US 201100925O1A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0092501 A1 Heiser et al. (43) Pub. Date: Apr. 21, 2011

(54) NOVEL INHIBITORS C07D 47L/04 (2006.01) A63L/437 (2006.01) (75) Inventors: Ulrich Heiser, Halle/Saale (DE): A6IP35/00 (2006.01) Daniel Ramsbeck, Halle/Saale A6IP 29/00 (2006.01) (DE); Robert Sommer, Halle/Saale A6IP 25/00 (2006.01) (DE); Antje Meyer, Halle/Saale A6IP35/04 (2006.01) (DE); Torsten Hoffmann, A6IP3/00 (2006.01) Halle/Saale (DE); Livia Boehme, A6IP5/00 (2006.01) Halle/Saale (DE); Hans-Ulrich (52) U.S. Cl...... 514/234.5: 548/306.1: 514/394; Demuth, Halle/Saale (DE) 514/322:546/199: 54.4/139; 546/1.12: 514/300 (73) Assignee: propodrug AG, Halle/Saale (57) ABSTRACT The invention relates to novel pyrrolidine derivatives of for (21) Appl. No.: 12/880,369 mula (I): (22) Filed: Sep. 13, 2010 (I) Related U.S. Application Data R2 R3 (60) Provisional application No. 61/241,432, filed on Sep. RSX, 11, 2009. V / Y-Z Publication Classification (51) Int. Cl. wherein R, R and Rare as defined herein, as inhibitors of A 6LX 3/535 (2006.01) glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the CO7D 403/02 (2006.01) intramolecular cyclization of N-terminal glutamine residues A6 IK 3/484 (2006.01) into pyroglutamic acid (5-oxo-prolyl, pClu) under libera A6 IK 3L/454 (2006.01) tion of ammonia and the intramolecular cyclization of N-ter CO7D 40/02 (2006.01) minal glutamate residues into pyroglutamic acid under lib CO7D 413/14 (2006.01) eration of water. US 2011/00925O1 A1 Apr. 21, 2011

NOVELINHIBITORS pronounced sequence homology to bacterial aminopepti dases (Bateman, R. C. et al. 2001 Biochemistry 40, 11246 CROSS-REFERENCE TO RELATED 11250), leading to the conclusion that the QCs from plants APPLICATIONS and animals have different evolutionary origins. 0001. This application claims priority from U.S. Provi 0006 Recently, it was shown that recombinant human QC sional Application Ser. No. 61/241,432 filed on Sep. 11, 2009, as well as QC-activity from brain extracts catalyze both, the which is incorporated herein by reference in its entirety. N-terminal glutaminyl as well as glutamate cyclization. Most striking is the finding, that cyclase-catalyzed Glu-conver MATERIAL INCORPORATED BY REFERENCE sion is favored around pH 6.0 while Gln-conversion to pGlu derivatives occurs with a pH-optimum of around 8.0. Since 0002 The Sequence Listing, which is a part of the present the formation of pClu-AB-related peptides can be suppressed disclosure, includes a computer readable form comprising by inhibition of recombinant human QC and QC-activity nucleotide and/or amino acid sequences of the present inven from pig pituitary extracts, the enzyme QC is a target in drug tion. The Subject matter of the Sequence Listing is incorpo development for treatment of Alzheimer's disease. rated herein by reference in its entirety. 0007 Inhibitors of QC are described in WO 2004/098.625, FIELD OF THE INVENTION WO 2004/098591, WO 2005/03.9548, WO 2005/075436, WO 2008/055945, WO 2008/055947, WO 2008/055950, 0003. The invention relates to novel pyrrolidine deriva WO2008/065141, WO 2008/110523, WO 2008/128981, WO tives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC 2008/128982, WO 2008/128983, WO 2008/128984, WO catalyzes the intramolecular cyclization of N-terminal 2008/128985, WO 2008/128986, WO 2008/128987 and WO glutamine residues into pyroglutamic acid (5-oxo-prolyl, 2010/O26212. pGlu) under liberation of ammonia and the intramolecular 0008 EP 02011 349.4 discloses polynucleotides encod cyclization of N-terminal glutamate residues into pyro ing insect glutaminyl cyclase, as well as polypeptides glutamic acid under liberation of water. encoded thereby and their use in methods of screening for agents that reduce glutaminyl cyclase activity. Such agents BACKGROUND OF THE INVENTION are useful as pesticides. 0004 Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues DEFINITIONS into pyroglutamic acid (pGlu) liberating ammonia. A QC was first isolated by Messer from the latex of the tropical plant 0009. The terms “k” or “K” and “K” are binding con Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). stants, which describe the binding of an inhibitor to and the 24 years later, a corresponding enzymatic activity was dis Subsequent release from an enzyme. Another measure is the covered in animal pituitary (Busby, W. H. J. etal. 1987J Biol “ICs value, which reflects the inhibitor concentration, Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 which at a given substrate concentration results in 50% Proc Natl AcadSci USA 84,3628-3632). For the mammalian enzyme activity. QC, the conversion of Gln into pGlu by QC could be shown (0010. The term “DPIV-inhibitor” or “dipeptidyl peptidase for the precursors of TRH and GnRH (Busby, W. H. J. et al. IV inhibitor is generally known to a person skilled in the art 1987J Biol Chem 262,8532-8536; Fischer, W. H. and Spiess, and means enzyme inhibitors, which inhibit the catalytic J. 1987 Proc Natl AcadSci USA 84,3628-3632). In addition, activity of DP IV or DPIV-like enzymes. initial localization experiments of QC revealed a co-localiza (0011 “DP IV-activity” is defined as the catalytic activity tion with its putative products of catalysis in bovine pituitary, of dipeptidyl peptidase IV (DPIV) and DPIV-like enzymes. further improving the Suggested function in peptide hormone These enzymes are post-proline (to a lesser extent post-ala synthesis (Bockers, T. M. et al. 1995 J Neuroendocrinol 7, nine, post-serine or post-glycine) cleaving serine proteases 445-453). In contrast, the physiological function of the plant found in various tissues of the body of a mammal including QC is less clear. In the case of the enzyme from C. papaya, a kidney, liver, and intestine, where they remove dipeptides role in the plant defense against pathogenic microorganisms from the N-terminus of biologically active peptides with a was suggested (El Moussaoui, A. etal 2001 Cell Mol Life Sci high specificity when proline oralanine form the residues that 58, 556-570). Putative QCs from other plants were identified by sequence comparisons recently (Dahl, S. W. et al. 2000 are adjacent to the N-terminal amino acid in their sequence. Protein Expr Purif 20, 27-36). The physiological function of (0012. The term “PEP-inhibitor” or “prolyl endopeptidase these enzymes, however, is still ambiguous. inhibitor' is generally known to a person skilled in the art and 0005. The QCs known from plants and animals show a means enzyme inhibitors, which inhibit the catalytic activity strict specificity for L-Glutamine in the N-terminal position of prolyl endopeptidase (PEP prolyl oligopeptidase, POP). of the substrates and their kinetic behavior was found to obey (0013 “PEP-activity” is defined as the catalytic activity of the Michaelis-Mentenequation (Pohl, T. etal. 1991 Proc Natl an endoprotease that is capable to hydrolyze post proline Acad Sci USA 88, 10059-10063: Consalvo, A. P. et al. 1988 bonds in peptides or proteins where the proline is in amino Anal Biochem 175, 131-138; Gololobov, M.Y. et al. 1996 acid position 3 or higher counted from the N-terminus of a Biol Chem Hoppe Seyler 377,395-398). A comparison of the peptide or protein Substrate. primary structures of the QCs from C. papaya and that of the 0014. The term “QC as used herein comprises glutaminyl highly conserved QC from mammals, however, did not reveal cyclase (QC) and QC-like enzymes. QC and QC-like any sequence homology (Dahl, S.W. et al. 2000 Protein Expr enzymes have identical or similar enzymatic activity, further Purif 20, 27-36). Whereas the plant QCs appear to belong to defined as QC activity. In this regard, QC-like enzymes can a new enzyme family (Dahl, S. W. et al. 2000 Protein Expr fundamentally differ in their molecular structure from QC. Purif 20, 27-36), the mammalian QCs were found to have a Examples of QC-like enzymes are the glutaminyl-peptide US 2011/00925O1 A1 Apr. 21, 2011 cyclotransferase-like proteins (QPCTLs) from human (Gen 0016. The term “EC as used herein comprises the activity Bank NM 017659), mouse (GenBank BC058181), Macaca of QC and QC-like enzymes as glutamate cyclase (EC), fur fascicularis (GenBank AB168255), Macaca mulatta (Gen ther defined as EC activity. Bank XM 001110995), Canis familiaris (GenBank (0017. The term “EC activity” as used herein is defined as XM 541552), Rattus norvegicus (GenBank intramolecular cyclization of N-terminal glutamate residues XM 001066591), Mus musculus (GenBank BC058181) and into pyroglutamic acid (p.Glu) by QC. See therefore scheme Bos taurus (GenBank BTO26254). 3.

