneration in Down Syndrome, Parkinson's disease and Recently, increased levels of the pentapeptide QYNAD Chorea Huntington, comprising the administration of a thera were identified in the cerebrospinal fluid (CSF) of patients peutically active amount of at least one compound of formula suffering from multiple sclerosis or Guillain-Barré syndrome 40 (I) to a mammal, preferably a human. compared to healthy individuals (Brinkmeier H. et al. 2000, Even preferably, the present invention provides a method Nature Medicine 6, 808–811). There is a big controversy in of treatment and corresponding uses for the treatment of the literature about the mechanism of action of the pentapep rheumatoid arthritis, atherosclerosis, pancreatitis and rest tide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially its efficacy enosis. to interact with and block sodium channels resulting in the 45 Pharmaceutical Combinations promotion of axonal dysfunction, which are involved in In a preferred embodiment, the present invention provides inflammatory autoimmune diseases of the central nervous a composition, preferably a pharmaceutical composition, system. But recently, it could be demonstrated that not comprising at least one QC inhibitor optionally in combina QYNAD, but its cyclized, pyroglutamated form, pEYNAD, is tion with at least one other agent selected from the group the active form, which blocks Sodium channels resulting in 50 consisting of nootropic agents, neuroprotectants, antiparkin the promotion of axonal dysfunction. Sodium channels are Sonian drugs, amyloid protein deposition inhibitors, beta expressed at high density in myelinated axons and play an amyloid synthesis inhibitors, antidepressants, anxiolytic obligatory role in conducting action potentials along axons drugs, antipsychotic drugs and anti-multiple Sclerosis drugs. within the mammalian brain and spinal cord. Therefore, it is Most preferably, said QC inhibitor is a compound of for speculated that they are involved in several aspects of the 55 mula (I) of the present invention. pathophysiology of inflammatory autoimmune diseases, More specifically, the aforementioned other agent is especially multiple sclerosis, the Guillain-Barré syndrome selected from the group consisting of beta-amyloid antibod and chronic inflammatory demyelinizing polyradiculoneur ies, cysteine protease inhibitors, PEP-inhibitors, LiCl, acetyl opathy. cholinesterase (AChE) inhibitors, PIMT enhancers, inhibi Furthermore, QYNAD is a substrate of the enzyme 60 tors of beta secretases, inhibitors of gamma secretases, glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in inhibitors of aminopeptidases, preferably inhibitors of dipep the brain of mammals, especially in human brain. Glutaminyl tidyl peptidases, most preferably DPIV inhibitors; inhibitors cyclase catalyzes effectively the formation of plYNAD from of neutral endopeptidase, inhibitors of Phosphodiesterase-4 its precursor QYNAD. (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor Accordingly, the present invention provides the use of the 65 antagonists, NMDA receptor antagonists, Sigma-1 receptor compounds of formula (I) for the preparation of a medica inhibitors, histamine H3 antagonists, immunomodulatory ment for the prevention oralleviation or treatment of a disease agents, immunosuppressive agents, MCP-1 antagonists oran US 9, 181,233 B2 33 34 agent selected from the group consisting of ANTEGREN TNFantagonists, e.g. Solimastat, lenercept (syn. to RO-45 (natalizumab), NEURELAN (fampridine-SR), CAMPATH 2081, TENEFUSE (lenercept)), onercept (sTNFR1), (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), CC-1069, paclitaxel, ANERGIX.MS (AG 284), SH636, DIFFERIN TNFalpha, e.g. etanercept (syn. to ENBREL (etanercept), (CD 271, adapalene), BAY 361677 (interleukin-4), matrix TNR-001) metalloproteinase-inhibitors (e.g., BB 76163), interferon-tau CD28 antagonists, e.g. abatacept, (trophoblastin) and SAIK-MS. Lck tyrosine kinase inhibitors, Furthermore, the other agent may be, for example, an anti cathepsin K inhibitors, anxiety drug or antidepressant selected from the group con analogs of the neuron-targeting membrane transporter pro sisting of 10 tein taurine and the plant-derived calpain inhibitor leu (a) BenZodiazepines, e.g. alprazolam, chlordiazepoxide, peptin, e.g., NEURODUR (C-201), clobazam, clonazepam, cloraZepate, diazepam, fludiaz chemokine receptor-1 (CCR1) antagonist, e.g. BX-471, epam, loflazepate, lorazepam, methaqualone, CCR2 antagonists, OXaZepam, praZepam, tranxene, 15 AMPA receptor antagonists, e.g. ER-167288-01 and (b) Selective serotonin re-uptake inhibitors (SSRIs), e.g. ER-099487, E-2007, talampanel, citalopram, fluoxetine, fluvoxamine, escitalopram, Ser potassium channel blockers, e.g. fampridine, traline, paroxetine, tosyl-proline-phenylalanine Small-molecule antagonists of (c) Tricyclic antidepressants, e.g. amitryptiline, clomi the VLA-4/VCAM interaction, e.g. TBC-3342, pramine, desipramine, doxepin, imipramine cell adhesion molecule inhibitors, e.g. TBC-772, (d) Monoamine oxidase (MAO) inhibitors, antisense oligonucleotides, e.g. EN-101, (e) AZapirones, e.g. buspirone, tandopsirone, antagonists of free immunoglobulin light chain (Ig|LC) (f) Serotonin-norepinephrine reuptake inhibitors (SN binding to mast cell receptors, e.g. F-991, RIs), e.g. Venlafaxine, dulloxetine, apoptosis inducing antigens, e.g. Apogen MS, (g) Mirtazapine, 25 alpha-2 adrenoceptor agonist, e.g. tizanidine (syn. to (h) Norepinephrine reuptake inhibitors (NRIs), e.g. ZANAFLEX (tizanidine), Ternelin, Sirdalvo, Sirdalud, reboxetine, Mionidine), (i) Bupropione, copolymer of L-tyrosine, L-lysine, L-glutamic acid and (j) Nefazodone, L-alanine, e.g. glatiramer acetate (syn. to COPAXONE (k) beta-blockers, 30 (glatiramer acetate), COP-1, copolymer-1), (1) NPY-receptor ligands: NPYagonists or antagonists. topoisomerase II modulators, e.g. mitoxantrone hydro In a further embodiment, the other agent may be, for chloride, example, an anti-multiple Sclerosis drug selected from the adenosine deaminase inhibitor, e.g. cladribine (syn. to group consisting of LEUSTATIN, (cladribine), MYLINAX (cladribine), a) dihydroorotate dehydrogenase inhibitors, e.g. 35 RWJ-26251), SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. interleukin-10, e.g. ilodecakin (syn. to TENOVIL (ilode to HMR-1715, MNA-279), cakin), Sch-52000, CSIF), b) autoimmune Suppressant, e.g. lacquinimod, interleukin-12 antagonists, e.g. lisofylline (syn. to c) paclitaxel, CT-1501R, LSF, lysofylline), d) antibodies, e.g. AGT-1, anti-granulocyte-macrophage 40 Ethanminium, e.g. SRI-62-834 (syn. to CRC-8605, NSC colony-stimulating factor (GM-CSF) monoclonal anti 614383), body, Nogo receptor modulators, ABT-874, CAMPATH immunomodulators, e.g. SAIK-MS, PNU-156804, alpha (alemtuzumab), anti-OX40 antibody, CNTO-1275, fetoprotein peptide (AFP). IPDS, DN-1921, natalizumab (syn. to AN-100226, ANTE retinoid receptor agonists, e.g. adapalene (syn. to DIF GREN (natalizumab), VLA-4 Mab), daclizumab (syn. 45 FERIN (adapalene), CD-271), to ZENEPAX (daclizumab), Ro-34-7375, SMART anti TGF-beta, e.g. GDF-1 (growth and differentiation factor Tac), J-695, priliximab (syn. to CENTARA (priliximab), 1), CEN-000029, cM-T412), MRA, Dantes, anti-IL-12-an TGF-beta-2, e.g. BETAKINE(povidone-iodine), tibody, MMP inhibitors, e.g. glycomed, peptide nucleic acid (PNA) preparations, e.g. reticulose, 50 phosphodiesterase 4 (PDE4) inhibitors, e.g. RPR-122818, interferon alpha, e.g. Alfaferone, human alpha interferon purine nucleoside phosphorylase inhibitors, e.g. 9-(3-py (syn. to OMNIFERON (Alfaferone), Alpha Leukof ridylmethyl)-9-deazaguanine, peldesine (syn. to BCX eron), 34, TO-200), interferon beta, e.g. FRONE (interferon beta-1a). alpha-4/beta-1 integrin antagonists, e.g. ISIS-104278, AVONEX (interferon beta-1a), REBIF (betron), inter 55 antisense alpha-4 integrin (CD49d), e.g. ISIS-17044, ISIS feron beta analogs, interferon beta-transferrin fusion 27104, protein, BETASERON (recombinant interferon beta cytokine-inducing agents, e.g. nucleosides, ICN-17261, 1b), cytokine inhibitors, interferon tau, heat shock protein vaccines, e.g. HSPPC-96, peptides (e.g., AT-008, ANERGIX.MS IMMUNOKINE 60 neuregulin growth factors, e.g. GGF-2 (syn. to neuregulin, (alpha-Immunokine-NNSO3), cyclic peptides like glial growth factor 2), ZD-73491), cathepsin S-inhibitors, therapeutic enzymes, e.g. soluble CD8 (sCD8)), bropirimine analogs, e.g. PNU-56169, PNU-63693, multiple Sclerosis-specific autoantigen-encoding plasmid Monocyte chemoattractant protein-1 inhibitors, e.g. and cytokine-encoding plasmid, e.g. BHT-3009: 65 benzimidazoles like MCP-1 inhibitors, LKS-1456, inhibitor of TNF-alpha (e.g., BLX-1002, thalidomide, PD-064036, PD-064126, PD-084486, PD-172084, SH-636), PD-172386. US 9, 181,233 B2 35 36 Further, the present invention provides pharmaceutical humanized antibodies are disclosed in WO 2008/011348. A compositions e.g. for parenteral, enteral or oral administra method for producing a vaccine composition for treating an tion, comprising at least one QC inhibitor, optionally in com amyloid-associated disease is disclosed in WO 2007/068411. bination with at least one of the other aforementioned agents. Suitable cysteine protease inhibitors are inhibitors of These combinations provide a particularly beneficial cathepsin B. Inhibitors of cathepsin Band compositions con effect. Such combinations are therefore shown to be effective taining such inhibitors are described, e.g. in WO 2006/ and useful for the treatment of the aforementioned diseases. 060473, WO 2006/042103, WO 2006/0398.07, WO 2006/ Accordingly, the invention provides a method for the treat 021413, WO 2006/021409, WO 2005/097103, WO 2005/ ment of these conditions. 007 199, WO2004/084830, WO 2004/078908, WO 2004/ The method comprises either co-administration of at least 10 026851, WO 2002/094881, WO 2002/027418, WO 2002/ one QC inhibitor and at least one of the other agents or the 021509, WO 1998/046559, WO 1996/021655. sequential administration thereof. Examples of suitable PIMT enhancers are 10-ami Co-administration includes administration of a formula noaliphatyl-dibenzb.foxepines described in WO 98/15647 tion, which comprises at least one QC inhibitor and at least and WO 03/057204, respectively. Further useful according to one of the other agents or the essentially simultaneous admin 15 the present invention are modulators of PIMT activity istration of separate formulations of each agent. described in WO 2004/039773. Beta-amyloid antibodies and compositions containing the Inhibitors of beta secretase and compositions containing same are described, e.g. in WO 2006/137354, WO 2006/ such inhibitors are described, e.g. in WO03/059346, 118959, WO 2006/103116, WO 2006/095041, WO 2006/ WO2006/099352, WO2006/078576, WO2006/060109, 081171, WO 2006/066233, WO 2006/066171, WO 2006/ WO2006/057983, WO2006/057945, WO2006/055434, 066089, WO 2006/066049, WO 2006/055178, WO 2006/ WO2006/044497, WO2006/034296, WO2006/034277, 046644, WO 2006/039470, WO 2006/036291, WO 2006/ WO2006/029850, WO2006/026204, WO2006/014944, 026408, WO 2006/016644, WO 2006/014638, WO 2006/ WO2006/014762, WO2006/002004, U.S. Pat. No. 0.14478, WO 2006/008661, WO 2005/123775, WO 2005/ 7,109,217, WO2005/113484, WO2005/103043, WO2005/ 120571, WO 2005/105998, WO 2005/081872, WO 2005/ 25 103020, WO2005/065195, WO2005/051914, WO2005/ 080435, WO 2005/028511, WO 2005/025616, WO 2005/ 044830, WO2005/032471, WO2005/018545, WO2005/ 025516, WO 2005/023858, WO 2005/018424, WO 2005/ 004803, WO2005/004802, WO2004/062625, WO2004/ 0.11599, WO 2005/000193, WO 2004/108895, WO 2004/ 043916, WO2004/013098, WO03/099202, WO03/043987, 098631, WO 2004/080419, WO 2004/071408, WO 2004/ WO03/03 9454, U.S. Pat. No. 6,562,783, WO02/098849 and 0.69182, WO 2004/067561, WO 2004/044204, WO 2004/ 30 WOO2/O96897. 032868, WO 2004/031400, WO 2004/029630, WO 2004/ Suitable examples of beta secretase inhibitors for the pur 029629, WO 2004/024770, WO 2004/024090, WO 2003/ pose of the present invention are WY-25105 (Wyeth); 104437, WO 2003/089460, WO 2003/086310, WO 2003/ Posiphen, (+)-phenserine (Torrey Pines/NIH); LSN 077858, WO 2003/074081, WO 2003/070760, WO 2003/ 2434074, LY-2070275, LY-2070273, LY-2070102 (Eli 063760, WO 2003/055514, WO 2003/051374, WO 2003/ 35 Lilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, 048204, WO 2003/045128, WO 2003/040183, WO 2003/ PNU-33312, PNU-38.773, PNU-90530 (Elan/Pfizer); KMI 039467, WO 2003/016466, WO 2003/015691, WO 2003/ 370, KMI-358, kmi-008 (Kyoto University); OM-99-2, 0.14162, WO 2003/012141, WO 2002/088307, WO 2002/ OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca/AS 088306, WO 2002/074240, WO 2002/046237, WO 2002/ tex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 046222, WO 2002/041842, WO 2001/062801, WO 2001/ 40 (De Novo Pharmaceuticals Ltd.) and CT-21166 (CoMentis 0.12598, WO 2000/077178, WO 2000/072880, WO 2000/ Inc.). 063250, WO 1999/060024, WO 1999/027944, WO 1998/ Inhibitors of gamma Secretase and compositions contain 04.4955, WO 1996/025435, WO 1994/017197, WO 1990/ ing such inhibitors are described, e.g. in WO2005/008250, 014840, WO 1990/O12871, WO 1990/012870, WO 1989/ WO2006/004880, U.S. Pat. Nos. 7,122,675, 7,030,239, OO6242. 45 6,992,081, 6,982.264, WO2005/097768, WO2005/028440, The beta-amyloid antibodies may be selected from, for WO2004/101562, U.S. Pat. Nos. 6,756,511, 6,683,091, example, polyclonal, monoclonal, chimenic or humanized WO03/066592, WO03/014075, WO03/013527, WO02/ antibodies. Furthermore, said antibodies may be useful to 36555, WO01/.53255, U.S. Pat. Nos. 7,109,217, 7,101,895, develop active and passive immune therapies, i.e. Vaccines 7,049,296, 7,034,182, 6,984,626, WO2005/040126, and monoclonal antibodies. 50 WO2005/030731, WO2005/014553, U.S. Pat. No. Suitable examples of beta-amyloid antibodies are ACU 6,890,956, EP 1334085, EP 1263774, WO2004/101538, 5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, WO2004/00958, WO2004/089911, WO2004/073630, RI-1219, RI-409, RN-1219 (Rinat Neuroscience Corp (Pfizer WO2004/069826, WO2004/039370, WO2004/031139, Inc)); the nanobody therapeutics of Ablynx/Boehringer WO2004/03 1137, U.S. Pat. Nos. 6,713,276, 6,686,449, Ingelheim; beta-amyloid-specific humanized monoclonal 55 WO03/091278, U.S. Pat. Nos. 6,649,196, 6,448,229, WO01/ antibodies of Intellect Neurosciences/IBL: m266, m266.2 77144 and WOO1/66564. (Eli Lilly & Co.); AAB-02 (Elan): bapineuzumab (Elan); Suitable gamma secretase inhibitors for the purpose of the BAN-2401 (Bioarctic Neuroscience AB); ABP-102 (Abio present invention are GSI-953, WAY-GSI-A, WAY-GSI-B gen Pharma SpA); BA-27, BC-05 (Takeda); R-1450 (Roche): (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, ESBA-212 (ESBATech AG); AZD-3102 (AstraZeneca) and 60 L-852631, L-852646 (Merck & Co. Inc.); LY-450139, beta-amyloid antibodies of Mindset BioPharmaceuticals Inc. LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, Especially preferred are antibodies, which recognize the BMS-433796 (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. N-terminus of the AB peptide. A suitable antibody, which Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); and recognizes the AB-N-Terminus is, for example Acl-24 (AC NGX-555 (TorreyPines Therapeutics Inc.). Immune SA). 65 DPIV-inhibitors and compositions containing such inhibi A monoclonal antibody against beta-amyloid peptide is tors are described, e.g. in U.S. Pat. Nos. 6,011,155; 6,107, disclosed in WO 2007/068412. Respective chimeric and 317; 6,110,949; 6,124,305; 6,172,081; WO99/61431, WO99/ US 9, 181,233 B2 37 38 67278, WO99/67279, DE 1983.4591, WO97/40832, WO95/ (ii) peptide structures, disclosed in WO 03/002593, e.g. trip 15309, WO98/19998, WO00/07617, WO99/38501, WO99/ eptides; 46272, WO99/38501, WO01/68603, WO01/40180, WO01/ (iii) peptidylketones, disclosed in WO 03/033524: 81337, WO01/81304, WO01/55105, WO02/02560, WO01/ (vi) substituted aminoketones, disclosed in WO 03/04.0174: 34594, WO02/38541, WO02/083128, WO03/072556, (v) topically active DP IV-inhibitors, disclosed in WO WO03/002593, WO03/000250, WO03/000180, WO03/ 01/14318; 000181, EP1258476, WO03/002553, WO03/002531, WO03/ (vi) prodrugs of DPIV-inhibitors, disclosed in WO99/67278 002530, WO03/004496, WO03/004498, WO03/024942, and WO99/67279; and WO03/024965, WO03/033524, WO03/035057, WO03/ (v) glutaminyl based DP IV-inhibitors, disclosed in WO 035067, WO03/037327, WO03/04.0174, WO03/045977, 10 O3/072556 and WO 2004/099.134. WO03/055881, WO03/057144, WO03/057666, WO03/ Suitable beta amyloid synthesis inhibitors for the purpose 068748, WO03/068757, WO03/082817, WO03/101449, of the present invention are for example Bisnorcymserine WO03/101958, WO03/104229, WO03/74500, WO2004/ (Axonyx Inc.); (R)-flurbiprofen (MCP-7869: FLURIZAN 007446, WO2004/007468, WO2004/018467, WO2004/ (tarenflurbil)) (Myriad Genetics); nitroflurbiprofen (NicOx); 018468, WO2004/018469, WO2004/026822, WO2004/ 15 BGC-20-0406 (Sankyo Co. Ltd.) and BGC-20-0466 (BTG 032836, WO2004/033455, WO2004/037169, WO2004/ plc.). 