USOO854.1596B2

(12) United States Patent (10) Patent No.: US 8,541,596 B2 Heiser et al. (45) Date of Patent: Sep. 24, 2013

(54) INHIBITORS OTHER PUBLICATIONS (75) Inventors: Ulrich Heiser, Halle/Saale (DE); Daniel Souillac, et al., Characterization of Delivery Systems, Differential Scanning Calorimetry in Encyclopedia of Controlled Drug Delivery, Ramsbeck, Halle/Saale (DE); Torsten 1999, John Wiley & Sons, pp. 212-227.* Hoffmann, Halle/Saale (DE); Livia Vippagunta et al., Advanced Drug Delivery Reviews, 48 (2001), pp. Boehme, Halle/Saale (DE) 3-26. Abuzar et al., Synthesis of N-Aryl- & N-Heteroaryl-benzimidazoles (73) Assignee: Probiodrug AG, Halle/Saale (DE) as Potential Anthelmintics, Indian Journal of Chemistry, 1980, pp. 599-600, vol. 19B. (*) Notice: Subject to any disclaimer, the term of this Brauniger et al., Darstellung von DesaZaanalogen des Kinetins, patent is extended or adjusted under 35 Archiv der Pharmazie, 1966, pp. 13 and 194-196, vol. 299. No. 3, in U.S.C. 154(b) by 0 days. German. Chemical Abstracts Service Registration No. (CAS RN) 1069857 (21) Appl. No.: 13/091,276 25-5, entered Nov. 2, 2008, 1 page. Chemical Abstracts Service Registration No. (CAS RN) 1137428 (22) Filed: Apr. 21, 2011 36-4, entered Apr. 21, 2009, 1 page. Gallagher et al., Synthesis and photolysis of azido (65) Prior Publication Data benzobthiophens, -benzothiazoles, -benzimidazoles, and -inda Zoles: Novel 6,7-Diamino-benzothiazoles, -benzimidazoles, and -in US 2011 FO262388A1 Oct. 27, 2011 dazoles and 6-Diethylamino-8H-thiazolo-5,4-c azepines, J Chem Soc Perkin I, 1980, pp. 2362-2370. Related U.S. Application Data JP62-024244 published Feb. 2, 1987, English abstract, downloaded Provisional application No. 61/326,401, filed on Apr. from PAJ, 1 page. (60) JP63-250385 published Oct. 18, 1988, English abstract, downloaded 21, 2010. from PAJ, 1 page. Int. C. Molnar, In 4.5-Stellung ungleich substituierte o-Nitraniline, (51) Helvectica Chemica Acta, 1963, pp. 1779-1783, vol. 63, in German. A6 IK3I/484 (2006.01) Roy et al., Syntheses of 4,6-Dinitro-5-substituted-amino CO7D 235/08 (2006.01) benzimidazoles & 4,6-Dinitro-2-methyl-5-substituted (52) U.S. C. aminobenzimidazoles, Indian J Chem, 1979, pp. 164-166, vol. 17B. USPC ...... 548/304.4; 546/176: 548/126; 548/156; Soskic et al., Sythesis of N-n-Propyl-N-(2-arylethyl)-5-(1H 514/314: 514/362; 514/367: 514/394 benzimidazol-2-thione)-ethylamines and Related Compounds as (58) Field of Classification Search Potential Dopaminergic Ligands, Arzneim.-Forsch./Drug Res., USPC ...... 548/304.4 1996, pp. 741-746, vol. 46. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — Laura L. Stockton U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Dentons US LLP 5,106,862 A * 4/1992 Briving et al...... 514,394 6,582,351 B1* 6/2003 Sawada et al...... 546,118 (57) ABSTRACT FOREIGN PATENT DOCUMENTS JP 62-024244 2, 1987 Novel heterocyclic derivatives as inhibitors of glutaminyl JP 62,055644. A * 3, 1987 cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular JP 63-250385 10, 1988 cyclization of N-terminal glutamine residues into pyro WO WOOOf 42022 A1 T 2000 glutamic acid (5-oxo-prolyl, pClu) under liberation of WO WOO1/O577O A1 1, 2001 WO WOO3,O77914 A1 9, 2003 ammonia and the intramolecular cyclization of N-terminal WO WO-2007/002092 A1 * 1, 2007 glutamate residues into pyroglutamic acid under liberation of WO WO2007/053.131 A2 5/2007 Water. WO WO2007/053.131 A3 5/2007 WO WO2008/O5595.0 A1 5, 2008 WO WO2008/128985 A1 10, 2008 18 Claims, No Drawings US 8,541,596 B2 1. 2 INHIBITORS Recently, it was shown that recombinant human QC as well as QC-activity from brain extracts catalyze both, the N-ter CROSS-REFERENCE TO RELATED minal glutaminyl as well as glutamate cyclization. Most strik APPLICATIONS ing is the finding, that cyclase-catalyzed Glu-conversion is favored around pH 6.0 while Gln-conversion to pGlu-deriva This application claims priority to U.S. Provisional Appli tives occurs with a pH-optimum of around 8.0. Since the cation Ser. No. 61/326,401, filed on Apr. 21, 2010, which is formation of pClu-AB-related peptides can be suppressed by incorporated herein by reference in its entirety. inhibition of recombinant human QC and QC-activity from pig pituitary extracts, the enzyme QC is a target in drug MATERIAL INCORPORATED-BY-REFERENCE 10 development for treatment of Alzheimer's disease. Inhibitors of QC are described in WO 2004/098625, WO The Sequence Listing, which is a part of the present dis 2004/098591, WO 2005/039548, WO 2005/075436, WO closure, includes a computer readable form comprising 2008/055945, WO 2008/055947, WO 2008/055950 and nucleotide and/or amino acid sequences of the present inven WO2008/0651.41. tion. The Subject matter of the Sequence Listing is incorpo 15 EP 02011 349.4 discloses polynucleotides encoding insect rated herein by reference in its entirety. glutaminyl cyclase, as well as polypeptides encoded thereby and their use in methods of Screening for agents that reduce FIELD OF THE INVENTION glutaminyl cyclase activity. Such agents are useful as pesti cides. The invention relates to inhibitors of glutaminyl cyclase WOOO/42022 discloses a series of MEK inhibitors which (QC, EC 2.3.2.5). QC catalyzes the intramolecular cycliza are claimed to be useful in the treatment of proliferative tion of N-terminal glutamine residues into pyroglutamic acid diseases such as cancer. WO 03/077914 discloses a series of (5-oxo-prolyl, pClu) under liberation of ammonia and the MEK inhibitors which are claimed to be useful in the treat intramolecular cyclization of N-terminal glutamate residues ment of hyperproliferative diseases Such as cancer and into pyroglutamic acid under liberation of water. inflammation. Roy and Bhaduri (1979) Indian J Chem 17B. 25 164-166 discloses the synthesis of 4,6-dinitro-5-substituted BACKGROUND OF THE INVENTION amino-benzoimidazole compounds. Soskic et al (1996) Arz neimittel-Forschung 46(8), 741-746 discloses the synthesis Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the of benzoimidazole ethylamine compounds which are claimed intramolecular cyclization of N-terminal glutamine residues to be useful as dopaminergic ligands. Braeuniger etal (1966) into pyroglutamic acid (pGlu) liberating ammonia. A QC 30 Archiv der Pharmazie 299(3), 193-196 discloses a series of was first isolated by Messer from the latex of the tropical plant benzimidazole compounds which are claimed to be useful as Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). stimulants for plant growth. WO 2007/053131 discloses a 24 years later, a corresponding enzymatic activity was dis series of acrylamide derivatives which are claimed to be use covered in animal pituitary (Busby, W. H. J. etal. 1987J Biol ful as antibiotic agents. WO 01/05770 discloses a series of Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 35 benzoimidazolone derivatives which are claimed to be useful Proc Natl AcadSci USA 84,3628-3632). For the mammalian as cCMP-PDE inhibitors. QC, the conversion of Gln into pGlu by QC could be shown Definitions for the precursors of TRH and GnRH (Busby, W. H. J. et al. The terms “k,” or “K” and “K” are binding constants, 1987J Biol Chem 262,8532-8536; Fischer, W. H. and Spiess, which describe the binding of an inhibitor to and the subse J. 1987 Proc Natl AcadSci USA 84,3628-3632). In addition, 40 quent release from an enzyme. Another measure is the “ICso initial localization experiments of QC revealed a co-localiza value, which reflects the inhibitor concentration, which at a tion with its putative products of catalysis in bovine pituitary, given substrate concentration results in 50% enzyme activity. further improving the Suggested function in peptide hormone The term “DP IV-inhibitor” or “dipeptidyl peptidase IV synthesis (Bockers, T. M. et al. 1995 J Neuroendocrinol 7, inhibitor' is generally known to a person skilled in the art and 445-453). In contrast, the physiological function of the plant means enzyme inhibitors, which inhibit the catalytic activity QC is less clear. In the case of the enzyme from C. papaya, a 45 of DP IV or DPIV-like enzymes. role in the plant defense against pathogenic microorganisms “DP IV-activity” is defined as the catalytic activity of was suggested (El Moussaoui, A. etal. 2001 Cell Mol LifeSci dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. 58, 556-570). Putative QCs from other plants were identified These enzymes are post-proline (to a lesser extent post-ala by sequence comparisons recently (Dahl, S. W. et al. 2000 nine, post-serine or post-glycine) cleaving serine proteases Protein Expr Purif 20, 27-36). The physiological function of 50 found in various tissues of the body of a mammal including these enzymes, however, is still ambiguous. kidney, liver, and intestine, where they remove dipeptides The QCs known from plants and animals show a strict from the N-terminus of biologically active peptides with a specificity for L-Glutamine in the N-terminal position of the high specificity when proline oralanine form the residues that substrates and their kinetic behavior was found to obey the are adjacent to the N-terminal amino acid in their sequence. Michaelis-Menten equation (Pohl, T. et al. 1991 Proc Natl 55 The term “PEP-inhibitor” or “prolyl endopeptidase inhibi Acad Sci USA 88, 10059-10063: Consalvo, A. P. et al. 1988 tor” is generally known to a person skilled in the art and Anal Biochem 175, 131-138; Gololobov, M.Y. et al. 1996 means enzyme inhibitors, which inhibit the catalytic activity Biol Chem Hoppe Seyler 377,395-398). A comparison of the of prolyl endopeptidase (PEP prolyl oligopeptidase, POP). primary structures of the QCs from C. papaya and that of the “PEP-activity” is defined as the catalytic activity of an highly conserved QC from mammals, however, did not reveal endoprotease that is capable to hydrolyze post proline bonds any sequence homology (Dahl, S.W. et al. 2000 Protein Expr 60 in peptides or proteins where the proline is in amino acid Purif 20, 27-36). Whereas the plant QCs appear to belong to position 3 or higher counted from the N-terminus of a peptide a new enzyme family (Dahl, S. W. et al. 2000 Protein Expr or protein Substrate. Purif 20, 27-36), the mammalian QCs were found to have a The term “QC as used herein comprises glutaminyl pronounced sequence homology to bacterial aminopepti cyclase (QC) and QC-like enzymes. QC and QC-like dases (Bateman, R. C. et al. 2001 Biochemistry 40, 11246 65 enzymes have identical or similar enzymatic activity, further 11250), leading to the conclusion that the QCs from plants defined as QC activity. In this regard, QC-like enzymes can and animals have different evolutionary origins. fundamentally differ in their molecular structure from QC. US 8,541,596 B2 3 4 Examples of QC-like enzymes are the glutaminyl-peptide The term “QC-inhibitor “glutaminyl cyclase inhibitor is cyclotransferase-like proteins (QPCTLs) from human (Gen generally known to a person skilled in the art and means Bank NM 017659), mouse (GenBank BC058181), Macaca enzyme inhibitors, which inhibit the catalytic activity of fascicularis (GenBank AB168255), Macaca mulatta (Gen glutaminyl cyclase (QC) or its glutamylcyclase (EC) activity. Bank XM 001110995), Canis familiaris (GenBank 5 XM 541552), Rattus norvegicus (GenBank Potency of QC Inhibition XM 001066591), Mus musculus (GenBank BC058181) and In light of the correlation with QC inhibition, in preferred Bos taurus (GenBank BTO26254). embodiments, the Subject method and medical use utilize an The term “QC activity” as used herein is defined as agent with an ICs for QC inhibition of 10 uM or less, more intramolecular cyclization of N-terminal glutamine residues preferably of 1 uMorless, even more preferably of 0.1 uMor into pyroglutamic acid (p.Glu) or of N-terminal L-homo 10 less or 0.01 uM or less, or most preferably 0.001 uM or less. glutamine or L-B-homoglutamine to a cyclic pyro-homo Indeed, inhibitors with K, values in the lower micromolar, glutamine derivative under liberation of ammonia. See there preferably the nanomolar and even more preferably the pico fore schemes 1 and 2. molar range are contemplated. Thus, while the active agents are described herein, for convenience, as “QC inhibitors, it 15 will be understood that Such nomenclature is not intending to Scheme 1: Cyclization of glutamine by QC limit the subject of the invention to a particular mechanism of peptide action. peptide Molecular Weight of QC Inhibitors NH HN In general, the QC inhibitors of the subject method or NH O medical use will be small molecules, e.g., with molecular HN -4- weights of 500 g/mole or less, 400 g/mole or less, preferably QC of 350 g/mole or less, and even more preferably of 300 g/mole NH or less and even of 250 g/mole or less. The term “subject' as used herein, refers to an animal, 25 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 30 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 peptide which includes alleviation of the symptoms of the disease or disorder being treated. NH H As used herein, the term “pharmaceutically acceptable' NH O 35 embraces both human and veterinary use: For example the HN -4- term “pharmaceutically acceptable' embraces a veterinarily QC acceptable compound or a compound acceptable in human NH medicine and health care. Throughout the description and the claims the expression 40 “alkyl, unless specifically limited, denotes a C- alkyl 2 O O group, Suitably a Cls alkyl group, e.g. Calkyl group, e.g. C. alkyl group. Alkyl groups may be straight chain or NH2 branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, The term “EC as used herein comprises the activity of QC 45 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. 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 50 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 unchanged glutamyl peptides by QC (EC) peptide peptide peptide peptide