Scheme 3: N-terminal cyclization of uncharged glutamyl peptides by QC (EC) peptide pepeptide pils peptide NH NH HN H GE) HN HN O H2O O O O QC/EC GE) QC/EC NH2 NH

O o O OH H2N Oe O

0015 The term “QC activity” as used herein is defined as (0018. The term “QC-inhibitor” “glutaminyl cyclase intramolecular cyclization of N-terminal glutamine residues inhibitor' is generally known to a person skilled in the art and into pyroglutamic acid (p.Glu) or of N-terminal L-homo means enzyme inhibitors, which inhibit the catalytic activity glutamine or L-B-homoglutamine to a cyclic pyro-homo of glutaminyl cyclase (QC) or its glutamylcyclase (EC) activ glutamine derivative under liberation of ammonia. See there ity. fore schemes 1 and 2. Potency of QC Inhibition 0019. In light of the correlation with QC inhibition, in Scheme 1: Cyclization of glutamine by QC preferred embodiments, the subject method and medical use utilize an agent with an ICs for QC inhibition of 10 LM or peptide peptide less, more preferably of 1 uMorless, even more preferably of NH HN 0.1 uMorless or 0.01 uMorless, or most preferably 0.001 uM NH O or less. Indeed, inhibitors with K values in the lower micro HN molar, preferably the nanomolar and even more preferably O the picomolar range are contemplated. Thus, while the active QC agents are described herein, for convenience, as “QC inhibi NH tors', it will be understood that such nomenclature is not intending to limit the Subject of the invention to a particular mechanism of action. O NH2 O Molecular Weight of QC Inhibitors 0020. In general, the QC inhibitors of the subject method or medical use will be small molecules, e.g., with molecular weights of 500 g/mole or less, 400 g/mole or less, preferably of 350 g/mole or less, and even more preferably of 300 g/mole Scheme 2: Cyclization of L-homoglutamine by QC or less and even of 250 g/mole or less. peptide peptide 0021. The term “subject as used herein, refers to an ani mal, preferably a mammal, most preferably a human, who has NH HN NH O been the object of treatment, observation or experiment. HN 0022. The term “therapeutically effective amount’ as used O herein, means that amount of active compound or pharma QC NH ceutical agent that elicits the biological or medicinal response in a tissue system, animal or human being sought by a researcher, Veterinarian, medical doctor or other clinician, 29 O which includes alleviation of the symptoms of the disease or disorder being treated. NH2 0023. As used herein, the term “pharmaceutically accept able' embraces both human and veterinary use: For example the term “pharmaceutically acceptable' embraces a veteri US 2011/00925O1 A1 Apr. 21, 2011 narily acceptable compound or a compound acceptable in group is a cycloalkyl group. A further example of a carbocy human medicine and health care. clyl group is a cycloalkenyl group. 0031. The expression "heterocyclyl', unless specifically 0024. Throughout the description and the claims the limited, refers to a carbocyclyl group wherein one or more expression “alkyl, unless specifically limited, denotes a (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms C-12 alkyl group, Suitably a C-8 alkyl group, e.g. C- alkyl selected from N, S and O. A specific example of a heterocy group, e.g. C. alkyl group. Alkyl groups may be straight clyl group is a cycloalkyl group (e.g. cyclopentyl or more chain or branched. Suitable alkyl groups include, for particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3. example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), particularly 1 or 2, especially 1) ring atoms are replaced by butyl (e.g. n-butyl, iso-butyl, sec-butyl and tert-butyl), pentyl heteroatoms selected from N, S or O. Exemplary heterocyclyl groups containing one hetero atom include pyrrolidine, tet (e.g. n-pentyl), hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl)and rahydrofuran and piperidine, and exemplary heterocyclyl octyl (e.g. n-octyl). The expression “alk’, for example in the groups containing two hetero atoms include morpholine and expressions “alkoxy”, “haloalkyl and “thioalkyl should be piperazine. A further specific example of a heterocyclyl group interpreted in accordance with the definition of “alkyl'. is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein Exemplary alkoxy groups include methoxy, ethoxy, propoxy one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pen ring atoms are replaced by heteroatoms selected from N. S toxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and and O. An example of Such a group is dihydropyranyl (e.g. octoxy (e.g. n-octoxy). Exemplary thioalkyl groups include 3,4-dihydro-2H-pyran-2-yl-). methylthio-. Exemplary haloalkyl groups include fluoroalkyl 0032. The expression “aryl, unless specifically limited, denotes a C-12 aryl group, Suitably a Co-o aryl group, more e.g. CFs. suitably a Cls aryl group. Aryl groups will contain at least 0025. The expression “alkenyl', unless specifically lim one aromatic ring (e.g. one, two or three rings). An example of ited, denotes a C- alkenyl group, Suitably a C- alkenyl a typical aryl group with one aromatic ring is phenyl. An group, e.g. a C2-alkenyl group, which contains at least one example of a typical aryl group with two aromatic rings is double bond at any desired location and which does not naphthyl. contain any triple bonds. Alkenyl groups may be straight 0033. The expression "heteroaryl', unless specifically chain or branched. Exemplary alkenyl groups including one limited, denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4. Suitably 1, 2 or 3) ring atoms are replaced by double bond include propenyl and butenyl. Exemplary alk heteroatoms selected from N, S and O, or elsea 5-membered enyl groups including two double bonds include pentadienyl, aromatic ring containing one or more (e.g. 1, 2, 3, or 4. e.g. (1E, 3E)-pentadienyl. suitably 1, 2 or 3) ring atoms selected from N, S and O. 0026. The expression “alkynyl', unless specifically lim Exemplary monocyclic heteroaryl groups having one het ited, denotes a C- alkynyl group, Suitably a C- alkynyl eroatom include: five membered rings (e.g. pyrrole, furan, group, e.g. a C2-alkynyl group, which contains at least one thiophene); and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary triple bond at any desired location and may or may not also monocyclic heteroaryl groups having two heteroatoms contain one or more double bonds. Alkynyl groups may be include: five membered rings (e.g. pyrazole, oxazole, isox straight chain or branched. Exemplary alkynyl groups include azole, thiazole, isothiazole, imidazole. Such as imidazol-1-yl, propynyl and butynyl. imidazol-2-yl imidazol-4-yl); six membered rings (e.g. 0027. The expression “alkylene' denotes a chain of for pyridazine, pyrimidine, pyrazine). Exemplary monocyclic mula —(CH), wherein n is an integer e.g. 2-5, unless heteroaryl groups having three heteroatoms include: 1,2,3- specifically limited. triazole and 1,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary 0028. The expression “cycloalkyl, unless specifically bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), limited, denotes a Co cycloalkyl group (i.e. 3 to 10 ring benzofuran, benzthiophene, quinoline, isoquinoline, inda carbon atoms), more suitably a Cs cycloalkyl group, e.g. a Zole, benzimidazole, benzthiazole, quinazoline and purine. C. cycloalkyl group. Exemplary cycloalkyl groups include 0034. The expression"-alkylaryl', unless specifically lim cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep ited, denotes an aryl residue which is connected via an alky tyl and cyclooctyl. A most Suitable number of ring carbon lene moiety e.g. a Calkylene moiety. atoms is three to six. 0035. The expression "-alkylheteroaryl', unless specifi cally limited, denotes a heteroaryl residue which is connected 0029. The expression “cycloalkenyl, unless specifically via an alkylene moiety e.g. a Calkylene moiety. limited, denotes a Cso cycloalkenyl group (i.e. 5 to 10 ring 0036. The term “halogen' or “halo' comprises fluorine carbonatoms), more Suitably a Css cycloalkenyl group e.g. a (F), chlorine (Cl) and bromine (Br). Cs cycloalkenyl group. Exemplary cycloalkenyl groups 0037. The term “amino” refers to the group -NH. include cyclopropenyl, cyclohexenyl, cycloheptenyl and 0038. The term “phenyl substituted by phenyl refers to cyclooctenyl. A most Suitable number of ring carbonatoms is biphenyl. five to six. 0039. The term “ rurrr " ' denotes a single bond 0030 The expression “carbocyclyl', unless specifically where the stereochemistry is not defined. limited, denotes any ring system in which all the ring atoms 0040. When benzimidazolyl is shown as benzimidazol-5- are carbon and which contains between three and twelve ring yl, which is represented as: carbon atoms, Suitably between three and ten carbon atoms and more Suitably between three and eight carbon atoms. Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic, and tricyclic ring sys tems, in particular monocyclic and bicyclic ring systems. Other carbocylcyl groups include bridged ring systems (e.g. bicyclo2.2.1]heptenyl). A specific example of a carbocyclyl US 2011/00925O1 A1 Apr. 21, 2011