041795, WO2004/043940, WO2004/048352, WO2004/ Suitable amyloid protein deposition inhibitors for the pur 05.0022, WO2004/052850, WO2004/058266, WO2004/ pose of the present invention are for example SP-233 (Sa 064778, WO2004/069162, WO2004/071454, WO2004/ maritan Pharmaceuticals); AZD-103 (Ellipsis Neurothera 076433, WO2004/076434, WO2004/087053, WO2004/ peutics Inc.); AAB-001 (Bapineuzumab), AAB-002, ACC 089362, WO2004/099185, WO2004/103276, WO2004/ 001 (Elan Corp plc.); COLOSTRININ (proline-rich 103993, WO2004/108730, WO2004/110436, WO2004/ polypeptide complex produced from colostrum, ReGen 111041, WO2004/112701, WO2005/000846, WO2005/ Therapeutics plc.); Tramiprosate (Neurochem); AdPEDI 000848, WO2005/011581, WO2005/016911, WO2005/ (amyloid-beta 1-6)11) (Vaxin Inc.); MPI-127585, 023762, WO2005/025554, WO2005/026148, WO2005/ 25 MPI-423948 (Mayo Foundation); SP-08 (Georgetown Uni 030751, WO2005/033106, WO2005/037828, WO2005/ versity); ACU-5A5 (Acumen/Merck); Transthyretin (State 040095, WO2005/044195, WO2005/047297, WO2005/ University of New York); PTI-777, DP-74, DP 68, 051950, WO2005/056003, WO2005/056013, WO2005/ EXEBRYL (ProteoTech Inc.); m266 (Eli Lilly & Co.); EGb 058849, WO2005/075426, WO2005/082348, WO2005/ 761 (Dr. Willmar Schwabe GmbH); SPI-014 (Satori Pharma 085246, WO2005/087235, WO2005/095339, WO2005/ 30 ceuticals Inc.); ALS-633, ALS-499 (Advanced Life Sciences 095343, WO2005/095381, WO2005/108382, WO2005/ Inc.): AGT-160 (ArmaCien Technologies Inc.); TAK-070 113510, WO2005/116014, WO2005/116029, WO2005/ (Takeda Pharmaceutical Co. Ltd.); CHF-5022, CHF-5074, 118555, WO2005/120494, WO2005/121089, WO2005/ CHF-5096 and CHF-5105 (Chiesi Farmaceutici SpA.). 121131, WO2005/123685, WO2006/995613; WO2006/ Suitable PDE-4 inhibitors for the purpose of the present 009886: WO2006/013104; WO2006/017292; WO2006/ 35 invention are for example Doxofylline (Instituto Biologico 019965; WO2006/020017; WO2006/023750; WO2006/ Chemioterapica ABC SpA.); idudilast eye drops, tipelukast, 039325; WO2006/041976: WO2006/047248: WO2006/ ibudilast (Kyorin Pharmaceutical Co. Ltd.); theophylline 058.064; WO2006/058628: WO2006/066747; WO2006/ (Elan Corp.); cilomilast (GlaxoSmithKline plc.); Atopik O6677O and WO2006/068978. (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659, Suitable DP IV-inhibitors for the purpose of the present 40 CP-220629, PDE 4d inhibitor BHN (Pfizer Inc.); arofylline, invention are for example Sitagliptin, des-fluoro-sitagliptin LAS-37779 (Almirall Prodesfarma S.A.); roflumilast, (Merck & Co. Inc.); vildagliptin, DPP-728, SDZ-272-070 hydroxypumafentrine (Altana AG), tetomilast (Otska Phar (Novartis); ABT-279, ABT-341 (Abbott Laboratories); dena maceutical Co. Ltd.); tipelukast, ibudilast (Kyorin Pharma gliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322 (Takeda ceutical), CC-10004 (Celgene Corp.); HT-0712, IPL-4088 San Diego Inc.); tallabostat (Point Therapeutics Inc.); 45 (Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 Ro-0730699, R-1499, R-1438 (Roche Holding AG): (Memory Pharmaceuticals Corp.); oglemilast, GRC-4039 FE-999011 (Ferring Pharmaceuticals);TS-021 (Taisho Phar (Glenmark Pharmaceuticals Ltd.); AWD-12-281, ELB-353, maceutical Co. Ltd.); GRC-8200 (Glenmark Pharmaceuti ELB-526 (Elbion AG); EHT-0202 (Exon Hit Therapeutics cals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding S.A.); ND-1251 (Neuro3d S.A.); 4AZA-PDE4 (4 AZA Bio Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); 50 science NV.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottap SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi harm SpA.); GP-0203, NCS-613 (Centre National de la Pharma Corp.); DP-893, CP-867534-01 (Pfizer Inc.); TSL Recherche Scientifique); KF-19514 (Kyowa Hakko Kogyo 225, TMC-2A (Tanabe Seiyaku Co. Ltd.); PHX-1149 (Phe Co. Ltd.). ONO-6126 (Ono Pharmaceutical Co. Ltd.); nomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.); OS-0217 (Dainippon Pharmaceutical Co. Ltd.); IBFB PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 55 130011, IBFB-150007, IBFB-130020, IBFB-140301 (IBFB (ActivX Biosciences Inc.); sulphostin (Zaidan Hojin); Pharma GmbH); IC-485 (ICOS Corp.); RBX-14016 and KR-62436 (Korea Research Institute of Chemical Technol RBX-11082 (Ranbaxy Laboratories Ltd.). A preferred PDE ogy); P32/98 (Probiodrug AG); BI-A, BI-B (Boehringer 4-inhibitor is Rolipram. Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. MAO inhibitors and compositions containing such inhibi Ltd.); and NNC-72-2138 (Novo Nordisk A/S). 60 tors are described, e.g. in WO2006/091988, WO2005/ Other preferred DPIV-inhibitors are 007614, WO2004/089351, WO01/26656, WO01/12176, (i) dipeptide-like compounds, disclosed in WO99/61431, e.g. WO99/57120, WO99/57119, WO99/13878, WO98/4.0102, N-Valyl prolyl, O-benzoyl hydroxylamine, alanyl pyrroli WO98/01157, WO96/20946, WO94/07890 and WO92/ dine, isoleucyl thiazolidine like L-allo-isoleucyl thiazoli 21333. dine, L-threo-isoleucyl pyrrolidine and salts thereof, espe 65 Suitable MAO-inhibitors for the purpose of the present cially the fumaric salts, and L-allo-isoleucyl pyrrolidine invention are for example Linezolid (Pharmacia Corp.); and salts thereof; RWJ-416457 (RW Johnson Pharmaceutical Research Insti US 9, 181,233 B2 39 40 tute); budipine (Altana AG); GPX-325 (BioResearch Ire 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO land); isocarboxazid; phenelZine; tranylcypromine; indanta 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO dol (Chiesi Farmaceutici SpA.); moclobemide (Roche 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO Holding AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; (Burroughs Wellcome Co.); CX-157 (Krenitsky Pharmaceu WO 00/30674, U.S. Pat. Nos. 5,552,411, 5,663,192 and ticals Inc.); desoxypeganine (HF Arzneimittelforschung 5,567,714; 6,114.336, Japanese patent application JP GmbH & Co. KG); bifemelane (Mitsubishi-Tokyo Pharma 09157253; international patent applications WO 94/00486, ceuticals Inc.); RS-1636 (Sankyo Co. Ltd.); esuprone (BASF WO 93/12139, WO95/00161 and WO 99/15498: U.S. Pat. AG); rasagiline (Teva Pharmaceutical Industries Ltd.); lados No. 5,328,899; German patent application DE 393 9797; tigil (Hebrew University of Jerusalem); safinamide (Pfizer) 10 European patent applications EP 355 794 and EP 355 793; and NW-1048 (Newron Pharmaceuticals SpA.). and Japanese patent applications JP 06116284 and JP Suitable histamine H3 antagonists for the purpose of the 07267988. Preferred NPY antagonists include those com present invention are, e.g. ABT-239, ABT-834 (Abbott Labo pounds that are specifically disclosed in these patent docu ratories): 3874-H1 (Aventis Pharma); UCL-2173 (Berlin ments. More preferred compounds include amino acid and Free University), UCL-1470 (BioProjet, Societe Civile de 15 non-peptide-based NPY antagonists. Amino acid and non Recherche); DWP-302 (Daewoong Pharmaceutical Co Ltd); peptide-based NPY antagonists which may be mentioned GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); include those disclosed in European patent applications EPO cipralisant, GT-2203 (Gliatech Inc.); Ciproxifan (INSERM), 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378: 1S,2S-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane international patent applications WO 94/17035, WO (Hokkaido University); JNJ-17216498, JNJ-5207852 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO (Johnson & Johnson); NNC-0038-0000-1049 (Novo Nordisk 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO A/S); and Sch-79687 (Schering-Plough). 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO PEP inhibitors and compositions containing such inhibi 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO tors are described, e.g. in JP 01042465, JP 03031298, JP 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and 04208299, WO 00/71144, U.S. Pat. No. 5,847,155; JP 25 WO 99/15498: U.S. Pat. Nos. 5,552,411, 5,663,192 and 09040693, JP 10077300, JP 05331072, JP 05015314, WO 5,567,714; and Japanese patent application JP 09157253. 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP Preferred amino acid and non-peptide-based NPY antago 01068396, EP 0709373, U.S. Pat. No. 5,965,556, U.S. Pat. nists include those compounds that are specifically disclosed Nos. 5,756,763, 6,121,311, JP 63264454, JP 64000069, JP in these patent documents. 63162672, EP 0268190, EP 0277588, EP 0275482, U.S. Pat. 30 Particularly preferred compounds include amino acid Nos. 4,977,180, 5,091,406, 4,983,624, 5,112,847, 5,100,904, based NPY antagonists. Amino acid-based compounds, 5,254,550, 5,262,431, 5,340,832, 4,956,380, EP 0303434, JP which may be mentioned include those disclosed in interna 03056486, JP 01143897, JP 1226880, EP 0280956, U.S. Pat. tional patent applications WO 94/17035, WO 97/19911, WO No. 4,857,537, EP 0461677, EP 0345428, JP 02275858, U.S. 97/19913, WO 97/19914 or, preferably, WO 99/15498. Pre Pat. No. 5,506,256, JP 06192298, EP 0618.193, JP 03255080, 35 ferred amino acid-based NPY antagonists include those that EP 0468469, U.S. Pat. No. 5,118,811, JP 05025125, WO are specifically disclosed in these patent documents, for 9313065, JP 05201970, WO 9412474, EP 0670309, EP example BIBP3226 and, especially, (R) N-2-(dipheny 0451547, JP 06339390, U.S. Pat. Nos. 5,073,549, 4,999,349, lacetyl)-(R) N-1-(4-hydroxy-phenyl)ethyl arginine EP 0268281, U.S. Pat. No. 4,743,616, EP 0232849, EP amide (Example 4 of international patent application WO 0224272, JP 621 14978, JP 621 14957, U.S. Pat. Nos. 4,757, 40 99/15498). 083, 4,810,721, 5,198.458, 4,826,870, EP 0201742, EP M1 receptor agonists and compositions containing Such 0201741, U.S. Pat. No. 4,873,342, EP 0172458, JP inhibitors are described, e.g. in WO2004/087158, WO91/ 61037764, EP 0201743, U.S. Pat. No. 4,772,587, EP 10664. 0372484, U.S. Pat. No. 5,028,604, WO 91/18877, JP Suitable M1 receptor antagonists for the purpose of the 04009367, JP 04235162, U.S. Pat. No. 5,407,950, WO 45 present invention are for example CDD-0102 (Cognitive 95/01352, JP 01250370, JP 02207070, U.S. Pat. No. 5,221, Pharmaceuticals); Cevimeline (Evoxac) (Snow Brand Milk 752, EP 0468339, JP 04211648, WO 99/46272, WO 2006/ Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics): O5872O and PCTAEP2006/061428. sabcomeline (GlaxoSmithKline); alvameline (H Lundbeck Suitable prolyl endopeptidase inhibitors for the purpose of A/S); LY-593093 (Eli Lilly & Co.); VRTX-3 (Vertex Phar the present invention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe 50 maceuticals Inc.); WAY-132983 (Wyeth) and CI-101 7/(PD Pro-Benzothiazole (Probiodrug), Z-321 (Zeria Pharmaceuti 151832) (Pfizer Inc.). cal Co Ltd.); ONO-1603 (Ono Pharmaceutical Co Ltd); JTP Acetylcholinesterase inhibitors and compositions contain 4819 (Japan Tobacco Inc.) and S-17092 (Servier). ing such inhibitors are described, e.g. in WO2006/071274, Other Suitable compounds that can be used according to the WO2006/070394, WO2006/040688, WO2005/092009, present invention in combination with QC-inhibitors are 55 WO2005/079789, WO2005/039580, WO2005/027975, NPY, an NPY mimetic or an NPY agonist or antagonist or a WO2004/084884, WO2004/037234, WO2004/032929, ligand of the NPY receptors. WO03/101458, WO03/091220, WO03/082820, WO03/ Preferred according to the present invention are antago 020289, WO02/32412, WO01/85145, WO01/78728, WO01/ nists of the NPY receptors. 66096, WO00/02549, WO01/00215, WO00/15205, WO00/ Suitable ligands or antagonists of the NPY receptors are 60 23057, WO00/33840, WO00/30446, WO00/23057, WO00/ 3a.4.5.9b-tetrahydro-1h-benzeindol-2-yl amine-derived 15205, WO00/09483, WO00/07600, WO00/02549, WO99/ compounds as disclosed in WO 00/68197. 47131, WO99/07359, WO98/30243, WO97/38993, WO97/ NPY receptor antagonists which may be mentioned 13754, WO94/29255, WO94/20476, WO94/19356, WO93/ include those disclosed in European patent applications EP 0 O3O34 and WO92/19238. 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378: 65 Suitable acetylcholinesterase inhibitors for the purpose of international patent applications WO 94/17035, WO the present invention are for example Donepezil (Eisai Co. 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO Ltd.); rivastigmine (Novartis AG): (-)-phenserine (Tor US 9, 181,233 B2 41 42 reyPines Therapeutics); ladostigil (Hebrew University of tensin II receptor but do not resultinactivation of the receptor. Jerusalem); huperzine A (Mayo Foundation); galantamine As a consequence of the blockade of the AT1 receptor, these (Johnson & Johnson); Memoquin (Universita di Bologna); antagonists can, e.g. be employed as antihypertensive agents. SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 Suitable angiotensin II receptor blockers which may be (Sankyo Co. Ltd.); physostigmine (Forest Laboratories Inc.); employed in the combination of the present invention include NP-0361 (Neuropharma SA); ZT-1 (Debiopharm); tacrine AT, receptor antagonists having differing structural features, (Warner-Lambert Co.); metrifonate (Bayer Corp.) and INM preferred are those with non-peptidic structures. For 176 (Whanlin). example, mention may be made of the compounds that are NMDA receptor antagonists and compositions containing selected from the group consisting of Valsartan (EP 443983), such inhibitors are described, e.g. in WO2006/094674, 10 WO2006/058236, WO2006/058059, WO2006/010965, losartan (EP 253310), candesartan (EP 459136), eprosartan WO2005/000216, WO2005/102390, WO2005/079779, (EP 403159), irbesartan (EP 454511), olmesartan (EP WO2005/079756, WO2005/072705, WO2005/070429, 503785), tasosartan (EP 539086), telmisartan (EP522314), WO2005/055996, WO2005/035522, WO2005/009421, the compound with the designation E-41 77 of the formula WO2005/000216, WO2004/092189, WO2004/039371, 15 WO2004/028522, WO2004/009062, WO03/010159, WO02/ 072542, WO02/34718, WO01/98262, WO01/94321, WO01/ 92204, WO01/81295, WOO1/32640, WO01/10833, WO01/ I OH 10831, WO00/56711, WO00/29023, WO00/001.97, WO99/ N 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/ 3.1986, WO95/26352, WO95/26350, WO95/26349, WO95/ 26342, WO95/12594, WO95/02602, WO95/02601, WO94/ 25 20109, WO94/13641, WO94/09016 and WO93/25534. the compound with the designation SC-52458 of the follow Suitable NMDA receptor antagonists for the purpose of the ing formula present invention are for example Memantine (Merz & Co. GmbH); topiramate (Johnson & Johnson); NEURODEX (AVP-923)(Center for Neurologic Study); EN-3231 (Endo 30 Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS -5161 (CeNeS Pharmaceuticals Inc.); dexanabinol (HU-211: Sinnabidol: PA-50211) (Phar mos); EPICEPT NP-1 (amitriptyline hydrochloride, ket amine) (Dalhousie University); indantadol (V-3381; CNP 35 3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter Ltd.); traxo prodil (CP-101606), besonprodil (PD-196860, CI-1041) (Pfizer Inc.); CGX-1007 (Cognetix Inc.); delucemine (NPS 1506) (NPSPharmaceuticals Inc.); EVT-101 (Roche Holding 40 AG); acamprosate (Synchroneuron LLC.); CR-3991, CR-2249, CR-3394 (Rottapharm SpA.); AV-101 (4-CI and the compound with the designation the compound kynurenine (4-CI-KYN)), 7-chloro-kynurenic acid (7-CI ZD-8731 of the formula KYNA) (VistaGen); NPS-1407 (NPS Pharmaceuticals Inc.); YT-1006 (Yaupon Therapeutics Inc.); ED-1812(Sosei R&D 45 Ltd.); himantane (hydrochloride N-2-(adamantly)-hexam H ethylen-imine) (RAMS); Lancicemine (AR-R-15896) (As %ys traZeneca); EVT-102, Ro-25-6981 and Ro-63-1908 (Hoff V mann-La Roche AG/Evotec). Furthermore, the present invention relates to combination 50 therapies useful for the treatment of atherosclerosis, resteno sis or arthritis, administering a QC inhibitor in combination with another therapeutic agent selected from the group con ) / \ ( ) ( ) sisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium 55 or, in each case, a pharmaceutically acceptable salt thereof. channel blockers (CCB); beta-blockers; platelet aggregation Preferred AT1-receptor antagonists are those agents that inhibitors; cholesterol absorption modulators; HMG-Co-A have been approved and reached the market, most preferred is reductase inhibitors; high density lipoprotein (HDL) increas Valsartan, or a pharmaceutically acceptable Salt thereof. ing compounds; renin inhibitors; IL-6 inhibitors; antiinflam The interruption of the enzymatic degradation of angio matory corticosteroids; antiproliferative agents; nitric oxide 60 tensin to angiotensin II with ACE inhibitors is a successful donors; inhibitors of extracellular matrix synthesis; growth variant for the regulation of blood pressure and thus also factor or cytokine signal transduction inhibitors; MCP-1 makes available a therapeutic method for the treatment of antagonists and tyrosine kinase inhibitors providing benefi hypertension. cial or synergistic therapeutic effects over each monotherapy A suitable ACE inhibitor to be employed in the combina component alone. 