NH NH HN HN G HN HN O H2O O O O al al QC/EC GE) QC/EC NH2 NH

O O O O OH HN O O G US 8,541,596 B2 5 6 oxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy membered rings (e.g. pyridazine, pyrimidine, pyrazine). (e.g. n-octoxy). Exemplary thioalkyl groups include meth Exemplary monocyclic heteroaryl groups having three het ylthio-. Exemplary haloalkyl groups include fluoroalkyl e.g. eroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exem CF. plary monocyclic heteroaryl groups having four heteroatoms The expression “alkenyl', unless specifically limited, include tetrazole. Exemplary bicyclic heteroaryl groups denotes a C2-12 alkenyl group, Suitably a C2-alkenyl group. include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, e.g. a Calkenyl group, which contains at least one double quinoline, isoquinoline, indazole, benzimidazole, benzthiaz bond at any desired location and which does not contain any ole, quinazoline and purine. triple bonds. Alkenyl groups may be straight chain or The expression "-alkylaryl', unless specifically limited, branched. Exemplary alkenyl groups including one double 10 bond include propenyl and butenyl. Exemplary alkenyl denotes an aryl residue which is connected via an alkylene groups including two double bonds include pentadienyl, e.g. moiety e.g. a Calkylene moiety. (1E.3E)-pentadienyl. The expression "-alkylheteroaryl', unless specifically lim The expression “alkynyl', unless specifically limited, ited, denotes a heteroaryl residue which is connected via an denotes a C-12 alkynyl group, Suitably a C2-alkynyl group. 15 alkylene moiety e.g. a Calkylene moiety. e.g. a C- alkynyl group, which contains at least one triple The term “halogen' or “halo' comprises fluorine (F), chlo bond at any desired location and may or may not also contain rine (Cl) and bromine (Br). one or more double bonds. Alkynyl groups may be straight The term “amino” refers to the group —NH. chain or branched. Exemplary alkynyl groups include propy The term “phenyl substituted by phenyl refers to biphe nyl and butynyl. nyl. The expression “alkylene' denotes a chain of formula The term “v denotes a single bond where the stere —(CH), wherein n is an integer e.g. 2-5, unless specifi ochemistry is not defined. cally limited. When benzimidazolyl is shown as benzimidazol-5-yl, The expression “cycloalkyl, unless specifically limited, which is represented as: denotes a Co cycloalkyl group (i.e. 3 to 10 ring carbon 25 atoms), more Suitably a C-8 cycloalkyl group, e.g. a C cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep tyl and cyclooctyl. A most Suitable number of ring carbon atoms is three to six. 30 arlcor The expression "heterocyclyl', unless specifically limited, 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 the person skilled in the art will appreciate that benzimidazol and O. A specific example of a heterocyclyl group is a 6-yl, which is represented as: cycloalkyl group (e.g. cyclopentyl or more particularly cyclo 35 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 NN-s-s one hetero atom include pyrrolidine, tetrahydrofuran and pip eridine, and exemplary heterocyclyl groups containing two 40 -XCR 15 hetero atoms include morpholine, piperazine, dioxolane and dioxane. A further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one is an equivalent structure. As employed herein, the two forms or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring of benzimidazolyl are covered by the term “benzimidazol-5- atoms are replaced by heteroatoms selected from N, S and O. 45 y1”. An example of Such a group is dihydropyranyl (e.g. 3,4- Stereoisomers: dihydro-2H-pyran-2-yl-). All possible stereoisomers of the claimed compounds are The expression “aryl', unless specifically limited, denotes included in the present invention. a Caryl group, Suitably a Co aryl group, more Suitably Where the compounds according to this invention have at a Ces aryl group. Aryl groups will contain at least one aro 50 least one chiral center, they may accordingly exist as enanti matic ring (e.g. one, two or three rings). An example of a omers. Where the compounds possess two or more chiral typical aryl group with one aromatic ring is phenyl. An centers, they may additionally exist as diastereomers. It is to example of a typical aryl group with two aromatic rings is be understood that all such isomers and mixtures thereof are naphthyl. encompassed within the scope of the present invention. The expression "heteroaryl', unless specifically limited, 55 Preparation and Isolation of Stereoisomers: denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or Where the processes for the preparation of the compounds 4, Suitably 1, 2 or 3) ring atoms are replaced by heteroatoms according to the invention give rise to a mixture of stereoiso selected from N, S and O, or else a 5-membered aromatic ring mers, these isomers may be separated by conventional tech containing one or more (e.g. 1, 2, 3, or 4, Suitably 1, 2 or 3) niques such as preparative chromatography. The compounds ring atoms selected from N, S and O. Exemplary monocyclic 60 may be prepared in racemic form, or individual enantiomers heteroaryl groups having one heteroatom include: five mem may be prepared either by enantiospecific synthesis or by bered rings (e.g. pyrrole, furan, thiophene); and six mem resolution. The compounds may, for example, be resolved bered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl into their components enantiomers by standard techniques, and pyridin-4-yl). Exemplary monocyclic heteroaryl groups Such as the formation of diastereomeric pairs by salt forma having two heteroatoms include: five membered rings (e.g. 65 tion with an optically active acid, such as (-)-di-p-toluoyl-d- pyrazole, oxazole, isoxazole, thiazole, isothiazole, imida tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed Zole, such as imidazol-1-yl, imidazol-2-ylimidazol-4-yl); six by fractional crystallization and regeneration of the free base. US 8,541,596 B2 7 8 The compounds may also be resolved by formation of dias prodrug derivatives are described, for example, in “Design of tereomeric esters or amides, followed by chromatographic Prodrugs’, ed. H. Bundgaard, Elsevier, 1985. separation and removal of the chiral auxiliary. Alternatively, Protective Groups: the compounds may be resolved using a chiral HPLC column. During any of the processes for preparation of the com Pharmaceutically Acceptable Salts: pounds of the present invention, it may be necessary and/or In view of the close relationship between the free com desirable to protect sensitive or reactive groups on any of the pounds and the compounds in the form of their salts or Sol molecules concerned. This may be achieved by means of Vates, whenever a compound is referred to in this context, a conventional protecting groups, such as those described in corresponding salt, Solvate or polymorph is also intended, Protective Groups in Organic Chemistry, ed. J. F. W. provided such is possible or appropriate under the circum 10 McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Stances. Wuts, Protective Groups in Organic Synthesis, John Wiley & Salts and solvates of the compounds of formula (I) and Sons, 1991, fully incorporated herein by reference. The pro physiologically functional derivatives thereof which are suit tecting groups may be removed at a convenient Subsequent able for use in medicine are those wherein the counter-ion or stage using methods known from the art. associated solvent is pharmaceutically acceptable. However, 15 As used herein, the term “composition' is intended to salts and Solvates having non-pharmaceutically acceptable encompass a product comprising the claimed compounds in counter-ions or associated Solvents are within the scope of the the therapeutically effective amounts, as well as any product present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically which results, directly or indirectly, from combinations of the acceptable salts and Solvates. claimed compounds. Suitable salts according to the invention include those Carriers and Additives for Galenic Formulations: formed with both organic and inorganic acids or bases. Phar Thus, for liquid oral preparations, such as for example, maceutically acceptable acid addition salts include those Suspensions, elixirs and Solutions, Suitable carriers and addi formed from hydrochloric, hydrobromic, sulfuric, nitric, cit tives may advantageously include water, glycols, oils, alco ric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroace hols, flavoring agents, preservatives, coloring agents and the tic, triphenylacetic, Sulfamic, Sulfanilic, succinic, oxalic, 25 like; for Solid oral preparations such as, for example, pow fumaric, maleic, malic, mandelic, glutamic, aspartic, oxalo ders, capsules, gelcaps and tablets, Suitable carriers and addi acetic, methanesulfonic, ethanesulfonic, arylsulfonic (for tives include starches, Sugars, diluents, granulating agents, example p-toluenesulfonic, benzenesulfonic, naphthalene lubricants, binders, disintegrating agents and the like. Sulfonic or naphthalenedisulfonic), Salicylic, glutaric, glu Carriers, which can be added to the mixture, include nec conic, tricarballylic, cinnamic, Substituted cinnamic (for 30 essary and inert pharmaceutical excipients, including, but not example, phenyl, methyl, methoxy or halo Substituted cin limited to, Suitable binders, Suspending agents, lubricants, namic, including 4-methyl and 4-methoxycinnamic acid). flavorants, Sweeteners, preservatives, coatings, disintegrating ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1 agents, dyes and coloring agents. or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example Soluble polymers as targetable drug carriers can include naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or polyvinylpyrrolidone, pyran copolymer, polyhydroxypropy 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, ben 35 lmethacrylamidephenol, polyhydroxyethylaspartamide-phe Zeneacrylic (for example 1,4-benzenediacrylic), isethionic nol, or polyethyleneoxidepolyllysine substituted with palmi acids, perchloric, propionic, glycolic, hydroxyethane toyl residue. Furthermore, the compounds of the present Sulfonic, pamoic, cyclohexanesulfamic, Salicylic, saccharinic invention may be coupled to a class of biodegradable poly and trifluoroacetic acid. Pharmaceutically acceptable base mers useful in achieving controlled release of a drug, for salts include ammonium salts, alkali metal salts such as those 40 example, polyactic acid, polyepsilon caprolactone, polyhy of sodium and potassium, alkaline earth metal salts such as droxybutyeric acid, polyorthoesters, polyacetals, polydihy those of calcium and magnesium and salts with organic bases dropyrians, polycyanoacrylates and cross-linked or amphip Such as dicyclohexylamine and N-methyl-D-glucamine. athic block copolymers of hydrogels. All pharmaceutically acceptable acid addition salt forms of Suitable binders include, without limitation, starch, gela the compounds of the present invention are intended to be 45 tin, natural Sugars such as glucose or betalactose, corn Sweet embraced by the scope of this invention. eners, natural and synthetic gums such as acacia, tragacanth Polymorph Crystal Forms: or sodium oleate, Sodium Stearate, magnesium Stearate, Furthermore, some of the crystalline forms of the com Sodium benzoate, Sodium acetate, sodium chloride and the pounds may exist as polymorphs and as Such are intended to like. be included in the present invention. In addition, some of the 50 Disintegrators include, without limitation, starch, methyl compounds may form solvates with water (i.e. hydrates) or cellulose, agar, bentonite, Xanthan gum and the like. common organic solvents, and Such solvates are also intended to be encompassed within the scope of this invention. The SUMMARY OF THE INVENTION compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their According to the invention there is provided a compound of crystallization. 55 Prodrugs: formula (I): The present invention further includes within its scope (I) prodrugs of the compounds of this invention. In general. Such (R) prodrugs will be functional derivatives of the compounds X- -R2 which are readily convertible in vivo into the desired thera 60 peutically active compound. Thus, in these cases, the methods of treatment of the present invention, the term “administer ing shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified com 65 or a pharmaceutically acceptable salt, Solvate or polymorph pound in vivo after administration to the subject. Conven thereof, including all tautomers and stereoisomers thereof tional procedures for the selection and preparation of suitable wherein: US 8,541,596 B2 9 10 X represents a bond or a —(CH)-group. Such that when X with the proviso that the compound of formula (I) is other represents -(CH2). , neither R'nor R represent propyl: than: m represents an integer selected from 1 to 3: 5-diethylamino-benzimidazolyl; R" represents hydrogen, —Coalkyl, -aryl, -Coalkylaryl, N-benzyl-1H-benzodimidazol-5-amine (E2); -cycloalkyl, -Calkylcycloalkyl, -Calkyl-Het, -aryl N-(4-methoxybenzyl)-3H-benzodimidazol-5-amine (E4); fused to heterocyclyl. —Calkylaryl fused to heterocy N-(4-nitrobenzyl)-3H-benzodimidazol-5-amine: clyl, -aryl Substituted by heteroaryl, —Calkylaryl Sub (1H-benzodimidazol-5-yl)-N-methylmethanamine; stituted by heteroaryl, -aryl substituted by phenyl, 4-(benzoimidazol-5-ylamino)-3-nitrobenzonitrile; —Calkylaryl substituted by phenyl, -aryl substituted by 6-(benzimidazol-5-yl)amino-5-nitronicotinonitrile; phenoxy or —Calkylaryl Substituted by phenoxy; 10 4-(1H-benzimidazol-5-ylamino)-3-nitrobenzotrifluoride; and in which any of aforesaid aryl, heterocyclyl, het 5-amino-6-(benzimidazol-5-yl)aminonicotinonitrile; and eroaryl, phenyl or phenoxy groups may optionally be 3-amino-4-(benzimidazol-5-ylamino)benzonitrile. Substituted by one or more groups selected from Other objects and features will be in part apparent and in Calkyl, Calkenyl, C-alkynyl, Chaloalkyl, part pointed out hereinafter. —Cathioalkyl, -SOC-alkyl, -SOC-alkyl, 15 Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, DETAILED DESCRIPTION OF THE INVENTION —SOC scycloalkyl, -SOC cycloalkyl, Calk enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) The first compound of the proviso, 5-diethylamino-benz OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, imidazolyl, is a commercially available compound having no cyano, hydroxyl, —C(O)OH, -NH. NHC alkyl, associated therapeutic indication. —N(Calkyl)(Calkyl). —C(O)N(Calkyl) The second compound of the proviso, N-benzyl-1H-benzo (Calkyl), —C(O)NH2. —C(O)NH(Calkyl) and dimidazol-5-amine, is referred to in Braeuniger etal (1966) Archiv der Pharmazie 299(3), 193-196 as compound (IV). —C(O)NH(Cocycloalkyl); The third compound of the proviso, N-(4-methoxybenzyl)- R represents —C-alkyl, -aryl, -C-alkylaryl, -cy 25 3H-benzodimidazol-5-amine, is referred to in Braeunigeret cloalkyl, -Calkylcycloalkyl, -Calkyl-Het, -aryl all (1966) Archiv der Pharmazie 299(3), 193-196 as com fused to heterocyclyl. —Calkylaryl fused to heterocy pound (VI). clyl, -aryl Substituted by heteroaryl, —Calkylaryl Sub The fourth compound of the proviso, N-(4-nitrobenzyl)- stituted by heteroaryl, -aryl substituted by phenyl, 3H-benzodimidazol-5-amine, is referred to in Braeunigeret —Calkylaryl substituted by phenyl, -aryl substituted by 30 all (1966) Archiv der Pharmazie 299(3), 193-196 as com phenoxy or —Calkylaryl Substituted by phenoxy: pound (VIII). and in which any of aforesaid aryl, heterocyclyl, het The fifth compound of the proviso, (1H-benzodimidazol eroaryl, phenyl or phenoxy groups may optionally be 5-yl)-N-methylmethanamine, is referred to as an intermedi Substituted by one or more groups selected from 35 ate used in the preparation of Example 76 in WO 2007/ Calkyl, Calkenyl, C-alkynyl, Chaloalkyl, O53131. —Cathioalkyl, —SOC-alkyl, Cigalkoxy-, The sixth compound of the proviso, 4-(benzoimidazol-5- —O—C-scycloalkyl, C-scycloalkyl, -SOC-scy ylamino)-3-nitrobenzonitrile, is referred to as Preparation 12 cloalkyl, -SOC-cycloalkyl, Calkenyloxy-, (22) in WO 01/05770. Calkynyloxy-, -C(O)Calkyl, —C(O)OC-alkyl, 40 The seventh compound of the proviso, 6-(benzimidazol-5- Calkoxy-C-alkyl-, nitro, halogen, cyano, hydroxyl, yl)amino-5-nitronicotinonitrile, is referred to as Preparation 9 (8) in WO 01/05770. —C(O)CH, -NH. NHC alkyl, - N(Calkyl) The eighth compound of the proviso, 4-(1H-benzimidazol (Calkyl). —C(O)N(Calkyl)(Calkyl), —C(O) 5-ylamino)-3-nitrobenzotrifluoride, is referred to as Prepara NH, —C(O)NH(Calkyl) and —C(O)NH(Cocy tion 12 (10) in WO 01/05770. cloalkyl); 45 The ninth compound of the proviso, 5-amino-6-(benzimi Het represents a bicyclic heteroaryl group; dazol-5-yl)aminonicotinonitrile, is referred to as Preparation in which said bicyclic heteroaryl group may be optionally 15 (58) in WO 01/05770. Substituted by one or more groups selected from The tenth compound of the proviso, 3-amino-4-(benzimi Calkyl, Calkenyl, C-alkynyl, Chaloalkyl, dazol-5-ylamino)benzonitrile, is referred to as Preparation 15 —Cathioalkyl, —SOC-alkyl, Cigalkoxy-, 50 (60) in WO 01/05770. —O—C-scycloalkyl, C-scycloalkyl, -SOC-scy In one particular aspect of the invention which may be cloalkyl, -SOC-cycloalkyl, Calkenyloxy-, mentioned, there is provided a compound of formula (I): Calkynyloxy-, -C(O)Calkyl, —C(O)OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, cyano, hydroxyl, —C(O)CH, NH, -NHC alkyl, - N(Calkyl) 55 (I) (R) 2 (Calkyl). —C(O)N(Calkyl)(Calkyl). —C(O) X R NH, —C(O)NH(Calkyl) and —C(O)NH(Cocy N N a N 1 cloalkyl); in represents an integer selected from 0 to 3. Such that when in (N 21 R represents 2, said R groups do not both represent nitro; and 60 M R" represents C-alkyl, Calkenyl, C2-alkynyl, Cha H loalkyl, -Cathioalkyl, -SOC-alkyl, -SOC-alkyl, Calkoxy-, -O-C cycloalkyl, C-scycloalkyl, or a pharmaceutically acceptable salt, Solvate or polymorph —SOCscycloalkyl, -SOC cycloalkyl, Calkeny thereof, including all tautomers and stereoisomers thereof loxy-, Calkynyloxy-, -C(O)Calkyl, Calkoxy 65 wherein: Calkyl-, nitro, halogen, cyano, hydroxyl, -NH2, X represents a bond or a —(CH2)-group; —NHC alkyl and —N(Calkyl)(Calkyl); m represents an integer selected from 1 to 3:

US 8,541,596 B2 13 14 groups include 2,3-difluoro-4-methylphenyl, 2-fluoro-5-(tri include 4-benzyloxy-phenyl-, 4-(3-methylbenzyloxy)phe fluoromethyl)phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hy nyl- and 4-(4-methylbenzyloxy)phenyl-. droxy-5-methylphenyl-, 3-fluoro-4-(trifluoromethyl)phe When R' or R represents arylor-Calkylaryl fused to nyl-, 3-fluoro-5-(trifluoromethyl)phenyl-, 2-fluoro-4- heterocyclyl, examples include benzo 1.3dioxo-4-yl-, 3,4- (trifluoromethyl)phenyl-, 2-fluoro-3-(methyl)phenyl-, dihydro-benzo 1,4-dioxepin-9-yl and 2,3-dihydro-benzo1, 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4-methoxyphe 4 dioxin-4-yl-. nyl-, 4-chloro-3-(trifluoromethyl)phenyl-, 4-chloro-3-meth Suitably, R' represents hydrogen, Calkyl (e.g. methyl), ylphenyl, 4-bromo-4-ethylphenyl, 2,3,5,6-tetrafluoro-4-(me —Calkylaryl (e.g. —CH2-phenyl, -(CH2)-phenyl, thyl)phenyl-, 2,6-difluoro-4-(methoxy)phenyl- and 2-fluoro —(CH-)-phenyl or —CH-naphthyl), —Calkyl-Het (e.g. 4.5-(dimethoxy)phenyl-. 10 —CH-benzothiazolyl, —CH-benzothiadiazolyl, —CH When R' or R represents arylor-Calkylaryl, said aryl benzothiophenyl, —CH2-quinolinyl), —Calkylaryl fused suitably represents optionally substituted naphthyl. to heterocyclyl (e.g. dihydrobenzodioxepinyl) or—Calky Examples include unsubstituted naphthyl (e.g. naphthalen-1- laryl substituted by heteroaryl (e.g. —CH2-phenyl substi yl, naphthalen-2-yl, naphthalen-3-yl) as well as Substituted tuted by thiophenyl). naphthyl (e.g. 4-methyl-naphthalen-2-yl-, 5-methyl-naph 15 Suitably, R represents—C-alkyl (e.g. butyl, pentan-2-yl thalen-3-yl-, 7-methyl-naphthalen-3-y- and 4-fluoro-naph or isobutyl), -aryl (e.g. phenyl), —Calkylaryl (e.g. —CH thalen-2-yl-). phenyl, —CH2-naphthyl, -CH(CH)-phenyl, -(CH2)- When R' or R represents cycloalkyl or - Calkylcy phenyl or —(CH2)-phenyl), —Calkylcycloalkyl (e.g. cloalkyl said cycloalkyl Suitably represents optionally Substi —CH2-cyclohexyl), —Calkyl-Het (e.g. —CH-ben tuted cycloalkyl. Examples of cycloalkyl include cyclopro Zothiazolyl, —CH-benzothiadiazolyl, —CH-ben pyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Zothiophenyl or —CH-quinolinyl), —Calkylaryl fused to Examples of substituted carbocyclyl include 2-methyl-cyclo heterocyclyl (e.g. dihydrobenzodioxepinyl) or —Calky hexyl-, 3-methyl-cyclohexyl- and 4-methyl-cyclohexyl-. laryl substituted by heteroaryl (e.g. —CH-phenyl substi When R' or R represents - Calkyl-Het, suitable tuted by thiophenyl). In one embodiment, R represents a examples of Het include bicyclic rings (e.g. 9 or 10 membered 25 group other than —C-alkyl. In a further embodiment, R rings) which may optionally be substituted. Example 9 mem represents -aryl (e.g. phenyl), —Calkylaryl (e.g. —CH2 bered rings include 1H-indolyl (e.g. 1H-indol-3-yl, 1H-indol phenyl, —CH2-naphthyl, -CH(CH)-phenyl, -(CH2)- 5-yl), benzothiophenyl (e.g. benzobthiophen-3-yl, particu phenyl or —(CH)-phenyl), —Calkylcycloalkyl (e.g. larly 2-benzobthiophen-3-yl), benzo 1,2,5-oxadiazolyl —CH2-cyclohexyl), —Calkyl-Het (e.g. —CH-ben (e.g. benzo 1,2,5-oxadiazol-5-yl), benzodthiazolyl (e.g. 30 Zothiazolyl, —CH-benzothiadiazolyl, —CH-ben benzodthiazol-2-yl), benzo[1,2,5-thiadiazolyl (e.g. benzo Zothiophenyl or —CH2-quinolinyl), —Calkylaryl fused to 1,2,5-thiadiazol-5-yl, benzol.2,5thiadiazol-6-yl). heterocyclyl (e.g. dihydrobenzodioxepinyl) or - Calky Example 10 membered rings include quinolinyl (e.g. quino laryl substituted by heteroaryl (e.g. —CH-phenyl substi lin-3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-8-yl). Specific tuted by thiophenyl). Substituents that may be mentioned are one or more e.g. 1, 2 35 In one embodiment, R' represents hydrogen and R repre or 3 groups selected from halogen, hydroxyl, alkyl (e.g. sents Calkyl (e.g. butyl, pentan-2-ylor isobutyl), -aryl (e.g. methyl) and alkoxy- (e.g. methoxy-). Example Substituted phenyl), —Calkylaryl (e.g. —CH2-phenyl, -CH2-naph 9-membered rings include 1-methyl-1H-indol-3-yl, 2-me thyl, -CH(CH-)-phenyl or —(CH-)-phenyl), —Calkyl thyl-1H-indol-3-yl, 6-methyl-1H-indol-3-yl and 5-chlo cycloalkyl (e.g. —CH2-cyclohexyl), —Calkyl-Het (e.g. robenzobthiophen-3-yl. Example substituted 10 membered 40 —CH-benzothiazolyl, —CH-benzothiadiazolyl, —CH rings include 2-chloro-quinolin-3-yl, 8-hydroxy-quinolin-2- benzothiophenyl or—CH2-quinolinyl), —C-alkylaryl Sub y1, 2-methyl-quinolin-6-yl, oxo-chromenyl (e.g. 4-oxo-4H stituted by heteroaryl (e.g. —CH-phenyl substituted by chromen-3-yl) and 6-methyl-4-oxo-4H-chromen-3-yl. thiophenyl) or —Calkylaryl fused to heterocyclyl (e.g. When R' or R represents aryl or C-alkylaryl substi dihydrobenzodioxepinyl); wherein said phenyl group is tuted by phenyl or aryl or —Calkylaryl substituted by a 45 optionally Substituted by one or more halogen (e.g. chlorine, heteroaryl group (such as a monocyclic heteroaryl), in which fluorine or bromine), Calkoxy (e.g. methoxy), Calkyl any of aforesaid phenyl and heteroaryl groups may optionally (e.g. methyl or ethyl), —C-thioalkyl (e.g. thiomethyl) or be substituted, typically the aryl ring connected directly to the —N(Calkyl)(Calkyl) (e.g. —NMe2) groups; and nitrogenatom is unsubstituted and the terminal phenyl ring or wherein said Het group is optionally substituted by one or the monocyclic heteroaryl ring is optionally Substituted by 50 more halogen (e.g. chlorine) or Calkyl (e.g. methyl) one, two or three Substitutents (e.g. one or two, e.g. one). groups. Typically the terminal phenyl or monocyclic heteroaryl group In one embodiment, R' represents C-alkyl (e.g. methyl) is unsubstituted. Typically the terminal phenyl or monocyclic and R represents -aryl (e.g. phenyl) or -Coalkylaryl (e.g. heteroaryl group Substitutes the aryl ring (i.e. phenyl) at the —CH2-phenyl); wherein said phenyl group is optionally sub 4-position. 55 stituted by one or more halogen (e.g. fluorine) or Calkoxy When R' or R represents aryl or - Calkylaryl substi (e.g. methoxy) groups. tuted by phenyl in which any of aforesaid aryl or phenyl In one embodiment, R' represents —C-alkylaryl (e.g. groups may optionally be substituted, examples include -bi —CH2-phenyl, -(CH2)2-phenyl, -(CH2)-phenyl or phenyl-4-yl and —CH2-biphenyl-4-yl. —CH2-naphthyl) and R represents —C-alkylaryl (e.g. When R' or R represents aryl or C-alkylaryl substi 60 —CH2-phenyl or —CH2-naphthyl), —C-alkylcycloalkyl tuted by a monocyclic heteroaryl group, in which any of (e.g. —CH2-cyclohexyl) or —Calkyl (e.g. butyl, isobutyl aforesaid aryland heteroaryl groups may optionally be Sub or pentan-2-yl); wherein said phenyl groups are optionally stituted, examples include (4-thiophen-2-yl)-benzyl- and (4- Substituted by one or more halogen (e.g. chlorine, fluorine or (oxazol-5-yl)phenyl-. bromine), cyano, Calkyl (e.g. methyl, ethyl, isopropyl. When R' or R represents aryl or C-alkylaryl substi 65 t-butyl), Calkoxy (e.g. methoxy), —Cathioalkyl (e.g. thi tuted by phenyloxy in which any of aforesaid aryl and phe omethyl) or —N(Calkyl)(Calkyl) (e.g. —NMe) nyloxy groups may optionally be substituted, examples groups. US 8,541,596 B2 15 16 In one embodiment, R' and R both represent - Calky (b) preparing a compound of formula (I) wherein X repre laryl (e.g. —CH2-phenyl, -(CH2)-phenyl, -(CH)-phe sents a bond, R' represents hydrogen and R represents nyl or —CH2-naphthyl); wherein said phenyl groups are —Calkylaryl, -Calkyl-Het, —Calkylaryl fused to optionally Substituted by one or more halogen (e.g. chlorine, heterocyclyl. —Calkylaryl Substituted by heteroaryl, fluorine or bromine), cyano, Calkyl (e.g. methyl, ethyl, —Calkylaryl Substituted by phenyl or —Calkylaryl isopropyl, t-butyl), Calkoxy (e.g. methoxy), —Cathio Substituted by phenoxy, by alkylating a compound of for alkyl (e.g. thiomethyl) or —N(Calkyl)(Calkyl) (e.g. mula (III): —NMe) groups. In one embodiment, R' and R both represent - Calky laryl fused to heterocyclyl (e.g. dihydrobenzodioxepinyl). 10 (III) In one embodiment, R' and R both represent - Calky (R) laryl substituted by heteroaryl (e.g. —CH2-phenyl substi tuted by thiophenyl). In one embodiment, R' represents —Calkyl-Het (e.g. N r21 15 —CH-benzothiazolyl, —CH-benzothiadiazolyl, —CH M benzothiophenyl, -CH2-quinolinyl) and R represents —Calkyl-Het (e.g. —CH-benzothiazolyl, —CH-ben Zothiadiazolyl, —CH-benzothiophenyl, —CH2-quinolinyl) wherein R* and n are as defined above for compounds of or—Calkylcarbocyclyl (e.g. —CH2-phenyl); wherein said formula (I) and Cy' represents the aryl or Het group of R. Het groups are optionally Substituted by one or more halogen Process (b) typically comprises addition of a compound of (e.g. chlorine) or Calkyl (e.g. methyl) groups; and wherein formula (III) to a suitable reducing agent, Such as sodium said phenyl group is optionally substituted by one or more borohydride, in a Suitable solvent, Such as ethanol at room —Cathioalkyl (e.g. thiomethyl), Calkyl (e.g. ethyl), temperature. A non-limiting example of the methodology of Calkoxy (e.g. methoxy), halogen (e.g. chlorine) or 25 process (b) is described in Method 2 herein. —N(Calkyl)(Calkyl)(e.g. —NMe2) groups. (c) preparing a compound of formula (I) wherein X represents In one embodiment, R' and R both represent—Calkyl a bond, R' represents hydrogen and R represents Het (e.g. —CH-benzothiazolyl, —CH-benzothiadiazolyl, —Calkyl, -Calkylaryl, —Calkylcycloalkyl, —CH-benzothiophenyl, —CH2-quinolinyl); wherein said —Calkyl-Het, —Calkylaryl fused to heterocyclyl, Het groups are optionally Substituted by one or more halogen 30 (e.g. chlorine) or Calkyl (e.g. methyl) groups. —Calkylaryl Substituted by heteroaryl, -Calkylaryl In one embodiment, R' represents aryl (e.g. phenyl)and R' substituted by phenyl or - Calkylaryl substituted by represents —Calkylaryl (e.g. —CH2-phenyl). phenoxy, by reacting a compound of formula (IV): Suitably, X represents a bond or a —CH2-group. More suitably, X represents a bond. When X represents a 35 —(CH2)-group, m suitably represents an integer selected (IV) from 1 or 2, more suitably 1. (R) Suitably, in represents an integer from 0 to 2, more suitably 0 or 1. In one embodiment, in represents 0. When present, it & xn N will be appreciated that the R' substituent will be located on 40 N 21 the phenyl ring of the benzimidazolyl group. M Processes H According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) wherein R* and n are as defined above for compounds of which comprises: 45 (a) preparing a compound of formula (I) wherein X represents formula (I), with a compound of formula H–CO R: a bond by reacting a compound of formula (II) wherein R is as defined above for compounds of formula (I). Process (c) typically comprises reaction in a suitable solvent, such as methanol followed by addition of a suitable reducing (II) agent, such as sodium borohydride. A non-limiting example 50 of the methodology of process (c) is described in Method 3 N y Ll herein. (d) preparing a compound of formula (I) wherein: X repre N r 21 sents a bond, R' represents hydrogen and R is as defined M 55 above; or X represents a bond and R' and R represent identical groups, by reacting a compound of formula (IV): wherein R* and n are as defined above for compounds of formula (I) and L' represents a suitable leaving group, such as (IV) bromine, with a compound of formula NHR'R'', wherein R' 60 (R) and Rare as defined above for compounds of formula (I). Process (a) typically comprises reaction in a Suitable solvent, such as THF in the presence of 2-dicyclohexylphosphino-2'- ( Prs n N 2 (N,N-dimethylamino)biphenyl, Pd dba and lithiumbis(tri M methylsilyl)amide, followed by heating under an Argon 65 H atmosphere to 65° C. for 24 h. A non-limiting example of the methodology of process (a) is described in Method 1 herein. US 8,541,596 B2 17 18 oran optionally protecting derivative thereof, wherein R* and in are as defined above for compounds of formula (I), with a (V) compound of formula L-R, wherein L' represents a suitable (R) leaving group such as bromine and R is as defined above for compounds of formula (I). Process (d) typically comprises dissolving the compound of formula (IV) in a suitable sol ( Prs vent, such as DMF followed by treatment with the compound N 21 of formula L-R and potassium carbonate. A non-limiting ? example of the methodology of process (d) is described in 10 Methods 4 and 5 herein. wherein R, nand Rareas defined for compounds of formula (e) preparing a compound of formula (I) wherein X represents (I), with a compound of formula L. R', wherein L' repre a —(CH2)-group, by reacting a compound of formula sents a suitable leaving group such as bromine and R" rep (VI): resents an R' group as defined for compounds of formula (I) other than hydrogen. This interconversion typically com 15 prises dissolving the compound of formula (V) in a Suitable (VI) solvent, such as DMF followed by treatment with the com (R) pound of formula L. R" and potassium carbonate. A non N x N (CH2)- 2) O limiting example of the methodology of this interconversion is described in Method 6 herein. (N 2 H (g) deprotecting a compound of formula (I) which is pro M tected. H Compounds of formula (I) and intermediate compounds may also be prepared using techniques analogous to those wherein R' and n are as defined above for compounds of 25 known to a skilled person, or described herein. formula (I), with a compound of formula HNR'R'', wherein Novel intermediates are claimed as an aspect of the present R" and Rare as defined above for compounds of formula (I). invention. Process (f) typically comprises dissolving the compound of Therapeutic Uses formula (VI) in a suitable solvent, such as tetrahydrofuran, Physiological Substrates of QC (EC) in mammals are, e.g. 30 amyloid beta-peptides (3-40), (3-42), (11-40 and (11-42), followed by addition of the compound of formula HNR'R'', ABri, ADan, Gastrin, Neurotensin, FPP, CCL 2, CCL 7, CCL NaBH(AcO) and ethanol. A non-limiting example of the 8, CCL 16, CCL 18, Fractalkine, Orexin A, Gln)-glucagon methodology of process (f) is described in Method 7 herein. (3-29), Gln)-substance P(5-11) and the peptide QYNAD. (f) interconversion of compounds of formula (I). One such For further details see table 1. The compounds and/or com example of an interconversion reaction comprises prepar binations according to the present invention and pharmaceu ing a compound of formula (I) wherein R' represents a 35 tical compositions comprising at least one inhibitor of QC group other than hydrogen by reacting a compound of (EC) are useful for the treatment of conditions that can be formula (V): treated by modulation of QC activity. TABL E 1. Amino acid sequences of physiologica 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- British Dementia, Familial Gly-Leu-Met-Val-Gly-Gly-Val-Val- Danish Dementia, Down Ile-Ala 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- British Dementia, Familial Gly-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-lile-lle-Gly-Leu- British Dementia, Familial Met-Val-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- British Dementia, Familial Met-Val-Gly-Gly-Val-Val Danish Dementia, Down Syndrome US 8,541,596 B2 19 20 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 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- Alzheimer's Disease, Familial Met-Val-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- Alzheimer's Disease, Familial Met-Val-Gly-Gly-Val-Val British Dementia, Familial Danish Dementia, Down Syndrome