the person skilled in the art will appreciate that benzimidazol ric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroace 6-yl, which is represented as: tic, triphenylacetic, Sulfamic, Sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxalo acetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalene Sulfonic or naphthalenedisulfonic), Salicylic, glutaric, glu conic, tricarballylic, cinnamic, Substituted cinnamic (for example, phenyl, methyl, methoxy or halo Substituted cin namic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1 is an equivalent structure. As employed herein, the two forms or 3-hydroxy-2-naphthoic), naphthaleneacrylic (for example of benzimidazolyl are covered by the term “benzimidazol-5- naphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or y1”.99 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, ben Zeneacrylic (for example 1,4-benzenediacrylic), isethionic Stereoisomers: acids, perchloric, propionic, glycolic, hydroxyethane 0041 All possible stereoisomers of the claimed com Sulfonic, pamoic, cyclohexanesulfamic, Salicylic, Saccharinic pounds are included in the present invention. and trifluoroacetic acid. Pharmaceutically acceptable base 0042. Where the compounds according to this invention salts include ammonium salts, alkali metal salts such as those have at least one chiral center, they may accordingly exist as of sodium and potassium, alkaline earth metal salts such as enantiomers. Where the compounds possess two or more those of calcium and magnesium and salts with organic bases chiral centers, they may additionally exist as diastereomers. It Such as dicyclohexylamine and N-methyl-D-glucamine. is to be understood that all such isomers and mixtures thereof 0047 All pharmaceutically acceptable acid addition salt are encompassed within the scope of the present invention. forms of the compounds of the present invention are intended to be embraced by the scope of this invention. Preparation and Isolation of Stereoisomers: Polymorph Crystal Forms: 0043. Where the processes for the preparation of the com pounds according to the invention give rise to a mixture of 0048. Furthermore, some of the crystalline forms of the Stereoisomers, these isomers may be separated by conven compounds may exist as polymorphs and as such are intended tional techniques such as preparative chromatography. The to be included in the present invention. In addition, some of compounds may be prepared in racemic form, or individual the compounds may form Solvates with water (i.e. hydrates) enantiomers may be prepared either by enantiospecific Syn or common organic solvents, and Such solvates are also thesis or by resolution. The compounds may, for example, be intended to be encompassed within the Scope of this inven resolved into their components enantiomers by standard tech tion. The compounds, including their salts, can also be niques, such as the formation of diastereomeric pairs by salt obtained in the form of their hydrates, or include other sol formation with an optically active acid, such as (-)-di-p- vents used for their crystallization. toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the Prodrugs: free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromato 0049. The present invention further includes within its graphic separation and removal of the chiral auxiliary. Alter Scope prodrugs of the compounds of this invention. In gen natively, the compounds may be resolved using a chiral eral, such prodrugs will be functional derivatives of the com HPLC column. pounds which are readily convertible in vivo into the desired therapeutically active compound. Thus, in these cases, the Pharmaceutically Acceptable Salts: methods of treatment of the present invention, the term “administering shall encompass the treatment of the various 0044. In view of the close relationship between the free disorders described with prodrug versions of one or more of compounds and the compounds in the form of their salts or the claimed compounds, but which converts to the above Solvates, whenever a compound is referred to in this context, specified compound in vivo after administration to the Sub a corresponding salt, Solvate or polymorph is also intended, ject. Conventional procedures for the selection and prepara provided such is possible or appropriate under the circum tion of suitable prodrug derivatives are described, for Stances. example, in “Design of Prodrugs’, ed. H. Bundgaard, 0045 Salts and solvates of the compounds of formula (I) Elsevier, 1985. and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion Protective Groups: or associated solvent is pharmaceutically acceptable. How ever, salts and Solvates having non-pharmaceutically accept 0050. During any of the processes for preparation of the able counter-ions or associated Solvents are within the scope compounds of the present invention, it may be necessary of the present invention, for example, for use as intermediates and/or desirable to protect sensitive or reactive groups on any in the preparation of other compounds and their pharmaceu of the molecules concerned. This may be achieved by means tically acceptable salts and Solvates. of conventional protecting groups, such as those described in 0046 Suitable salts according to the invention include Protective Groups in Organic Chemistry, ed. J. F. W. those formed with both organic and inorganic acids or bases. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Pharmaceutically acceptable acid addition salts include those Wuts, Protective Groups in Organic Synthesis, John Wiley & formed from hydrochloric, hydrobromic, sulfuric, nitric, cit Sons, 1991, fully incorporated herein by reference. The pro US 2011/00925O1 A1 Apr. 21, 2011 tecting groups may be removed at a convenient Subsequent dropyrians, polycyanoacrylates and cross-linked or amphip stage using methods known from the art. athic block copolymers of hydrogels. 0051 A protecting group or protective group is introduced 0061 Suitable binders include, without limitation, starch, into a molecule by chemical modification of a functional gelatin, natural Sugars such as glucose or betalactose, corn group in order to obtain chemoselectivity in a Subsequent Sweeteners, natural and synthetic gums such as acacia, traga chemical reaction. Protecting groups are e.g. alcohol protect canth or Sodium oleate, sodium Stearate, magnesium Stearate, ing groups, amine protecting groups, carbonyl protecting Sodium benzoate, Sodium acetate, sodium chloride and the groups, carboxylic acid protecting groups and phosphate pro like. tecting groups. 0062 Disintegrators include, without limitation, starch, 0052 Examples for alcohol protecting groups are acetyl methyl cellulose, agar, bentonite, Xanthan gum and the like. (Ac), benzoyl (BZ), benzyl (Bn, Bnl) B-methoxyethoxym ethyl ether (MEM), mimethoxytrityl bis-(4-methoxyphenyl) ABBREVIATIONS phenylmethyl, DMT, methoxymethyl ether (MOM), meth 0063 (DHQ)PHAL hydroquinine 1,4-phthalazinediyl oxytrityl (4-methoxyphenyl)diphenylmethyl, MMT), diether p-methoxybenzyl ether (PMB), methylthiomethyl ether, piv AcOHacetic acid aloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl, DAD diode array detector Tr), silyl ethers (such as trimethylsilyl ether (TMS), tert DCC dicyclohexyl carbodiimide butyldimethylsilyl ether (TBDMS), tert-butyldimethylsily loxymethyl ether (TOM), and triisopropylsilyl ether (TIPS)); DEA Diethylamine methyl ethers and ethoxyethyl ethers (EE). 0064 DHAP/DAHC dihydroxyacetone phosphate/dihy 0053 Suitable amine protecting groups are selected from dro-5-azacytidine carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or DMF dimethylformamide MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethy DMSO dimethylsulfoxide loxycarbonyl (FMOC), acetyl (Ac), benzoyl (BZ), benzyl EDTA ethylenediamine-N,N,N',N'-tetraacetic acid (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl EtOAc ethyl acetate (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), and other sul EtOH ethanol fonamides (Nosyl & Nps). FPLC fast performance liquid chromatography 0054 Suitable carbonyl protecting groups are selected HPLC high performance liquid chromatography from acetals and ketals, acylals and dithianes. IPA isopropanole 0055 Suitable carboxylic acid protecting groups are LD-TOF laser-desorption time-of-flight mass spectrometry selected from methyl esters, benzyl esters, tert-butyl esters, ML mother lye silyl esters, orthoesters, and oxazoline. MS mass spectromtry 0056. Examples for phosphate protecting groups are NMR nuclear magnetic resonance 2-cyanoethyl and methyl (Me) Pd dba tris(dibenzylideneacetone)dipalladium 0057. As used herein, the term “composition' is intended TEA triethylamine to encompass a product comprising the claimed compounds TFA trifluoroacetic acid in the therapeutically effective amounts, as well as any prod THF tetrahydrofuran uct which results, directly or indirectly, from combinations of TLC thin layer chromatography the claimed compounds. TMSCN trimethylsilyl cyanide

Carriers and Additives for Galenic Formulations: SUMMARY OF THE INVENTION 0058. Thus, for liquid oral preparations, such as for 0065 According to the invention there are provided a example, Suspensions, elixirs and solutions, Suitable carriers compound of formula (I): and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for Solid oral preparations such as, for example, (I) powders, capsules, gelcaps and tablets, Suitable carriers and additives include starches, Sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Z RY XM 0059 Carriers, which can be added to the mixture, include R11 N Ny necessary and inert pharmaceutical excipients, including, but not limited to, Suitable binders, Suspending agents, lubricants, flavorants, Sweeteners, preservatives, coatings, disintegrating or a pharmaceutically acceptable salt, Solvate or polymorph agents, dyes and coloring agents. thereof, including all tautomers and stereoisomers thereof 0060 Soluble polymers as targetable drug carriers can wherein: include polyvinylpyrrolidone, pyran copolymer, polyhydrox I0066) R' represents heteroaryl, -carbocyclyl-heteroaryl, ypropylmethacrylamidephenol, polyhydroxyethylasparta —Calkenylheteroaryl, -Calkylheteroaryl, or (CH) mide-phenol, or polyethyleneoxidepolyllysine substituted CRR (CH), heteroaryl wherein a and b independently with palmitoyl residue. Furthermore, the compounds of the represent integers 0-5 provided that a+b=0-5 and RandR present invention may be coupled to a class of biodegradable are alkylene which together with the carbon to which they polymers useful in achieving controlled release of a drug, for are attached form a C-C cycloalkyl group: example, polyactic acid, polyepsilon caprolactone, polyhy 0067 in which any of aforesaid heteroaryl groups may droxybutyeric acid, polyorthoesters, polyacetals, polydihy optionally be substituted by one or more groups selected US 2011/00925O1 A1 Apr. 21, 2011