65 tion of the present inventionis, e.g. a compound selected from Angiotensin II receptor blockers are understood to be those the group consisting alacepril, benazepril, benazeprilat, cap active agents that bind to the AT1-receptor Subtype of angio topril, ceronapril, cilaZapril, delapril, enalapril, enaprilat, US 9, 181,233 B2 43 44 fosinopril, imidapril, lisinopril, moveltopril, perindopril, from the group consisting of atorvastatin, cerivastatin, fluv quinapril, ramipril, spirapril, temocapril and trandolapril, or astatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and in each case, a pharmaceutically acceptable salt thereof. simvastatin, or in each case, a pharmaceutically acceptable Preferred ACE inhibitors are those agents that have been salt thereof. marketed, most preferred are benazepril and enalapril. 5 Preferred HMG-Co-A reductase inhibitors are those A diuretic is, for example, a thiazide derivative selected agents, which have been marketed, most preferred is atorv from the group consisting of chlorothiazide, hydrochlorothi astatin, pitavastatin or simvastatin, or a pharmaceutically azide, methylclothiazide, and chlorothalidon. The most pre acceptable salt thereof. ferred diuretic is hydrochlorothiazide. A diuretic furthermore HDL-increasing compounds include, but are not limited to, comprises a potassium sparing diuretic Such as amiloride or 10 cholesterol ester transfer protein (CETP) inhibitors. triameterine, or a pharmaceutically acceptable salt thereof. Examples of CETP inhibitors include JTT7O5 disclosed in The class of CCBs essentially comprises dihydropyridines Example 26 of U.S. Pat. No. 6,426,365 issued Jul. 30, 2002, (DHPs) and non-DHPs, such as diltiazem-type and Vera and pharmaceutically acceptable salts thereof. pamil-type CCBs. Inhibition of interleukin 6 mediated inflammation may be A CCB useful in said combination is preferably a DHP 15 achieved indirectly through regulation of endogenous choles representative selected from the group consisting of amlo terol synthesis and isoprenoid depletion or by direct inhibi dipine, felodipine, ryosidine, isradipine, lacidipine, nicar tion of the signal transduction pathway utilizing interleukin-6 dipine, nifedipine, niguldipine, niludipine, nimodipine, nisol inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, dipine, nitrendipine and nivaldipine, and is preferably a non interleukin-6 antisense oligonucleotide (ASON), gp130 pro DHP representative selected from the group consisting of tein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, flunarizine, prenylamine, diltiazem, fendiline, gallopamil, serine/threonine kinase inhibitors/antibodies, mitogen-acti mibefradil, anipamil, tiapamil and Verapamil, and in each vated protein (MAP) kinase inhibitors/antibodies, phosphati case, a pharmaceutically acceptable salt thereof. All, these dylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear CCBs are therapeutically used, e.g. as anti-hypertensive, anti factor kappaB (NF-kB) inhibitors/antibodies, IKB kinase angina pectoris or anti-arrhythmic drugs. 25 (IKK) inhibitors/antibodies, activator protein-1 (AP-1) Preferred CCBs comprise amlodipine, diltiazem, israd inhibitors/antibodies, STAT transcription factors inhibitors/ ipine, nicardipine, nifedipine, nimodipine, nisoldipine, antibodies, altered IL-6, partial peptides of IL-6 or IL-6 nitrendipine and Verapamil or, e.g. dependent on the specific receptor, or SOCS (Suppressors of cytokine signaling) pro CCB, a pharmaceutically acceptable salt thereof. Especially tein, PPARgamma and/or PPAR beta/delta activators/ligands preferred as DHP is amlodipine or a pharmaceutically accept 30 or a functional fragment thereof. able salt thereof, especially the besylate. An especially pre A suitable antiinflammatory corticosteroid is dexametha ferred representative of non-DHPS is verapamil or a pharma SO. ceutically acceptable salt, especially the hydrochloride, Suitable antiproliferative agents are cladribine, rapamycin, thereof. Vincristine and taxol. Beta-blockers suitable for use in the present invention 35 A suitable inhibitor of extracellular matrix synthesis is include beta-adrenergic blocking agents (beta-blockers), halofuginone. which compete with epinephrine for beta-adrenergic recep A Suitable growth factor or cytokine signal transduction tors and interfere with the action of epinephrine. Preferably, inhibitor is, e.g. the ras inhibitor R115777. the beta-blockers are selective for the beta-adrenergic recep A suitable tyrosine kinase inhibitor is tyrphostin. tor as compared to the alpha-adrenergic receptors, and so do 40 Suitable renin inhibitors are described, e.g. in WO 2006/ not have a significant alpha-blocking effect. Suitable beta 116435. A preferred renin inhibitor is aliskiren, preferably in blockers include compounds selected from acebutolol. the form of the hemi-fumarate salt thereof. atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, MCP-1 antagonists may, e.g. be selected from anti-MCP-1 labetalol, metoprolol, nadolol, oXprenolol, penbutolol, pin antibodies, preferably monoclonal or humanized monoclonal dolol, propranolol, Sotalol and timolol. Where the beta 45 antibodies, MCP-1 expression inhibitors, CCR2-antagonists, blocker is an acid or base or otherwise capable of forming TNF-alpha inhibitors, VCAM-1 gene expression inhibitors pharmaceutically acceptable salts or prodrugs, these forms and anti-C5a monoclonal antibodies. are considered to be encompassed herein, and it is understood MCP-1 antagonists and compositions containing Such that the compounds may be administered in free form or in the inhibitors are described, e.g. in WO02/070509, WO02/ form of a pharmaceutically acceptable salt or a prodrug. Such 50 081463, WO02/060900, US2006/670364, US2006/677365, as a physiologically hydrolyzable and acceptable ester. For WO2006/097624, US2006/316449, WO2004/056727, example, metoprolol is suitably administered as its tartrate WO03/053368, WO00/198289, WO00/157226, WO00/ salt, propranolol is suitably administered as the hydrochlo 046195, WO00/0461.96, WO00/046199, WO00/046198, ride salt, and so forth. WO00/046197, WO99/046991, WO99/007351, WO98/ Platelet aggregation inhibitors include PLAVIX(R) (clopi 55 006703, WO97/012615, WO2005/105133, WO03/037376, dogrel bisulfate), PLETAL(R) (cilostazol) and aspirin. WO2006/125202, WO2006/085961, WO2004/024921, Cholesterol absorption modulators include ZETIAR) WO2006/074265. (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical Co. Suitable MCP-1 antagonists are, for instance, C-243 (Telik Japan). Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis HMG-Co-A reductase inhibitors (also called beta-hy 60 Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG): droxy-beta-methylglutaryl-co-enzyme-A reductase inhibi CC-1 1006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis); tors or statins) are understood to be those active agents which MLN-1202 (Millenium Pharmaceuticals Inc.); AGI-1067, may be used to lower lipid levels including cholesterol in AGIX-4207, AGI-1096 (AtherioGenics Inc.); PRS-211095, blood. PRS-211092 (Pharmos Corp.); anti-C5a monoclonal anti The class of HMG-Co-A reductase inhibitors comprises 65 bodies, e.g. neutraZumab (G2 Therapies Ltd.); AZD-6942 compounds having differing structural features. For example, (AstraZeneca plc.); 2-mercaptoimidazoles (Johnson & mention may be made of the compounds, which are selected Johnson); TE1-E00526, TEI-6122 (Deltagen); RS-504393 US 9, 181,233 B2 45 46 (Roche Holding AG); SB-282241, SB-380732, ADR-7 examples 1-89, in combination with interferones, pref (GlaxoSmithKline); anti-MCP-1 monoclonal antibodies erably betaferon, for the prevention and/or treatment of (Johnson & Johnson). multiple Sclerosis, Combinations of QC-inhibitors with MCP-1 antagonists a QC inhibitor, preferably a QC inhibitor of formula (I), may be useful for the treatment of inflammatory diseases in more preferably a QC inhibitor selected from any one of general, including neurodegenerative diseases. examples 1-89, in combination with interferones, pref Combinations of QC-inhibitors with MCP-1 antagonists erably Rebif, for the prevention and/or treatment of mul are preferred for the treatment of Alzheimer's disease. tiple Sclerosis Most preferably the QC inhibitor is combined with one or a QC inhibitor, preferably a QC inhibitor of formula (I), more compounds selected from the following group: 10 more preferably a QC inhibitor selected from any one of PF-43603.65, m266, bapineuzumab, R-1450, Posiphen, (+)- examples 1-89, in combination with Copaxone, for the phenserine, MK-0752, LY-450139, E-2012, (R)-flurbipro prevention and/or treatment of multiple Sclerosis, fen, AZD-103, AAB-001 (Bapineuzumab), Tramiprosate, a QC inhibitor, preferably a QC inhibitor of formula (I), EGb-761, TAK-070, Doxofylline, theophylline, cilomi 15 more preferably a QC inhibitor selected from any one of last, tofimilast, roflumilast, tetomilast, tipelukast, ibudi examples 1-89, in combination with dexamethasone, for last, HT-0712, MEM-1414, oglemilast, Linezolid, the prevention and/or treatment of restenosis, budipine, isocarboxazid, phenelzine, tranylcypromine, a QC inhibitor, preferably a QC inhibitor of formula (I), indantadol, moclobemide, rasagiline, ladostigil, Safina more preferably a QC inhibitor selected from any one of mide, ABT-239, ABT-834, GSK-189254A, Ciproxifan, examples 1-89, in combination with dexamethasone, for JNJ-17216498, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Ben the prevention and/or treatment of atherosclerosis, Zothiazole, Z-321, ONO-1603, JTP-4819, S-17092, a QC inhibitor, preferably a QC inhibitor of formula (I), BIBP3226; (R) N-2-(diphenylacetyl)-(R) N-1-(4-hy more preferably a QC inhibitor selected from any one of droxyphenyl)ethyl arginine amide, Cevimeline, Sabcome examples 1-89, in combination with dexamethasone, for line, (PD-151832), Donepezil, rivastigmine, (-)- 25 the prevention and/or treatment of rheumatid arthritis, phenserine, ladostigil, galantamine, tacrine, metrifonate, a QC inhibitor, preferably a QC inhibitor of formula (I), Memantine, topiramate, AVP-923. EN-3231, neramexane, more preferably a QC inhibitor selected from any one of Valsartan, benazepril, enalapril, hydrochlorothiazide, examples 1-89, in combination with HMG-Co-A-reduc amlodipine, diltiazem, isradipine, nicardipine, nifedipine, tase inhibitors, for the prevention and/or treatment of nimodipine, nisoldipine, nitrendipine, Verapamil, amlo 30 restenosis, wherein the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, dipine, acebutolol, atenolol, betaxolol, bisoprolol, car lovastatin, pitavastatin, pravastatin, rosuvastatin and teolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, simvastatin, oXprenolol, penbutolol, pindolol, propranolol, Sotalol, a QC inhibitor, preferably a QC inhibitor of formula (I), timolol, PLAVIX(R) (clopidogrel bisulfate), PLETAL(R) 35 more preferably a QC inhibitor selected from any one of (cilostazol), aspirin, ZETIAR (ezetimibe) and KT6-971, examples 1-89, in combination with HMG-Co-Areduc statins, atorvastatin, pitavastatin or simvastatin; dexam tase inhibitors, for the prevention and/or treatment of ethasone, cladribine, rapamycin, Vincristine, taxol. atherosclerosis wherein the HMG-Co-A-reductase aliskiren, C-243, ABN-912, SSR-150106, MLN-1202 and inhibitor is selected from atorvastatin, cerivastatin, flu betaferon. 40 vastatin, lovastatin, pitavastatin, pravastatin, rosuvasta In particular, the following combinations are considered: tin and simvastatin, a QC inhibitor, preferably a QC inhibitor of formula (I), a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of more preferably a QC inhibitor selected from any one of examples 1-89, in combination with Atorvastatin for the examples 1-89, in combination with HMG-Co-Areduc treatment and/or prevention of artherosclerosis, 45 tase inhibitors, for the prevention and/or treatment of a QC inhibitor, preferably a QC inhibitor of formula (I), rheumatoid arthritis wherein the HMG-Co-A-reductase more preferably a QC inhibitor selected from any one of inhibitor is selected from atorvastatin, cerivastatin, flu examples 1-89, in combination with immunosuppres vastatin, lovastatin, pitavastatin, pravastatin, rosuvasta sive agents, preferably rapamycin for the prevention tin and simvastatin, and/or treatment of restenosis, 50 a QC inhibitor, preferably a QC inhibitor of formula (I), a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of more preferably a QC inhibitor selected from any one of examples 1-89, in combination with amyloid-beta anti examples 1-89, in combination with immunosuppres bodies for the prevention and/or treatment of mild cog sive agents, preferably paclitaxel for the prevention and/ nitive impairment, wherein the amyloid-beta antibody is or treatment of restenosis, 55 Acl-24, a QC inhibitor, preferably a QC inhibitor of formula (I), a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any one of more preferably a QC inhibitor selected from any one of examples 1-89, in combination with AChE inhibitors, examples 1-89, in combination with amyloid-beta anti preferably Donepezil, for the prevention and/or treat bodies for the prevention and/or treatment of Alzhe ment of Alzheimer's disease, 60 imer's disease, wherein the amyloid-beta antibody is a QC inhibitor, preferably a QC inhibitor of formula (I), Acl-24, more preferably a QC inhibitor selected from any one of a QC inhibitor, preferably a QC inhibitor of formula (I), examples 1-89, in combination with interferones, pref more preferably a QC inhibitor selected from any one of erably Aronex, for the prevention and/or treatment of examples 1-89, in combination with amyloid-beta anti multiple Sclerosis, 65 bodies for the prevention and/or treatment of neurode a QC inhibitor, preferably a QC inhibitor of formula (I), generation in Down Syndrome, wherein the amyloid more preferably a QC inhibitor selected from any one of beta antibody is Acl-24, US 9, 181,233 B2 47 48 a QC inhibitor, preferably a QC inhibitor of formula (I), water, glycols, oils, alcohols, flavoring agents, preservatives, more preferably a QC inhibitor selected from any one of coloring agents and the like; for Solid oral preparations such examples 1-89, in combination with beta-secretase as, for example, powders, capsules, gelcaps and tablets, Suit inhibitors for the prevention and/or treatment of mild able carriers and additives include starches, Sugars, diluents, cognitive impairment, wherein the beta-secretase granulating agents, lubricants, binders, disintegrating agents inhibitor selected from WY-25105, GW-840736X and and the like. Because of their ease in administration, tablets CTS-21166, and capsules represent the most advantageous oral dosage a QC inhibitor, preferably a QC inhibitor of formula (I), unit form, in which case solid pharmaceutical carriers are more preferably a QC inhibitor selected from any one of obviously employed. If desired, tablets may be Sugar coated examples 1-89, in combination with beta-secretase 10 or enteric coated by standard techniques. For parenterals, the inhibitors for the prevention and/or treatment of Alzhe carrier will usually comprise sterile water, though otheringre imer's disease, wherein the beta-secretase inhibitor is dients, for example, for purposes such as aiding Solubility or selected from WY-25105, GW-840736X and CTS for preservation, may be included. 21166, Injectable Suspensions may also prepared, in which case a QC inhibitor, preferably a QC inhibitor of formula (I), 15 appropriate liquid carriers, Suspending agents and the like more preferably a QC inhibitor selected from any one of may be employed. The pharmaceutical compositions herein examples 1-89, in combination with beta-secretase will contain, per dosage unit, e.g., tablet, capsule, powder, inhibitors for the prevention and/or treatment of neuro injection, teaspoonful and the like, an amount of the active degeneration in Down Syndrome, wherein the beta ingredient(s) necessary to deliver an effective dose as secretase inhibitor is selected from WY-25105, described above. The pharmaceutical compositions herein GW-840736X and CTS-21166, will contain, per dosage unit, e.g., tablet, capsule, powder, a QC inhibitor, preferably a QC inhibitor of formula (I), injection, Suppository, teaspoonful and the like, from about more preferably a QC inhibitor selected from any one of 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be examples 1-89, in combination with gamma-secretase given at a dosage of from about 0.1-300 mg/kg per day (pre inhibitors for the prevention and/or treatment of mild 25 ferred 1-50 mg/kg per day) of each active ingredient or com cognitive impairment, wherein the gamma-secretase bination thereof. The dosages, however, may be varied inhibitor is selected from LY-450 139, LY-411575 and depending upon the requirement of the patients, the severity AN-37124, of the condition being treated and the compound being a QC inhibitor, preferably a QC inhibitor of formula (I), employed. The use of either daily administration or post more preferably a QC inhibitor selected from any one of 30 periodic dosing may be employed. examples 1-89, in combination with gamma-secretase Preferably these compositions are in unit dosage forms inhibitors for the prevention and/or treatment of Alzhe from such as tablets, pills, capsules, powders, granules, sterile imer's disease, wherein the gamma-secretase inhibitor parenteral Solutions or Suspensions, metered aerosol or liquid is selected from LY-450139, LY-411575 and AN-37124, sprays, drops, ampoules, autoinjector devices or Supposito a QC inhibitor, preferably a QC inhibitor of formula (I), 35 ries; for oral parenteral, intranasal. Sublingual or rectal more preferably a QC inhibitor selected from any one of administration, or for administration by inhalation or insuf examples 1-89, in combination with gamma-secretase flation. Alternatively, the composition may be presented in a inhibitors for the prevention and/or treatment of neuro form Suitable for once-weekly or once-monthly administra degeneration in Down Syndrome, wherein the gamma tion; for example, an insoluble salt of the active compound, secretase inhibitor is selected from LY-450139, 40 Such as the decanoate salt, may be adapted to provide a depot LY-411575 and AN-37124. preparation for intramuscular injection. For preparing Solid Such a combination therapy is in particular useful for AD, compositions such as tablets, the principal active ingredientis FAD, FDD and neurodegeneration in Down syndrome as well mixed with a pharmaceutical carrier, e.g. conventional tablet as atherosclerosis, rheumatoid arthritis, restenosis and pan ing ingredients such as corn starch, lactose, Sucrose, Sorbitol, creatitis. 