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

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

Gastrin 17 OGPWL EEEEEAYGWM DF Gastrin stimulates the stomach Swiss-Prot: (amide) mucosa to produce and secrete PO1350 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.

Neurotensin OLYENKPRRP YIL Neurotensin plays an endocrine Swiss-Prot: or paracrine role in the P3 O990 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: the biosynthesis of TSH in the P2O396 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: gonadotropins; it stimulates the PO1148 secretion of both luteinizing and follicle-stimulating hormones.

CCL16 (Small QPKVPEW VNTPSTCCLK Shows chemotactic activity for inducible YYEKWLPRRL WWGYRKALNC lymphocytes and monocytes but not cytokine A16) HLPAIIFWTK RNREWCTNPN neutrophills. Also shows potent Swiss-Prot: DDWVOEYIKD PNLPLLPTRN myelosuppressive activity, O15467 LSTWKIITAK NGOPOLLNSQ 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. US 8,541,596 B2 21 22 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 CCL8 (Small QPDSVSI PITCCFNVIN Chemotactic factor that attracts inducible RKIPIORLES YTRITNIOCP monocytes, lymphocytes, cytokine A8) KEAWIFKTKR GKEWCADPKE basophills and eosinophills. May Swiss-Prot: DSMKHL DOIFONLKP play a role in neoplasia and P8OOfs inflammatory host responses. This protein can bind heparin.

CCL2 (MCP-1, QPDAINA PVTCCYNFTN Chemotactic factor that attracts Small inducible RKISWORLAS YRRITSSKCP monocytes and basophills but cytokine A2) KEAVIFKTIV AKEICADPKO not neutrophills or eosinophills. Swiss-Prot: DSMDHL DKOTOTPKT Augments monocyte anti-tumor P135 OO 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 OKFIVDYSET SPOCPKPGVI lymphocytes but not monocytes cytokine A18) LLTKRGROIC ADPNKKWVOK or granulocytes. May be Swiss-Prot: YISD LKLNA involved in B cell migration into Pss?f.4 B cell follicles in lymph nodes. 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 The soluble form is chemotactic (neurotactin) SKIPVALLIH YOONOASCGK for T cells and monocytes, but Swiss-Prot: RAIILETROH RLFCADPKEO not for neutrophills. The P78423 WWKDAMOHLD ROAAALTRNG membrane-bound form promotes GTFEKOIGEV KPRTTPAAGG adhesion of those leukocytes MDESWWLEPE ATGESSSLEP to endothelial cells. May play TPSSOEAQRA LGTSPELPTG a role in regulating leukocyte WTGSSGTRLP PTPKAODGGP adhesion and migration processes VGTELFRVPP VSTAATWOSS at the endothelium binds to APHOPGPSLW AEAKTSEAPS CX3 CR1. 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 A7) KKIPKORLES YRRTTSSHCP monocytes and eosinophills, but cytokine REAVIFKTKL DKEICADPTO not neutrophills. Augments Swiss-Prot: KWVODFMKHL DKKTOTPKL monocyte anti-tumor activity. P8OO 98 Also induces the release of gelatinase B. This protein can bind heparin. Binds to CCR1, CCR2 and CCR3.

Orexin A OPLPDCCROK TCSCRLYELL Neuropeptide that plays a (Hypocretin-1) HGAGNHAAGI LTL significant role in the regulation Swiss-Prot of food intake and sleep O4361.2 Wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a broader role in the US 8,541,596 B2 23 24 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 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.