from C-alkyl, C2-alkenyl, C2-alkynyl, Chaloalkyl, by one or more groups selected from methyl, phenyl, —Cathioalkyl, -SOC-alkyl, -SOC-alkyl, Oxo, halogen, hydroxyl and Calkoxy: Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, R represents H, —Calkyl or aryl; —SOC scycloalkyl, -SOC cycloalkyl, Calk 0.074 enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) 0075 in which aforesaid aryl may optionally be substi OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, tuted by one or more groups selected from Calkyl, cyano, hydroxyl, —C(O)OH, -NH2, —NHC alkyl, Calkenyl, C-alkynyl. —O—C-scycloalkyl, —N(Calkyl)(Calkyl). —C(O)N(Calkyl)(C. C-scycloalkyl, -SOC-scycloalkyl, -SOC-cy 4alkyl). —C(O)NH2. —C(O)NH(Calkyl) and cloalkyl, Calkenyloxy-, Calkynyloxy-, -C(O)Cl. —C(O)NH(Cocycloalkyl); 6alkyl, —C(O)OC-alkyl, Calkoxy-C-alkyl-, nitro, 0068 and in which any of aforesaid carbocyclyl groups halogen, cyano, hydroxyl. —C(O)CH, -NH2, may optionally be substituted by one or more groups —NHC alkyl, - N(Calkyl)(Calkyl), —C(O)N Selected from Calkyl, Oxo, halogen and Calkoxy; (Calkyl)(Calkyl), —C(O)NH2. —C(O)NH(C- 0069 R represents H, Cisalkyl, aryl, heteroaryl, car 4alkyl) and, —C(O)NH(Cocycloalkyl); bocyclyl, heterocyclyl. —Calkylaryl, -Calkylhet eroaryl, -Calkylcarbocyclyl or —Calkylheterocy (0076) or R and Rare joined to form a carbocyclyl ring clyl; which is optionally substituted by one or more C-alkyl 0070 in which any of aforesaid aryl and heteroaryl groups; groups may optionally be substituted by one or more 10077 or R and Rare joined to form a carbocyclyl ring groups selected from Cigalkyl, C2-galkenyl, C2-galky which is fused to phenyl, wherein aforesaid carbocyclyl nyl, Chaloalkyl, -Cathioalkyl, -SOC-alkyl, and/or phenyl may optionally be substituted by one or more —SOC alkyl, Calkoxy-, -O-C-scycloalkyl, groups selected from Calkyl, halogen and Calkoxy; C-scycloalkyl, -SOC-scycloalkyl, -SOC-cy (0078 or R and Rare joined to form a carbocyclyl ring cloalkyl, Calkenyloxy-, Calkynyloxy-, -C(O)Cl. which is fused to monocyclic heteroaryl, whereinaforesaid 6alkyl, —C(O)OC-alkyl, Calkoxy-C-alkyl-, carbocyclyl and/or heteroaryl may optionally be substi Calkoxy-Calkoxy-, nitro, halogen, haloCalkyl, tuted by one or more groups selected from Calkyl, halo haloCalkoxy, cyano, hydroxyl. —C(O)OH, -NH2, gen and Calkoxy, —NHC alkyl, -N (Calkyl)(Calkyl, —N(C. 4alkyl)(Calkyl)-N(Calkyl)(Calkyl). —C. (0079 X represents C—O, O, S, CR7R, —O—CH2—, or 4alkyl-N(Calkyl)(Calkyl). —Caalkoxy-N(C. —CH2—CH2—, 4alkyl)(Calkyl). —N(C-cycloalkyl)(C- 0080 Y represents CHR, C=O or C–S: scycloalkyl). —N(—Calkyl-Calkoxy)(—C. I0081 Z represents - N-R, O or CHR', such that when 6alkyl-Calkoxy), —C(O)N(Calkyl)(Calkyl). X represents O or S. Z must represent CHR'. - C(O)NH2, C(O)NH(Calkyl) and C(O)NH (Calocycloalkyl); I0082 or X and Z represent two adjacent carbonatoms of a 0071 and in which any of aforesaid carbocyclyl and phenyl ring which is fused in that position and which is heterocyclyl groups may optionally be substituted by optionally Substituted by one or more halogen or C-alkyl one or more groups selected from Calkyl, oxo, halo groups; gen, —C(O)Calkyl and Calkoxy; I0083) R' represents H, -C(O)Calkyl or -NH: I0072 or R represents phenyl substituted by phenyl, phe 10084) R' and Rindependently represent H, C, alkyl nyl Substituted by a monocyclic heteroaryl group, phenyl or aryl; substituted by phenoxy, phenyl substituted by heterocy 0085 in which said aforesaid aryl may be optionally clyl phenyl substituted by heterocyclyl wherein said het Substituted by Calkyl, Calkenyl, C-alkynyl, erocyclyl is substituted by phenyl, phenyl substituted by —SOC alkyl, Calkoxy-, -O-C-scycloalkyl, —O—Calkyl-heterocyclyl phenyl Substituted by ben C-scycloalkyl, -SOCscycloalkyl, -SOC-cy Zyloxy, phenyl substituted by carbocyclyl phenyl substi cloalkyl, Calkenyloxy-, Calkynyloxy-, -C(O)Cl. tuted by carbocyclyl wherein said carbocyclyl is substi tuted by heterocyclyl phenyl substituted by 6alkyl, —C(O)OC-alkyl, Calkoxy-C-alkyl-, nitro, —O-carbocyclyl, heterocyclyl substituted by phenyl, car halogen, cyano, hydroxyl. —C(O)CH, -NH2, bocyclyl substituted by phenyl, phenyl fused to carbocy —NHC alkyl, - N(Calkyl)(Calkyl), —C(O)N clyl phenyl fused to heterocyclyl. —Calkyl(phenyl Sub (Calkyl)(Calkyl), —C(O)NH2. —C(O)NH(C. stituted by phenyl), —Calkyl(phenyl Substituted by a 4alkyl) and, —C(O)NH(Cocycloalkyl); monocyclic heteroaryl group), —Calkyl(phenyl substi 0086 RandR' independently represent H or methyl: tuted by a monocyclic heterocyclyl group), —Calkyl provided that the moiety —Y—Z—X— represents a moiety (phenyl substituted by an —O-carbocyclyl group), —C. other than–C(=O) N(-R) C(=O)– or -C(=S) 4alkyl(phenyl Substituted by benzyloxy), —Calkyl N(-R) C(=O)-. (optionally substituted phenyl fused to optionally Substituted carbocyclyl or —Calkyl (optionally Substi I0087. Other objects and features will be in part apparent tuted phenyl fused to optionally substituted heterocyclyl); and in part pointed out hereinafter. 0073 in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one DETAILED DESCRIPTION OF THE INVENTION or more groups selected from Calkyl, halogen and Calkoxy, and in which any of aforesaid carbocyclyl I0088. In one particular embodiment of the invention, there and heterocyclyl groups may optionally be substituted is provided a compound of formula (I): US 2011/00925O1 A1 Apr. 21, 2011

phenyl fused to optionally Substituted carbocyclyl or—C. 4alkyl (optionally substituted phenyl fused to optionally (I) substituted heterocyclyl); 0.096 in which any of aforesaid phenyl, benzyloxy and heteroaryl groups may optionally be substituted by one Z RY XM or more groups selected from Calkyl, halogen and R11 N Ny Calkoxy, and in which any of aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl, phenyl, or a pharmaceutically acceptable salt, Solvate or polymorph OXO, halogen and Caalkoxy. thereof, including all tautomers and stereoisomers thereof 0097 R represents H, -Calkyl or aryl; wherein: 0.098 in which aforesaid aryl may optionally be substi I0089) R' represents heteroaryl, -carbocyclyl-heteroaryl, tuted by one or more groups selected from Calkyl, —Calkenylheteroaryl, -Calkylheteroaryl, or (CH2) C2-galkenyl, C2-alkynyl, Chaloalkyl, -C-thio CRR (CH), heteroaryl wherein a and b independently alkyl, -SOC alkyl, -SOC-alkyl, Calkoxy-, represent integers 0-5 provided that a+b=0-5 and RandR —O—Cecycloalkyl, Cecycloalkyl, -SOC-scy are alkylene which together with the carbon to which they cloalkyl, -SOC-cycloalkyl, Calkenyloxy-, are attached form a C-C cycloalkyl group; Calkynyloxy-, -C(O)Calkyl, —C(O)OC-alkyl, 0090 in which any of aforesaid heteroaryl groups may Calkoxy-C-alkyl-, nitro, halogen, cyano, hydroxyl, optionally be substituted by one or more groups selected —C(O)CH, NH, -NHC alkyl, - N(Calkyl) from C-alkyl, C2-alkenyl, C2-alkynyl, Chaloalkyl, (Calkyl). —C(O)N(Calkyl)(Calkyl). —C(O) —Cathioalkyl, -SOC-alkyl, -SOC-alkyl, NH, —C(O)NH(Calkyl) and, —C(O)NH(Cocy Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, cloalkyl); —SOCscycloalkyl, -SOC-cycloalkyl, Calk (0099 or Rand Rare joined to form a carbocyclyl ring enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) which is optionally Substituted by one or more C-alkyl OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, groups; cyano, hydroxyl, —C(O)OH, -NH. NHC alkyl, I0100 or R and Rare joined to form a carbocyclyl ring —N(Calkyl)(Calkyl). —C(O)N(Calkyl)(C. which is fused to phenyl, wherein aforesaid carbocyclyl 4alkyl), C(O)NH, C(O)NH(Calkyl) and and/or phenyl may optionally be substituted by one or more —C(O)NH(Cocycloalkyl); groups selected from Calkyl, halogen and Calkoxy; 0091 and in which any of aforesaid carbocyclyl groups 10101 or R and Rare joined to form a carbocyclyl ring may optionally be substituted by one or more groups which is fused to monocyclic heteroaryl, whereinaforesaid selected from Calkyl, Oxo, halogen and Calkoxy: carbocyclyl and/or heteroaryl may optionally be substi 0092 R represents H, Cisalkyl, aryl, heteroaryl, car tuted by one or more groups selected from Calkyl, halo bocyclyl, heterocyclyl. —Calkylaryl, -Calkylhet gen and Calkoxy, eroaryl. —Calkylcarbocyclyl or —Calkylheterocy 0102 X represents C—O, O, S, CR7R, —O—CH2—, or clyl; —CH2—CH2—, 0093 in which any of aforesaid aryl and heteroaryl (0103 Y represents CHR, C=O or C–S: groups may optionally be substituted by one or more 0104 Z represents-N-R, O or CHR', such that when groups selected from Cigalkyl, C2-galkenyl, C2-galky X represents O or S. Z must represent CHR': nyl, Chaloalkyl, -SOC-alkyl, -SOC alkyl, 0105 or X and Z represent two adjacent carbonatoms of a Calkoxy-, -O-C scycloalkyl, C-scycloalkyl, phenyl ring which is fused in that position and which is —SOCscycloalkyl, -SOC-cycloalkyl, Calk optionally substituted by one or more halogen or C-alkyl enyloxy-, Calkynyloxy-, -C(O)Calkyl, —C(O) groups; OC-alkyl, Calkoxy-C-alkyl-, nitro, halogen, I0106) R' represents H, C-alkyl, -C(O)Calkyl or haloCalkyl, haloCalkoxy, cyano, hydroxyl, —NH; —C(O)CH, NH, -NHC alkyl, - N(Calkyl) I0107 R and Rindependently represent H, C, alkyl (Calkyl). —C(O)N(Calkyl)(Calkyl). —C(O) or aryl; NH, —C(O)NH(Calkyl) and —C(O)NH(Cocy 0.108 in which said aforesaid aryl may be optionally cloalkyl); Substituted by Calkyl, Calkenyl, C-alkynyl, 0094) and in which any of aforesaid carbocyclyl and Chaloalkyl, —C-thioalkyl, -SOC-alkyl, heterocyclyl groups may optionally be substituted by —SOC alkyl, Calkoxy-, -O-C-scycloalkyl, one or more groups selected from Calkyl, oxo, halo C-scycloalkyl, -SOC-scycloalkyl, -SOC-cy gen and Calkoxy. cloalkyl, Calkenyloxy-, Calkynyloxy-, -C(O)Cl. 0095 or R represents phenyl substituted by phenyl, phe 6alkyl, —C(O)OC-alkyl, Calkoxy-C-alkyl-, nitro, nyl Substituted by a monocyclic heteroaryl group, phenyl halogen, cyano, hydroxyl. —C(O)OH, -NH2, substituted by phenoxy, phenyl substituted by heterocy —NHC alkyl, - N(Calkyl)(Calkyl), —C(O)N clyl phenyl Substituted by —O—Calkyl-heterocyclyl, (Calkyl)(Calkyl), —C(O)NH2. —C(O)NH(C. phenyl substituted by benzyloxy, phenyl fused to carbocy 4alkyl) and, —C(O)NH(Cocycloalkyl); clyl phenyl fused to heterocyclyl. —Calkyl(phenyl Sub 0109 RandR' independently represent H or methyl: stituted by phenyl), —Calkyl(phenyl Substituted by a provided that the moiety —Y—Z—X— represents a moiety monocyclic heteroaryl group), —Calkyl(phenyl Substi other than–C(=O) N(-R) C(=O)– or –C(=S) tuted by benzyloxy), —Calkyl (optionally substituted N(-R) C(=O)-. US 2011/00925O1 A1 Apr. 21, 2011