45 talc, Stearic acid, magnesium Stearate, dicalcium phosphate Such combination therapies might result in a better thera or gums, and other pharmaceutical diluents, e.g. water, to peutic effect (less proliferation as well as less inflammation, a form a solid preformulation composition containing a homo stimulus for proliferation) than would occur with either agent geneous mixture of a compound of the present invention, or a alone. pharmaceutically acceptable salt thereof. When referring to With regard to the specific combination of inhibitors of QC 50 these preformulation compositions as homogeneous, it is and further compounds it is referred in particular to WO meant that the active ingredient is dispersed evenly through 2004/098.625 in this regard, which is incorporated herein by out the composition so that the composition may be readily reference. Subdivided into equally effective dosage forms such as tab Pharmaceutical Compositions lets, pills and capsules. This solid preformulation composi To prepare the pharmaceutical compositions of this inven 55 tion is then subdivided into unit dosage forms of the type tion, at least one compound of formula (I) optionally in com described above containing from 0.1 to about 500 mg of each bination with at least one of the other aforementioned agents active ingredient or combinations thereof of the present can be used as the active ingredient(s). The active invention. ingredient(s) is intimately admixed with a pharmaceutical The tablets or pills of the compositions of the present carrier according to conventional pharmaceutical compound 60 invention can be coated or otherwise compounded to provide ing techniques, which carrier may take a wide variety of a dosage form affording the advantage of prolonged action. forms depending of the form of preparation desired for For example, the tablet or pill can comprise an inner dosage administration, e.g., oral or parenteral Such as intramuscular. and an outer dosage component, the latter being in the form of In preparing the compositions in oral dosage form, any of the an envelope over the former. The two components can be usual pharmaceutical media may be employed. Thus, for 65 separated by an enteric layer which serves to resist disinte liquid oral preparations, such as for example, Suspensions, gration in the stomach and permits the inner component to elixirs and solutions, Suitable carriers and additives include pass intact into the duodenum or to be delayed in release. A US 9, 181,233 B2 49 50 variety of material can be used for such enteric layers or Such polymers can include polyvinylpyrrolidone, pyran coatings, such materials including a number of polymeric copolymer, polyhydroxypropylmethacrylamidephenol, acids with Such materials as shellac, cetyl alcohol and cellu polyhydroxyethylaspartamid-ephenol, or polyethyl eneox lose acetate. idepolyllysine substituted with palmitoyl residue. Further This liquid forms in which the compositions of the present more, the compounds of the present invention may be coupled invention may be incorporated for administration orally or by to a class of biodegradable polymers useful in achieving injection include, aqueous solutions, Suitably flavoured Syr controlled release of a drug, for example, polyactic acid, ups, aqueous or oil suspensions, and flavoured emulsions polyepsilon caprolactone, polyhydroxybutyeric acid, poly with edible oils such as cottonseed oil, Sesame oil, coconut oil orthoesters, polyacetals, polydihydropyrians, polycyanoacry or peanut oil, as well as elixirs and similar pharmaceutical 10 lates and cross-linked or amphipathic block copolymers of vehicles. Suitable dispersing or Suspending agents for aque hydrogels. ous Suspensions, include synthetic and natural gums such as Compounds or combinations of this invention may be tragacanth, acacia, alginate, dextran, Sodium carboxymethyl administered in any of the foregoing compositions and cellulose, methylcellulose, polyvinylpyrrolidone or gelatin. according to dosage regimens established in the art whenever The pharmaceutical composition may contain between 15 treatment of the addressed disorders is required. about 0.01 mg and 100 mg, preferably about 5 to 50 mg. of The daily dosage of the products may be varied over a wide each compound, and may be constituted into any form Suit able for the mode of administration selected. Carriers include range from 0.01 to 1.000 mg per mammal per day. For oral necessary and inert pharmaceutical excipients, including, but administration, the compositions are preferably provided in not limited to, binders, Suspending agents, lubricants, fla the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, Vorants, Sweeteners, preservatives, dyes, and coatings. Com 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milli positions suitable for oral administration include Solid forms, grams of each active ingredient or combinations thereof for Such as pills, tablets, caplets, capsules (each including imme the symptomatic adjustment of the dosage to the patient to be diate release, timed release and Sustained release formula treated. An effective amount of the drug is ordinarily supplied tions), granules, and powders, and liquid forms, such as solu at a dosage level of from about 0.1 mg/kg to about 300 mg/kg tions, syrups, elixirs, emulsions, and Suspensions. Forms 25 of body weight per day. Preferably, the range is from about 1 useful for parenteral administration include Sterile Solutions, to about 50 mg/kg of body weight per day. The compounds or emulsions and Suspensions. combinations may be administered on a regimen of 1 to 4 Advantageously, compounds of the present invention may times per day. be administered in a single daily dose, or the total daily Optimal dosages to be administered may be readily deter dosage may be administered in divided doses of two, three or 30 mined by those skilled in the art, and will vary with the four times daily. Furthermore, compounds for the present particular compound used, the mode of administration, the invention can be administered in intranasal form via topical strength of the preparation, the mode of administration, and use of Suitable intranasal vehicles, or via transdermal skin the advancement of disease condition. In addition, factors patches well known to those of ordinary skill in that art. To be associated with the particular patient being treated, including administered in the form of transdermal delivery system, the 35 patient age, weight, diet and time of administration, will dosage administration will, of course, be continuous rather result in the need to adjust dosages. than intermittent throughout the dosage regimen. In a further aspect, the invention also provides a process for For instance, for oral administration in the form of a tablet preparing a pharmaceutical composition comprising at least or capsule, the active drug component can be combined one compound of formula (I), optionally in combination with with an oral, non-toxic pharmaceutically acceptable inert at least one of the other aforementioned agents and a phar carrier Such as ethanol, glycerol, water and the like. More 40 maceutically acceptable carrier. over, when desired or necessary, Suitable binders; lubricants, The compositions are preferably in a unit dosage forminan disintegrating agents and coloring agents can also be incor amount appropriate for the relevant daily dosage. porated into the mixture. Suitable binders include, without Suitable dosages, including especially unit dosages, of the limitation, starch, gelatin, natural Sugars such as glucose or compounds of the present invention include the known dos betalactose, corn Sweeteners, natural and synthetic gums such 45 ages including unit doses for these compounds as described as acacia, tragacanth or Sodium oleate, sodium Stearate, mag or referred to in reference text such as the British and US nesium Stearate, Sodium benzoate, Sodium acetate, sodium Pharmacopoeias, Remington's Pharmaceutical Sciences chloride and the like. Disintegrators include, without limita (Mack Publishing Co.), Martindale The Extra Pharmaco tion, starch, methyl cellulose, agar, bentonite, Xanthan gum poeia (London, The Pharmaceutical Press) (for example see and the like. 50 the 31st Edition page 341 and pages cited therein) or the The liquid forms in suitable flavored suspending or dis above mentioned publications. persing agents such as the synthetic and natural gums, for Compositions and methods described herein utilizing example, tragacanth, acacia, methyl-cellulose and the like. molecular biology protocols can be according to a variety of For parenteral administration, sterile Suspensions and Solu standard techniques known to the art (see, e.g., Sambrook and tions are desired. Isotonic preparations which generally con Russel (2006) Condensed Protocols from Molecular Clon tain Suitable preservatives are employed when intravenous 55 ing: A Laboratory Manual, Cold Spring Harbor Laboratory administration is desired. Press, ISBN-10: 0879697717: Ausubel et al. (2002) Short The compounds or combinations of the present invention Protocols in Molecular Biology, 5th ed., Current Protocols, can also be administered in the form of liposome delivery ISBN-10: 0471250929; Sambrook and Russel (2001) systems, such as Small unilamellar vesicles, large unilamellar Molecular Cloning: A Laboratory Manual, 3d ed., Cold vesicles, and multilamellar vesicles. Liposomes can be 60 Spring Harbor Laboratory Press, ISBN-10: 0879695773: formed from a variety of phospholipids, such as cholesterol, Elhai, J. and Wolk, C. P. 1988. Methods in Enzymology 167, Stearylamine or phosphatidylcholines. 747-754; Studier (2005) Protein Expr Purif. 41(1), 207-234: Compounds or combinations of the present invention may Gellissen, ed. (2005) Production of Recombinant Proteins: also be delivered by the use of monoclonal antibodies as Novel Microbial and Eukaryotic Expression Systems, Wiley individual carriers to which the compound molecules are 65 VCH, ISBN-10: 3527310363; Baneyx (2004) Protein coupled. The compounds of the present invention may also be Expression Technologies, Taylor & Francis, ISBN-10: coupled with soluble polymers as targetable drug carriers. 0.954523253). US 9, 181,233 B2 51 52 Definitions and methods described herein are provided to or more steps and can also cover other unlisted steps. Simi better define the present disclosure and to guide those of larly, any composition or device that “comprises.” “has or ordinary skill in the art in the practice of the present disclo “includes one or more features is not limited to possessing sure. Unless otherwise noted, terms are to be understood only those one or more features and can cover other unlisted according to conventional usage by those of ordinary skill in 5 features. the relevant art. In some embodiments, numbers expressing quantities of All methods described herein can be performed in any ingredients, properties such as molecular weight, reaction suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all conditions, and so forth, used to describe and claim certain examples, or exemplary language (e.g. "Such as') provided embodiments of the present disclosure are to be understood as 10 being modified in some instances by the term “about.” In with respect to certain embodiments herein is intended some embodiments, the term “about is used to indicate that merely to better illuminate the present disclosure and does not a value includes the standard deviation of the mean for the pose a limitation on the scope of the present disclosure oth device or method being employed to determine the value. In erwise claimed. No language in the specification should be Some embodiments, the numerical parameters set forth in the 15 construed as indicating any non-claimed element essential to written description and attached claims are approximations the practice of the present disclosure. that can vary depending upon the desired properties sought to Groupings of alternative elements or embodiments of the be obtained by a particular embodiment. In some embodi present disclosure disclosed herein are not to be construed as ments, the numerical parameters should be construed in light limitations. Each group member can be referred to and of the number of reported significant digits and by applying claimed individually or in any combination with other mem ordinary rounding techniques. Notwithstanding that the bers of the group or other elements found herein. One or more numerical ranges and parameters setting forth the broad members of a group can be included in, or deleted from, a Scope of some embodiments of the present disclosure are group for reasons of convenience or patentability. When any approximations, the numerical values set forth in the specific Such inclusion or deletion occurs, the specification is herein examples are reported as precisely as practicable. The 25 deemed to contain the group as modified thus fulfilling the numerical values presented in Some embodiments of the written description of all Markush groups used in the present disclosure may contain certain errors necessarily appended claims. resulting from the standard deviation found in their respective Citation of a reference herein shall not be construed as an testing measurements. The recitation of ranges of values admission that Such is prior art to the present disclosure. herein is merely intended to serve as a shorthand method of 30 Having described the present disclosure in detail, it will be referring individually to each separate value falling within the apparent that modifications, variations, and equivalent range. Unless otherwise indicated herein, each individual embodiments are possible without departing the scope of the value is incorporated into the specification as if it were indi present disclosure defined in the appended claims. Further vidually recited herein. more, it should be appreciated that all examples in the present In some embodiments, the terms “a” and “an and “the 35 disclosure are provided as non-limiting examples. and similar references used in the context of describing a particular embodiment (especially in the context of certain of EXAMPLES the following claims) can be construed to cover both the singular and the plural, unless specifically noted otherwise. In The following non-limiting examples are provided to fur Some embodiments, the term 'or' as used herein, including 40 ther illustrate the present disclosure. It should be appreciated the claims, is used to mean “and/or unless explicitly indi by those of skill in the art that the techniques disclosed in the cated to refer to alternatives only or the alternatives are mutu examples that follow represent approaches the inventors have ally exclusive. found function well in the practice of the present disclosure, The terms “comprise.” “have and “include” are open and thus can be considered to constitute examples of modes ended linking verbs. Any forms or tenses of one or more of 45 for its practice. However, those of skill in the art should, in these verbs, such as "comprises.” “comprising.” “has.” “hav light of the present disclosure, appreciate that many changes ing,” “includes” and “including.” are also open-ended. For can be made in the specific embodiments that are disclosed example, any method that “comprises.” “has or “includes’ and still obtain a like or similar result without departing from one or more steps is not limited to possessing only those one the spirit and scope of the present disclosure.