Glutamate is found in positions 3, 11 and 22 of the amyloid cessed forms (progastrin and glycine-extended gastrin), is O-peptide. Among them the mutation from glutamic acid (E) also a growth factor for the gastrointestinal tract. It has been to glutamine (Q) in position 22 (corresponding to amyloid 25 established that the major trophic effect of amidated gastrin is precursor protein APP 693, Swissprot PO5067) has been for the oxyntic mucosa of stomach, where it causes increased described as the so called Dutch type cerebroarterial amyloi proliferation of gastric stem cells and ECL cells, resulting in dosis mutation. increased parietal and ECL cell mass. On the other hand, the The B-amyloid peptides with a pyroglutamic acid residue major trophic target of the less processed gastrin (e.g. gly in position 3, 11 and/or 22 have been described to be more 30 cine-extended gastrin) appears to be the colonic mucosa cytotoxic and hydrophobic than the amyloid O-peptides 1-40 (Koh, T.J. and Chen, D. 2000 Regul Pept 9337–44). (42/43) (Saido T. C. 2000 Medical Hypotheses 54(3): 427 Neurotensin (NT) is a neuropeptide implicated in the 429). pathophysiology of schizophrenia that specifically modulates The multiple N-terminal variations, e.g. Abeta(3-40), neurotransmitter systems previously demonstrated to be mis Abeta(3-42), Abeta(11-40) and Abeta (11-42) can be gener- 35 regulated in this disorder. Clinical studies in which cere ated by the 6-secretase enzyme 6-site amyloid precursor pro brospinal fluid (CSF) NT concentrations have been measured tein-cleaving enzyme (BACE) at different sites (Huse J.T. et revealed a subset of schizophrenic patients with decreased al. 2002 J. Biol. Chem. 277 (18): 16278-16284), and/or by CSFNT concentrations that are restored by effective antip aminopeptidase or dipeptidylaminopeptidase processing sychotic drug treatment. Considerable evidence also exists from the full length peptides Abeta(1-40) and Abeta(1-42). In 40 concordant with the involvement of NT systems in the mecha all cases, cyclization of the then N-terminal occurring nism of action of antipsychotic drugs. The behavioral and glutamic acid residue is catalyzed by QC. biochemical effects of centrally administered NT remarkably Transepithelial transducing cells, particularly the gastrin resemble those of systemically administered antipsychotic (G) cell, co-ordinate gastric acid secretion with the arrival of drugs, and antipsychotic drugs increase NT neurotransmis food in the stomach. Recent work showed that multiple active 45 Sion. This concatenation of findings led to the hypothesis that products are generated from the gastrin precursor, and that NT functions as an endogenous antipsychotic. Moreover, there are multiple control points in gastrin biosynthesis. Bio typical and atypical antipsychotic drugs differentially alter synthetic precursors and intermediates (progastrin and Gly NT neurotransmission in nigrostriatal and mesolimbic gastrins) are putative growth factors; their products, the ami dopamine terminal regions, and these effects are predictive of dated gastrins, regulate epithelial cell proliferation, the 50 side effect liability and efficacy, respectively (Binder, E. B. et differentiation of acid-producing parietal cells and histamine al. 2001 Biol Psychiatry 50 856-872). secreting enterochromaffin-like (ECL) cells, and the expres Fertilization promoting peptide (FPP), a tripeptide related sion of genes associated with histamine synthesis and storage to thyrotrophin releasing hormone (TRH), is found in seminal in ECL cells, as well as acutely stimulating acid secretion. plasma. Recent evidence obtained in vitro and in vivo showed Gastrin also stimulates the production of members of the 55 that FPP plays an important role in regulating sperm fertility. epidermal growth factor (EGF) family, which in turn inhibit Specifically, FPP initially stimulates nonfertilizing (unca parietal cell function but stimulate the growth of surface pacitated) spermatozoa to “switch on and become fertile epithelial cells. Plasma gastrin concentrations are elevated in more quickly, but then arrests capacitation so that spermato subjects with Helicobacter pylori, who are known to have Zoa do not undergo spontaneous acrosome loss and therefore increased risk of duodenal ulcer disease and gastric cancer 60 do not lose fertilizing potential. These responses are mim (Dockray, G.J. 1999 J Physiol 15315-324). icked, and indeed augmented, by adenosine, known to regu The peptide hormone gastrin, released from antral G cells, late the adenylyl cyclase (AC)/cAMP signal transduction is known to stimulate the synthesis and release of histamine pathway. Both FPP and adenosine have been shown to stimu from ECL cells in the oxyntic mucosa via CCK-2 receptors. late cAMP production in uncapacitated cells but inhibit it in The mobilized histamine induces acid secretion by binding to 65 capacitated cells, with FPP receptors somehow interacting the H(2) receptors located on parietal cells. Recent studies with adenosine receptors and G proteins to achieve regulation Suggest that gastrin, in both its fully amidated and less pro of AC. These events affect the tyrosine phosphorylation state US 8,541,596 B2 25 26 of various proteins, some being important in the initial fications introduced in PyrELA and AchELA, these two “switching on', others possibly being involved in the derivatives probably have lower affinity than ELA for the acrosome reaction itself. Calcitonin and angiotensin II, also specific class I major histocompatibility complex. Conse found in seminal plasma, have similar effects in vitro on quently, in order to conserve full activity of ELA, the forma uncapacitated spermatozoa and can augment responses to tion of PyrELA must be avoided (Beck A. et al. 2001, J Pept FPP. These molecules have similar effects in vivo, affecting Res 57(6):528-38.). fertility by stimulating and then maintaining fertilizing poten Orexin A is a neuropeptide that plays a significant role in tial. Either reductions in the availability of FPP, adenosine, the regulation of food intake and sleep-wakefulness, possibly calcitonin, and angiotensin II or defects in their receptors by coordinating the complex behavioral and physiologic contribute to male infertility (Fraser, L. R. and Adeoya 10 responses of these complementary homeostatic functions. It Osiguwa, S.A. 2001 Vitam Horm 63, 1-28). plays also a role in the homeostatic regulation of energy CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and frac metabolism, autonomic function, hormonal balance and the talkine play an important role in pathophysiological condi regulation of body fluids. tions, such as Suppression of proliferation of myeloid pro Recently, increased levels of the pentapeptide QYNAD genitor cells, neoplasia, inflammatory host responses, cancer, 15 were identified in the cerebrospinal fluid (CSF) of patients psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, suffering from multiple sclerosis or Guillain-Barré syndrome humoral and cell-mediated immunity responses, leukocyte compared to healthy individuals (Brinkmeier H. et al. 2000, adhesion and migration processes at the endothelium, inflam Nature Medicine 6, 808–811). There is a big controversy in matory bowel disease, restenosis, pulmonary fibrosis, pulmo the literature about the mechanism of action of the pentapep nary hypertention, liver fibrosis, liver cirrhosis, nephroscle tide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially its efficacy rosis, Ventricular remodeling, heart failure, arteriopathy after to interact with and block sodium channels resulting in the organ transplantations and failure of vein grafts. promotion of axonal dysfunction, which are involved in A number of studies have underlined in particular the cru inflammatory autoimmune diseases of the central nervous cial role of MCP-1 for the development of atherosclerosis system. But recently, it could be demonstrated that not (Gu, L., et al., (1998) Mol. Cell 2, 275-281; Gosling, J., et al., 25 QYNAD, but its cyclized, pyroglutamated form, pEYNAD, is (1999) J. Clin. Invest 103, 773-778); rheumatoid arthritis the active form, which blocks sodium channels resulting in (Gong, J. H., et al., (1997).J. Exp. Med 186, 131-137; Ogata, the promotion of axonal dysfunction. Sodium channels are H., et al., (1997).JPathol. 182, 106-114); pancreatitis (Bhatia, expressed at high density in myelinated axons and play an M., et al., (2005) Am. J Physiol Gastrointest. Liver Physiol obligatory role in conducting action potentials along axons 288, G1259-G1265); Alzheimer's disease (Yamamoto, M., et 30 within the mammalian brain and spinal cord. Therefore, it is al., (2005) Am. J Pathol. 166, 1475-1485); lung fibrosis speculated that they are involved in several aspects of the (Inoshima, I., et al., (2004) Am. J Physiol Lung Cell Mol. pathophysiology of inflammatory autoimmune diseases, Physiol 286, L1038-L1044); renal fibrosis (Wada, T., et al., especially multiple sclerosis, the Guillain-Barré syndrome (2004).J. Am. Soc. Nephrol. 15.940-948), and graft rejection and chronic inflammatory demyelinizing polyradiculoneur (Saiura, A., et al., (2004) Arterioscler: Thromb. Vasc. Biol. 24. 35 opathy. 1886-1890). Furthermore, MCP-1 might also play a role in Furthermore, QYNAD is a substrate of the enzyme gestosis (Katabuchi, H., et al., (2003) Med Electron Microsc. glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in 36, 253-262), as a paracrine factor in tumor development the brain of mammals, especially in human brain. Glutaminyl (Ohta, M., et al., (2003) Int.J Oncol. 22,773-778; Li, S., et al., cyclase catalyzes effectively the formation of plYNAD from (2005) J. Exp. Med 202, 617-624), neuropathic pain (White, 40 its precursor QYNAD. F. A., et al., (2005) Proc. Natl. Acad. Sci. U.S.A) and AIDS Accordingly, the present invention provides the use of the (Park, I. W., Wang, J. F., and Groopman, J. E. (2001) Blood compounds of formula (I) for the preparation of a medica 97, 352-358: Coll, B., et al., (2006) Cytokine 34, 51-55). ment for the prevention oralleviation or treatment of a disease 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 45 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 MC1 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 50 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 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 55 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 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, 60 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 65 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. US 8,541,596 B2 27 28 In a preferred embodiment, the present invention provides (h) Norepinephrine reuptake inhibitors (NRIs), e.g. the use of inhibitors of QC (EC) activity in combination with reboxetine, other agents, especially for the treatment of neuronal dis (i) Bupropione, eases, artherosclerosis and multiple Sclerosis. (j) Nefazodone, The present invention also provides a method of treatment (k) beta-blockers, of the aforementioned diseases comprising the administration (1) NPY-receptor ligands: NPYagonists or antagonists. ofatherapeutically active amount of at least one compound of In a further embodiment, the other agent may be, for formula (I) to a mammal, preferably a human. example, an anti-multiple Sclerosis drug selected from the Most preferably, said method and corresponding uses are group consisting of for the treatment of a disease selected from the group con 10 a) dihydroorotate dehydrogenase inhibitors, e.g. sisting of mild cognitive impairment, Alzheimer's disease, SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. Familial British Dementia, Familial Danish Dementia, neu to HMR-1715, MNA-279), rodegeneration in Down Syndrome, Parkinson's disease and b) autoimmune Suppressant, e.g. lacquinimod, Chorea Huntington, comprising the administration of a thera c) paclitaxel, peutically active amount of at least one compound of formula 15 d) antibodies, e.g. AGT-1, anti-granulocyte-macrophage (I) to a mammal, preferably a human. colony-stimulating factor (GM-CSF) monoclonal anti Even preferably, the present invention provides a method body, Nogo receptor modulators, ABT-874, alemtu of treatment and corresponding uses for the treatment of Zumab (CAMPATH), anti-OX40 antibody, CNTO rheumatoid arthritis, atherosclerosis, pancreatitis and rest 1275, DN-1921, natalizumab (syn. to AN-100226, enosis. Antegren, VLA-4 Mab), daclizumab (syn. to Zenepax, Pharmaceutical Combinations Ro-34-7375, SMART anti-Tac), J-695, priliximab (syn. In a preferred embodiment, the present invention provides to Centara, CEN-000029, cM-T412), MRA, Dantes, a composition, preferably a pharmaceutical composition, anti-IL-12-antibody, comprising at least one QC inhibitor optionally in combina e) peptide nucleic acid (PNA) preparations, e.g. reticulose, tion with at least one other agent selected from the group 25 f) interferon alpha, e.g. Alfaferone, human alpha interferon consisting of nootropic agents, neuroprotectants, antiparkin (syn. to Omniferon, Alpha Leukoferon), Sonian drugs, amyloid protein deposition inhibitors, beta g) interferon beta, e.g. Frone, interferon beta-1a like amyloid synthesis inhibitors, antidepressants, anxiolytic Avonex, Betron (Rebif), interferon beta analogs, inter drugs, antipsychotic drugs and anti-multiple Sclerosis drugs. feron beta-transferrin fusion protein, recombinant inter Most preferably, said QC inhibitor is a compound of for 30 feron beta-1b like Betaseron, mula (I) of the present invention. h) interferon tau, More specifically, the aforementioned other agent is i) peptides, e.g. AT-008, AnergiX.MS, Immunokine (al selected from the group consisting of beta-amyloid antibod pha-Immunokine-NNSO3), cyclic peptides like ies, cysteine protease inhibitors, PEP-inhibitors, LiCl, acetyl ZD-7349, cholinesterase (AChE) inhibitors, PIMT enhancers, inhibi 35 j) therapeutic enzymes, e.g. soluble CD8 (SCD8), tors of beta secretases, inhibitors of gamma secretases, k) multiple Sclerosis-specific autoantigen-encoding plas inhibitors of aminopeptidases, preferably inhibitors of dipep mid and cytokine-encoding plasmid, e.g. BHT-3009: tidyl peptidases, most preferably DPIV inhibitors; inhibitors 1) inhibitor of TNF-alpha, e.g. BLX-1002, thalidomide, of neutral endopeptidase, inhibitors of Phosphodiesterase-4 SH-636, (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor 40 m) TNF antagonists, e.g. Solimastat, lenercept (syn. to antagonists, NMDA receptor antagonists, Sigma-1 receptor RO-45-2081, Tenefuse), onercept (sTNFR1), CC-1069, inhibitors, histamine H3 antagonists, immunomodulatory n) TNF alpha, e.g. etanercept (syn. to Enbrel, TNR-001) agents, immunosuppressive agents, MCP-1 antagonists oran o). CD28 antagonists, e.g. abatacept, agent selected from the group consisting of antegren (natali p) Lck tyrosine kinase inhibitors, Zumab), Neurelan (fampiridine-SR), campath (alemtu 45 q) cathepsin K inhibitors, Zumab), IR 208, NBI5788/MSP 771 (tiplimotide), paclitaxel, r) analogs of the neuron-targeting membrane transporter Anergix.MS (AG 284), SH636, Differin (CD 271, ada protein taurine and the plant-derived calpain inhibitor palene), BAY361677 (interleukin-4), matrix-metalloprotein leupeptin, e.g. Neurodur, ase-inhibitors (e.g. BB 76163), interferon-tau (trophoblastin) s) chemokine receptor-1 (CCR1) antagonist, e.g. BX-471, and SAIK-MS. 50 t) CCR2 antagonists, Furthermore, the other agent may be, for example, an anti u) AMPA receptor antagonists, e.g. ER-167288-01 and anxiety drug or antidepressant selected from the group con ER-099487, E-2007, talampanel, sisting of V) potassium channel blockers, e.g. fampridine, (a) BenZodiazepines, e.g. alprazolam, chlordiazepoxide, w) tosyl-proline-phenylalanine Small-molecule antago clobazam, clonazepam, cloraZepate, diazepam, fludiaz 55 nists of the VLA-4/VCAM interaction, e.g. TBC-3342, epam, loflazepate, lorazepam, methaqualone, X) cell adhesion molecule inhibitors, e.g. TBC-772, OXaZepam, praZepam, tranxene, y) antisense oligonucleotides, e.g. EN-101, (b) Selective serotonin re-uptake inhibitors (SSRIs), e.g. Z) antagonists of free immunoglobulin light chain (Ig|LC) citalopram, fluoxetine, fluvoxamine, escitalopram, Ser binding to mast cell receptors, e.g. F-991, traline, paroxetine, 60 aa) apoptosis inducing antigens, e.g. Apogen MS, (c) Tricyclic antidepressants, e.g. amitryptiline, clomi bb) alpha-2 adrenoceptor agonist, e.g. tizanidine (syn. to pramine, desipramine, doxepin, imipramine Zanaflex, Ternelin, Sirdalvo, Sirdalud, Mionidine), (d) Monoamine oxidase (MAO) inhibitors, cc) copolymer of L-tyrosine, L-lysine, L-glutamic acid and (e) AZapirones, e.g. buspirone, tandopsirone, L-alanine, e.g. glatiramer acetate (syn. to Copaxone, (f) Serotonin-norepinephrine reuptake inhibitors (SN 65 COP-1, copolymer-1), RIs), e.g. Venlafaxine, dulloxetine, dd)topoisomerase II modulators, e.g. mitoxantrone hydro (g) Mirtazapine, chloride, US 8,541,596 B2 29 30 ee) adenosine deaminase inhibitor, e.g. cladribine (syn. to 104437, WO 2003/089460, WO 2003/086310, WO 2003/ Leustatin, Mylinax, RWJ-26251), 077858, WO 2003/074081, WO 2003/070760, WO 2003/ ff) interleukin-10, e.g. ilodecakin (syn. to Tenovil, Sch 063760, WO 2003/055514, WO 2003/051374, WO 2003/ 52000, CSIF), 048204, WO 2003/045128, WO 2003/040183, WO 2003/ gg) interleukin-12 antagonists, e.g. lisofylline (syn. to 039467, WO 2003/016466, WO 2003/015691, WO 2003/ CT-1501 R, LSF, lysofylline), 0.14162, WO 2003/012141, WO 2002/088307, WO 2002/ hh) Ethanaminum, e.g. SR1-62-834 (syn. to CRC-8605, 088306, WO 2002/074240, WO 2002/046237, WO 2002/ NSC-614383), 046222, WO 2002/041842, WO 2001/062801, WO 2001/ ii) immunomodulators, e.g. SAIK-MS, PNU-156804, 0.12598, WO 2000/077178, WO 2000/072880, WO 2000/ alpha-fetoprotein peptide (AFP), IPDS, 10 063250, WO 1999/060024, WO 1999/027944, WO 1998/ i) retinoid receptor agonists, e.g. adapalene (syn. to Dif 04.4955, WO 1996/025435, WO 1994/0171.97, WO 1990/ ferin, CD-271), 014840, WO 1990/O12871, WO 1990/012870, WO 1989/ kk) TGF-beta, e.g. GDF-1 (growth and differentiation fac OO6242. tor 1), The beta-amyloid antibodies may be selected from, for ll) TGF-beta-2, e.g. BetaKine, 15 example, polyclonal, monoclonal, chimenic or humanized mm) MMP inhibitors, e.g. glycomed, antibodies. Furthermore, said antibodies may be useful to nn) phosphodiesterase 4 (PDE4) inhibitors, e.g. RPR develop active and passive immune therapies, i.e. Vaccines 122818, and monoclonal antibodies. Suitable examples of beta-amy oo) purine nucleoside phosphorylase inhibitors, e.g. 9-(3- loid antibodies are ACU-5A5, huC091 (Acumen/Merck); pyridylmethyl)-9-deazaguanine, peldesine (syn. to PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat BCX-34, TO-200), Neuroscience Corp (Pfizer Inc)); the nanobody therapeutics pp.) alpha-4/beta-1 integrin antagonists, e.g. ISIS-104278, of Ablynx/Boehringer Ingelheim; beta-amyloid-specific qq) antisense alpha-4 integrin (CD49d), e.g. ISIS-17044, humanized monoclonal antibodies of Intellect Neuro ISIS-27104, sciences/IBL: m266, m266.2 (Eli Lilly & Co.); AAB-02 rr) cytokine-inducing agents, e.g. nucleosides, ICN-17261, 25 (Elan); bapineuzumab (Elan); BAN-2401 (Bioarctic Neuro SS) cytokine inhibitors, science AB); ABP-102 (Abiogen Pharma SpA); BA-27, tt) heat shock protein vaccines, e.g. HSPPC-96, BC-05 (Takeda); R-1450 (Roche); ESBA-212 (ESBATech uu) neuregulin growth factors, e.g. GGF-2 (syn. to neu AG); AZD-3102 (AstraZeneca) and beta-amyloid antibodies regulin, glial growth factor 2), of Mindset BioPharmaceuticals Inc. VV) cathepsin S-inhibitors, 30 Especially preferred are antibodies, which recognize the ww) bropirimine analogs, e.g. PNU-56169, PNU-63693, N-terminus of the AB peptide. A suitable antibody, which XX) Monocyte chemoattractant protein-1 inhibitors, e.g. recognizes the AB-N-Terminus is, for example Acl-24 (AC benzimidazoles like MCP-1 inhibitors, LKS-1456, Immune SA). PD-064036, PD-064126, PD-084486, PD-172084, A monoclonal antibody against beta-amyloid peptide is PD-172386. 35 disclosed in WO 2007/068412. Respective chimeric and 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 40 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 45 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 50 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/ 55 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/ 60 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/ 65 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): US 8,541,596 B2 31 32 Posiphen, (+)-phenserine (Torrey Pines/NIH); LSN 118555, WO2005/120494, WO2005/121089, WO2005/ 2434074, LY-2070275, LY-2070273, LY-2070102 (Eli Lilly 121131, WO2005/123685, WO2006/995613; WO2OO67 & Co.); PNU-159775A, PNU-178025A, PNU-17820A, 009886; WO2006/013104; WO2006/017292; WO2OO67 PNU-33312, PNU-38773, PNU-90530 (Elan/Pfizer); KMI 019965; WO2006/020017; WO2006/023750; WO2OO67 370, KMI-358, kmi-008 (Kyoto University); OM-99-2, 039325; WO2006/041976: WO2006/047248; WO2OO67 OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca/AS 058.064; WO2006/058628; WO2006/066747; WO2OO67 tex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 O6677O and WO2O06/068978. (De Novo Pharmaceuticals Ltd.) and CT-21166 (CoMentis Suitable DP IV-inhibitors for the purpose of the present Inc.). invention are for example Sitagliptin, des-fluoro-sitagliptin Inhibitors of gamma Secretase and compositions contain 10 ing such inhibitors are described, e.g. in WO2005/008250, (Merck & Co. Inc.); vildagliptin, DPP-728, SDZ-272-070 WO2006/004880, U.S. Pat. Nos. 7,122,675, 7,030,239, (Novartis); ABT-279, ABT-341 (Abbott Laboratories); dena 6,992,081, 6,982,264, WO2005/097768, WO2005/028440, gliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322 (Takeda WO2004/101562, U.S. Pat. Nos. 6,756,511, 6,683,091, San Diego Inc.); tallabostat (Point Therapeutics Inc.); WO03/066592, WO03/014075, WO03/013527, WO02/ 15 Ro-0730699, R-1499, R-1438 (Roche Holding AG): 36555, WO01/.53255, U.S. Pat. Nos. 7,109,217, 7,101,895, FE-999011 (Ferring Pharmaceuticals);TS-021 (Taisho Phar 7,049,296, 7,034,182, 6,984,626, WO2005/040 126, maceutical Co. Ltd.); GRC-8200 (Glenmark Pharmaceuti WO2005/030731, WO2005/014553, U.S. Pat. No. cals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding 6,890,956, EP 1334085, EP 1263774, WO2004/101538, Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); WO2004/00958, WO2004/089911, WO2004/073630, SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi WO2004/069826, WO2004/039370, WO2004/031139, Pharma Corp.); DP-893, CP-867534-01 (Pfizer Inc.); TSL WO2004/03 1137, U.S. Pat. Nos. 6,713,276, 6,686,449, 225, TMC-2A (Tanabe Seiyaku Co. Ltd.); PHX-1149 (Phe WO03/091278, U.S. Pat. Nos. 6,649,196, 6,448,229, WO01/ nomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.); 77144 and WOO1/66564. PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 Suitable gamma secretase inhibitors for the purpose of the 25 (ActivX Biosciences Inc.); sulphostin (Zaidan Hojin); present invention are GSI-953, WAY-GSI-A, WAY-GSI-B KR-62436 (Korea Research Institute of Chemical Technol (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, ogy); P32/98 (Probiodrug AG); BI-A, BI-B (Boehringer L-852631, L-852646 (Merck & Co. Inc.); LY-450139, Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. LY-411575, AN-37124 (Eli Lilly & Co.); BMS-299897, Ltd.); and NNC-72-2138 (Novo Nordisk NS). BMS-433796 (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. 30 Other preferred DPIV-inhibitors are Ltd.); EHT-0206, EHT-206 (ExonHit Therapeutics SA); and (i) dipeptide-like compounds, disclosed in WO99/61431, e.g. NGX-555 (TorreyPines Therapeutics Inc.). N-Valyl prolyl, O-benzoyl hydroxylamine, alanyl pyrroli DPIV-inhibitors and compositions containing such inhibi dine, isoleucyl thiazolidine like L-allo-isoleucyl thiazoli tors are described, e.g. in U.S. Pat. Nos. 6,011,155; 6,107, dine, L-threo-isoleucyl pyrrolidine and salts thereof, espe 317; 6,110,949; 6,124,305; 6,172,081; WO99/61431, WO99/ 35 cially the fumaric salts, and L-allo-isoleucyl pyrrolidine 67278, WO99/67279, DE 1983.4591, WO97/40832, WO95/ and salts thereof; 15309, WO98/19998, WO00/07617, WO99/38501, WO99/ (ii) peptide structures, disclosed in WO 03/002593, e.g. trip 46272, WO99/38501, WO01/68603, WO01/40180, WO01/ eptides; 81337, WO01/81304, WO01/55105, WO02/02560, WO01/ (iii) peptidylketones, disclosed in WO 03/033524: 34594, WO02/38541, WO02/083128, WO03/072556, 40 (vi) substituted aminoketones, disclosed in WO 03/04.0174: WO03/002593, WO03/000250, WO03/000180, WO03/ (v) topically active DP IV-inhibitors, disclosed in WO 000181, EP1258476, WO03/002553, WO03/002531, WO03/ 01/14318; 002530, WO03/004496, WO03/004498, WO03/024942, (vi) prodrugs of DPIV-inhibitors, disclosed in WO99/67278 WO03/024965, WO03/033524, WO03/035057, WO03/ and WO99/67279; and 035067, WO03/037327, WO03/04.0174, WO03/045977, 45 (v) glutaminyl based DP IV-inhibitors, disclosed in WO WO03/055881, WO03/057144, WO03/057666, WO03/ O3/072556 and WO 2004/099.134. 068748, WO03/068757, WO03/082817, WO03/101449, Suitable beta amyloid synthesis inhibitors for the purpose WO03/101958, WO03/104229, WO03/74500, WO2004/ of the present invention are for example Bisnorcymserine 007446, WO2004/007468, WO2004/018467, WO2004/ (Axonyx Inc.); (R)-flurbiprofen (MCP-7869: Flurizan) 018468, WO2004/018469, WO2004/026822, WO2004/ 50 (Myriad Genetics): nitroflurbiprofen (NicOx); BGC-20-0406 032836, WO2004/033455, WO2004/037169, WO2004/ (Sankyo Co. Ltd.) and BGC-20-0466 (BTG 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/ 55 peutics Inc.); AAB-001 (Bapineuzumab), AAB-002, ACC 089362, WO2004/099185, WO2004/103276, WO2004/ 001 (Elan Corp plc.); Colostrinin (ReCien Therapeutics plc.); 103993, WO2004/108730, WO2004/110436, WO2004/ Tramiprosate (Neurochem); AdPEDI-(amyloid-beta1-6)11) 111041, WO2004/112701, WO2005/000846, WO2005/ (Vaxin Inc.); MPI-127585, MPI-423948 (Mayo Foundation): 000848, WO2005/011581, WO2005/016911, WO2005/ SP-08 (Georgetown University); ACU-5A5 (Acumen/ 023762, WO2005/025554, WO2005/026148, WO2005/ 60 Merck); Transthyretin (State University of New York); PTI 030751, WO2005/033106, WO2005/037828, WO2005/ 777, DP-74, DP 68, Exebryl (ProteoTech Inc.); m266 (Eli 040095, WO2005/044195, WO2005/047297, WO2005/ Lilly & Co.); EGb-761 (Dr. Willmar Schwabe GmbH); SPI 051950, WO2005/056003, WO2005/056013, WO2005/ 014 (Satori Pharmaceuticals Inc.); ALS-633, ALS-499 (Ad 058849, WO2005/075426, WO2005/082348, WO2005/ vanced Life Sciences Inc.); AGT-160 (ArmaCien Technolo 085246, WO2005/087235, WO2005/095339, WO2005/ 65 gies Inc.); TAK-070 (Takeda Pharmaceutical Co. Ltd.); CHF 095343, WO2005/095381, WO2005/108382, WO2005/ 5022, CHF-5074, CHF-5096 and CHF-5105 (Chiesi 113510, WO2005/116014, WO2005/116029, WO2005/ Farmaceutici SpA.). US 8,541,596 B2 33 34 Suitable PDE-4 inhibitors for the purpose of the present 537, EP 0461677, EP 0345428, JP 02275858, U.S. Pat. No. invention are for example Doxofylline (Instituto Biologico 5,506,256, JP 06192298, EP 0618.193, JP 03255080, EP Chemioterapica ABC SpA.); idudilast eye drops, tipelukast, 0468469, U.S. Pat. No. 5,118,811, JP 05025125, WO ibudilast (Kyorin Pharmaceutical Co. Ltd.); theophylline 9313065, JP 05201970, WO 9412474, EP 0670309, EP (Elan Corp.); cilomilast (GlaxoSmithKline plc.); Atopik 5 0451547, JP 06339390, U.S. Pat. Nos. 5,073,549, 4,999,349, (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659, EP 0268281, U.S. Pat. No. 4,743,616, EP 0232849, EP CP-220629, PDE 4d inhibitor BHN (Pfizer Inc.); arofylline, 0224272, JP 62114978, JP 62114957, U.S. Pat. Nos. 4,757, LAS-37779 (Almirall Prodesfarma S.A.); roflumilast, 083, 4,810,721, 5,198.458, 4,826,870, EP 0201742, EP hydroxypumafentrine (Altana AG), tetomilast (Otska Phar 0201741, U.S. Pat. No. 4,873,342, EP 0172458, JP maceutical Co. Ltd.); tipelukast, ibudilast (Kyorin Pharma 10 61037764, EP 0201743, U.S. Pat. No. 4,772,587, EP ceutical), CC-10004 (Celgene Corp.); HT-0712, IPL-4088 0372484, U.S. Pat. No. 5,028,604, WO 91/18877, JP (Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 04009367, JP 04235162, U.S. Pat. No. 5,407,950, WO (Memory Pharmaceuticals Corp.); oglemilast, GRC-4039 95/01352, JP 01250370, JP 02207070, U.S. Pat. No. 5,221, (Glenmark Pharmaceuticals Ltd.); AWD-12-281, ELB-353, 752, EP 0468339, JP 04211648, WO 99/46272, WO 2006/ ELB-526 (Elbion AG); EHT-0202 (Exon Hit Therapeutics 15 O5872O and PCTAEP2006/061428. S.A.); ND-1251 (Neuro3d S.A.); 4AZA-PDE4 (4 AZA Bio Suitable prolyl endopeptidase inhibitors for the purpose of science NV.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottap the present invention are, e.g. Fmoc-Ala-Pyrr-CN, Z-Phe harm SpA.); GP-0203, NCS-613 (Centre National de la Pro-Benzothiazole (Probiodrug), Z-321 (Zeria Pharmaceuti Recherche Scientifique); KF-19514 (Kyowa Hakko Kogyo cal Co Ltd.); ONO-1603 (Ono Pharmaceutical Co Ltd);JTP Co. Ltd.); ONO-6126 (Ono Pharmaceutical Co. Ltd.); 4819 (Japan Tobacco Inc.) and S-17092 (Servier). OS-0217 (Dainippon Pharmaceutical Co. Ltd.); IBFB Other Suitable compounds that can be used according to the 130011, IBFB-150007, IBFB-130020, IBFB-140301 (IBFB present invention in combination with QC-inhibitors are Pharma GmbH); IC-485 (ICOS Corp.); RBX-14016 and NPY, an NPY mimetic or an NPY agonist or antagonist or a RBX-11082 (Ranbaxy Laboratories Ltd.). A preferred PDE ligand of the NPY receptors. 4-inhibitor is Rolipram. 25 Preferred according to the present invention are antago MAO inhibitors and compositions containing such inhibi nists of the NPY receptors. tors are described, e.g. in WO2006/091988, WO2005/ Suitable ligands or antagonists of the NPY receptors are 007614, WO2004/089351, WO01/26656, WO01/12176, 3a,4,5,9b-tetrahydro-1h-benzeindol-2-yl amine-derived WO99/57120, WO99/57119, WO99/13878, WO98/4.0102, compounds as disclosed in WO 00/68197. WO98/01157, WO96/20946, WO94/07890 and WO92/ 30 NPY receptor antagonists which may be mentioned 21333. include those disclosed in European patent applications EPO Suitable MAO-inhibitors for the purpose of the present 614 911 EP 0 747 357, EP 0 747 356 and EP 0 747 378; invention are for example Linezolid (Pharmacia Corp.); international patent applications WO 94/17035, WO RWJ-416457 (RW Johnson Pharmaceutical Research Insti 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO tute); budipine (Altana AG); GPX-325 (BioResearch Ire 35 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 40 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) European patent applications EP 355 794 and EP 355 793; and NW-1048 (Newron Pharmaceuticals SpA.). 45 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 non-peptide-based NPY antagonists. Amino acid and non Recherche); DWP-302 (Daewoong Pharmaceutical Co Ltd); 50 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 55 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO NS); 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 WO 99/15498: U.S. Pat. Nos. 5,552,411, 5,663,192 and 09040693, JP 10077300, JP 05331072, JP 05015314, WO 60 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. Nos. 5,965,556, 5,756,763, nists include those compounds that are specifically disclosed 6,121,311, JP 63264454, JP 64000069, JP 63.162672, EP in these patent documents. 0268190, EP 0277588, EP 0275482, U.S. Pat. Nos. 4,977, Particularly preferred compounds include amino acid 180, 5,091,406, 4,983,624, 5,112,847, 5,100,904, 5,254,550, 65 based NPY antagonists. Amino acid-based compounds, 5,262,431, 5,340,832, 4,956,380, EP 0303434, JP 03056486, which may be mentioned include those disclosed in interna JP 01143897, JP 1226880, EP 0280956, U.S. Pat. No. 4,857, tional patent applications WO 94/17035, WO 97/19911, WO US 8,541,596 B2 35 36 97/19913, WO 97/19914 or, preferably, WO 99/15498. Pre prodil (CP-101606), besonprodil (PD-196860, CI-1041) ferred amino acid-based NPY antagonists include those that (Pfizer Inc.); CGX-1007 (Cognetix Inc.); delucemine (NPS are specifically disclosed in these patent documents, for 1506) (NPSPharmaceuticals Inc.); EVT-101 (Roche Holding example BIBP3226 and, especially, (R) N-2-(dipheny AG); acamprosate (Synchroneuron LLC.); CR-3991, lacetyl)-(R)-N-1-(4-hydroxy-phenyl)ethylarginine amide CR-2249, CR-3394 (Rottapharm SpA.); AV-101 (Example 4 of international patent application WO (4-C1 -kynurenine (4-Cl -KYN)), 7-chloro-kynurenic acid 99/15498). (7-Cl-KYNA) (VistaGen); NPS-1407 (NPS Pharmaceuticals M1 receptor agonists and compositions containing Such Inc.); YT-1006 (Yaupon Therapeutics Inc.); ED-1812 (Sosei inhibitors are described, e.g. in WO2004/087158, WO91/ R&D Ltd.); himantane (hydrochloride N-2-(adamantly)-hex 10664. 10 amethylen-imine) (RAMS); Lancicemine (AR-R-15896) Suitable M1 receptor antagonists for the purpose of the (AstraZeneca); EVT-102, Ro-25-6981 and Ro-63-1908 present invention are for example CDD-0102 (Cognitive (Hoffmann-La Roche AG/Evotec). Pharmaceuticals); Cevimeline (Evoxac) (Snow Brand Milk Furthermore, the present invention relates to combination Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics): therapies useful for the treatment of atherosclerosis, resteno sabcomeline (GlaxoSmithKline); alvameline (H Lundbeck 15 sis or arthritis, administering a QC inhibitor in combination NS); LY-593093 (Eli Lilly & Co.); VRTX-3 (Vertex Pharma with another therapeutic agent selected from the group con ceuticals Inc.); WAY-132983 (Wyeth) and CI-101 7/(PD sisting of inhibitors of the angiotensin converting enzyme 151832) (Pfizer Inc.). (ACE); angiotensin II receptor blockers; diuretics; calcium Acetylcholinesterase inhibitors and compositions contain channel blockers (CCB); beta-blockers; platelet aggregation ing such inhibitors are described, e.g. in WO2006/071274, inhibitors; cholesterol absorption modulators; HMG-Co-A WO2006/070394, WO2006/040688, WO2005/092009, reductase inhibitors; high density lipoprotein (HDL) increas WO2005/079789, WO2005/039580, WO2005/027975, ing compounds; renin inhibitors; IL-6 inhibitors; antiinflam WO2004/084884, WO2004/037234, WO2004/032929, matory corticosteroids; antiproliferative agents; nitric oxide WO03/101458, WO03/091220, WO03/082820, WO03/ donors; inhibitors of extracellular matrix synthesis; growth 020289, WO02/32412, WO01/85145, WO01/78728, WO01/ factor or cytokine signal transduction inhibitors; MCP-1 66096, WO00/02549, WO01/00215, WO00/15205, WO00/ 25 antagonists and tyrosine kinase inhibitors providing benefi 23057, WO00/33840, WO00/30446, WO00/23057, WO00/ cial or synergistic therapeutic effects over each monotherapy 15205, WO00/09483, WO00/07600, WO00/02549, WO99/ component alone. 47131, WO99/07359, WO98/30243, WO97/38993, WO97/ Angiotensin II receptor blockers are understood to be those 13754, WO94/29255, WO94/20476, WO94/19356, WO93/ active agents that bind to the AT1-receptor Subtype of angio O3O34 and WO92/19238. 30 tensin II receptor but do not resultinactivation of the receptor. Suitable acetylcholinesterase inhibitors for the purpose of As a consequence of the blockade of the AT1 receptor, these the present invention are for example Donepezil (Eisai Co. antagonists can, e.g. be employed as antihypertensive agents. Ltd.); rivastigmine (Novartis AG): (-)-phenserine (Tor Suitable angiotensin II receptor blockers which may be reyPines Therapeutics); ladostigil (Hebrew University of employed in the combination of the present invention include Jerusalem); huperzine A (Mayo Foundation); galantamine AT, receptor antagonists having differing structural features, (Johnson & Johnson); Memoquin (Universita di Bologna); 35 preferred are those with non-peptidic structures. For SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 example, mention may be made of the compounds that are (Sankyo Co. Ltd.); physostigmine (Forest Laboratories Inc.); selected from the group consisting of Valsartan (EP 443983), NP-0361 (Neuropharma SA); ZT-1 (Debiopharm); tacrine losartan (EP 253310), candesartan (EP 459136), eprosartan (Warner-Lambert Co.); metrifonate (Bayer Corp.) and INM (EP 403159), irbesartan (EP 454511), olmesartan (EP 176 (Whanlin). 