0110. When carbocyclyl and heterocyclyl are substituted, from alkyl (e.g. Calkyl Such as Me), alkoxy- (e.g. Ca they are typically substituted by 1 or 2 substituents (e.g. 1 alkoxy- Such as OMe) and halogen (e.g. F). A suitable het substituent). Typically the substituent is methyl. More typi eroaryl group is imidazolyl, particularly imidazol-1-yl. An cally carbocyclyl and heterocyclyl groups are unsubstituted. exemplary -alkenylheteroaryl group is 3-imidazol-1-yl-prop 0111. When aryl and heteroaryl are substituted, they are 2-enyl-. typically substituted by 1, 2 or 3 (e.g. 1 or 2) substituents. I0115. When R' represents - Calkylheteroaryl, Substituents for aryl and heteroaryl are selected from Calkyl (e.g. methyl), Calkenyl (e.g. buten-3-yl), examples of C alkyl include Cisalkyl or Calkyl, espe Calkynyl (e.g. butyn-3-yl), Chaloalkyl (e.g. fluorom cially C-salkyl or C alkyl, in particular propyl, and ethyl, trifluoromethyl), —Cathioalkyl (e.g. —S-methyl), examples of heteroaryl groups include monocyclic (e.g. 5 or —SOC-alkyl (e.g. —SOmethyl), —SOC-alkyl (e.g. 6 membered, particularly 5 membered) rings especially rings —SO-methyl), Calkoxy- (e.g. methoxy, ethoxy), containing nitrogen atoms e.g. 1 or 2 nitrogen atoms. Afore —O—C-scycloalkyl (e.g. —O-cyclopentyl), Cscycloalkyl mentioned heteroaryl groups may either be unsubstituted (e.g. cyclopropyl, cyclohexyl). —SOC scycloalkyl (e.g. (which is most typical) or may suitably be substituted by one —SOcyclohexyl), —SOC cycloalkyl (e.g. —SOcyclo or more (e.g. 1 or 2) Substituents selected from alkyl (e.g. Ca propyl), Calkenyloxy- (e.g. —O-buten-2-yl), C-alkyny alkyl Such as Me), alkoxy- (e.g. C. alkoxy- Such as OMe) loxy- (e.g. —O-buten-2-yl), —C(O)Calkyl (e.g. —C(O) and halogen (e.g. F). A Suitable heteroaryl group is imidazol ethyl), —C(O)OC-alkyl (e.g. —C(O)O-methyl), 1-yl. A particularly suitable -alkylheteroaryl group is 3-imi Calkoxy-C-alkyl- (e.g. methoxy-ethyl-), nitro, halogen dazol-1-yl-propyl-. (e.g. fluoro, chloro, bromo), cyano, hydroxyl. —C(O)OH, I0116. When R' represents - Calkylheteroaryl, —NH, -NHC alkyl (e.g. - NHmethyl), N(Calkyl) examples wherein alkyl is branched include: (Calkyl) (e.g. —N(methyl)), —C(O)N(Calkyl)(C- 4alkyl)(e.g. —C(O)N(methyl)), —C(O)NH2. —C(O)NH (Calkyl) (e.g. —C(O)NHmethyl), —C(O)NH(C. 1scycloalkyl)(e.g. —C(O)NHcyclopropyl). More typically, Substituents will be selected from Calkyl (e.g. methyl), Chaloalkyl (e.g. Co-fluoroalkyl, e.g. CFs). Cigalkoxy (e.g. OMe), halogen and hydroxy. Cl); (1) I0112. When R' represents heteroaryl, examples include monocyclic (e.g. 5 and 6 membered) and bicyclic (e.g. 9 and 10 membered, particularly 9 membered) heteroaryl rings, especially rings containing nitrogen atoms (e.g. 1 or 2 nitro (1) CX), gen atoms). A suitable bicyclic heteroaryl ring is a 9-mem bered heteroaryl ring containing 1 or 2 nitrogen atoms, espe 0117. When R' represents (CH) CRR (CH), het cially a benzene ring fused to a 5-membered ring containing eroaryl whereina and b independently represent integers 0-5 one or two nitrogen atoms (e.g. 1 H-benzoimidazolyl). Most provided that a+b=0-5 and R and R are alkylene which Suitably the point of attachment is through a benzenering, e.g. together with the carbon to which they are attached form a the group is 1H-benzoimidazol-5-yl. Aforementioned het C-C cycloalkyl group, examples include: eroaryl groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g. 1 or 2) Substituents selected from alkyl (e.g. C. alkyl Such as Me), alkoxy- (e.g. C. alkoxy- Such as OMe) and halogen (e.g. F). I0113. When R' represents—Cls-carbocyclyl-heteroaryl, examples of carbocyclyl include cycloalkyl (e.g. cyclohexyl) and cycloalkenyl (e.g. cyclohexenyl), examples of heteroaryl groups include monocyclic (e.g. 5 or 6 membered, particu 10118 Particular examples of R' heteroaryl groups include larly 5 membered) rings especially rings containing nitrogen a 5-membered ring containing 2 or 3 nitrogen atoms, which atoms e.g. 1 or 2 nitrogen atoms. Aforementioned heteroaryl ring may optionally be substituted (e.g. in particular by one or groups may either be unsubstituted (which is more typical) or two groups, such as methyl, for example: may suitably be substituted by one or more (e.g. 1 or 2) Substituents selected from alkyl (e.g. C. alkyl Such as Me), alkoxy- (e.g. Calkoxy- such as OMe) and halogen (e.g. F). A suitable heteroaryl group is imidazol-1-yl. An exemplary —Cs-carbocyclyl-heteroaryl group is 3-imidazol-1-yl-cy clohexyl-. I0114) When R' represents - Coalkenyheteroaryl, examples of Calkenyl include Calkenyl, in particular propenyl and examples of heteroaryl groups include mono cyclic (e.g. 5 or 6 membered, particularly 5 membered) rings especially rings containing nitrogenatoms e.g. 1 or 2 nitrogen atoms. Aforementioned heteroaryl groups may either be unsubstituted (which is more typical) or may suitably be substituted by one or more (e.g. 1 or 2) substituents selected US 2011/00925O1 A1 Apr. 21, 2011

luoromethyl)phenyl-, 4-chloro-3-methylphenyl, -continued 4-chlorophenyl-, 4-fluorophenyl- and 4-propoxyphenyl-. (0123. When R represents optionally substituted aryland aryl represents naphthyl, examples include unsubstituted naphthyl (e.g. naphthalen-1-yl, naphthalen-2-yl, naphthalen 3-yl) as well as Substituted naphthyl (e.g. 4-methyl-naphtha sy len-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen 3-y- and 4-fluoro-naphthalen-2-yl-). (0.124. When R represents optionally substituted het I0119) Other examples of R' heteroaryl groups include a eroaryl, examples include monocyclic rings (e.g. 5 or 6 mem 9-membered bicyclic ring containing 2 nitrogenatoms, which bered rings) and bicyclic rings (e.g. 9 or 10 membered rings) ring may optionally be substituted, for example: which may optionally be substituted. Example 5 membered rings include pyrrolyl (e.g. pyrrol-2-yl) and imidazolyl (e.g. 1H-imidazol-2-yl or 1H-imidazol-4-yl), pyrazolyl (e.g. 1H-pyrazol-3-yl), furanyl (e.g. furan-2-yl), thiazolyl (e.g. thiazol-2-yl), thiophenyl (e.g. thiophen-2-yl, thiophen-3-yl). Example 6 membered rings include pyridinyl (e.g. pyridin (CO - KDOX 2-yland pyridin-4-yl). Specific Substituents that may be men tioned are one or more e.g. 1, 2 or 3 groups selected from X = O, S halogen, hydroxyl, alkyl (e.g. methyl) and alkoxy- (e.g. meth oxy-). Example substituted 5 membered rings include 4.5- dimethyl-furan-2-yl-, 5-hydroxymethyl-furan-2-yl-, 5-me thyl-furan-2-yl- and 6-methyl-pyridin-2-yl-. An example CC (IC Substituted 6-membered ring is 1-oxy-pyridin-4-yl-. Example 9 membered rings include 1H-indolyl (e.g. 1H-in dol-3-yl, 1H-indol-5-yl), benzothiophenyl (e.g. benzob. 0120 Clearly, the heteroaryl groups shown above may thiophen-3-yl, particularly 2-benzobthiophen-3-yl), benzo also be present as part of a larger R' function such as —Cs. 1,2,5-oxadiazolyl (e.g. benzo 1,2,5-oxadiazol-5-yl), 8-carbocyclyl-heteroaryl, -Calkenylheteroaryl or —C. benzo 1,2,5-thiadiazolyl (e.g. benzo[1,2,5-thiadiazol-5-yl, 6alkylheteroaryl. benzo 1,2,5thiadiazol-6-yl). Example 10 membered rings I0121) When R represents - Cisalkyl, examples include include quinolinyl (e.g. quinolin-3-yl, quinolin-4-yl, quino methyl, ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g. lin-8-yl). Specific substituents that may be mentioned are one n-butyl-sec-butyl, isobutyl and tert-butyl), pentyl (e.g. n-pen or more e.g. 1, 2 or 3 groups selected from halogen, hydroxyl, tyl, 3.3-dimethylpropyl), hexyl, heptyl and octyl. alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-). Example I0122) When R represents optionally substituted aryl, aryl substituted 9-membered rings include 1-methyl-1H-indol-3- may typically represent phenyl. Exemplary Substituted phe y1. 