Mol Example Structure Name Formula Weight

5-(4-benzyl-4H-1,2,4-triazol- C6H3Ns 275.308 3-yl)-1H-benzodimidazole

US 9, 181,233 B2 105 106 General Synthesis Description: -continued (A) 4-Benzyl-1,2,4-Triazoles N Ny N N Method 1

(N \-Air H

10 CH(OEt) 1H-Benzimidazole-5-carboxylic acid dimethylaminometh -e- reflux ylene-hydrazide Dimethylformamide dimethyl acetal (19 g, 15.90 mmol) was added to a suspension of 1H-benzodimidazole-5-car 15 bohydrazide (3.50 g. 19.88 mmol) in 1:1 toluene; methanol (60 mL) and refluxed overnight. The volatiles were evapo rated in vacuo to afford crude compound which was triturated SeN N with 6% methanol in chloroform (10 mL), precipitated solid was filtered and dried under reduced pressure to afford 3.20 g 21 NH2 (69.56%%) 1H-benzimidazole-5-carboxylic acid dimethy 1500 C. laminomethylene-hydrazide as brown solid. General Procedure N A mixture of 1H-benzimidazole-5-carboxylic acid dim 25 ethylaminomethylene-hydrazide (1 eq) and substituted ben R Zylamine (2 eq) in glacial acetic acid (5 mL) was heated in a N sealed tube at 130-135° C. for 48 h. The solvent was evapo rated in vacuo to afford crude compound. The crude com 21 N 2N pound was purified by conducting two Successive preparative 30 TLC procedures a) 7% methanol in chloroform followed by, b) 7% methanol in ethyl acetate--2% ammonia solution as eluent to afford the product. (B) 1,2,4-Oxadiazoles N 35 H

5-(1,3,4-oxadiazol-2-yl)-1H-benzodimidazole HNOHxHCI Benzimidazol-5-carbohydrazide (1.77 g; 10 mmol) was 40 HCOOH K2CO3 Her Her suspended in formic acid orthoethylester (20 ml) and heated 5NHC EtOH to reflux for 5 h. The solvent was evaporated and the residue reflux reflux was used without further purification. MS m/z: 187.3 M+H" HN N General Procedure 45 NH2 \-h 5-(1,3,4-Oxadiazol-2-yl)-1H-benzodimidazole (1 eq.) OH was treated with the respective benzylamine (0.5 ml) and heated to 150° C. over night. After cooling the mixture was HN NH directly purified by semi-preparative HPLC. 50

Method 2

O N N -NH. Me2NCH(OMe) \-h ( H HeToluenefMeOH OH N H O HN NH R N A1NNH, -- -- CDI AcOH DMF O OH r.t. -> 110°C.

65 N US 9, 181,233 B2 107 108 -continued -continued 1. R R O NH N

O NH \ Lawesson 2 THF reflux 10

N N \- NH \-h 15 t N-Hydroxy-1H-benzodimidazole-5-carboxamidine O NH R Step 1: 1H-Benzodimidazole-5-carbonitrile -- -e- 3,4-Diaminobenzonitrile (5.0 g; 37 mmol) was dissolved 1. THFDCC in 5 NHCl (200 ml). After addition of formic acid (20 ml) the HO O r.t. mixture was heated to reflux for 3 h. After cooling to room N temperature, the mixture was basified by means of aqueous \- NH NH-solution and put into a fridge. The precipitated solid was collected by filtration, washed with water and used without 25 further purification. Yield: 3.6 g (67.6%) MS m/z.: 144.2 1. R R M+H" O NH N O NH { \ Step 2: N-Hydroxy-1H-benzodimidazole-5-carboxamidine Lawesson 2 He A solution of 5-cyanobenzimidazole (1.43 g; 10 mmol: 1 30 reflux eq.) in EtOH (30 ml) was treated with KCO (2.76 g; 20 mmol; 2 eq.) and hydroxylaminehydrochloride (765 mg; 11 mmol; 1.1 eq.) and heated to reflux over night. After cooling to room temperature, the mixture was diluted with EtO. The 35 N N resulting solid was collected by filtration, washed with EtO \- NH \-h and water and used without further purification. Yield: 1.28 g R (72.7%); MS m/z. 177.3 M+H" NH N General Procedure 40 \ The respective carboxylic acid (1 eq.) was dissolved in O NH S 2 N DMF (5 ml), treated with carbonyldiimidazole (1 eq.) and R Lawesson stirred at room temperature for 1 h. N-Hydroxy-benzimida -- -e- MeCN Zol-5-carboxamidine (1 eq.) was added and the mixture was 45 1. POCl. heated to 110°C. over night. After cooling to room tempera HO O reflux ture, the mixture was diluted with water until a precipitate was N N formed, basified by means of sat. NaHCO-solution and \-h \- NH extracted with EtOAc (3x25ml). The combined organic lay 50 ers were dried over NaSO, evaporated and the residue was purified by flash chromatography on silica using a CHCl/ General Procedures MeOH gradient. Method 1 BenZimidazol-5-carbohydrazide (1 eq.) was Suspended in (C) 1,3,4-Thiadiazoles 55 dry THF (10 ml). After addition of TEA (1.1 eq.) the respec tive acid chloride (1.1 eq.) was added dropwise and the reac NH2 tion was stirred at room temperature for 3 h. The mixture was then quenched with water and extracted with EtOAc (3x25 O NH ml). The combined organic layers were dried over NaSO R 60 and evaporated. The remains were redissolved in acetonitrile TEA (10 ml), treated with Lawesson’s reagent (1.5 eq.) and heated -- He THF to reflux for 1 h. After cooling to roomtemperature the mix C O r.t. ture was quenched with water, basified by means of 2 N NaOH and extracted with EtOAc (3x25ml). The combined 65 organic layers were dried over NaSO4, evaporated and the residue was purified by flash chromatography on silica using a CHC1/MeOH gradient. US 9, 181,233 B2 109 110 Method 2 Benzimidazol-5-carboxamidrazone N,N-Dicyclohexylcarbodiimide (1 eq) and the respective Step 1: Benzimidazol-5-(ethylcarboxiimidate)-dihydrochlo carboxylic acid (1 eq.) were dissolved in THF (10 ml) and ride stirred at room temperature for 1 h. Benzimidazol-5-carbo 5-Cyanobenzimidazole (1.43 g; 10 mmol) was suspended hydrazide (1 eq.) was added and the mixture was stirred at 50° in dry EtOH (20 ml). HCl-gas was bubbled through the ice C. overnight. After cooling to room temperature, Lawesson’s cooled suspension for 15 min. The reaction flask was sealed reagent (1.5 eq.) was added and the mixture was refluxed for and the mixture was stirred at room temperature for 48 h. 5h. After cooling, the mixture was quenched by means of sat. EtO was added and the solid was collected by filtration, NaHCO-solution and extracted with EtOAc (3x25ml). The washed with EtO and EtOH and was used without further combined organic layers were dried over Na2SO, evaporated 10 purification. Yield: 2.19 g (83.6%); MS m/z.: 190.3 M+H" and the residue was purified by semi-preparative HPLC. Step 2: Benzimidazol-5-carboxamidrazone Method 3 The residue of Step 1 was suspended in dry EtOH (20 ml) Benzimidazol-5-carbohydrazide (1 eq.) and the respective and treated with hydrazine-monohydrate (1.5 g; 30 mmol). carboxylic acid were suspended in acetonitrile (10 ml). 15 The mixture was stirred at room temperature for 3 h. The Lawesson’s reagent (1.5 eq.) and POCl (1.5 eq.) were added precipitated solid was collected by filtration and washed with and the mixture was heated to reflux over night. After cooling a small amount of water. The product was used without fur to room temperature, the mixture was basified by means of ther purification. Yield: 0.75 g (51.2%); MS m/z. 176.4 sat. NaHCO-solution and extracted with EtOAc (3x25ml). M+H" The combined organic layers were dried over NaSO, evapo General Procedure rated and the residue was purified by semi-preparative HPLC. A solution of the respective carboxylic acid (1 eq.) in DMF (D) 4H-1,2,4-Triazoles (5 ml) was treated with carbonyldiimidazole (1 eq.) and stirred at room temperature for 1 h. After the addition of benzimidazol-5-carboxamidrazone (175 mg; 1 mmol), the 25 N mixture was heated to 110° C. and stirred for 24 h. After HN O cooling to room temperature, water was added until a precipi tate was formed. The mixture was basified by means of sat. NaHCO-solution and extracted with EtOAc (3x25ml). The HCI NH4xH2O combined organic layers were dried over NaSO, evaporated EtOH EtOH 30 and the residue was purified by flash chromatography using a O C. -> r.t. GE) r.t. CHCl/MeOH gradient. HN "V 2 C. (E) Thiazoles NH2 \-H NH2 35 O OH O C HN NH DBU EtOOCCH2NC THF -- r.t. HN N \-h \-h -- NH2 NH HN NH O R 2 C. -- CDI HCI DMF -as MeOH O OH r.t. -> 110°C. reflux -- N HN \ NH \-h R O 1. DBU R EtOOCCH2NC 55 -- ls THF, r.t. SN /S N N -\ 2. HCI, MeOH HN 2 \ O OH M N/ reflux R 60