40 503785), tasosartan (EP 539086), telmisartan (EP522314), NMDA receptor antagonists and compositions containing the compound with the designation E-41 77 of the formula such inhibitors are described, e.g. in WO2006/094674, WO2006/058236, WO2006/058059, WO2006/010965, WO2005/000216, WO2005/102390, WO2005/079779, WO2005/079756, WO2005/072705, WO2005/070429, 45 OH WO2005/055996, WO2005/035522, WO2005/009421, WO2005/000216, WO2004/092189, WO2004/039371, WO2004/028522, WO2004/009062, WO03/010159, WO02/ 072542, WO02/34718, WO01/98262, WO01/94321, WO01/ 92204, WO01/81295, WOO1/32640, WO01/10833, WO01/ 50 10831, WO00/56711, WO00/29023, WO00/001.97, WO99/ 53922, WO99/48891, WO99/45963, WO99/01416, WO99/ 07413, WO99/01416, WO98/50075, WO98/50044, WO98/ the compound with the designation SC-52458 of the follow 10757, WO98/05337, WO97/32873, WO97/23216, WO97/ ing formula 23215, WO97/23214, WO96/14318, WO96/08485, WO95/ 55 3.1986, WO95/26352, WO95/26350, WO95/26349, WO95/ 26342, WO95/12594, WO95/02602, WO95/02601, WO94/ 20109, WO94/13641, WO94/09016 and WO93/25534. Suitable NMDA receptor antagonists for the purpose of the present invention are for example Memantine (Merz & Co. GmbH); topiramate (Johnson & Johnson); AVP-923 (Neuro 60 dex) (Center for Neurologic Study); EN-3231 (Endo Phar f maceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuticals Inc.); dex anabinol (HU-211: Sinnabidol: PA-50211) (Pharmos); Epi Cept NP-1 (Dalhousie University); indantadol (V-3381: 65 CNP-3381) (Vernalis); perzinfotel (EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Richter Ltd.); traxo US 8,541,596 B2 37 38 and the compound with the designation the compound blockers include compounds selected from acebutolol, ZD-8731 of the formula atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oXprenolol, penbutolol, pin dolol, propranolol, Sotalol and timolol. Where the beta H blocker is an acid or base or otherwise capable of forming %ys pharmaceutically acceptable salts or prodrugs, these forms V are considered to be encompassed herein, and it is understood that the compounds may be administered in free form or in the form of a pharmaceutically acceptable salt or a prodrug. Such 10 as a physiologically hydrolyzable and acceptable ester. For ) / \ () ( ) example, metoprolol is Suitably administered as its tartrate salt, propranolol is suitably administered as the hydrochlo or, in each case, a pharmaceutically acceptable salt thereof. ride salt, and so forth. Preferred AT1-receptor antagonists are those agents that 15 Platelet aggregation inhibitors include PLAVIX(R) (clopi have been approved and reached the market, most preferred is dogrel bisulfate), PLETAL(R) (cilostazol) and aspirin. Valsartan, or a pharmaceutically acceptable Salt thereof. Cholesterol absorption modulators include ZETIAR) The interruption of the enzymatic degradation of angio (ezetimibe) and KT6-971 (Kotobuki Pharmaceutical Co. tensin to angiotensin II with ACE inhibitors is a successful Japan). variant for the regulation of blood pressure and thus also HMG-Co-A reductase inhibitors (also called beta-hy makes available a therapeutic method for the treatment of droxy-beta-methylglutaryl-co-enzyme-A reductase inhibi hypertension. tors or statins) are understood to be those active agents which A suitable ACE inhibitor to be employed in the combina may be used to lower lipid levels including cholesterol in tion of the present inventionis, e.g. a compound selected from blood. the group consisting alacepril, benazepril, benazeprilat, cap 25 The class of HMG-Co-A reductase inhibitors comprises topril, ceronapril, cilaZapril, delapril, enalapril, enaprilat, compounds having differing structural features. For example, fosinopril, imidapril, lisinopril, moveltopril, perindopril, mention may be made of the compounds, which are selected quinapril, ramipril, spirapril, temocapril and trandolapril, or from the group consisting of atorvastatin, cerivastatin, fluv in each case, a pharmaceutically acceptable salt thereof. astatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and Preferred ACE inhibitors are those agents that have been 30 marketed, most preferred are benazepril and enalapril. simvastatin, or in each case, a pharmaceutically acceptable A diuretic is, for example, a thiazide derivative selected salt thereof. from the group consisting of chlorothiazide, hydrochlorothi Preferred HMG-Co-A reductase inhibitors are those azide, methylclothiazide, and chlorothalidon. The most pre agents, which have been marketed, most preferred is atorv ferred diuretic is hydrochlorothiazide. A diuretic furthermore 35 astatin, pitavastatin or simvastatin, or a pharmaceutically comprises a potassium sparing diuretic Such as amiloride or acceptable salt thereof. triameterine, or a pharmaceutically acceptable salt thereof. HDL-increasing compounds include, but are not limited to, The class of CCBs essentially comprises dihydropyridines cholesterol ester transfer protein (CETP) inhibitors. (DHPs) and non-DHPs, such as diltiazem-type and Vera Examples of CETP inhibitors include JTT7O5 disclosed in pamil-type CCBs. 40 Example 26 of U.S. Pat. No. 6,426,365 issued Jul. 30, 2002, A CCB useful in said combination is preferably a DHP and pharmaceutically acceptable salts thereof. representative selected from the group consisting of amlo Inhibition of interleukin 6 mediated inflammation may be dipine, felodipine, ryosidine, isradipine, lacidipine, nicar achieved indirectly through regulation of endogenous choles dipine, nifedipine, niguldipine, niludipine, nimodipine, nisol terol synthesis and isoprenoid depletion or by direct inhibi dipine, nitrendipine and nivaldipine, and is preferably a non 45 tion of the signal transduction pathway utilizing interleukin-6 DHP representative selected from the group consisting of inhibitor/antibody, interleukin-6 receptor inhibitor/antibody, flunarizine, prenylamine, diltiazem, fendiline, gallopamil, interleukin-6 antisense oligonucleotide (ASON), gp130 pro mibefradil, anipamil, tiapamil and Verapamil, and in each tein inhibitor/antibody, tyrosine kinase inhibitors/antibodies, case, a pharmaceutically acceptable salt thereof. All these serine/threonine kinase inhibitors/antibodies, mitogen-acti CCBs are therapeutically used, e.g. as anti-hypertensive, anti 50 vated protein (MAP) kinase inhibitors/antibodies, phosphati angina pectoris or anti-arrhythmic drugs. dylinositol 3-kinase (PI3K) inhibitors/antibodies, Nuclear Preferred CCBs comprise amlodipine, diltiazem, israd factor kappaB (NF-KB) inhibitors/antibodies, IKB kinase ipine, nicardipine, nifedipine, nimodipine, nisoldipine, (IKK) inhibitors/antibodies, activator protein-1 (AP-1) nitrendipine and Verapamil or, e.g. dependent on the specific inhibitors/antibodies, STAT transcription factors inhibitors/ CCB, a pharmaceutically acceptable salt thereof. Especially 55 antibodies, altered IL-6, partial peptides of IL-6 or IL-6 preferred as DHP is amlodipine or a pharmaceutically accept receptor, or SOCS (Suppressors of cytokine signaling) pro able salt thereof, especially the besylate. An especially pre tein, PPARgamma and/or PPAR beta/delta activators/ligands ferred representative of non-DHPs is verapamil or a pharma or a functional fragment thereof. ceutically acceptable salt, especially the hydrochloride, A suitable antiinflammatory corticosteroid is dexametha thereof. 60 SO. Beta-blockers suitable for use in the present invention Suitable antiproliferative agents are cladribine, rapamycin, include beta-adrenergic blocking agents (beta-blockers), Vincristine and taxol. which compete with epinephrine for beta-adrenergic recep A suitable inhibitor of extracellular matrix synthesis is tors and interfere with the action of epinephrine. Preferably, halofuginone. the beta-blockers are selective for the beta-adrenergic recep 65 A Suitable growth factor or cytokine signal transduction tor as compared to the alpha-adrenergic receptors, and so do inhibitor is, e.g. the ras inhibitor R115777. not have a significant alpha-blocking effect. Suitable beta A suitable tyrosine kinase inhibitor is tyrphostin. US 8,541,596 B2 39 40 Suitable renin inhibitors are described, e.g. in WO 2006/ examples 1-94, in combination with Atorvastatin for the 116435. A preferred renin inhibitor is aliskiren, preferably in treatment and/or prevention of artherosclerosis, the form of the hemi-fumarate salt thereof. a QC inhibitor, preferably a QC inhibitor of formula (I), MCP-1 antagonists may, e.g. be selected from anti-MCP-1 more preferably a QC inhibitor selected from any one of antibodies, preferably monoclonal or humanized monoclonal examples 1-94, in combination with immunosuppres antibodies, MCP-1 expression inhibitors, CCR2-antagonists, sive agents, preferably rapamycin for the prevention TNF-alpha inhibitors, VCAM-1 gene expression inhibitors and/or treatment of restenosis, and anti-05a monoclonal antibodies. a QC inhibitor, preferably a QC inhibitor of formula (I), MCP-1 antagonists and compositions containing Such more preferably a QC inhibitor selected from any one of inhibitors are described, e.g. in WO02/070509, WO02/ 10 examples 1-94, in combination with immunosuppres 081463, WO02/060900, US2006/670364, US2006/677365, sive agents, preferably paclitaxel for the prevention and/ WO2006/097624, US2006/316449, WO2004/056727, or treatment of restenosis, WO03/053368, WO00/198289, WO00/157226, WO00/ a QC inhibitor, preferably a QC inhibitor of formula (I), 046195, WO00/0461.96, WO00/046199, WO00/046198, more preferably a QC inhibitor selected from any one of WO00/046197, WO99/046991, WO99/007351, WO98/ 15 examples 1-94, in combination with AChE inhibitors, 006703, WO97/012615, WO2005/105133, WO03/037376, preferably Donepezil, for the prevention and/or treat WO2006/125202, WO2006/085961, WO2004/024921, ment of Alzheimer's disease, WO2006/074265. a QC inhibitor, preferably a QC inhibitor of formula (I), Suitable MCP-1 antagonists are, for instance, C-243 (Telik more preferably a QC inhibitor selected from any one of Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Actimis examples 1-94, in combination with interferones, pref Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis AG): erably Aronex, for the prevention and/or treatment of CC-1 1006 (Celgene Corp.); SSR-150106 (Sanofi-Aventis); multiple Sclerosis, MLN-1202 (Millenium Pharmaceuticals Inc.): AG1-1067, a QC inhibitor, preferably a QC inhibitor of formula (I), AGIX-4207, AGM 096 (AtherioGenics Inc.); PRS-211095, more preferably a QC inhibitor selected from any one of PRS-211092 (Pharmos Corp.); anti-05a monoclonal antibod 25 examples 1-94, in combination with interferones, pref ies, e.g. neutraZumab (G2 Therapies Ltd.); AZD-6942 (Astra erably betaferon, for the prevention and/or treatment of Zeneca plc.); 2-mercaptoimidazoles (Johnson & Johnson); multiple Sclerosis, TEI-E00526, TEI-6122 (Deltagen); RS-504393 (Roche a QC inhibitor, preferably a QC inhibitor of formula (I), Holding AG); SB-282241, SB-380732, ADR-7 (GlaxoSmith more preferably a QC inhibitor selected from any one of Kline); anti-MCP-1 monoclonal antibodies(Johnson & 30 examples 1-94, in combination with interferones, pref Johnson). erably Rebif, for the prevention and/or treatment of mul Combinations of QC-inhibitors with MCP-1 antagonists tiple sclerosis may be useful for the treatment of inflammatory diseases in a QC inhibitor, preferably a QC inhibitor of formula (I), general, including neurodegenerative diseases. more preferably a QC inhibitor selected from any one of Combinations of QC-inhibitors with MCP-1 antagonists 35 examples 1-94, in combination with Copaxone, for the are preferred for the treatment of Alzheimer's disease. prevention and/or treatment of multiple 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: more preferably a QC inhibitor selected from any one of PF-4360365, m266, bapineuzumab, R-1450, Posiphen, examples 1-94, in combination with dexamethasone, for (+)-phenserine, MK-0752, LY-450139, E-2012, (R)-flurbi 40 the prevention and/or treatment of restenosis, profen, AZD-103, AAB-001 (Bapineuzumab), Tramiprosate, a QC inhibitor, preferably a QC inhibitor of formula (I), EGb-761, TAK-070, Doxofylline, theophylline, cilomilast, more preferably a QC inhibitor selected from any one of tofimilast, roflumilast, tetomilast, tipelukast, ibudilast, examples 1-94, in combination with dexamethasone, for HT-0712, MEM-1414, oglemilast, Linezolid, budipine, iso the prevention and/or treatment of atherosclerosis, carboxazid, phenelZine, tranylcypromine, indantadol, 45 a QC inhibitor, preferably a QC inhibitor of formula (I), moclobemide, rasagiline, ladostigil, Safinamide, ABT-239, more preferably a QC inhibitor selected from any one of ABT-834, GSK-189254A, Ciproxifan, JNJ-17216498, examples 1-94, in combination with dexamethasone, for Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-Benzothiazole, Z-321, the prevention and/or treatment of rheumatid arthritis, ONO-1603, JTP-4819, S-17092, BIBP3226; (R) N-2- a QC inhibitor, preferably a QC inhibitor of formula (I), (diphenylacetyl)-(R) N-1-(4-hydroxyphenyl)ethylargin 50 more preferably a QC inhibitor selected from any one of ine amide, Cevimeline, sabcomeline, (PD-151832), Done examples 1-94, in combination with HMG-Co-A-reduc pezil, rivastigmine, (-)-phenserine, ladostigil, galantamine, tase inhibitors, for the prevention and/or treatment of tacrine, metrifonate, Memantine, topiramate, AVP-923, restenosis, wherein the HMG-Co-A-reductase inhibitor EN-3231, neramexane, Valsartan, benazepril, enalapril, is selected from atorvastatin, cerivastatin, fluvastatin, hydrochlorothiazide, amlodipine, diltiazem, isradipine, nica 55 lovastatin, pitavastatin, pravastatin, rosuvastatin and rdipine, nifedipine, nimodipine, nisoldipine, nitrendipine, simvastatin, Verapamil, amlodipine, acebutolol, atenolol, betaxolol, biso a QC inhibitor, preferably a QC inhibitor of formula (I), prolol, carteolol, carvedilol, esmolol, labetalol, metoprolol. more preferably a QC inhibitor selected from any one of nadolol, oXprenolol, penbutolol, pindolol, propranolol. examples 1-94, in combination with HMG-Co-Areduc Sotalol, timolol, PLAVIX(R) (clopidogrel bisulfate), PLE 60 tase inhibitors, for the prevention and/or treatment of TAL(R) (cilostazol), aspirin, ZETIAR (ezetimibe) and KT6 atherosclerosis wherein the HMG-Co-A-reductase 971, statins, atorvastatin, pitavastatin or simvastatin; dexam inhibitor is selected from atorvastatin, cerivastatin, flu ethasone, cladribine, rapamycin, Vincristine, taxol, alliskiren, vastatin, lovastatin, pitavastatin, pravastatin, rosuvasta C-243, ABN-912, SSR-150106, MLN-1202 and betaferon. tin and simvastatin, In particular, the following combinations are considered: 65 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 1-94, in combination with HMG-Co-Areduc US 8,541,596 B2 41 42 tase inhibitors, for the prevention and/or treatment of Such a combination therapy is in particular useful for AD, rheumatoid arthritis wherein the HMG-Co-A-reductase FAD, FDD and neurodegeneration in Down syndrome as well inhibitor is selected from atorvastatin, cerivastatin, flu as atherosclerosis, rheumatoid arthritis, restenosis and pan vastatin, lovastatin, pitavastatin, pravastatin, rosuvasta creatitis. tin and simvastatin, 5 Such combination therapies might result in a better thera a QC inhibitor, preferably a QC inhibitor of formula (I), peutic effect (less proliferation as well as less inflammation, a more preferably a QC inhibitor selected from any one of stimulus for proliferation) than would occur with either agent examples 1-94, in combination with amyloid-beta anti alone. bodies for the prevention and/or treatment of mild cog With regard to the specific combination of inhibitors of QC 10 and further compounds it is referred in particular to WO nitive impairment, wherein the amyloid-beta antibody is 2004/098.625 in this regard, which is incorporated herein by Act-24, reference. a QC inhibitor, preferably a QC inhibitor of formula (I), Pharmaceutical Compositions more preferably a QC inhibitor selected from any one of To prepare the pharmaceutical compositions of this inven examples 1-94, in combination with amyloid-beta anti 15 tion, at least one compound of formula (I) optionally in com bodies for the prevention and/or treatment of Alzhe bination with at least one of the other aforementioned agents imer's disease, wherein the amyloid-beta antibody is can be used as the active ingredient(s). The active ingred Act-24, ient(s) is intimately admixed with a pharmaceutical carrier a QC inhibitor, preferably a QC inhibitor of formula (I), according to conventional pharmaceutical compounding more preferably a QC inhibitor selected from any one of techniques, which carrier may take a wide variety of forms examples 1-94, in combination with amyloid-beta anti depending of the form of preparation desired for administra bodies for the prevention and/or treatment of neurode tion, e.g., oral or parenteral Such as intramuscular. In prepar generation in Down Syndrome, wherein the amyloid ing the compositions in oral dosage form, any of the usual beta antibody is Act-24, pharmaceutical media may be employed. Thus, for liquid oral a QC inhibitor, preferably a QC inhibitor of formula (I), 25 preparations, such as for example, Suspensions, elixirs and more preferably a QC inhibitor selected from any one of Solutions, Suitable carriers and additives include water, gly examples 1-94, in combination with beta-secretase cols, oils, alcohols, flavoring agents, preservatives, coloring inhibitors for the prevention and/or treatment of mild agents and the like; for Solid oral preparations such as, for cognitive impairment, wherein the beta-secretase example, powders, capsules, gelcaps and tablets, Suitable car 30 riers and additives include starches, Sugars, diluents, granu inhibitor is selected from WY-25105, GW-840736X and lating agents, lubricants, binders, disintegrating agents and CTS-21166, the like. a QC inhibitor, preferably a QC inhibitor of formula (I), Because of their ease in administration, tablets and cap more preferably a QC inhibitor selected from any one of Sules represent the most advantageous oral dosage unit form, examples 1-94, in combination with beta-secretase 35 in which case Solid pharmaceutical carriers are obviously inhibitors for the prevention and/or treatment of Alzhe employed. If desired, tablets may be Sugar coated or enteric imer's disease, wherein the beta-secretase inhibitor is coated by standard techniques. For parenterals, the carrier selected from WY-25105, GW-840736X and CTS will usually comprise sterile water, though other ingredients, 21166, for example, for purposes such as aiding solubility or for a QC inhibitor, preferably a QC inhibitor of formula (I), 40 preservation, may be included. more preferably a QC inhibitor selected from any one of Injectable Suspensions may also prepared, in which case examples 1-94, in combination with beta-secretase appropriate liquid carriers, Suspending agents and the like inhibitors for the prevention and/or treatment of neuro may be employed. The pharmaceutical compositions herein degeneration in Down Syndrome, wherein the beta will contain, per dosage unit, e.g., tablet, capsule, powder, secretase inhibitor is selected from WY-25105, 45 injection, teaspoonful and the like, an amount of the active GW-840736X and CTS-21166, ingredient(s) necessary to deliver an effective dose as a QC inhibitor, preferably a QC inhibitor of formula (I), described above. The pharmaceutical compositions herein more preferably a QC inhibitor selected from any one of will contain, per dosage unit, e.g., tablet, capsule, powder, examples 1-94, in combination with gamma-secretase injection, Suppository, teaspoonful and the like, from about inhibitors for the prevention and/or treatment of mild 50 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be cognitive impairment, wherein the gamma-secretase given at a dosage of from about 0.1-300 mg/kg per day (pre ferred 1-50 mg/kg per day) of each active ingredient or com inhibitor is selected from LY-450 139, LY-411575 and bination thereof. The dosages, however, may be varied AN-37124, depending upon the requirement of the patients, the severity a QC inhibitor, preferably a QC inhibitor of formula (I), 55 of the condition being treated and the compound being more preferably a QC inhibitor selected from any one of employed. The use of either daily administration or post examples 1-94, in combination with gamma-secretase periodic dosing may be employed. inhibitors for the prevention and/or treatment of Alzhe Preferably these compositions are in unit dosage forms imer's disease, wherein the gamma-secretase inhibitor from Such as tablets, pills, capsules, powders, granules, sterile is selected from LY-450139, LY-411575 and AN-37124, 60 parenteral Solutions or Suspensions, metered aerosol or liquid a QC inhibitor, preferably a QC inhibitor of formula (I), sprays, drops, ampoules, autoinjector devices or Supposito more preferably a QC inhibitor selected from any one of ries; for oral parenteral, intranasal. Sublingual or rectal examples 1-94, in combination with gamma-secretase administration, or for administration by inhalation or insuf inhibitors for the prevention and/or treatment of neuro flation. Alternatively, the composition may be presented in a degeneration in Down Syndrome, wherein the gamma 65 form Suitable for once-weekly or once-monthly administra secretase inhibitor is selected from LY-450139, tion; for example, an insoluble salt of the active compound, LY-411575 and AN-37124. Such as the decanoate salt, may be adapted to provide a depot US 8,541,596 B2 43 44 preparation for intramuscular injection. For preparing Solid an oral, non-toxic pharmaceutically acceptable inert carrier compositions such as tablets, the principal active ingredientis Such as ethanol, glycerol, water and the like. Moreover, when mixed with a pharmaceutical carrier, e.g. conventional tablet desired or necessary, Suitable binders; lubricants, disintegrat ing ingredients such as corn starch, lactose, Sucrose, Sorbitol, ing agents and coloring agents can also be incorporated into talc, Stearic acid, magnesium Stearate, dicalcium phosphate the mixture. Suitable binders include, without limitation, or gums, and other pharmaceutical diluents, e.g. water, to starch, gelatin, natural Sugars such as glucose or betalactose, form a solid preformulation composition containing a homo corn Sweeteners, natural and synthetic gums such as acacia, geneous mixture of a compound of the present invention, or a tragacanth or Sodium oleate, Sodium Stearate, magnesium pharmaceutically acceptable salt thereof. When referring to Stearate, Sodium benzoate, sodium acetate, sodium chloride these preformulation compositions as homogeneous, it is 10 meant that the active ingredient is dispersed evenly through and the like. Disintegrators include, without limitation, out the composition so that the composition may be readily starch, methylcellulose, agar, bentonite, Xanthan gum and the Subdivided into equally effective dosage forms such as tab like. lets, pills and capsules. This solid preformulation composi The liquid forms in suitable flavored suspending or dis tion is then subdivided into unit dosage forms of the type 15 persing agents such as the synthetic and natural gums, for described above containing from 0.1 to about 500 mg of each example, tragacanth, acacia, methyl-cellulose and the like. active ingredient or combinations thereof of the present For parenteral administration, sterile Suspensions and solu invention. tions are desired. Isotonic preparations which generally con The tablets or pills of the compositions of the present tain Suitable preservatives are employed when intravenous invention can be coated or otherwise compounded to provide administration is desired. a dosage form affording the advantage of prolonged action. The compounds or combinations of the present invention For example, the tablet or pill can comprise an inner dosage can also be administered in the form of liposome delivery and an outer dosage component, the latter being in the form of systems, such as Small unilamellar vesicles, large unilamellar an envelope over the former. The two components can be vesicles, and multilamellar vesicles. Liposomes can be separated by an enteric layer which serves to resist disinte 25 formed from a variety of phospholipids, such as cholesterol, gration in the stomach and permits the inner component to Stearylamine or phosphatidylcholines. pass intact into the duodenum or to be delayed in release. A Compounds or combinations of the present invention may variety of material can be used for such enteric layers or also be delivered by the use of monoclonal antibodies as coatings, such materials including a number of polymeric individual carriers to which the compound molecules are acids with Such materials as shellac, cetyl alcohol and cellu 30 coupled. The compounds of the present invention may also be lose acetate. coupled with Soluble polymers as targetable drug carriers. This liquid forms in which the compositions of the present Such polymers can include polyvinylpyrrollidone, pyran invention may be incorporated for administration orally or by copolymer, polyhydroxypropylmethacrylamidephenol, injection include, aqueous solutions, Suitably flavoured Syr polyhydroxyethylaspartamid-ephenol, or polyethyl eneox ups, aqueous or oil suspensions, and flavoured emulsions 35 idepolyllysine substituted with palmitoyl residue. Further with edible oils such as cottonseed oil, Sesame oil, coconut oil more, the compounds of the present invention may be coupled or peanut oil, as well as elixirs and similar pharmaceutical to a class of biodegradable polymers useful in achieving vehicles. Suitable dispersing or Suspending agents for aque controlled release of a drug, for example, polyactic acid, ous Suspensions, include synthetic and natural gums such as polyepsilon caprolactone, polyhydroxybutyeric acid, poly tragacanth, acacia, alginate, dextran, Sodium carboxymethyl 40 orthoesters, polyacetals, polydihydropyrians, polycyanoacry cellulose, methylcellulose, polyvinylpyrrolidone or gelatin. lates and cross-linked or amphipathic block copolymers of The pharmaceutical composition may contain between hydrogels. about 0.01 mg and 100 mg, preferably about 5 to 50 mg. of Compounds or combinations of this invention may be each compound, and may be constituted into any form Suit administered in any of the foregoing compositions and able for the mode of administration selected. Carriers include 45 according to dosage regimens established in the art whenever necessary and inert pharmaceutical excipients, including, but treatment of the addressed disorders is required. not limited to, binders, Suspending agents, lubricants, fla The daily dosage of the products may be varied over a wide Vorants, Sweeteners, preservatives, dyes, and coatings. Com range from 0.01 to 1.000 mg per mammal per day. For oral positions suitable for oral administration include Solid forms, administration, the compositions are preferably provided in Such as pills, tablets, caplets, capsules (each including imme 50 the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, diate release, timed release and Sustained release formula 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milli tions), granules, and powders, and liquid forms, such as solu grams of each active ingredient or combinations thereof for tions, syrups, elixirs, emulsions, and Suspensions. Forms the symptomatic adjustment of the dosage to the patient to be useful for parenteral administration include Sterile Solutions, treated. An effective amount of the drug is ordinarily supplied emulsions and Suspensions. 55 at a dosage level of from about 0.1 mg/kg to about 300 mg/kg Advantageously, compounds of the present invention may of body weight per day. Preferably, the range is from about 1 be administered in a single daily dose, or the total daily to about 50 mg/kg of body weight per day. The compounds or dosage may be administered in divided doses of two, three or combinations may be administered on a regimen of 1 to 4 four times daily. Furthermore, compounds for the present times per day. invention can be administered in intranasal form via topical 60 Optimal dosages to be administered may be readily deter use of Suitable intranasal vehicles, or via transdermal skin mined by those skilled in the art, and will vary with the patches well known to those of ordinary skill in that art. To be particular compound used, the mode of administration, the administered in the form of transdermal delivery system, the strength of the preparation, the mode of administration, and dosage administration will, of course, be continuous rather the advancement of disease condition. In addition, factors than intermittent throughout the dosage regimen. 65 associated with the particular patient being treated, including For instance, for oral administration in the form of a tablet patient age, weight, diet and time of administration, will or capsule, the active drug component can be combined with result in the need to adjust dosages. US 8,541,596 B2 45 46 In a further aspect, the invention also provides a process for the claims, is used to mean “and/or unless explicitly indi preparing a pharmaceutical composition comprising at least cated to refer to alternatives only or the alternatives are mutu one compound of formula (I), optionally in combination with ally exclusive. at least one of the other aforementioned agents and a phar The terms “comprise.” “have” and “include” are open ended linking verbs. Any forms or tenses of one or more of maceutically acceptable carrier. these verbs, such as “comprises.” “comprising.” “has.” “hav The compositions are preferably in a unit dosage forminan ing,” “includes” and “including are also open-ended. For amount appropriate for the relevant daily dosage. example, any method that “comprises.” “has or “includes’ Suitable dosages, including especially unit dosages, of the one or more steps is not limited to possessing only those one compounds of the present invention include the known dos or more steps and can also cover other unlisted steps. Simi ages including unit doses for these compounds as described 10 larly, any composition or device that “comprises.” “has or or referred to in reference text such as the British and US “includes one or more features is not limited to possessing Pharmacopoeias, Remington’s Pharmaceutical Sciences only those one or more features and can cover other unlisted (Mack Publishing Co.), Martindale The Extra Pharmaco features. poeia (London, The Pharmaceutical Press) (for example see All methods described herein can be performed in any the 31st Edition page 341 and pages cited therein) or the 15 suitable order unless otherwise indicated herein or otherwise above mentioned publications. clearly contradicted by context. The use of any and all Definitions and methods described herein are provided to examples, or exemplary language (e.g. "Such as') provided better define the present disclosure and to guide those of with respect to certain embodiments herein is intended ordinary skill in the art in the practice of the present disclo merely to better illuminate the present disclosure and does not sure. Unless otherwise noted, terms are to be understood pose a limitation on the scope of the present disclosure oth according to conventional usage by those of ordinary skill in erwise claimed. No language in the specification should be the relevant art. construed as indicating any non-claimed element essential to In some embodiments, numbers expressing quantities of the practice of the present disclosure. ingredients, properties such as molecular weight, reaction Groupings of alternative elements or embodiments of the conditions, and so forth, used to describe and claim certain 25 present disclosure disclosed herein are not to be construed as embodiments of the present disclosure are to be understood as limitations. Each group member can be referred to and being modified in some instances by the term “about.” In claimed individually or in any combination with other mem some embodiments, the term “about is used to indicate that bers of the group or other elements found herein. One or more a value includes the standard deviation of the mean for the members of a group can be included in, or deleted from, a device or method being employed to determine the value. In 30 group for reasons of convenience or patentability. When any some embodiments, the numerical parameters set forth in the such inclusion or deletion occurs, the specification is herein written description and attached claims are approximations deemed to contain the group as modified thus fulfilling the that can vary depending upon the desired properties sought to written description of all Markush groups used in the be obtained by a particular embodiment. In some embodi appended claims. ments, the numerical parameters should be construed in light 35 Citation of a reference herein shall not be construed as an of the number of reported significant digits and by applying admission that Such is prior art to the present disclosure. ordinary rounding techniques. Notwithstanding that the Having described the present disclosure in detail, it will be numerical ranges and parameters setting forth the broad apparent that modifications, variations, and equivalent Scope of some embodiments of the present disclosure are embodiments are possible without departing the scope of the approximations, the numerical values set forth in the specific 40 present disclosure defined in the appended claims. Further examples are reported as precisely as practicable. The more, it should be appreciated that all examples in the present numerical values presented in Some embodiments of the disclosure are provided as non-limiting examples. present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective EXAMPLES testing measurements. The recitation of ranges of values 45 herein is merely intended to serve as a shorthand method of The following non-limiting examples are provided to fur referring individually to each separate value falling within the ther illustrate the present disclosure. It should be appreciated range. Unless otherwise indicated herein, each individual by those of skill in the art that the techniques disclosed in the value is incorporated into the specification as if it were indi examples that follow represent approaches the inventors have vidually recited herein. 50 found function well in the practice of the present disclosure, In some embodiments, the terms “a” and “an and “the and thus can be considered to constitute examples of modes and similar references used in the context of describing a for its practice. However, those of skill in the art should, in particular embodiment (especially in the context of certain of light of the present disclosure, appreciate that many changes the following claims) can be construed to cover both the can be made in the specific embodiments that are disclosed singular and the plural, unless specifically noted otherwise. In 55 and still obtain a like or similar result without departing from Some embodiments, the term 'or' as used herein, including the spirit and scope of the present disclosure.