2-methyl-1H-indol-3-yl, 6-methyl-1H-indol-3-yl. nyl groups include 3-methylphenyl-, 2,3-dichlorophenyl-, Example substituted 10 membered rings include 2-chloro 2,3-difluorophenyl-, 2,4-dichlorophenyl-, 2,4-difluororophe quinolin-3-yl, 8-hydroxy-quinolin-2-yl, oxo-chromenyl (e.g. nyl-, 2,4-dimethoxyphenyl-, 2,4-dimethylphenyl-, 2,4-bis 4-oxo-4H-chromen-3-yl) and 6-methyl-4-oxo-4H-chromen (trifluoromethyl)phenyl-, 2,4,6-trifluorophenyl-, 2,4,6-trim 3-yl. ethylphenyl-, 2,6-dichlorophenyl-, 2,6-difluorophenyl-, 2,6- (0.125. When R represents carbocyclyl, examples include dimethoxyphenyl-, 2,6-difluoro-4-(methoxy)phenyl-, cycloalkyl and cycloalkenyl. Examples of cycloalkyl include 2-isopropyl-6-methylphenyl-, 3-(cyclopentyloxy)-4-meth cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo oxyphenyl-, 3,4,5-trimethoxyphenyl-, 3,4-dimethoxyphe heptyl. Examples of cycloalkenyl include cyclohexenyl (e.g. nyl-, 3,4-dichlorophenyl-, 3,4-difluorophenyl-, 3,4-dimeth cyclohex-2-enyl, cyclohex-3-enyl). Examples of substituted ylphenyl-, 3,4,5-trifluorophenyl-, 3.5-bis(trifluororomethyl) carbocyclyl include 2-methyl-cyclohexyl-, 3-methyl-cyclo phenyl-, 3,5-dimethoxyphenyl-, 2-methoxyphenyl-, hexyl-, 4-methyl-cyclohexyl-, 2-methyl-cyclohex-2-enyl, 3-methoxyphenyl-, 4-(trifluoromethyl)phenyl-, 4-bromo-2- 2-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl, 3-me (trifluoromethyl)phenyl-, 4-bromophenyl-, 4-chloro-3-(trif thyl-cyclohex-3-enyl. luoromethyl)phenyl-, 4-chlorophenyl-, 4-cyanophenyl-, I0126. When R represents heterocyclyl (which may 4-ethoxyphenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4-isopro optionally be substituted), examples include tetrahydrofura pylphenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4-pro nyl, morpholinyl, piperidinyl, 3,4-dihydro-2H-pyranyl, pyr poxyphenyl-, 4-butoxyphenyl-, 4-pentoxyphenyl-, 4-isopro rolidinyl, methyltetrahydrofuranyl- (e.g. 5-methyltetrahy pyloxyphenyl-, 4-tetrafluoroethyloxyphenyl-. Alternatively, drofuran-2-yl-). R may represent unsubstituted phenyl-. Further exemplary I0127. When R represents —Calkylaryl, examples Substituted phenyl groups include 2,3,4-trifluorophenyl, 2.3- include -alkyl(substituted phenyl) e.g. in which phenyl is difluoro-4-methylphenyl, 2-bromo-4-fluorophenyl-, Substituted by one or more groups selected from alkyl, fluo 2-bromo-5-fluorophenyl-, 2-chlorophenyl-, 2-fluorophenyl-, roalkyl, halogen and alkoxy (e.g. methyl, trifluoromethyl, 2-fluoro-5-(trifluoromethyl)phenyl-, 2-hydroxy-3-methox tert-butyl, chloro, fluoro and methoxy) and, for example, yphenyl-, 2-hydroxy-5-methylphenyl-, 3-chlorophenyl-, alkyl is C alkyl. Another specific group is -alkyl (bicyclic 3-fluorophenyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, aryl) e.g. wherein bicyclic aryl is optionally substituted naph 3-fluoro-5-(trifluoromethyl)phenyl-, 2-fluoro-4-(trifluorom thyl. A further specific group is benzyl. ethyl)phenyl-, 3-fluoro-4-(methoxy)phenyl-, 3-hydroxy-4- I0128. When R represents—Calkylheteroaryl in which methoxyphenyl-, 4-bromo-2-fluorophenyl, 4-chloro-3-(trif heteroaryl is optionally substituted, examples include meth US 2011/00925O1 A1 Apr. 21, 2011 ylheteroaryland -ethylheteroaryl (e.g. 1-heteroarylethyl- and 4-benzyloxy-phenyl-methyl-, 4-(3-methylbenzyloxy)phe 2-heteroarylethyl-), -propylheteroaryl and -butylheteroaryl nyl-methyl- and 4-(4-methylbenzyloxy)phenyl-methyl-. in which heteroaryl is optionally substituted. Specific I0140. When R represents —Calkyl(optionally substi examples of -alkylheteroaryl groups include pyridinylm tuted phenyl fused to optionally substituted carbocyclyl), ethyl-, N-methyl-pyrrol-2-methyl-N-methyl-pyrrol-2-ethyl-, examples include indanyl-methyl- (e.g. indan-4-yl-methyl-, N-methyl-pyrrol-3-methyl-, N-methyl-pyrrol-3-ethyl-, 2-methyl-indan-4-yl-methyl-), indenyl-methyl- and tetrali 2-methyl-pyrrol-1-methyl-, 2-methyl-pyrrol-1-ethyl-, 3-me nyl-methyl-. thyl-pyrrol-1-methyl-, 3-methyl-pyrrol-1-ethyl-, 4-pyridino I0141 When R represents —Calkyl(optionally substi methyl-, 4-pyridino-ethyl-, 2-(thiazol-2-yl)-ethyl-, 2-ethyl tuted phenyl fused to optionally substituted heterocyclyl); indol-1-methyl-, 2-ethyl-indol-1-ethyl-, 3-ethyl-indol-1- examples include benzo. 1.3dioxo-4-yl-methyl- and 2,3-di methyl-, 3-ethyl-indol-1-ethyl-, 4-methyl-pyridin-2-methyl-, hydro-benzo 1.4 dioxin-4-yl-methyl-. 4-methyl-pyridin-2-yl-ethyl-, 4-methyl-pyridin-3-methyl-, I0142. When R represents - Calkyl, examples include 4-methyl-pyridin-3-ethyl-. methyl, ethyl, propyl (e.g. n-propyl, isopropyl)and butyl (e.g. 0129. When R represents —Calkyl-carbocyclyl n-butyl-sec-butyl, isobutyl and tert-butyl). (which may optionally be substituted), examples include I0143. When R represents optionally substituted aryl, aryl -methyl-cyclopentyl, -methyl-cyclohexyl, -ethyl-cyclohexyl, may typically represent phenyl. Exemplary Substituted phe -propyl-cyclohexyl, -methyl-cyclohexenyl, -ethyl-cyclohex nyl groups include 2,4-dichlorophenyl-, 2,4-difluororophe enyl, -methyl(4-methylcyclohexyl) and -propyl (3-methylcy nyl-, 2,4-dimethoxyphenyl-, 2,4-dimethylphenyl-, 2,4-bis clyohexyl). (trifluoromethyl)phenyl-, 2,4,6-trifluorophenyl-, 2.4.6- I0130. When R represents —Calkylheterocyclyl trimethylphenyl-, 2,6-dichlorophenyl-, 2,6-difluorophenyl-, (which may optionally be substituted); examples include 2,6-dimethoxyphenyl-, 2-isopropyl-6-methylphenyl-, 3-(cy -methyl-tetrahydrofuranyl (e.g. -methyl-tetrahydrofuran-2- clopentyloxy)-4-methoxyphenyl-, 3,4,5-trimethoxyphenyl-, yl, -methyl-tetrahydrofuran-3-yl), -ethyl-tetrahydrofuranyl, 3,4-dimethoxyphenyl-, 3,4-dichlorophenyl-, 3,4-dimeth -methyl-piperidinyl. ylphenyl-, 3,4,5-trifluorophenyl-, 3,5-bis(trifluororomethyl) I0131 When R represents phenyl substituted by phenyl or phenyl-, 3,5-dimethoxyphenyl-, 3-methoxyphenyl-, 4-(trif phenyl Substituted by a monocyclic heteroaryl group, in luoromethyl)phenyl-, 4-bromo-2-(trifluoromethyl)phenyl-, which any of aforesaid phenyl and heteroaryl groups may 4-bromophenyl-, 4-chloro-3-(trifluoromethyl)phenyl-, optionally be substituted, typically the phenyl ring connected 4-chlorophenyl-, 4-cyanophenyl-, 4-ethoxyphenyl-, 4-eth directly to the nitrogen atom is unsubstituted and the terminal ylphenyl-, 4-fluorophenyl-, 4-isopropylphenyl-, 4-methox phenyl ring or the monocyclic heteroaryl ring is optionally yphenyl-. Alternatively, R may represents unsubstituted phe Substituted by one, two or three Substitutents (e.g. one or two, nyl-. Further exemplary Substituted phenyl groups include e.g. one). Typically the terminal phenyl or monocyclic het 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-chlo eroaryl group is unsubstituted. Typically the terminal phenyl rophenyl-, 2-fluoro-5-(trifluoromethyl)phenyl-, 2-hydroxy or monocyclic heteroaryl group Substitutes the other phenyl 3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-chlo group at the 4-position. rophenyl-, 3-fluoro-4-(trifluoromethyl)phenyl-, 3-hydroxy (0132) When R represents phenyl substituted by phenyl in 4-methoxyphenyl-, 4-chloro-3-(trifluoromethyl)phenyl-, which any of aforesaid phenyl groups may optionally be 4-chlorophenyl-, 4-fluorophenyl- and 4-propoxyphenyl-. Substituted, examples include -biphenyl-4-yl. I0144) When R and R are joined to form a carbocyclyl I0133. When R represents phenyl substituted by a mono ring, which is optionally Substituted by one or more C-alkyl cyclic heteroaryl group, in which any of aforesaid phenyland groups, examples include cycloalkyl (e.g. cyclopropyl, cyclo heteroaryl groups may optionally be substituted, examples pentyl and cyclohexyl) and cycloalkenyl (e.g. cyclohexenyl). include 4-(oxazol-5-yl)phenyl-. (0145 When R and R are joined to form a carbocyclyl I0134) When R represents phenyl substituted by benzy ring which is fused to phenyl; examples include indanyl (e.g. loxy in which any of aforesaid phenyl and benzyloxy groups indan-2-yl) and tetralinyl. may optionally be substituted, examples include 4-benzy I0146 When R and R are joined to form a carbocyclyl loxy-phenyl-, 4-(3-methylbenzyloxy)phenyl- and 4-(4-meth ring which is fused to monocyclic heteroaryl; examples ylbenzyloxy)phenyl-. include 5-membered carbocyclyl fused to 6-membered het eroaryl, 6-membered carbocyclyl fused to 6-membered het 0135) When R represents optionally substituted phenyl eroaryl, 5-membered carbocyclyl fused to 5-membered het fused to optionally substituted carbocyclyl, examples include eroaryl and 6-membered carbocyclyl fused to 5-membered indanyl (e.g. indan-4-yl-, 2-methyl-indan-4-yl-), indenyl and heteroaryl. The monocyclic heteroaryl to which carbocyclyl tetralinyl. is fused contains at least one heteroatom (e.g. one, two or I0136. When R represents optionally substituted phenyl three heteroatoms, e.g. one or two, e.g. one heteroatom). fused to optionally substituted heterocyclyl, examples 10147 When R represents - Cisalkyl examples include include benzo. 1.3dioxo-4-yl- and 2,3-dihydro-benzo 1.4 methyl, ethyl, propyl (e.g. n-propyl, isopropyl), butyl (e.g. dioxin-4-yl-. n-butyl-sec-butyl, isobutyl and tert-butyl), pentyl (e.g. n-pen 0137 When R represents - Calkyl(phenyl substituted tyl, 3.3-dimethylpropyl), hexyl, heptyl and octyl. by phenyl), examples include biphenyl-4-yl-methyl-. 10148 When R represents —C(O)Calkyl; examples I0138. When R represents - C, alkyl(phenyl substituted include —C(O)C alkyl such as —C(O)methyl, —C(O) by a monocyclic heteroaryl group), examples include 4-(OX ethyl, —C(O)propyl and —C(O)butyl. azol-5-yl)phenyl-methyl-. 10149 Suitably, R' represents heteroaryl or - Calkyl I0139 When R represents - C, alkyl(phenyl substituted heteroaryl. by benzyloxy) in which any of aforesaid phenyl and benzy I0150. In one embodiment, R' represents heteroaryl. In a loxy groups may optionally be substituted, examples include further embodiment, R' represents unsubstituted heteroaryl US 2011/00925O1 A1 Apr. 21, 2011