O C NH 65 US 9, 181,233 B2 111 112 Benzimidazol-5-aminomethylketon-dihydrochloride Step 1: Ethyl 5-(Benzimidazol-5-yl)oxazol-4-carboxylate Lawesson O O POCl3 Benzimidazol-5-carboxylic acid (1.62 g; 10 mmol; 1 eq.) TEA He was suspended in toluol (50 ml), treated with SOCl (3.63 ml; 5 us -- IN MeCN 50 mmol; 5 eq.) and heated to reflux over night. The volatiles R OH R2 reflux were evaporated and the remains were taken up with THF (50 ml). After cooling to 0°C. 1,8-diazabicyclo[5.4.0]undec-7-en R (1 R2 (2.23 ml; 15 mmol; 1.5 eq.) was added carefully. A mixture of A f isocyanoacetate (1.32 ml, 12 mmol; 1.2 eq.) and 1,8-diazabi 10 cyclo[5.4.0]undec-7-ene (4.46 ml, 30 mmol; 3 eq.) in THF General Procedure (50 ml) was added dropwise. After complete addition, the The respective aminomethylketon-hydrochloride (1 eq.) reaction was stirred at room temperature for 24 h. The reac and the respective carboxylic acid (1 eq.) were suspended in tion was diluted with water and extracted with EtOAc (3x100 acetonitrile (10 ml). Lawesson’s reagent (1.5 eq.), TEA (3 ml). The combined organic layers were dried over NaSO, 15 eq.) and POC1 (1.5 eq.) were added and the mixture was evaporated and the residue was purified by flash chromatog heated to reflux over night. After cooling to room temperature raphy on silica using a CHCl/MeCH gradient. Yield: 2.0 g the mixture was carefully basified by means of sat. NaHCO solution and extracted with EtOAc (3x25ml). The combined (78.0%); MS m/z: 258.3 M+H" organic layers were dried over NaSO, evaporated and the Step 2: Benzimidazol-5-aminomethylketone-dihydrochlo residue was purified by semi-preparative HPLC. ride (F) 1.2.3-Triazoles Ethyl 5-(benzimidazol-5-yl)oxazol-4-carboxylate (2.0 g; 7.8 mmol) was dissolved in MeOH (20 ml) and treated with conc. aqueous HCl (40 ml). The mixture was refluxed over 25 night. The solvent was removed in vacuo and the residue was N 1. CuI used without further purification. MS m/z. 176.3 M+H" Si DIPEA -- -- Amino-4-phenylbutan-2-one-hydrochloride THF Phenylpropionic acid (0.451 g; 3 mmol; 1 eq.) was dis ON r.t. solved in THF (10 ml), treated with Carbonyldiimidazole 30 (0.486 g; 3 mmol; 1 eq.) and stirred at room temperature for 1 h. The mixture was cooled to 0° C. and a solution of N isocyanoethylacetate (0.393 mil: 3.6 mmol; 1.2 eq.) and 1.8- diazabicyclo5.4.0]undec-7-ene (1.34 mil: 9 mmol; 3 eq.) in 35 THF (10 ml) was added dropwise. After complete addition, the mixture was stirred at room temperature for 24 h, then diluted with water and extracted with EtOAc (3x25ml). The combined organic layers were dried over Na2SO, evaporated 40 and the residue was purified by flash chromatography on ON ON silica using a CHCl/MeOH gradient. Yield: 0.319 g (43.4%); MS m/z: 246.3 M+H". The remains were dissolved in MeOH (5 ml), treated with conc. aqueous HCl (15 ml) and refluxed over night. The solvent was removed in vacuo and 4-Ethynyl-2-nitrobenzenamine the residue was used without further purification. MS m/z: 45 Step 1: 4-(2-(Trimethylsilyl)ethynyl)-2-nitrobenzenamine 164.4 M+H" 4-Iodo-2-nitroaniline (5.32 g, 20 mmol; 1 eq.) was dis solved in THF (20 ml). PdCl(PPh), (0.154 g; 0.22 mmol; Amino-4-(2,3-dimethonphenyl)butan-2-one-hydrochloride 0.011 eq.), copper(I)-iodide (0.084 g; 0.44 mmol; 0.022 eq.) 3-(2,3-Dimethoxyphenylpropionic acid (0.630 g.: 3 mmol; and DIPEA (10.5 mil: 60 mmol; 3 eq.) were added. To that 1 eq.) was dissolved in THF (10 ml), treated with carbonyl 50 mixture was added dropwise trimethylsilylacetylene (3.1 ml; diimidazole (0.486 g; 3 mmol; 1 eq.) and stirred at room 22 mmol. 1.1 eq.) at room temperature. After 3 h, the mixture was diluted with water and extracted with EtOAc (3x100ml). temperature for 1 h. The mixture was cooled to 0°C. and a The combined organic layers were dried over NaSO, evapo solution of isocyanoethylacetate (0.393 ml, 3.6 mmol; 1.2 rated and purified by flash chromatography on silica using a eq.) and 1,8-diazabicyclo5.4.0]undec-7-ene (1.34 mil: 9 55 CHCl/MeOH gradient. Yield: 3.96 g (84.6%); MS m/z. mmol; 3 eq.) in THF (10 ml) was added dropwise. After 235.3 M+H: 469.42M+H" complete addition the mixture was stirred at room tempera Step 2: 4-Ethynyl-2-nitrobenzenamine ture for 24 h, then diluted with water and extracted with 2-Nitro-4-(trimethylsilylethinyl)aniline (3.96 g; 16.9 EtOAc (3x25 ml). The combined organic layers were dried mmol; 1 eq.) was dissolved in MeCH (50 ml) and CHCl (50 60 ml) and treated with KCO (9.33 g; 67.6 mmol; 4 eq.). After over NaSO, evaporated and the residue was purified by flash stirring at room temperature for 5 h, the mixture was diluted chromatography on silica using a CHCl/MeOH gradient. with water. The organic layer was separated and the aqueous Yield: 0.517 g (56.5%); MS m/z: 306.1 M+H". The remains layer was extracted with CHCl (3x100 ml). The combined were dissolved in MeCH (5 ml), treated with conc. aqueous organic layers were dried over NaSO4, evaporated and the HCl (15 ml) and refluxed over night. The solvent was 65 residue was purified by flash chromatography on silica using removed in vacuo and the residue was used without further a CHCl/MeOH gradient. Yield: 2.06 g (75.1%); MS m/z. purification. MS m/z: 224.3 M+H" 163.4 M+H" US 9, 181,233 B2 113 114 Step 3 The respective 4-(1-alkyl-1,2,3-triazol-4-yl)-2-nitroa niline was dissolved in formic acid (5 ml) and formic acid orthoethylester (5 ml), treated with sodium formate (2.04 g; 30 mmol) and Pd/C and heated in a sealed tube to 110°C. for 24 h. After cooling to room temperature, the mixture was ON filtered through Celite and the volatiles were removed in NH2 vacuo. The remains were taken up with a small amount of 10 water, basified by means of sat. NaHCO-solution and CuSO4 x 5H2O extracted with EtOAc (3x25ml) The combined organic layers Na-ascorbat were dried over NaSO, evaporated and purified by flash DMSO/HO chromatography on silica using a CHCl/MeOH gradient. r.t. 15 K (G) 1,2,4-Triazolones/-thiones N-N W NH2 N N NCX

THF reflux 25 ON NH2

NaCHOO HCOOH Pd(C CH(OEt) 30 110° C.

35 5% Na2CO -e- reflux

40

45 General Procedure Step 1 A solution of NaNs (1 eq.) in DMSO (2 ml) was treated with the respective phenylethylbromide (1 eq.) and stirred at room temperature for 24 h. After that time, the reaction was 50 diluted with water (2 ml). Sodium ascorbate (0.1 eq.), 4-ethi nyl-2-nitroaniline (1 eq.) and CuSO4x5H2O (1 M solution in water, 0.2 eq.) were added sequentially and the mixture was stirred for a further 3 h. Water was added until a precipitate 55 was formed. The solid was collected by filtration, washed General Procedure with a small amount of water and was used without further purification. BenZimidazole-5-carbohydrazide (1 eq.) was Suspended in Step 2 THF (10 ml), treated with the respective isocyanate or A solution of the respective azide (1 eq.) in DMSO (2 ml) 60 isothiocyanate (1 eq.) and heated to reflux for 1 hour. The was diluted with water (2 ml). Sodium ascorbate (0.1 eq.), Solvent was removed in vacuo, the remains were taken up 4-ethinyl-2-nitroaniline (1 eq.) and CuSO4x5H2O (1 M solu with NaCO, (5% in HO, 20 ml) and heated to reflux for 3 tion in water, 0.2 eq.) were added sequentially and the mix hours. After cooling to room temperature, the mixture was ture was stirred for a further 3 h. Water was added until a neutralized by means of 4 NHCl and extracted with EtOAc precipitate was formed. The solid was collected by filtration, 65 (3x25 ml). The combined organic layers were dried over washed with a small amount of water and was used without NaSO, evaporated and the residue was purified by flash further purification. chromatography on silica using a CHCl/MeOH Gradient.