Process Example Structure Name M+H" Route N-Phenyl-1H- 2102 1 COO benzodimidazol-5-amine

US 8,541,596 B2 79 80 General Synthesis Description: -continued Method 1

Br

-- N N \-h 10 R Poddba BenZimidazol-5-amine (1 eq.) was Suspended in dry toluol nN.1 N LiN(TMS) (50 ml). After addition of the respective aldehyde (1.1 eq.), H -HX -- THF the mixture was heated to reflux for 3 h. The solvent was 2 650 C. removed in vacuo and the remains were dissolved in dry 15 EtOH (100 ml). This solution was added dropwise to a solu n = 0-2 tion of NaBH (1.5 eq.) in EtOH (50 ml) at room temperature. After stirring for 1 h the mixture was heated to reflux for an PCy2 additional 4 h. After the addition of 5 N NaOH (5 eq) the N reaction was stirred at 60° C. overnight. The solvent was concentrated by half, diluted with water and extracted by means of ethyl acetate (3x100 ml). The combined organic 1. O layers were dried over NaSO, evaporated and the residue R was purified by flash chromatography on silica using a NN pi N -HX 25 CHCl/MeOH gradient. 2 Method 3 NH2

30 R R 1. MeOH, molsieves 5-Bromobenzimidazole (1 eq.) was dissolved in THF (3 -- r r.t. ml). The respective amine (1.2 eq.), 2-dicyclohexylphos N 2. NaBH4 phino-2'-(N,N-dimethylamino)biphenyl (0.024 eq.; 2.4 mol \- NH O %), Pd dba (0.01 eq.; 1 mol%) and lithiumbis(trimethylsi 35 lyl)amide 1 M in THF (2.2 eq.) were added and the mixture was heated under argon atmosphere to 65° C. for 24 h. After HN l R cooling to room temperature the mixture was acidified by means of 5 NHCl aq. and stirring was continued for an additional 10 min. The mixture was poured into a sat. solution 40 of NaHCO and extracted by means of ethyl acetate (3x20 ml). The combined organic layers were dried over NaSO, evaporated and the residue was purified by flash chromatog raphy using basic Al-O and a CHC1/MeCH-gradient. Method 2 45 Benzimidazol-5-amine (1 eq.) was dissolved in MeOH (10 ml) and treated with the respective aldehyde or ketone (1.1 eq.). After the addition of molsieves 3 A the mixture was NH2 stirred at room temperature for 24h. NaBH (2 eq.) was added R and the mixture was stirred for 1 h and heated to reflux for 50 toluol additional 4 h. After the addition of 5 N NaOH (5 eq) the H reflux mixture was stirred at 60° C. overnight. The mixture was N diluted with water and extracted by means of ethyl acetate \-h O (3x25 ml). The combined organic layers were dried over 55 NaSO, evaporated and the residue was purified by flash N21 chromatography on silica using a CHCl/MeOH gradient. Method 4