or heteroaryl optionally Substituted by one or more C alkyl wherein B represents a bond, —CH2—, —CH2—CH2—, (e.g. methyl), halogen (e.g. fluorine) or Chaloalkyl (e.g. CH(Me) -, -CH(Me) CH or -CH-CH(Me) trifluoromethyl) groups. In another embodiment, R' repre and sents —Calkylheteroaryl. 0151. When R' represents heteroaryl, R' suitably repre R'' and R' independently represent H, C-alkyl (e.g. sents bicyclic heteroaryl, especially 9-membered bicyclic methyl), halogen (e.g. fluorine) or Chaloalkyl (e.g. trifluo heteroaryl. More suitably, R' represents a bicyclic heteroaryl romethyl). ring system and in particular a phenyl ring fused with a 5 (O155 In a third embodiment, R' represents membered heteroaryl ring containing one or more (e.g. one or two, Suitably one, more Suitably two) nitrogen atoms or a pyridine ring fused with a 5-membered heteroaryl ring con taining one or more (e.g. one or two, Suitably one, more suitably two) nitrogen atoms. When R' represents bicyclic heteroaryl, preferably the heteroaryl group does not contain S e-8- rh atoms. When R' represents a phenyl ring fused to a 5-mem R17 bered heteroaryl ring, preferably R' is linked to the core of formula (I) through the phenyl ring. When R' represents a pyridine ring fused to a 5-membered heteroaryl ring, prefer wherein C represents a bond, —CH2—, —CH2—CH2—, ably R' is linked to the core of formula (I) through the pyri CH(Me) -, -CH(Me) CH or - CH-CH(Me) dine ring. Suitably R' represents unsubstituted heteroaryl. In and particular, R' suitably represents 1H-benzoimidazolylorimi R'' and R' independently represent H, C-alkyl (e.g. dazol-2-alpyridine, particularly 1H-benzoimidazolyl, espe cially 1H-benzoimidazol-5-yl. methyl), halogen (e.g. fluorine) or Chaloalkyl (e.g. trifluo I0152. When R' represents —C-alkylheteroaryl, het romethyl). eroaryl is suitably monocyclic heteroaryl, especially 5-mem I0156. In a fourth embodiment, R' represents bered monocyclic heteroaryl. More suitably, when R' repre sents —Calkylheteroaryl, heteroaryl is suitably a 5 membered heteroaryl ring containing one or more (e.g. one or D two, Suitably one, more suitably two) nitrogen atoms. When R" represents —Calkylheteroaryl, preferably the het R18 eroaryl group does not contain Satoms. When R' represents (? N —Calkylheteroaryl, heteroaryl represents Substituted or al R19 unsubstituted imidazolyl. In particular, when R' represents —Calkylheteroaryl, heteroaryl Suitably represents Substi tuted or unsubstituted imidazoly-1-yl. When R' represents wherein D represents a bond, —CH2—, —CH2—CH2—, —Calkylheteroaryl and heteroaryl is Substituted imida CH(Me) -, -CH(Me) CH or -CH-CH(Me) Zoly-1-yl, imidazoly-1-yl is suitably substituted by methyl. and 0153. In one embodiment R' represents R" and R' independently represent H, C-alkyl (e.g. methyl), halogen (e.g. fluorine) or Chaloalkyl (e.g. trifluo romethyl); N R11 (O157 Suitably R' represents R12 N Na ar R13 N-s-"N.B R"-( 1. wherein A represents an unbranched Calkylene chain (e.g. N an unbranched Calkylene chain, e.g. an unbranched H R 15 Calkylene chain, e.g. an unbranched C-alkylene chain) or A represents a branched C-alkylene chain (e.g. wherein the one or more (e.g. one or two) branches consist of one or more (e.g. one or two) methyl groups at the same or different 0158. In one embodiment R' represents Hand R' repre positions) or A represents (CH2)CRR (CH), and sents H. In another embodiment R' represents H and R' R'', R'' and R' independently represent H or C-alkyl. represents C-alkyl. In a third embodiment R' represents 0154) In a second embodiment, R' represents Calkyl and R' represents H. In a fourth embodiment R'' represents methyl and R' represents H. In a further embodi ment, R'represents Hor methyland R'represents C-alkyl (e.g. methyl) or halogen (e.g. fluorine). 0159 Suitably B represents a bond, -CH or —CHCH . In one embodiment B represents a bond. (0160. In another embodiment, B represents —CH2—. In a third embodiment, B represents —CH2CH2—. US 2011/00925O1 A1 Apr. 21, 2011 12

(0161 Alternatively R' represents represents C-alkyl. In a third embodiment R' represents Calkyl and R' represents H. In a further embodiment, R'' represents H or methyl and R' represents C-alkyl (e.g. methyl) or halogen (e.g. fluorine). 0172 Suitably D represents a bond, —CH2—, or —CHCH . In one embodiment D represents a bond. In another embodiment, D represents —CH2—. In a third embodiment, D represents —CH2CH2—. (0173 More suitably R' represents R'' suitably represents H, R" suitably represents H or methyl. R" suitably represents H or methyl. s s (0162. In one embodiment of the invention, R' represents H and R' represents methyl. In another embodiment, R' & (CH2)4- or Cl (CH2)4- or represents methyl and R' represents H. In a third embodi ment, R' represents Hand R' represents H. N 0163 Suitably A represents an unbranched Cls alkylene ( chain. In one embodiment. A represents —(CH)—. In N another embodiment. A represents —(CH) . In a third H embodiment. A represents —(CH) . In further embodi ment, A represents —(CH2)5- More Suitably A represents (0174 Yet more suitably R' represents (CH) , —(CH) - or —(CH) . In one embodi ment, A represents —(CH2)—. In another embodiment. A represents —(CH2)4-. (0164. Alternatively. A represents a branched Cls alkylene O chain. ( N N (0165. In one embodiment A does not represent —(CH) N { 2 H 3 * 0166 When A represents a Cls alkylene chain, which is substituted by two alkylene substituents at the same position (0175 Most suitably, R' represents wherein the two alkylene substituents are joined to each other to form a C-s-spiro-cycloalkyl group, the spiro-cycloalkyl group is suitably C-spiro-cycloalkyl. (0167 Alternatively R' represents (N N H (0176) Suitably R represents H, Cisalkyl, Cscycloalkyl, NeX —Calkylcarbocyclyl, aryl, heteroaryl, heterocyclyl. —C. R17 4alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl wherein said (0168. In one embodiment R' represents Hand R7 repre heterocyclyl group is optionally Substituted by a methyl or sents H. In another embodiment R' represents H and R' phenyl group, phenyl Substituted by carbocyclyl phenyl Sub represents C-alkyl. In a third embodiment R' represents stituted by carbocyclyl wherein said carbocyclyl is substi C-alkyland R7 represents H. In a further embodiment, R' tuted by heterocyclyl phenyl substituted by —O-carbocy represents H or methyl and R7 represents C-alkyl (e.g. clyl, heterocyclyl substituted by phenyl, carbocyclyl methyl) or halogen (e.g. fluorine). Substituted by phenyl, -Calkyl(phenyl Substituted by a (0169 Suitably C represents a bond, —CH2—, or monocyclic heterocyclyl group), —Calkyl(phenyl Substi —CH2CH2—. In one embodiment C represents a bond. In tuted by an —O-carbocyclyl group), phenyl Substituted by another embodiment, C represents —CH2—. In a third —O—Calkyl-heterocyclyl or phenyl fused to heterocy embodiment, C represents —CH2CH2—. clyl, the aforesaid aryl, heteroaryl, phenyl and heterocyclyl (0170 Alternatively R' represents groups optionally being Substituted. (0177 More suitably R represents H, Cisalkyl, Cscy cloalkyl, aryl, heteroaryl, —Calkylaryl, phenyl Substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl wherein said heterocyclyl group is optionally Substituted by a methyl or phenyl group, phenyl Substituted by —O—C alkyl-heterocyclyl or phenyl fused to heterocy clyl, the aforesaid aryl, heteroaryl, phenyl and heterocyclyl groups optionally being Substituted. (0171 In one embodiment R' represents Hand R' repre (0178 Yet more suitably R represents Csalkyl, Cascy sents H. In another embodiment R' represents H and R' cloalkyl, aryl, heteroaryl, —Calkylaryl, phenyl Substituted US 2011/00925O1 A1 Apr. 21, 2011 by phenyl, phenyl substituted by phenoxy, phenyl substituted (0188 In one embodiment, R represents —Calkylaryl, by heterocyclyl wherein said heterocyclyl group is optionally the aforesaid aryl optionally being substituted. When R rep Substituted by a methyl or phenyl group, phenyl Substituted resents—C. alkylaryl, R suitably represents benzyl option by —O—C alkyl-heterocyclyl or phenyl fused to heterocy ally substituted by one or more Calkoxy (e.g. methoxy) or clyl, the aforesaid aryl, heteroaryl, phenyl and heterocyclyl halogen (e.g. chlorine or fluorine) groups. When R repre groups optionally being Substituted. sents optionally substituted benzyl, R suitably represents (0179. In one embodiment, R represent H. 4-methoxybenzyl, 4-chlorobenzyl or 4-fluorobenzyl. When 0180. In one embodiment, R represents Csalkyl. When R represents optionally substituted benzyl, Ralso suitably R represents Cisalkyl, R suitably represents i-propyl or represents 4-propoxybenzyl or 4-isopropoxybenzyl. In an alternative embodiment, R represents unsubstituted benzyl. t-butyl. When R represents - Calkylaryl, R suitably represents 0181. In one embodiment, R represents carbocyclyl. —C(H)(Me)-phenyl. When R represents —Calkylaryl, When R represents carbocyclyl, R suitably represents R suitably represents —(CH)-phenyl. cyclohexyl. (0189 In one embodiment, R represents optionally sub 0182. In one embodiment, R represents —Calkylcar stituted heteroaryl. When R represents optionally substituted bocyclyl. When R represents —Calkylcarbocyclyl, R heteroaryl, R suitably represents optionally substituted Suitably represents —CH2-cyclohexyl. thiophenyl. In an alternative embodiment, R represents 0183. In one embodiment, R represents optionally sub unsubstituted thiophenyl. stituted aryl. When R represents optionally substituted aryl, (0190. In one embodiment, R represents optionally sub R suitably represents optionally substituted phenyl or stituted heterocyclyl. When R represents optionally substi napthyl. tuted heteroaryl, R suitably represents unsubstituted dihy 0184. In one embodiment, R represents phenyl optionally drobenzodioxinyl or piperidinyl substituted by a C(O)Cl. Substituted by one or more groups selected from C alkyl 6alkyl (i.e. —COMe) group. (e.g. methyl), C- alkoxy (e.g. methoxy, ethoxy, propoxy, (0191 In one embodiment, R represents phenyl substi butoxy, pentoxy or isopropyloxy), hydroxyl, haloC alkyl tuted by phenyl, the aforesaid phenyl groups optionally being (e.g. trifluoromethyl), haloCo alkoxy (e.g. tetrafluoroethy substituted. When R represents phenyl substituted by phe loxy), halogen (e.g. chlorine or fluorine), Calkoxy-C. nyl, the aforesaid phenyl groups optionally being Substituted, 6alkyl-(e.g. —(CH2). OMe), Calkoxy-Calkoxy- (e.g. R suitably represents phenyl substituted by 3-phenyl, phenyl —O-(CH2). OMe), —N(Calkyl)(Calkyl)-N(C- substituted by 4-phenyl, phenyl substituted by 3-(3-chlo 4alkyl)(Calkyl) (e.g. —N(Me)—(CH), N(Me)), rophenyl), phenyl substituted by 4-(3-chlorophenyl), phenyl —N(Calkyl)(Calkyl)(e.g. —N(ethyl)(ethyl)), —N(C- substituted by 4-(3,4-dichlorophenyl) or 3-fluorophenyl sub scycloalkyl)(C-scycloalkyl)(e.g. —N(cyclopropyl)(cyclo stituted by 4-phenyl. In an alternative embodiment, when R propyl)), —Calkyl-N(Calkyl)(Calkyl)(e.g. —(CH2) represents phenyl substituted by phenyl, R suitably repre N(methyl)(methyl), —Calkoxy-N(Calkyl)(C- sents unsubstituted phenyl substituted by unsubstituted phe 4alkyl)(e.g. —O(CH2) N(methyl)(methyl)), —N(-C. nyl. 6alkyl-Calkoxy)(—Calkyl-Calkoxy) (e.g. (0192 In one embodiment, R represents optionally sub - N(CH),OMe)(CH)OMe)). stituted phenyl substituted by optionally substituted phenoxy. 