US 9, 181,233 B2 135 136 Example 84 2H); 7.02-7.04 (m, 2H); 7.23-7.27 (m, 3H); 7.52 (dd. 1H, J=1.7 Hz, J=8.7 Hz); 7.76 (d. 1H, J–8.7 Hz); 7.81 (m, 1H): 5-(1-((Phenylthio)methyl)-1H-1,2,3-triazol-4-yl)- 8.99 (s, 1H), 12.08 (s, 1H); HPLC (METHODA): rt 8.28 1H-benzodimidazole min (100%) The compound was synthesized starting from the respec Example 89 tive 4-(1-alkyl-1,2,3-triazol-4-yl)-2-nitroaniline described above according to method 3; yield: 0.053 g (25.3%); MS 5-(1H-Benzodimidazol-5-yl)-4-benzyl-2H-1,2,4- m/z. 308.2 M+H"; "H-NMR (DMSO de 400 MHz): 85.97 triazole-3(4H)-thione (s. 2H): 7.27-7.37 (m, 3H); 7.44-7.46 (m, 2H); 7.59-7.67 (m, 10 2H); 8.01 (brs, 1H); 8.22 (s, 1H); 8.51 (s, 1H); 12.48 (brs, The compound was synthesized starting from benzimida 1H); HPLC (METHODA): rt 11.23 min (97.2%) Zol-5-carbohydrazide (176 mg; 1 mmol) and benzylisothio cyanate (0.149 g; 0.13 ml; 1 mmol):Yield: 0.052 g (17%); MS Example 85 m/z:308.3 M+H"; "H-NMR (DMSO de 400 MHz): 85.33 15 (s. 2H); 6.97-6.99 (m, 2H); 7.15-7.22 (m, 3H); 7.44 (dd. 1H, 5-(1-(3,4-Dimethoxyphenethyl)-1H-1,2,3-triazol-4- J=1.7 Hz, J–8.7 Hz); 7.71 (d. 1H, J–8.7 Hz), 7.81 (brs, yl)-1H-benzodimidazole 1H); 8.79 (s, 1H): 14.08 (s, 1H); HPLC (METHODA):rt The compound was synthesized starting from the respec 10.47 min (100%) tive 4-(1-alkyl-1,2,3-triazol-4-yl)-2-nitroaniline described Activity Screening above according to method 3; yield: 0.097 g (37.0%); MS Fluorometric Assays m/z. 350.1 M+H"; "H-NMR (DMSO d 400 MHz): 83.14 All measurements were performed with a BioAssay (t, 2H, J–7.5 Hz); 3.67 (s, 3H); 3.68 (s, 3H); 4.61 (t, 2H, Reader HTS-7000Plus for microplates (Perkin Elmer) at 30° J–7.5 Hz); 6.72 (dd. 1H, J=1.7 Hz, J=8.3 Hz); 6.78 (d. 1H, C. QC activity was evaluated fluorometrically using H-Gln J=1.7 Hz); 6.83 (d. 1H, J=8.3 Hz):761-7.67 (m, 2H), 7.99 25 BNA. The samples consisted of 0.2 mM fluorogenic substrate, (brs, 1H), 8.24 (s, 1H); 8.48 (s, 1H); 12.56 (brs, 1H); HPLC 0.25 Upyroglutamyl aminopeptidase (Unizyme, Horsholm, (METHODA):rt 9.79 min (98.5%) Denmark) in 0.2 M Tris/HCl, pH 8.0 containing 20 mM EDTA and an appropriately diluted aliquot of QC in a final Example 86 volume of 250 ul. Excitation/emission wavelengths were 30 320/410 nm. The assay reactions were initiated by addition of 5-(1-(4-Methoxyphenethyl)-1H-1,2,3-triazol-4-yl)- glutaminyl cyclase. QC activity was determined from a stan 1H-benzodimidazole dard curve of B-naphthylamine under assay conditions. One unit is defined as the amount of QC catalyzing the formation The compound was synthesized starting from the respec of 1 umol pGlu-NA from H-Gln-BNA per minute under the tive 4-(1-alkyl-1,2,3-triazol-4-yl)-2-nitroaniline described 35 described conditions. above according to method 3; yield: 0.058 g (29.9%); MS In a second fluorometric assay, QC was activity determined m/z. 320.1 M+H"; "H-NMR (DMSO d6,400 MHz): 83.15 using H-Gln-AMC as substrate. Reactions were carried out at (t, 2H, J=7.1 Hz); 3.69 (s. 3H); 4.59 (t, 2H, J=7.1 Hz); 30° C. utilizing the NOVOStar reader for microplates (BMG 6.82-6.84 (m, 2H); 7.12-7.14 (m, 2H): 7.55-7.61 (m. 1H): 40 labtechnologies). The samples consisted of varying concen 7.66-7.71 (m, 1H); 7.94-8.04 (m. 1H); 8.22 (s, 1H); 8.48-8.49 trations of the fluorogenic Substrate, 0.1 Upyroglutamylami (m. 1H): 12.47-12.49 (m. 1H); HPLC (METHODA): rt nopeptidase (Qiagen) in 0.05 M Tris/HCl, pH 8.0 containing 10.85 min (99.8%) 5 mM EDTA and an appropriately diluted aliquot of QC in a Example 87 final volume of 250 ul. Excitation/emission wavelengths 45 were 380/460 nm. The assay reactions were initiated by addi 5-(1-(3-Methoxyphenethyl)-1H-1,2,3-triazol-4-yl)- tion of glutaminyl cyclase. QC activity was determined from 1H-benzodimidazole a standard curve of 7-amino-4-methylcoumarin under assay conditions. The kinetic data were evaluated using GraFit soft The compound was synthesized starting from the respec Wa. tive 4-(1-alkyl-1,2,3-triazol-4-yl)-2-nitroaniline described 50 Spectrophotometric Assay of QC above according to method 3; yield: 0.033 g (13.1%); MS This novel assay was used to determine the kinetic param m/z. 320.1 M+H"; "H-NMR (DMSO d 400 MHz): 83.20 eters for most of the QC substrates. QC activity was analyzed (t, 2H, J=7.2 Hz); 3.69 (s. 3H); 4.64 (t, 2H, J–7.3 Hz); spectrophotometrically using a continuous method, that was 6.76-6.80 (m,3H); 7.18 (t, 1H); 7.55-7.61 (m, 1H); 7.66-7.71 derived by adapting a previous discontinuous assay (Bate (m. 1H); 7.94-8.04 (m, 1H); 8.22 (s, 1H); 8.48-8.49 (m. 1H): 55 man, R. C. J. 1989 J Neurosci Methods 30, 23-28) utilizing 12.49 (bris, 1H); HPLC (METHOD (A): rt 10.85 min glutamate dehydrogenase as auxiliary enzyme. Samples con (99.7%) sisted of the respective QC substrate, 0.3 mMNADH, 14 mM C-Ketoglutaric acid and 30U/ml glutamate dehydrogenase in Example 88 a final volume of 250 ul. Reactions were started by addition of 60 QC and perused by monitoring of the decrease in absorbance 5-(1H-Benzodimidazol-5-yl)-4-benzyl-2H-1,2,4- at 340 nm for 8-15 min. triazol-3(4H)-one The initial velocities were evaluated and the enzymatic activity was determined from a standard curve of ammonia The compound was synthesized starting from benzimida under assay conditions. All samples were measured at 30°C., Zol-5-carbohydrazide (176 mg; 1 mmol) and benzylisocyan 65 using either the SPECTRAFluor Plus or the Sunrise (both ate (0.133 g; 0.123 ml; 1 mmol):Yield: 0.077 (26%); MS m/z. from TECAN) reader for microplates. Kinetic data was evalu 292.4 M+H: 'H-NMR (DMSO de 400 MHz): & 4.92 (s, ated using GraFit software. US 9, 181,233 B2 137 138 Inhibitor Assay nitrile, eluent (B) was water and eluent (C) 2% formic acid in For inhibitor testing, the sample composition was the same acetonitrile applying the following gradient: as described above, except of the putative inhibitory com pound added. For a rapid test of QC-inhibition, samples con tained 4 mM of the respective inhibitor and a substrate con Time min % Solvent B % Solvent C centration at 1 K. For detailed investigations of the O 90 5 inhibition and determination of K-values, influence of the 2.5 10 5 4 10 5 inhibitor on the auxiliary enzymes was investigated first. In 4.5 90 5 every case, there was no influence on either enzyme detected, 6 90 5 thus enabling the reliable determination of the QC inhibition. 10 The inhibitory constant was evaluated by fitting the set of The purities of all reported compounds were determined by progress curves to the general equation for competitive inhi the percentage of the peak area at 214 nm. bition using GraFit software. Mass-spectrometry, NMR-spectroscopy: Results 15 ESI-Mass spectra were obtained with a SCIEX API 365 Examples 1 to 18, 20 to 36,38 to 68,74 to 77, 81 to 87 and spectrometer (PerkinElmer) utilizing the positive ionization 89 were tested and gave hOCICs values of less than 10 uM. mode. Certain specific values are given in the table below: The "H NMR-Spectra (500 MHz) were recorded at a BRUKER AC 500. The solvent was DMSO-D, unless oth erwise specified. Chemical shifts are expressed as parts per Example no. hOCICso IM hOC K. LM million (ppm) downfiled from tetramethylsilan. Splitting pat 8 O.64 O.11 terns have been designated as follows: S (singulet), d (dou 9 O.76 O.2O blet), dd (doublet of doublet), t (triplet), m (multiplet) and br 10 O.48 O.08 22 O.S2 O.12 (broad signal). 24 O.85 O.23 25 MALDI-TOF Mass Spectrometry 39 O.80 O.13 Matrix-assisted laser desorption/ionization mass spec 46 O.64 O.18 47 O.40 O.O6 trometry was carried out using the Hewlett-Packard G2025 49 O.36 O.09 LD-TOF System with a linear time of flight analyzer. The 50 O.76 O.08 instrument was equipped with a 337 nm nitrogen laser, a 52 O.68 O.OS 30 potential acceleration source (5 kV) and a 1.0 m flight tube. S4 O.S9 O.O6 Detector operation was in the positive-ion mode and signals 55 O.49 O.08 57 O.83 O.13 are recorded and filtered using LeCroy 9350M digital storage 58 0.72 O.14 oscilloscope linked to a personal computer. Samples (5 Jul) 59 O.S6 O.12 were mixed with equal volumes of the matrix solution. For 60 O.45 O.04 35 matrix solution DHAP/DAHC was used, prepared by solving 61 O.76 O.17 62 O.48 O.08 30 mg 2,6'-dihydroxyacetophenone (Aldrich) and 44 mg 63 O.22 O.10 diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile/ 65 O.S3 O.12 0.1% TFA in water (1/1, V/v). A small volume (s1 ul) of the 67 O.08 O.O1 matrix-analyte-mixture was transferred to a probe tip and 68 O41 O.15 40 83 0.57 O.14 immediately evaporated in a vacuum chamber (Hewlett 84 0.57 O.12 Packard G2024A sample prep accessory) to ensure rapid and 85 O.47 O.10 homogeneous sample crystallization. 86 O.29 O.08 For long-term testing of Glu'-cyclization, AB-derived pep 87 0.55 O.12 tides were incubated in 100 ul 0.1 M sodium acetate buffer, 45 pH 5.2 or 0.1 M Bis-Tris buffer, pH 6.5 at 30° C. Peptides Analytical Methods were applied in 0.5 mMLAB(3-11)a or 0.15 mMAB(3-21)a HPLC: concentrations, and 0.2U QC is added all 24 hours. In case of Method A: The analytical HPLC-system consisted of a Af(3-21)a, the assays contained 1% DMSO. At different Merck-Hitachi device (model LaChromR) utilizing a times, samples are removed from the assay tube, peptides LUNAR RP 18 (5um), analytical column (length: 125 mm. 50 extracted using ZipTips (Millipore) according to the manu diameter: 4 mm), and a diode array detector (DAD) with facturer's recommendations, mixed with matrix solution (1:1 w214 nm as the reporting wavelength. The compounds were V/v) and Subsequently the mass spectra recorded. Negative analyzed using a gradient at a flow rate of 1 ml/min: whereby controls either contain no QC or heat deactivated enzyme. For eluent (A) was acetonitrile, eluent (B) was water, both con the inhibitor studies the sample composition was the same as taining 0.1% (v/v) trifluoroacetic acid applying the following 55 described above, with exception of the inhibitory compound gradient: 0 min-5 min->5% (A), 5 min-17 min->5-15% (A), added (5 mM or 2 mM of a test compound of the invention). 15 min-27 min->15-95% (A) 27 min-30 min->95% (A), Compounds and combinations of the invention may have Method B: 0 min-15 min->5-60% (A), 15 min-20 min->60 the advantage that they are, for example, more potent, more 95% (A), 20 min-23 min->95% (A), Method C: 0 min-20 selective, have fewer side-effects, have betterformulation and min->5-60% (A), 20 min-25 min->60-95% (A). 25 min-30 60 stability properties, have better pharmacokinetic properties, min->95% (A). be more bioavailable, be able to cross blood brain barrier and Method B: The analytical HPLC-system consisted of a are more effective in the brain of mammals, are more com Agilent MSD 1100 utilizing a Waters SunFire RP 18 (2.5um), patible or effective in combination with other drugs or be analytical column (length: 50 mm, diameter: 2.1 mm), and a more readily synthesized than other compounds of the prior diode array detector (DAD) with 254 nm as the reporting 65 art. wavelength. The compounds were analyzed using a gradient Throughout the specification and the claims which follow, at a flow rate of 0.6 mL/min: whereby eluent (A) was aceto unless the context requires otherwise, the word comprise’, US 9, 181,233 B2 139 140 and variations such as comprises and comprising, will be DMF dimethylformamide understood to imply the inclusion of a stated integer, step, DMSO dimethylsulfoxide group of integers or group of steps but not to the exclusion of EDTA ethylenediamine-N,N,N',N'-tetraacetic acid any other integer, step, group of integers or group of steps. EtOAc ethyl acetate All patents and patent applications mentioned throughout 5 EtOH ethanol the specification of the present invention are herein incorpo- FPLC fast performance liquid chromatography rated in their entirety by reference. HPLC high performance liquid chromatography The invention embraces all combinations of preferred and IPA isopropanol more preferred groups and embodiments of groups recited LD-TOF laser-desorption time-of-flight mass spectrometry above. 10 ML mother lye Abbreviations MS mass spectrometry (DHQ)PHAL hydroquinine 1,4-phthalazinediyldiether NMR nuclear magnetic resonance AcOHacetic acid Pd dba tris(dibenzylideneacetone)dipalladium DAD diode array detector TEA triethylamine DCC dicyclohexyl carbodiimide 15 TFA trifluoroacetic acid DEA Diethylamine THF tetrahydrofuran DHAP/DAHC dihydroxyacetone phosphate/dihydro-5-aza- TLC thin layer chromatography cytidine TMSCN trimethylsilyl cyanide

SEQUENCE LISTING

<16 Os NUMBER OF SEO ID NOS: 2O

<21 Os SEQ ID NO 1 &211s LENGTH: 42 212s. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs SEQUENCE: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1. 5 1O 15 Lieu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 2O 25 3 O Gly Lieu Met Val Gly Gly Val Val Ile Ala 35 4 O

<21 Os SEQ ID NO 2 &211s LENGTH: 4 O 212s. TYPE: PRT <213> ORGANISM: Homo sapiens <4 OOs SEQUENCE: 2 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1. 5 1O 15 Lieu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 2O 25 3 O Gly Lieu Met Val Gly Gly Val Val 35 4 O

<21 Os SEQ ID NO 3 &211s LENGTH: 4 O 212s. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs SEQUENCE: 3 Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Glin Llys Lieu Val 1. 5 1O 15 Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Lieu. 2O 25 3 O Met Val Gly Gly Val Val Ile Ala 35 4 O

<21 Os SEQ ID NO 4 &211s LENGTH: 38 US 9, 181,233 B2 141 142 - Continued

212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 4 Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Glin Llys Lieu Val 1. 5 1O 15 Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Lieu. 2O 25 3O Met Val Gly Gly Val Val 35

<210s, SEQ ID NO 5 &211s LENGTH: 17 212. TYPE: PRT <213> ORGANISM: Homo sapiens 22 Os. FEATURE: <221s NAME/KEY: MOD RES <222s. LOCATION: (17) . . (17) 223 OTHER INFORMATION: AMIDATION

<4 OOs, SEQUENCE: 5 Glin Gly Pro Trp Lieu. Glu Glu Glu Glu Glu Ala Tyr Gly Trp Met Asp 1. 5 1O 15

Phe

<210s, SEQ ID NO 6 &211s LENGTH: 13 212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 6 Glin Lieu. Tyr Glu Asn Llys Pro Arg Arg Pro Tyr Ile Lieu. 1. 5 1O

<210s, SEQ ID NO 7 &211s LENGTH: 10 212. TYPE: PRT <213> ORGANISM: Homo sapiens 22 Os. FEATURE: <221s NAME/KEY: MOD RES <222s. LOCATION: (10) ... (10) 223 OTHER INFORMATION: AMIDATION

<4 OO > SEQUENCE: 7 Gln His Trp Ser Tyr Gly Lieu. Arg Pro Gly 1. 5 1O

<210s, SEQ ID NO 8 &211s LENGTH: 97 212. TYPE: PRT <213> ORGANISM: Homo sapiens <4 OOs, SEQUENCE: 8 Gln Pro Llys Val Pro Glu Trp Val Asn Thr Pro Ser Thr Cys Cys Lieu. 1. 5 1O 15

Llys Tyr Tyr Glu, Llys Val Lieu Pro Arg Arg Lieu Val Val Gly Tyr Arg 2O 25 3O

Lys Ala Lieu. Asn. Cys His Lieu Pro Ala Ile Ile Phe Val Thir Lys Arg 35 4 O 45

Asn Arg Glu Val Cys Thr Asn Pro Asn Asp Asp Trp Val Glin Glu Tyr SO 55 6 O

Ile Lys Asp Pro Asn Lieu Pro Lieu. Lieu Pro Thr Arg Asn Lieu. Ser Thr 65 70 7s 8O US 9, 181,233 B2 143 144 - Continued

Val Lys Ile Ile Thr Ala Lys Asn Gly Glin Pro Gln Lieu. Lieu. Asn. Ser 85 90 95

Glin

<210s, SEQ ID NO 9 &211s LENGTH: 76 212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 9

Gln Pro Asp Ser Val Ser Ile Pro Ile Thir Phe Asn Wall Ile 1. 5 15

Asn Arg Lys Ile Pro Ile Glin Arg Luell Glu Ser Thir Arg Ile Thir 2O 25

Asn. Ile Glin Cys Pro Llys Glu Ala Wall Ile Phe Thir Arg Gly 35 4 O 45

Lys Glu Val Cys Ala Asp Pro Llys Glu Arg Trp Wall Arg Asp Ser Met SO 55 6 O

Llys His Lieu. Asp Glin Ile Phe Glin Asn Luell Pro 65 70

<210s, SEQ ID NO 10 &211s LENGTH: 76 212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 10

Glin Pro Asp Ala Ile Asn Ala Pro Wall Thir Asn Phe Thir 1. 5 15

Asn Arg Lys Ile Ser Val Glin Arg Luell Ala Ser Arg Arg Ile Thir 2O 25 3O

Ser Ser Lys Cys Pro Llys Glu Ala Wall Ile Phe Thir Ile Wall Ala 35 4 O 45

Lys Glu Ile Cys Ala Asp Pro Llys Glin Lys Trp Wall Glin Asp Ser Met SO 55 6 O

Asp His Lieu. Asp Llys Glin Thr Glin Thir Pro Thir 65 70

<210s, SEQ ID NO 11 &211s LENGTH: 68 212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 11