60 NH2 SAS N 2 -- Br -HR K2CO3 NaBH4 N DMF EtOH 65 \- N 2 r.t. n US 8,541,596 B2 81 82 -continued A solution of benzimidazol-5-amine (1 eq.) in DMF (5 ml) was treated with KCO (2.2 eq.) and the respective alkylha / \ lide (2.2 eq.) and stirred at room temperature for 24 h. The —7 R mixture was diluted with water and extracted by means of 5 ethyl acetate (3x25 ml). The combined organic layers were dried over NaSO, evaporated and the residue was purified N by flash chromatography on silica using a CHCl/MeOH S/S gradient. Method 6 -- ( ) 10 R \- Boc 5N NaOCH 15 --> R THF r.t. K2CO3 -- 1n -e- N Br R DMF --R N r.t. 2

R R N N 25 2HR ls-s,

N 30 N

N1-Boc-benzimidazol-5-amine (1 eq.) was dissolved in DMF (5 ml) and treated with KCO (2.5 eq.) and the respec The corresponding N-monosubstituted benzimidazol-5- tive benzylhalide (2.5 eq.). After stirring at room temperature 35 amine derivative (1 eq.) was dissolved in DMF (5 ml), treated for 24 h the mixture was diluted with water and extracted by with KCO (1.1 eq.) and the respective alkylhalide (1.1 eq.) means of ethyl acetate (3x25 ml). The combined organic and stirred at room temperature for 24 h. The mixture was layers were dried over NaSO and the solvent was removed diluted with water and extracted by means of ethyl acetate in vacuo. The residue was redissolved in THF (5 ml), treated (3x25 ml). The combined organic layers were dried over with 5N NaOCH (3 eq.) and stirred at room temperature for 40 NaSO, evaporated and the residue was purified by flash 1 h. The mixture was diluted with water and extracted by means of ethyl acetate (3x25 ml). The combined organic chromatography on silica using a CHCl/MeOH gradient. layers were dried over NaSO, evaporated and the residue Method 7 was purified by flash chromatography on silica using a 1H-Benzodimidazol-5-yl-methylamines CHCl/MeOH gradient. 45 Method 5 R H O NH2 NN R 50 R NaBH(AcO)3 AcOH K2CO3 -- HN n THF + 1 NR - DMF - R r.t. N r.t. \-h 55 R ls 1a R HN 1N R Benzimidazol-5-carbaldehyde (1 eq.) was dissolved in 60 THF (10 ml). The respective amine (1 eq.), NaBH(AcO) (1.5 eq.) and AcOH (1.5 eq.) were added and the mixture was -- stirred at room temperature overnight. The mixture was bas ified by means of 1 Maqueous NaOH and extracted with ethyl N N acetate (3x25 ml). The combined organic layers were dried 65 over NaSO and evaporated. The residue was purified by flash chromatography on silica using a CHCl/MeOH gradi ent.

US 8,541,596 B2 103 104 (400 MHz, DMSO d6): 8 0.89 (t, 3H, J=7.5 Hz); 1.32 (sext, Example 87 2H, J=7.5 Hz); 1.52-1.60 (m, 2H); 2.42 (s.3H); 3.37 (t, 2H, J–7.5 Hz); 4.47 (s. 2H); 6.68-6.71 (m, 2H); 7.15-7.20 (m, N-(4-Methoxybenzyl)-N-((naphthalen-2-yl)methyl)- 4H); 7.34 (d. 1H, J=8.7 Hz); 7.90 (s, 1H); 11.90 (brs, 1H): 3H-benzodimidazol-5-amine HPLC (METHODA):rt 16.31 min (99.7%) N-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine Example 84 (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with KCO (166 mg, 1.2 mmol; 1.2 eq.) and naphthalen-2- yl-methyl-bromide (265 mg, 1.2 mmol; 1.2 eq.) and stirred at N-(4-(Methylthio)benzyl)-N-isobutyl-1H-benzod 10 room temperature for 24 h. The mixture was diluted with imidazol-5-amine water and extracted with ethyl acetate (3x25 ml). The com bined organic layers were dried over NaSO and evaporated. The compound was synthesized starting from N-isobutyl The remains were taken up with THF (5 ml), treated with 5 N benzimidazol-5-amine (95 mg: 0.5 mmol; 1 eq.), 4-methylth NaOCH and stirred for 2 hat room temperature. The mixture iobenzylbromide (120 mg: 0.55 mmol; 1.1 eq.) and KCO, 15 was diluted with water and extracted with ethyl acetate (3x25 (76 mg: 0.55 mmol; 1.1 eq.) according to method 6; Yield: ml). The combined organic layers were dried over NaSO 0.066 g (40.6%); MS m/z: 326.4 M+H"; "H-NMR (400 and evaporated. The residue was purified by flash chromatog MHz, DMSO d6): 8 0.92 (d. 6H, J=6.6 Hz); 2.01-2.08 (m, raphy on silica using a CHCl/MeoH gradient. Yield: 0.058 1H); 2.41 (s.3H); 3.21 (d. 2H, J=7.1 Hz); 4.53 (s. 2H); 6.68 mg (14.8%); MS m/z: 394.2 M+H"; "H-NMR (500 MHz, (brs, 1H); 6.70 (dd. 1H, J=2.1 Hz, J=8.7 Hz); 7.13-7.18 (m, DMSO d6): 83.70 (s.3H); 4.68 (s. 2H); 4.80 (s. 2H); 6.76 (d. 4H); 7.34 (d. 1H, J=8.7 Hz); 7.90 (s, 1H); 11.91 (brs, 1H): 1H, J=2.1 Hz); 6.82 (dd. 1H, J=2.3 Hz, J=8.9 Hz); 6.87 HPLC (METHODA):rt 16.40 min (99.5%) 6.89 (m, 2H): 7.22-7.24 (m, 2H); 7.34 (d. 1H, J=8.9 Hz); 7.43-747 (m, 5H); 7.75 (brs, 1H); 7.79-7.81 (m, 1H); 7.85 Example 85 7.87 (m 2H); 7.94 (s, 1H); HPLC (METHODA): rt 18.12 25 min (95.6%) N-(4-(Methylthio)benzyl)-N-(pentan-2-yl)-1H-benzo Example 88 dimidazol-5-amine N-(4-Methoxybenzyl)-N-phenethyl-1H-benzod The compound was synthesized starting from N-(pentan 30 imidazol-5-amine 2-yl)benzimidazol-5-amine (102 mg 0.5 mmol; 1 eq.), 4-me N-Trityl-N-(4-methoxyphenyl)benzimidazol-5-amine thylthiobenzylbromide (120 mg: 0.55 mmol; 1.1 eq.) and (990 mg; 2 mmol; 1 eq.) was dissolved in THF (5 ml), cooled KCO (76 mg: 0.55 mmol; 1.1 eq) according to method 6: to 0°C. and treated with lithiumbis(trimethylsilyl)amide 1M Yield: 0.038 g (22.4%); MS m/z. 340.3 M+H"; "H-NMR 35 in THF (2.4 ml; 2.4 mmol; 1.2 eq.). Phenylethylbromide (400 MHz, DMSO d6): 8 0.85–0.89 (m, 3H); 1.12 (d. 3H, (0.330 ml; 2.4 mmol; 2.4 eq.) was added and the mixture was J=6.6 Hz); 1.33-1.47 (m, 3H); 1.61-1.68 (m. 1H); 2.40 (s, stirred at room temperature for 24 h. The mixture was diluted 3H); 3.92-3.94 (m. 1H, CH, N CH-CH); 4.30 (s. 2H): with water and extracted with ethyl acetate (3x25 ml). The 6.77-6.79 (m, 2H); 7.13-7.15 (m, 2H): 723-7.25 (m, 2H): combined organic layers were dried over NaSO and evapo 7.31-7.33 (m, 1H); 7.90 (s, 1H); 11.90 (bris, 1H); HPLC 40 rated. The residue was dissolved in MeCH (5 ml) and treated (METHODA):rt 16.75 min (85.6%) with TFA (1 ml). After heating to reflux for 1 h the mixture was poured into saturated NaHCO-solution and extracted Example 86 with ethyl acetate (3x25 ml). The combined organic layers were dried over NaSO and evaporated. The residue was 45 purified by flash chromatography on silica using a CHCl/ N-(4-Methoxybenzyl)-N-benzyl-3H-benzodimida MeOH gradient. Yield: 0.058 g (8.1%); MS m/z. 358.1 Zol-5-amine M+H"; "H-NMR (500 MHz, DMSO d6): 8 2.85 (t, 2H, J=7.9 Hz); 3.57 (t, 2H, J=7.9 Hz); 3.69 (s.3H); 4.44 (s.2H): N-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine 6.77-6.79 (m, 2H); 6.83-6.86 (m, 2H); 7.14-7.16 (m, 2H): (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated 50 7.18-7.21 (m. 1H): 723-7.25 (m, 2H): 728-7.30 (m, 2H): with KCO (166 mg, 1.2 mmol; 1.2 eq) and benzylbromide 7.38-7.39 (m, 1H); 7.92 (s, 1H); 11.92 (bris, 1H); HPLC (0.143 ml, 1.2 mmol; 1.2 eq.) and stirred at room temperature (METHODA):rt 16.74 min (96.3%) for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3x25 ml). The combined organic layers Example 89 were dried over NaSO and evaporated. The remains were 55 taken up with THF (5 ml), treated with 5 N NaOCH and N-(4-Methoxybenzyl)-N-(3-phenylpropyl)-3H-benzo stirred for 2 hat room temperature. The mixture was diluted dimidazol-5-amine with water and extracted with ethyl acetate (3x25 ml). The combined organic layers were dried over NaSO and evapo N-Boc-N-(4-Methoxybenzyl)benzimidazol-5-amine rated. The residue was purified by flash chromatography on 60 (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated silicausing a CHCl/MeOH gradient. Yield: 0.049 g (14.3%); with KCO (166 mg, 1.2 mmol; 1.2 eq.) and phenylpropyl MS m/z. 344.1 M+H"; "H-NMR (500 MHz, DMSO d6): 8 bromide (0.183 ml, 1.2 mmol; 1.2 eq.) and stirred at room 3.70 (s, 3H); 4.60 (s. 2H), 4.64 (s. 2H); 6.71 (d. 1H, J–2.1 temperature for 24 h. The mixture was diluted with water and Hz); 6.77 (dd. 1H, J=2.1 Hz, J=8.9 Hz); 6.85-6.88 (m, 2H): extracted with ethyl acetate (3x25ml). The combined organic 7.19-7.22 (m, 3H): 7.26-7.32 (m, 4H); 7.34 (d. 1H, J=8.9 65 layers were dried over NaSO and evaporated. The remains Hz); 7.99 (s, 1H); HPLC (METHODA): rt 15.26 min were taken up with THF (5 ml), treated with 5 NNaOCH and (99.8%) stirred for 2 hat room temperature. The mixture was diluted US 8,541,596 B2 105 106 with water and extracted with ethyl acetate (3x25 ml). The Example 93 combined organic layers were dried over NaSO and evapo rated. The residue was purified by flash chromatography on N-((1H-Benzodimidazol-5-yl)methyl)(4-methox silica using a CHCl/MeOH gradient. Yield: 0.015 g (4.0%); yphenyl)-N-methylmethanamine MS m/z. 372.1 M+H"; "H-NMR (500 MHz, DMSO d6): 8 1.84-190 (m, 2H); 2.62 (t, 2H, J=7.6 Hz); 3.39 (t, 2H, J=7.6 The compound was synthesized starting from benzimida Hz); 3.39 (s.3H); 4.45 (s. 2H); 6.71 (brs, 1H); 6.73 (dd. 1H, Zol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), 4-methoxy-N- J=2.1 Hz, J=8.9 Hz); 6.83-6.85 (m, 2H); 7.12-7.14 (m, 2H): methylaniline (137 mg g; 1 mmol; 1 eq.); NaBH(AcO) (318 7.16-7.19 (m, 3H): 7.24-7.27 (m, 2H); 7.36 (d. 1H, J=8.9 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml, 1.5 mmol; 1.5 10 eq.) as described above. Yield: 0.030 g (11%); MS m/z. 268.3 Hz); 8.08 (s, 1H); HPLC (METHODA): rt 16.97 min M+H"; "H-NMR (400 MHz, DMSO d6): 8 2.89 (s.3H): (93.2%) 3.64 (s, 3H); 4.53 (s. 2H); 6.71-6.78 (m, 4H); 7.05-7.07 (m, Example 90 1H); 7.35 (brs, 1H); 7.49 (d. 1H, J=8.3 Hz); 8.13 (s, 1H): 12.35 (brs, 1H); HPLC (METHODA):rt 6.28 min (90.3%) 15 N-Benzyl-N-phenyl-1H-benzodimidazol-5-amine Example 94 N-Trityl-N-phenyl-benzimidazol-5-amine (1.13 g; 2.5 N-((1H-Benzodimidazol-5-yl)methyl)(4-fluorophe mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0°C. and nyl)-N-methylmethanamine treated with lithiumbis(trimethylsilyl)amide 1M in THF (3 ml, 3 mmol; 1.2 eq.). BenZylbromide (3 mmol; 1.2 eq.) was The compound was synthesized starting from benzimida added and stirred at room temperature for 24 h. The mixture Zol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), 4-fluoro-N- was diluted with water and extracted with ethyl acetate (3x25 methylaniline (0.147 ml; 1 mmol; 1 eq.); NaBH(AcO) (318 ml). The combined organic layers were dried over NaSO mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml, 1.5 mmol; 1.5 and evaporated. The residue was dissolved in MeCH (5 ml) 25 eq.) as described above. Yield: 0.035 g (13%); MS m/z: 270.1 and treated with TFA (1 ml). After heating to reflux overnight M+H"; "H-NMR (400 MHz, DMSO d6): 8 2.05 (s, 3H): the mixture was poured into saturated NaHCO-solution and 3.47 (s. 2H); 3.57 (s. 2H); 7.11-7.16 (m, 3H); 7.35-7.36 (m, extracted with ethyl acetate (3x25ml). The combined organic 2H); 7.44-7.56 (m,2H); 8.14 (s, 1H); HPLC (METHODA): layers were dried over NaSO and evaporated. The residue rt 7.14 min (95.9%) was purified by flash chromatography on silica using a 30 Analytical Methods CHC1/MeoH gradient. Yield: 0.046 g (6.2%); MS m/z: The analytical HPLC-system consisted of a Merck-Hitachi 300.1 M+H"; "H-NMR, 500 MHz, 'H-NMR (500 MHz, device (model LaChromR) utilizing a Li-Chrospher R. 100 DMSO d6): 85.00 (s. 2H); 6.70-6.73 (m. 1H); 6.78-6.79 (m, RP 18 (5um). analytical column (length: 125 mm. diameter: 2H); 7.06-7.08 (m. 1H); 7.10-7.13 (m, 2H); 7.18-7.21 (m, 4 mm). and a diode array detector (DAD) with v-214 nm as 1H): 7.29-7.31 (m, 2H); 7.36-7.37 (m, 3H); 7.54 (d. 1H, 35 the reporting wavelength. The compounds were analyzed J=8.5 Hz); 8.30 (s, 1H); 12.32 (brs, 1H); HPLC (METHOD using a gradient at a flow rate of 1 mL/min: whereby eluent AI): rt 15.47 min (95.1%) (A) was acetonitrile. eluent (B) was water, both containing 0.1% (v/v) trifluoroacetic acid applying the following gradi Example 91 ent: Method A:0 min-5 min. 5% (A): 5 min-17 min, 5-15% 40 (A): 17 min-29 min, 15-95% (A): 29 min-32 min, 95% (A): N-((1H-Benzodimidazol-5-yl)methyl)benzenamine 32 min-33 min, 95-5% (A): 33 min-38 min, 5% (A); Method B: 0 min-25 min. 20-80% (A): 25 min-30 min. 80-95% (A): The compound was synthesized starting from benzimida 30 min-31 min. 95-20% (A): 31 min-40 min 20% (A). The Zol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), aniline (0.095 purities of all reported compounds were determined by the ml; 1 mmol; 1 eq.), NaBH(AcO) (318 mg: 1.5 mmol; 1.5 eq.) 45 percentage of the peak area at 214 nm. ESI-Mass spectra were and AcOH (0.095 ml, 1.5 mmol; 1.5 eq.) as described above. obtained with a SCIEX API 365 spectrometer (PerkinElmer) Yield: 0.160 g (71%); MS m/z: 224.3 M+H"; "H-NMR (400 utilizing the positive ionization mode. MHz, DMSO d6): 8 4.34-4.35 (m, 2H); 6.20.6.21 (m, 1H): Activity Screening 6.45-6.49 (m. 1H); 6.57-6.59 (m, 1H); 6.98-7.02 (m. 1H): Fluorometric Assays 7.17-7.26 (m, 2H); 7.39-7.43 (m, 1H); 7.49-7.52 (m, 2H): 50 All measurements were performed with a BioAssay 12.34-12.39 (brm, 1H); HPLC (METHODA): rt 8.16 min Reader HTS-7000Plus for microplates (Perkin Elmer) at 30° (97.3%) C. QC activity was evaluated fluorometrically using H-Gln BNA. The samples consisted of 0.2 mM fluorogenic substrate, Example 92 0.25 U pyroglutamyl aminopeptidase (Unizyme, Hesholm, 55 Denmark) in 0.2 M Tris/HCl, pH 8.0 containing 20 mM N-((1H-Benzodimidazol-5-yl)methyl)-2-phenyle EDTA and an appropriately diluted aliquot of QC in a final thanamine volume of 250 ul. Excitation/emission wavelengths were 320/410 nm. The assay reactions were initiated by addition of The compound was synthesized starting from benzimida glutaminyl cyclase. QC activity was determined from a stan Zol-5-carbaldehyde (146 mg, 1 mmol; 1 eq.), phenylethy 60 dard curve of /3-naphthylamine under assay conditions. One lamine (0.126 ml; 1 mmol; 1 eq.); NaBH(AcO) (318 mg, 1.5 unit is defined as the amount of QC catalyzing the formation mmol; 1.5 eq.) and AcOH (0.095 ml, 1.5 mmol; 1.5 eq.) as of 1 umol pGlu-BNA from H-Gln-/3NA per minute under the described above. Yield: 0.040 g (16%); MS m/z: 252.2 described conditions. M+H"; "H-NMR (400 MHz, DMSO d6): 83.30 (brs, 4H); In a second fluorometric assay, QC was activity determined 3.81 (s. 2H); 7.12-7.27 (m,9H); 8.13-8.14 (m, 1H); 12.30 (br 65 using H-Gln-AMC as substrate. Reactions were carried out at s, 1H); HPLC (METHODA):rt doublepeak 6.77/6.60 min 30° C. utilizing the NOVOStar reader for microplates (BMG (93.7%) labtechnologies). The samples consisted of varying concen US 8,541,596 B2 107 108 trations of the fluorogenic Substrate, 0.1 Upyroglutamylami analyzed using a gradientata flow rate of 1 mL/min: whereby nopeptidase (Qiagen) in 0.05 M Tris/HCl, pH 8.0 containing eluent (A) was acetonitrile, eluent (B) was water, both con 5 mM EDTA and an appropriately diluted aliquot of QC in a taining 0.1% (v/v) trifluoroacetic acid applying the following final volume of 250 ul. Excitation/emission wavelengths gradient: 0 min-5 min->5% (A), 5 min-17 min->5-15% (A), were 380/460 nm. The assay reactions were initiated by addi 15 min-27 min->15-95% (A) 27 min-30 min->95% (A), tion of glutaminyl cyclase. QC activity was determined from Method B: 0 min-15min->5-60% (A), 15 min-20 min->60 a standard curve of 7-amino-4-methylcoumarin under assay 95% (A), 20 min-23 min->95% (A), Method C: 0 min-20 conditions. The kinetic data were evaluated using GraFit soft min->5-60% (A), 20 min-25 min->60-95% (A). 25 min-30 Wa. min->95% (A). Spectrophotometric Assay of QC 10 Method B: The analytical HPLC-system consisted of a This novel assay was used to determine the kinetic param Agilent MSD 1100 utilizing a Waters SunFire RP 18 (2.5um), eters for most of the QC substrates. QC activity was analyzed analytical column (length: 50 mm, diameter: 2.1 mm), and a spectrophotometrically using a continuous method, that was diode array detector (DAD) with 254 nm as the reporting derived by adapting a previous discontinuous assay (Bate wavelength. The compounds were analyzed using a gradient man, R. C. J. 1989J Neurosci Methods 30, 23-28) utilizing 15 at a flow rate of 0.6 mL/min: whereby eluent (A) was aceto glutamate dehydrogenase as auxiliary enzyme. Samples con nitrile, eluent (B) was water and eluent (C) 2% formic acid in sisted of the respective QC substrate, 0.3 mMNADH, 14 mM acetonitrile applying the following gradient: a-Ketoglutaric acid and 30U/ml glutamate dehydrogenase in a final volume of 250 ul. Reactions were started by addition of QC and persued by monitoring of the decrease in absorbance at 340 nm for 8-15 min. Time min % Solvent B % Solvent C The initial velocities were evaluated and the enzymatic O 90 5 activity was determined from a standard curve of ammonia 2.5 10 5 under assay conditions. All samples were measured at 30°C., 4 10 5 using either the SPECTRAFIuor Plus or the Sunrise (both 25 4.5 90 5 from TECAN) reader for microplates. Kinetic data was evalu 6 90 5 ated using GraFit software. Inhibitor Assay The purities of all reported compounds were determined by For inhibitor testing, the sample composition was the same the percentage of the peak area at 214 nm. as described above, except for the putative inhibitory com 30 Mass-spectrometry, NMR-spectroscopy: pound added. For a rapid test of QC-inhibition, samples con ESI-Mass spectra were obtained with a SCIEX API 365 tained 4 mM of the respective inhibitor and a substrate con spectrometer (PerkinElmer) utilizing the positive ionization centration at 1 K. For detailed investigations of the mode. inhibition and determination of K-values, influence of the The "H NMR-Spectra (500 MHz) were recorded at a inhibitor on the auxiliary enzymes was investigated first. In 35 BRUKER AC 500. The solvent was DMSO-D unless oth every case, there was no influence on either enzyme detected, erwise specified. Chemial shifts are expressed as parts per thus enabling the reliable determination of the QC inhibition. million (ppm) downfiled from tetramethylsilan. Splitting pat The inhibitory constant was evaluated by fitting the set of terns have been designated as follows: S (singulet), d (dou progress curves to the general equation for competitive inhi blet), dd (doublet of doublet), t (triplet), m (multiplet) and br bition using GraFit software. 40 (broad signal). Results MALDI-TOF Mass Spectrometry Examples 10 to 11, 19-20, 23 to 27, 34, 37, 44 to 49, 51 to Matrix-assisted laser desorption/ionization mass spec 52, 54 to 57, 59 to 60, 62, 66 to 69, 71 to 72, 74 to 76, 78, 80 trometry was carried out using the Hewlett-Packard G2025 to 81, 83, 86 to 87 and 89 were tested and gave hOC ICso LD-TOF System with a linear time of flight analyzer. The values of less than 10 uM. Certain specific values are given in 45 instrument was equipped with a 337 nm nitrogen laser, a the table below: potential acceleration source (5 kV) and a 1.0 m flight tube. Detector operation was in the positive-ion mode and signals are recorded and filtered using LeCroy 9350M digital storage oscilloscope linked to a personal computer. Samples (5 Jul) Example no. hOC K. LM hOCICso M 50 were mixed with equal volumes of the matrix solution. For 2O O.346 3.99 matrix solution DHAP/DAHC was used, prepared by solving 23 O.473 3.65 30 mg 2,6'-dihydroxyacetophenone (Aldrich) and 44 mg 51 O.313 3.16 diammonium hydrogen citrate (Fluka) in 1 ml acetonitrile/ 52 O.305 3.06 S4 O.194 2.65 0.1% TFA in water (1/1, V/v). A small volume (s1 ul) of the 55 O.228 3.71 55 matrix-analyte-mixture was transferred to a probe tip and 56 O.271 4.12 immediately evaporated in a vacuum chamber (Hewlett 57 O.S19 3.41 Packard G2024A sample prep accessory) to ensure rapid and 8O 1.08 4.08 homogeneous sample crystallization. 87 3.14 For long-term testing of Glu'-cyclization, An-derived pep 60 tides were incubated in 100 ul 0.1 M sodium acetate buffer, Analytical Methods pH 5.2 or 0.1 M Bis-Tris buffer, pH 6.5 at 30° C. Peptides HPLC: were applied in 0.5 mMLAB(3-11)a or 0.15 mMAB(3-21)a Method A: The analytical HPLC-system consisted of a concentrations, and 0.2U QC is added all 24 hours. In case of Merck-Hitachi device (model LaChromR) utilizing a Af(3-21)a, the assays contained 1% DMSO. At different LUNAR RP 18 (5um), analytical column (length: 125 mm. 65 times, samples are removed from the assay tube, peptides diameter: 4 mm), and a diode array detector (DAD) with extracted using ZipTips (Millipore) according to the manu w214 nm as the reporting wavelength. The compounds were facturer's recommendations, mixed with matrix solution (1:1 US 8,541,596 B2 109 110 V/v) and Subsequently the mass spectra recorded. Negative controls either contain no QC or heat deactivated enzyme. For the inhibitor studies the sample composition was the same as Abbreviations described above, with exception of the inhibitory compound (DHQ),PHAL hydroquinine 14-phthalazinediyl diether added (5 mM or 2 mM of a test compound of the invention). 5 AcOH acetic acid Compounds and combinations of the invention may have DAD diode array detector the advantage that they are, for example, more potent, more DCC dicyclohexyl carbodiimide selective, have fewer side-effects, have betterformulation and DEA Diethylamine stability properties, have better pharmacokinetic properties, DHAPDAHC dihydroxyacetone phosphate dihydro-5-azacytidine be more bioavailable, be able to cross blood brain barrier and 10 DMF dimethylformamide DMSO dimethylsulfoxide are more effective in the brain of mammals, are more com EDTA ethylenediamine-N,N,N',N'-tetraacetic acid patible or effective in combination with other drugs or be EtOAC ethyl acetate more readily synthesized than other compounds of the prior EtOH ethanol art. FPLC fast performance liquid chromatography Throughout the specification and the claims which follow, 15 HPLC high performance liquid chromatography unless the context requires otherwise, the word comprise’, PA isopropanole and variations such as comprises and comprising, will be LD-TOF laser-desorption time-of-flight mass spectrometry ML mother lye understood to imply the inclusion of a stated integer, step, MS mass spectrometry group of integers or group of steps but not to the exclusion of NMR nuclear magnetic resonance any other integer, step, group of integers or group of steps. Poddba tris(dibenzylideneacetone)dipalladium All patents and patent applications mentioned throughout TEA triethylamine the specification of the present invention are herein incorpo TFA trifluoroacetic acid THF tetrahydrofuran rated in their entirety by reference. TLC thin layer chromatography The invention embraces all combinations of preferred and 2s TMscN trimethylsilyl cyanide more preferred groups and embodiments of groups recited above.

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 US 8,541,596 B2 111 112 - Continued <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 3O Met Val Gly Gly Val Val Ile Ala 35 4 O

<210s, SEQ ID NO 4 &211s LENGTH: 38 212. 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 222. 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 US 8,541,596 B2 113 114 - Continued

<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

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 Thr Cys Cys Phe Asin Val Ile 1. 5 1O 15

Asn Arg Lys Ile Pro Ile Glin Arg Lieu. Glu Ser Tyr Thr Arg Ile Thr 2O 25 30

Asn. Ile Glin Cys Pro Llys Glu Ala Val Ile Phe Llys Thr Lys Arg Gly 35 4 O 45

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

Llys His Lieu. Asp Glin Ile Phe Glin Asn Lieu Lys Pro 65 70 7s

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

<4 OOs, SEQUENCE: 10

Gln Pro Asp Ala Ile Asn Ala Pro Val Thr Cys Cys Tyr Asn Phe Thr 1. 5 1O 15

Asn Arg Lys Ile Ser Val Glin Arg Lieu Ala Ser Tyr Arg Arg Ile Thr 2O 25 3O

Ser Ser Lys Cys Pro Lys Glu Ala Val Ile Phe Lys Thr Ile Val Ala 35 4 O 45

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

Asp His Lieu. Asp Lys Glin Thr Glin Thr Pro Llys Thr 65 70 7s

<210s, SEQ ID NO 11 &211s LENGTH: 68 212. TYPE: PRT <213> ORGANISM: Homo sapiens US 8,541,596 B2 115 116 - Continued <4 OOs, SEQUENCE: 11

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

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

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

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

Lys Lieu. Asn Ala 65

<210s, SEQ ID NO 12 &211s LENGTH: 373 212. TYPE: PRT <213> ORGANISM: Homo sapiens <4 OOs, SEQUENCE: 12

Glin His His Gly Val Thr Lys Cys Asn Ile Thir Ser Met Thir 1. 5 15

Ser Lys Ile Pro Val Ala Lieu. Lieu. Ile His Tyr Glin Asn Glin Ala 2O 25 3O

Ser Cys Gly Lys Arg Ala Ile Ile Luell Glu Thir Arg His Arg Luell 35 4 O

Phe Cys Ala Asp Pro Llys Glu Glin Trp Wall Lys Asp Met Glin His SO 55 6 O

Lell Asp Arg Glin Ala Ala Ala Lieu Thir Arg ASn Gly Thir Phe Glu 65 70

Glin Ile Gly Glu Val Lys Pro Arg Thir Thir Pro Gly Gly 85 90 95

Met Asp Glu Ser Val Val Lieu. Glu Pro Glu Thir Ser Ser 1OO 105

Ser Lieu. Glu Pro Thr Pro Ser Ser Glin Glu Glin Arg Luell Gly 115 12 O 125

Thir Ser Pro Glu Lieu Pro Thr Gly Wall Thir Ser Ser Thir Arg 13 O 135 14 O

Lell Pro Pro Thr Pro Lys Ala Glin Asp Gly Pro Wall Thir Glu 145 150 160

Lell Phe Arg Val Pro Pro Val Ser Thir Ala Thir Trp Ser Ser 1.65 17O 17s

Ala Pro His Gln Pro Gly Pro Ser Luell Trp Glu Ala Lys Thir Ser 18O 185 19 O

Glu Ala Pro Ser Thr Glin Asp Pro Ser Thir Ala Ser Thir Ala Ser 195 2OO

Ser Pro Ala Pro Glu Glu Asn Ala Pro Ser Gly Glin Arg Wall Trp 21 O 215 22O

Gly Gln Gly Glin Ser Pro Arg Pro Glu Asn Ser Lell 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 Wal Ser Wall Wall Pro Wall Ser Ser Glu Gly Thir 26 O 265 27 O

Pro Ser Arg Glu Pro Val Ala Ser Gly Ser Trp Thir Pro Ala Glu 27s 28O 285 US 8,541,596 B2 117 118 - Continued 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 Lys 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: 76 212. 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 Thr 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 Lell 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 US 8,541,596 B2 119 120 - Continued

<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

<210s, SEQ ID NO 18 &211s LENGTH: 34 212. TYPE: PRT <213> ORGANISM: Artificial sequence 22 Os. FEATURE: <223> 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 2O 25 3O

Glu Asn

<210s, SEQ ID NO 19 &211s LENGTH: 34 212. TYPE: PRT <213> ORGANISM: Artificial sequence 22 Os. FEATURE: <223> 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 2O 25 3O

His Tyr

<210s, SEQ ID NO 2 O &211s LENGTH: 5 212. TYPE: PRT <213> ORGANISM: Artificial sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Synthetic peptide

<4 OOs, SEQUENCE: 2O Glin Tyr Asn Ala Asp 1. 5 US 8,541,596 B2 121 122 What is claimed is: in which said bicyclic heteroaryl group may be optionally 1. A compound of formula (I): Substituted by one or more groups selected from Coalkyl, C2-alkenyl, C2-alkynyl, Chaloalkyl, —C-thioalkyl, -SOC alkyl, -SOC alkyl, (I) Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, —SOC scycloalkyl, -SOC cycloalkyl, Calk N N enyloxy-, Calkynyloxy-, -C(O)OC-alkyl, —C(O) OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, (N R cyano, hydroxyl, —C(O)OH, -NH2, —NHC alkyl, H —N(Calkyl)(Calkyl). —C(O)N(Calkyl) 10 (Calkyl), —C(O)NH2. —C(O)NH(Calkyl) and or a pharmaceutically acceptable salt, tautomer, or stereoi —C(O)NH(Cocycloalkyl). Somers thereof wherein: 2. A compound as defined in claim 1, wherein R' represents X represents a bond or a —(CH)-group: Calkylaryl, —Calkyl-Het, —Calkylaryl fused to het m represents an integer selected from 1 to 3: erocyclyl or —Calkylaryl Substituted by heteroaryl. R" represents -aryl, -Coalkylaryl, -cycloalkyl, 15 3. A compound as defined in claim 1, wherein R represents —Calkylcycloalkyl, —Calkyl-Het, -aryl fused to -aryl, -Calkylaryl, -Calkylcycloalkyl, -Calkyl heterocyclyl, -Calkylaryl fused to heterocyclyl, Het, —Calkylaryl fused to heterocyclyl or —Calkylaryl -aryl Substituted by heteroaryl, -Calkylaryl Substi substituted by heteroaryl. tuted by heteroaryl, -aryl substituted by phenyl, —C. 6alkylaryl substituted by phenyl, -aryl substituted by 4. A compound as defined in claim 1, wherein R' represents phenoxy or —Calkylaryl Substituted by phenoxy: —Coalkylaryl and R represents —C-alkylaryl or and in which any of aforesaid aryl, heterocyclyl, het —Calkylcycloalkyl; wherein said aryl groups are option eroaryl, phenyl or phenoxy groups may optionally be ally Substituted by one or more halogen, cyano, Calkyl, Substituted by one or more groups selected from Calkoxy, —Cathioalkyl or —N(Calkyl)(Calkyl) Calkyl, Calkenyl, C-alkynyl, Chaloalkyl, groups. —Cathioalkyl, -SOC-alkyl, -SOC-alkyl, 25 5. A compound as defined in claim 1, wherein R' and R' Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, both represent —Calkylaryl; wherein said phenyl groups —SOCscycloalkyl, -SOC-cycloalkyl, Calk are optionally Substituted by one or more halogen, cyano, enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) Calkyl, Calkoxy, —Cathioalkyl or—N(Calkyl)(C. OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, 4alkyl) groups. cyano, hydroxyl, —C(O)OH, -NH. NHC alkyl, 30 6. A compound as defined in claim 1, wherein R' and R' —N(Calkyl)(Calkyl). —C(O)N(Calkyl) both represent—Coalkylaryl Substituted by to heteroaryl. (Calkyl), —C(O)NH2. —C(O)NH(Calkyl) and 7. A compound as defined in claim 1, wherein R' and R' —C(O)NH(Cocycloalkyl); R represents -aryl, -Coalkylaryl, -cycloalkyl, both represent—C-alkylaryl substituted by heteroaryl. —Calkylcycloalkyl, -Calkyl- Het, -aryl fused to 35 8. A compound as defined in claim 1, wherein R' represents heterocyclyl, -Calkylaryl fused to heterocyclyl, —Coalkyl-Het and R represents —C-alkyl-Het, -aryl Substituted by heteroaryl, -Calkylaryl Substi Calkylaryl, or —Calkyl cycloalkyl, wherein said Het tuted by heteroaryl, -aryl substituted by phenyl, —C. groups are optionally Substituted by one or more halogen or 6alkylaryl substituted by phenyl, -aryl substituted by Calkyl groups; and wherein said aryl group is optionally phenoxy or —Calkylaryl Substituted by phenoxy: 40 Substituted by one or more —Cathioalkyl, Calkyl, and in which any of aforesaid aryl, heterocyclyl, het Calkoxy, halogen or —N(Calkyl)(Calkyl) groups. eroaryl, phenyl or phenoxy groups may optionally be 9. A compound as defined in claim 1, wherein R' and R' Substituted by one or more groups selected from bothrepresent —Calkyl-Het; wherein said Het groups are Coalkyl, C2-galkenyl, C2-alkynyl, Chaloalkyl, optionally Substituted by one ormore halogen or Calky —Cathioalkyl, -SOC alkyl, -SOC alkyl, 45 groups. Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, 10. A compound as defined in claim 1, wherein R' repre —SOC scycloalkyl, -SOC cycloalkyl, Calk sents aryland R represents —C-alkylaryl. enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) 11. A compound as defined in claim 1, wherein X repre OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, sents a bondora —CH2-group. cyano, hydroxyl, —C(O)OH, -NH2, —NHC alkyl, 50 —N(Calkyl)(Calkyl). —C(O)N(Calkyl) 12. A compound as defined in claim 11, wherein X repre (Calkyl), —C(O)NH2. —C(O)NH(Calkyl) and sentsa bond. —C(O)NH(Cocycloalkyl); 13. A compound according to claim 1, wherein saidcom Het represents a bicyclic heteroaryl group; pound is selected from the group consisting of

N,N-Dibenzyl-1H benzodimidazol-5-amine;

N H o

US 8,541,596 B2 144 -continued N-(4-Methoxybenzyl)-N- phenethyl-1H benzodimidazol-5-amine;

O ( N N H N-(4-Methoxybenzyl)-N-(3- phenylpropyl)-3H benzodimidazol-5-amine; and

O N

H ( N N N-Benzyl-N-phenyl-1H benzodimidazol-5-amine;

N N

N

or a pharmaceutically accepted Salt thereof, including all (a) preparing a compound of formula (I) wherein X repre tautomers and stereoisomers. sents a bond by reacting a compound of formula (II) 14. A pharmaceutical composition comprising acompound 40 according to claim 1, optionally in combination with one or (II) moretherapeutically acceptable diluents or carriers. N Ll 15. The pharmaceutical composition of claim 14, which comprisesadditionally at least one compound, selected from ( the group consisting ofneuroprotectants, antiparkinsonian 45 N drugs, amyloid protein deposition inhibitors, betaamyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antip with a compound of formula NHR'R'', wherein 1' repre sychotic drugs andanti-multiple Sclerosis drugs. sents a suitable leaving group and R' and R are as 16. The pharmaceutical composition of claim 14, which defined in claim 1: comprisesadditionally at least one compound, selected from 50 (b) preparing a compound of formula (I) wherein X repre the group consisting of PEP-inhibitors. LiCl, inhibitors of sents a bond, R' is as defined inclaim 1 andR represents inhibitors of DP IV or DPIV-like enzymes,acetylcholinest —Calkylaryl, —Calkyl-Het, —Calkylaryl erase (ACE) inhibitors, PIMT enhancers, inhibitors of beta fused to heterocyclyl. —Calkylaryl Substituted by secretases.inhibitors of gamma secretases, inhibitors of neu heteroaryl, Calkylaryl Substituted by phenyl or tral endopeptidase, inhibitors of hosphodiesterase-4 (PDE 55 4), TNFalpha inhibitors, muscarinic M1 receptorantagonists, —Calkylaryl Substituted by phenoxy, by alkylatinga NMDA receptor antagonists, sigma-1 receptor inhibitors, compound of formula (III): histamine H3 antagonists, immunomodulatory agents, (III) immunosuppressive agents or an agentselected from the N N&-cy group consisting of antegren (natalizumab), Neurelan (fam 60 pridine-SR).campath (alemtuzumab), IR 208, NBI ( 5788/MSP 771 (tiplimotide), paclitaxel. Anergix.MS (AG N 284), SH636, Differin (CD 271, adapalene), BAY 36.1677 H (interleukin-4), matrix-metalloproteinase-inhibitors, inter feron-tau (trophoblastin) and SAIK-MS. 65 wherein Cy' represents the aryl or Het group of R: 17. A process for preparation of a compound of formula (I) (c) preparing a compound of formula (I) wherein X repre according to claim 1, which comprises: sents a bond, R' is as defined inclaim 1 andR represents US 8,541,596 B2 145 146 —Calkyl, —Calkylaryl, -Calkylcycloalkyl, (e) preparing a compound of formula (I) wherein X repre —Calkyl-Het, —Calkylaryl fused to heterocyclyl, sents a —(CH), -group, by reacting a compound of for —Calkylaryl Substituted by heteroaryl, -Calky mula (VI): laryl substituted by phenyl or—Calkyaryl substituted by phenoxy, by reacting a compound of formula (IV): (VI) (CH2)- (IV) Cr 10 N n ( H with a compound of formula HNR'R'', wherein R' and R' N are as defined in claim 1: H (f) interconversion of compounds of formula (I), Such as 15 preparing acompound of formula (I) wherein R' is as with a compound of formula H-CO-R, wherein R is as defined in claim 1 by reacting a compound of formula defined in claim 1: (V): (d) preparing a compound of formula (I) wherein: X rep resents a bond, R is as defined in claim 1 and R is as defined in claim 1; or X represents a bond and RandR (V) represent identical groups, by reacting a compound offormula (IV): (N NRI 25 (IV) N

N n with a compound of formula L. R", wherein R is as ( H defined in claim 1, L' represents a suitable leaving group 30 such as bromine and R' represents an R' group as N defined in claim1; and/or H (g) deprotecting a compound of formula (I) which is pro tected. or an optionally protecting derivative thereof with a com 18. The process of claim 17, wherein L' is bromine, L is pound of formula L-R, whereinL represents a suitable bromine, or L' bromine. leaving group and R is as defined in claim 1: k k k k k