Glin Val Gly Thr Asn Lys Glu Lieu. Cys Luell Wall Thir Ser Trp 1. 5 1O 15

Glin Ile Pro Gln Lys Phe Ile Val Asp Tyr Ser Glu Thir Ser Pro Glin 2O 25 3O

Cys Pro Llys Pro Gly Val Ile Leu Luell Thir Arg Gly Arg Glin Ile 35 4 O 45

Cys Ala Asp Pro Asn Llys Llys Trip Wall Glin Tyr Ile Ser Asp Luell SO 55 6 O

Llys Lieu. Asn Ala 65

<210s, SEQ ID NO 12 &211s LENGTH: 373 212. TYPE: PRT US 9, 181,233 B2 145 146 - Continued <213> ORGANISM: Homo sapiens <4 OOs, SEQUENCE: 12 Gln His His Gly Val Thr Lys Cys Asn Ile Thr Cys Ser Lys Met Thr 1. 5 1O 15 Ser Lys Ile Pro Val Ala Lieu. Lieu. Ile His Tyr Glin Glin Asn Glin Ala 2O 25 3O Ser Cys Gly Lys Arg Ala Ile Ile Lieu. Glu Thir Arg Gln His Arg Lieu. 35 4 O 45 Phe Cys Ala Asp Pro Llys Glu Gln Trp Wall Lys Asp Ala Met Gln His SO 55 6 O Lieu. Asp Arg Glin Ala Ala Ala Lieu. Thir Arg Asn Gly Gly. Thir Phe Glu 65 70 7s 8O Lys Glin Ile Gly Glu Val Llys Pro Arg Thir Thr Pro Ala Ala Gly Gly 85 90 95

Met Asp Glu Ser Val Val Lieu. Glu Pro Glu Ala Thr Gly G Ser Ser 1OO 105 1. Ser Lieu. Glu Pro Thr Pro Ser Ser Glin Glu Ala Glin Arg Ala Lieu. Gly 115 12 O 125 Thir Ser Pro Glu Lieu Pro Thr Gly Val Thr Gly Ser Ser Gly Thr Arg 13 O 135 14 O Lieu Pro Pro Thr Pro Lys Ala Glin Asp Gly Gly Pro Val Gly Thr Glu 145 150 155 160 Lieu. Phe Arg Val Pro Pro Val Ser Thr Ala Ala Thr Trp Glin Ser Ser 1.65 17O 17s Ala Pro His Gln Pro Gly Pro Ser Leu Trp Ala Glu Ala Lys Thr Ser 18O 185 19 O Glu Ala Pro Ser Thr Glin Asp Pro Ser Thr Glin Ala Ser Thr Ala Ser 195 2OO 2O5 Ser Pro Ala Pro Glu Glu Asn Ala Pro Ser Glu Gly Glin Arg Val Trp 21 O 215 22O Gly Glin Gly Glin Ser Pro Arg Pro Glu Asn. Ser Lieu. Glu Arg Glu Glu 225 23 O 235 24 O Met Gly Pro Val Pro Ala His Thr Asp Ala Phe Glin Asp Trp Gly Pro 245 250 255 Gly Ser Met Ala His Val Ser Val Val Pro Val Ser Ser Glu Gly Thr 26 O 265 27 O Pro Ser Arg Glu Pro Val Ala Ser Gly Ser Trp Thr Pro Lys Ala Glu 27s 28O 285 Glu Pro Ile His Ala Thr Met Asp Pro Glin Arg Lieu. Gly Val Lieu. Ile 29 O 295 3 OO Thr Pro Val Pro Asp Ala Glin Ala Ala Thr Arg Arg Glin Ala Val Gly 3. OS 310 315 32O Lieu. Lieu Ala Phe Lieu. Gly Lieu. Lieu. Phe Cys Lieu. Gly Val Ala Met Phe 3.25 330 335

Thr Tyr Glin Ser Lieu. Glin Gly Cys Pro Arg Llys Met Ala Gly Glu Met 34 O 345 35. O

Ala Glu Gly Lieu. Arg Tyr Ile Pro Arg Ser Cys Gly Ser Asn. Ser Tyr 355 360 365

Wall Lieu Val Pro Wall 37 O

<210s, SEQ ID NO 13 &211s LENGTH: 76 US 9, 181,233 B2 147 148 - Continued

212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 13 Gln Pro Val Gly Ile Asn. Thir Ser Thr Thr Cys Cys Tyr Arg Phe Ile 1. 5 1O 15 Asn Llys Lys Ile Pro Llys Glin Arg Lieu. Glu Ser Tyr Arg Arg Thir Thr 2O 25 3O Ser Ser His Cys Pro Arg Glu Ala Val Ile Phe Llys Thr Lys Lieu. Asp 35 4 O 45 Lys Glu Ile Cys Ala Asp Pro Thr Glin Llys Trp Val Glin Asp Phe Met SO 55 6 O Llys His Lieu. Asp Llys Llys Thr Glin Thr Pro Llys Lieu. 65 70 7s

<210s, SEQ ID NO 14 &211s LENGTH: 33 212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 14 Glin Pro Lieu Pro Asp Cys Cys Arg Glin Llys Thr Cys Ser Cys Arg Lieu. 1. 5 1O 15 Tyr Glu Lieu. Lieu. His Gly Ala Gly Asn His Ala Ala Gly Ile Lieu. Thir 2O 25 3O

Lell

<210s, SEQ ID NO 15 &211s LENGTH: 11 212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 15 Arg Pro Llys Pro Glin Glin Phe Phe Gly Lieu Met 1. 5 1O

<210s, SEQ ID NO 16 &211s LENGTH: 32 212. TYPE: PRT <213> ORGANISM: Artificial sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Synthetic peptide <4 OOs, SEQUENCE: 16 Glu Val His His Glin Llys Lieu Val Phe Phe Ala Glu Asp Val Gly Ser 1. 5 1O 15 Asn Lys Gly Ala Ile Ile Gly Lieu Met Val Gly Gly Val Val Ile Ala 2O 25 3O

<210s, SEQ ID NO 17 &211s LENGTH: 30 212. TYPE: PRT <213> ORGANISM: Artificial sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Synthetic peptide

<4 OOs, SEQUENCE: 17 Glu Val His His Glin Llys Lieu Val Phe Phe Ala Glu Asp Val Gly Ser 1. 5 1O 15

Asn Lys Gly Ala Ile Ile Gly Lieu Met Val Gly Gly Val Val 2O 25 3O US 9, 181,233 B2 149 150 - Continued

SEQ ID NO 18 LENGTH: 34 TYPE PRT ORGANISM: Artificial sequence FEATURE: OTHER INFORMATION: Synthetic peptide

<4 OOs, SEQUENCE: 18 Glu Ala Ser Asn. Cys Phe Ala Ile Arg His Phe Glu Asn Llys Phe Ala 1. 5 1O 15 Val Glu Thir Lieu. Ile Cys Ser Arg Thr Val Lys Lys Asn. Ile Ile Glu

Glu Asn

SEQ ID NO 19 LENGTH: 34 TYPE PRT ORGANISM: Artificial sequence FEATURE: OTHER INFORMATION: Synthetic peptide

<4 OOs, SEQUENCE: 19 Glu Ala Ser Asn. Cys Phe Ala Ile Arg His Phe Glu Asn Llys Phe Ala 1. 5 1O 15 Val Glu Thir Lieu. Ile Cys Phe Asn Lieu. Phe Lieu. Asn. Ser Glin Glu Lys

His Tyr

SEQ ID NO LENGTH: 5 TYPE PRT ORGANISM: Artificial sequence FEATURE: OTHER INFORMATION: Synthetic peptide

<4 OOs, SEQUENCE: 2O Glin Tyr Asn Ala Asp 1. 5

What is claimed is: X represents a linker selected from -(CH2), R. (CH), S R°, (CH2). S R°, (CH2). 1. A compound of formula (I): 45 O R, or -(CH.) SO, R: m represents an integer selected from 1 to 4: in represents an integer selected from 1 or 2; Y (I) p represents an integer selected from 0 to 2; R11 Yx R’ is selected from phenyl, phenyl substituted by phenyl, 50 phenyl substituted by phenoxy, phenyl fused to hetero cyclyl phenyl fused to substituted heterocyclyl, and or a pharmaceutically acceptable salt, Solvate or poly phenyl Substituted by one or more of Calkyl, C. morph thereof, including all tautomers and stereoiso alkoxy, Cathioalkyl, haloCalkyl, haloCalkoxy, or mers thereof wherein: halogen; 55 in which the substituted heterocyclyl is substituted by one R" represents; or more groups selected from methyl, phenyl, oxo, halo gen and Calkoxy. with the proviso that the compound of formula (I) is a N compound other than: 60 6-(5-(2,3-dimethoxyphenethyl)-1,3,4-thiadiazol-2-yl)1H ( imidazol-2-alpyridine; N H 6-(5-(4-(methylthio)phenethyl)-1,3,4-thiadiazol-2-yl)1H imidazol-2-alpyridine; or 6-(5-(2-chloro-3-methoxyphenethyl)-1,3,4-thiadiazol-2- Y represents a 5-membered heteroaryl group selected from 65 yl)1H-imidazo 1,2-alpyridine. triazolyl, a thiadiazolyl, a thiazolyl, a triazol-one or a 2. A compound according to claim 1, wherein Y represents triazol-thione; triazolyl or thiadiazolyl. US 9, 181,233 B2 151 152 3. A compound according to claim 1, wherein m represents -continued an integer selected from 1 to 3. 4. A compound according to claim3, wherein m represents Structure Name an integer selected from 1 or 2. 5. A compound according to claim 1, wherein in represents 5-(4-(2-fluorobenzyl)-4H 1. 1,2,4-triazol-3-yl)-1H benzodimidazole; 6. A compound according to claim 1, wherein p represents 1. 7. A compound according to claim 1, wherein R represents 10 phenyl, phenyl Substituted by phenoxy, or phenyl fused to heterocyclyl or substituted heterocyclyl. 8. A compound according to claim 7, wherein R represents phenyl substituted by phenoxy. 15 9. A compound according to claim 7, wherein R represents phenyl Substituted by one or more groups selected from C alkyl, Calkoxy, —C-thioalkyl, haloC-alkyl, haloC 5-(4-(4-fluorobenzyl)-4H alkoxy, or halogen. 1,2,4-triazol-3-yl)-1H 10. A compound according to claim 7, wherein R repre benzodimidazole;d sents phenyl Substituted by one or more groups selected from methyl, methoxy, ethoxy, methylthio, trifluoromethyl, trif luoromethoxy, chlorine, or fluorine. 11. A compound according to claim 7, wherein R repre 25 sents phenyl fused to heterocyclyl or substituted heterocyclyl. 12. A compound according to claim 1, wherein R is phenyl substituted by 4-phenoxy. 13. A compound or a pharmaceutically acceptable salt, 30 Solvate or polymorph thereof, including all tautomers and Stereoisomers of any one of the following:

35 5-(4-(4-chlorobenzyl)-4H Structure Name 1,2,4-triazol-3-yl)-1H benzodimidazole; 5-(4-benzyl-4H-1,2,4-triazol 3-yl)-1H-benzodimidazole;

40 N- C

45

50 5-(4-(3,4-difluorobenzyl)-4H 1,2,4-triazol-3-yl)-1H 5-(4-(3,4-dimethoxybenzyl)- benzodimidazole; 4H-1,2,4-triazol-3-yl)-1H benzodimidazole; 55

60

65

US 9, 181,233 B2 169 170 -continued 14. A pharmaceutical composition comprising a com pound according to claim 1 optionally in combination with Structure Name one or more therapeutically acceptable diluents or carriers. 15. A pharmaceutical composition according to claim 14, --O 5-(1-(4-methoxyphenethyl)- 1H-1,2,3-triazol-4-yl)-1H which comprises additionally at least one compound, benzodimidazole; selected from the group consisting of neuroprotectants, anti parkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic 10 drugs, antipsychotic drugs and anti-multiple Sclerosis drugs. 16. A pharmaceutical composition according to claim 14, which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCl, N inhibitors of inhibitors of DP IV or DP IV-like enzymes, 15 acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodi esterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 N receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodu \-h latory agents, immunosuppressive agents oran agent selected O 5-(1-(3-methoxyphenethyl)- from the group consisting of natalizumab, fampridine-SR, 1H-1,2,3-triazol-4-yl)-1H alemtuzumab, IR 208, NBI 5788/MSP 771 (tiplimotide), benzodimidazole; 25 paclitaxel, AG 284, SH636, CD271, adapalene, BAY361677 (interleukin-4), matrix-metalloproteinase-inhibitors, inter feron-tau (trophoblastin) and SAIK-MS. 17. A process for preparation of a compound of formula (I) according to claim 1, which comprises: 30 (a) preparing a compound of formula (I) wherein R' rep N-N W resents 1H-benzodimidazolyl from a compound offor S N mula (II):

35

(II) N 40

5-(1H-benzodimidazol-5-yl)- 4-benzyl-2H-1,2,4-triazol 3(4H)-one; or ON 45 NH2

wherein X and Y are as defined in claim 1: 50 (b) preparing a compound of formula (I) wherein Y repre sents 1,2,4-triazolyl by reacting a compound of formula (III):

4-benzyl-2H-1,2,4-triazole 55 3(4H)-thione. N. 60 wherein R' is as defined in claim 1, with a compound of formula X NH, wherein X is as defined in claim 1: 65 (c) preparing a compound of formula (I) wherein Y repre sents 1,2,4-triazolyl by reacting a compound of formula (IV): US 9, 181,233 B2 171 172 wherein R' is as defined in claim 1, with a compound of (IV) formula X-COOH, wherein X is as defined in claim 1: (f) preparing a compound of formula (I) wherein Y repre sents 4H-1,2,4-triazolyl by reacting a compound of for mula (VIII):

(VIII) N NH2 1N 10 wherein R' is as defined in claim 1, with a compound of in formula X NH, wherein X is as defined in claim 1: RI (d) preparing a compound of formula (I) wherein Y repre sents 1,3,4-thiadiazolyl from a compound of formula 15 wherein R' is as defined in claim 1, with a compound of (VI): formula X-COOH, wherein X is as defined in claim 1: (g) preparing a compound of formula (I) wherein Y repre sents thiazolyl by reacting a compound of formula (VI) R' COOH with a compound of formula X-CO— CH, NH, wherein R' and X areas defined in claim 1: 1. 2O (h) preparing a compound of formula (I) wherein Y repre O t sents 1,2,4-triazol-one or 1,2,4-triazol-thione from a O NH compound of formula (IX): N 25 RI (IX) wherein R' and X are as defined in claim 1: (e) preparing a compound of formula (I) wherein Y repre sents 1,3,4-thiadiazolyl by reacting a compound of for W 1. NH mula (VII): 's--" R1 t (VII)VII wherein R' and X are as defined in claim 1: s NH (i) interconversion of compounds of formula (I); or (j) deprotecting a compound of formula (I) which is pro tected.