0185. In a further embodiment, R represents phenyl When R represents optionally substituted phenyl substituted optionally substituted by one or more groups selected from by optionally substituted phenoxy, R suitably represents C. alkyl (e.g. methyl), C alkoxy (e.g. methoxy, ethoxy, phenyl substituted by 4-phenoxy. propoxy, butoxy, pentoxy or isopropyloxy), haloC alkyl (0193 In one embodiment, R represents optionally sub (e.g. trifluoromethyl), haloC alkoxy (e.g. tetrafluoroethy stituted phenyl substituted by optionally substituted hetero loxy) or halogen (e.g. chlorine or fluorine). cyclyl. When R represents optionally substituted phenyl sub 0186. In a yet further embodiment, R represents phenyl stituted by optionally substituted heterocyclyl, R suitably optionally substituted by one or more groups selected from represents 3-chlorophenyl substituted by 4-morpholinyl, Calkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy phenyl substituted by 4-piperazinyl substituted by 4N-me or isopropyloxy). In a still yet further embodiment, R repre thyl, 2-chlorophenyl substituted by 6-piperazinyl substituted sents phenyl optionally Substituted by a propoxy group. by 4N-ethyl, phenyl substituted by pyrrolidinyl, phenyl sub 0187. When R represents optionally substituted phenyl, stituted by piperidinyl substituted by 4N-methyl, phenyl sub R suitably represents 3-methylphenyl, 2-methoxyphenyl, stituted by tetrahydropyranyl or phenyl substituted by mor 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, pholinyl. 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pen (0194 In a further embodiment, R represents optionally toxyphenyl, 4-isopropyloxyphenyl, 4-tetrafluoroethylox substituted phenyl substituted by optionally substituted het yphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, erocyclyl. When R represents optionally substituted phenyl 2,6-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, substituted by optionally substituted heterocyclyl, R suitably 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluo represents 3-chlorophenyl substituted by 4-morpholinyl, rophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3-chloro phenyl substituted by 4-piperazinyl substituted by 4N-me 5-fluorophenyl, 3,5-difluorophenyl, 2,3,5-trifluorophenyl, thyl, phenyl substituted by 4-piperazinyl substituted by 2-fluoro-5-trifluoromethylphenyl, 3-fluoro-5-trifluorometh 4N-phenyl, phenyl substituted by 3-piperazinyl substituted ylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trif by 4N-phenyl or 2-chlorophenyl substituted by 6-piperazinyl luoromethylphenyl, 3-fluoro-4-methoxyphenyl or 2,6-dif substituted by 4N-ethyl. luoro-4-methoxyphenyl. In an alternative embodiment, R (0195) In one embodiment, R represents optionally sub represents unsubstituted phenyl. In an alternative embodi stituted phenyl substituted by heterocyclyl wherein said het ment, R represents unsubstituted naphthyl. erocyclyl is substituted by phenyl. When R represents US 2011/00925O1 A1 Apr. 21, 2011 optionally substituted phenyl substituted by heterocyclyl 0205 Suitably R represents Hor Rand Rare joined to wherein said heterocyclyl is substituted by phenyl, R suit form a carbocyclyl ring which is fused to phenyl. Most suit ably represents phenyl substituted by 4-piperazinyl substi ably R represents H. tuted by 4N-phenyl, phenyl substituted by 3-piperazinyl sub 0206 Suitably R' represents H. —Calkyl or—C(O)Cl. stituted by 4N-phenyl. 6alkyl. More suitably R' represents Hor—Csalkyl, e.g. H (0196) In one embodiment, R represents optionally sub or methyl. Most suitably R' represents H. stituted phenyl substituted by optionally substituted carbocy 0207. In one embodiment, X represents O, S or CRR or clyl wherein said carbocyclyl is substituted by optionally X and Z represent two adjacent carbon atoms of a phenyl ring substituted heterocyclyl. When R represents optionally sub which is fused in that position and is optionally substituted by stituted phenyl substituted by optionally substituted carbocy one or more halogen or C-alkyl groups. In a further embodi clyl wherein said carbocyclyl is substituted by optionally ment, X represents O.S or CR7R. substituted heterocyclyl, R suitably represents phenyl sub 0208. In one embodiment X represents O. In an alternative stituted by carbocyclyl (i.e. cyclohexyl) substituted by het embodiment X represents S. In an alternative embodiment X erocyclyl (i.e. morpholinyl). represents C—O. In an alternative embodiment, X represents (0197) In one embodiment, R represents optionally sub S or CRR. In an alternative embodiment X represents stituted phenyl substituted by —O Calkyl-heterocyclyl. O—CH2—, or —CH2—CH2—. In an alternative embodi When R represents optionally substituted phenyl substituted ment X and Zare joined to form a carbocyclic ring, e.g. a five by -O-C alkyl-heterocyclyl, R suitably represents phe or six membered carbocyclic ring. In an alternative embodi nyl Substituted by 4-O-(CH2)-morpholinyl, 4-O-(CH2)- ment, X and Z represent two adjacent carbon atoms of a morpholinyl, 2-O-(CH2)-morpholinyl or 4-O-(CH2)- phenyl ring which is fused in that position and is optionally piperazinyl. Substituted by one or more halogen or C-alkyl groups. (0198 In one embodiment, R represents optionally sub 0209. In one embodiment, RandR both represent hydro stituted phenyl substituted by optionally substituted carbocy gen or—Chalkyl, or one of R7 and R represents hydrogen clyl. When R represents optionally substituted phenyl sub and the other represents —Calkyl or an optionally Substi stituted by optionally substituted carbocyclyl, R suitably tuted aryl group. When one of R7 and R represents a —C. represents phenyl substituted by Css cycloalkyl (such as 4alkyl group, said group is suitably methyl. When one of R' cyclohexyl) wherein said C.s cycloalkyl may be optionally and R represents an optionally substituted aryl group, said Substituted by one or more oxo, halogen (i.e. fluorine), group is Suitably unsubstituted phenyl or phenyl Substituted hydroxyl or Calkoxy (i.e. methoxy) groups. by 4-propoxy. In one embodiment, RandR both represent (0199. In one embodiment, R represents optionally sub hydrogen. In an alternative embodiment, R7 and R both rep stituted phenyl substituted by —O-carbocyclyl. When R resent —Calkyl. In an alternative embodiment, one of R' represents optionally substituted phenyl substituted by —O- and R represents hydrogen and the other represents —C. carbocyclyl, R suitably represents unsubstituted phenyl sub 4alkyl (e.g. methyl). In an alternative embodiment, one of R' stituted by an —O—Cs cycloalkyl group (i.e. —O-cyclo and R represents hydrogen and the other represents an hexyl). optionally substituted aryl group (e.g. unsubstituted phenyl or (0200. In one embodiment, R represents optionally sub phenyl Substituted by a C- alkoxy group). stituted heterocyclyl substituted by optionally substituted phenyl. When R represents optionally substituted heterocy 0210. In one embodiment Y represents C—O, C=S or clyl substituted by optionally substituted phenyl, R suitably CH. In an alternative embodiment, Y represents C—O. In an represents unsubstituted piperidinyl substituted by unsubsti alternative embodiment Y represents C—S. In an alternative tuted phenyl. embodiment, Y represents CH. 0201 In one embodiment, R represents optionally sub (0211. In one embodiment, Z represents —N R' (e.g. stituted carbocyclyl substituted by optionally substituted phe NH or -N-NH), O or CHR' (e.g. CH, or CH-methyl), nyl. When R represents optionally substituted carbocyclyl or X and Z represent two adjacent carbon atoms of a phenyl substituted by optionally substituted phenyl, R suitably rep ring which is fused in that position and is optionally Substi resents unsubstituted Cls cycloalkyl (i.e. cyclohexyl) Substi tuted by one or more halogen or Calkyl groups. In one tuted by unsubstituted phenyl. embodiment, Z represents —NH. In an alternative embodi (0202) In one embodiment, R represents optionally sub ment, Z represents - N NH. In an alternative embodiment, stituted phenyl fused to optionally substituted heterocyclyl. Z represents O. In an alternative embodiment, Z represents When R represents optionally substituted phenyl fused to CH. In an alternative embodiment, Z represents CH-methyl. optionally substituted heterocyclyl, R suitably represents 0212. In one embodiment, X represents CRR, Y repre benzo-1,3-dioxolanyl, 4-methoxy(benzo-1,3-dioxolanyl), sents C=O and Z represents N. R. In a further embodi 6-methoxy(benzo-1,3-dioxolanyl), 2,2-difluoro(benzo-1,3- ment, X represents CHY represents C=O and Z represents dioxolanyl) or benzo-1,4-dioxanyl. —NH. In a further embodiment, X represents CH Me, Y 0203. In one embodiment, R represents - Calkyl(phe represents C=O and Z represents—NH.Inafurther embodi nyl substituted by a monocyclic heterocyclyl group). When ment, X represents CHY represents C=O and Z represents R represents —Calkyl(phenyl substituted by a monocy - N NH. clic heterocyclyl group), R suitably represents benzyl sub 0213 When X represents CRR, Y represents C=O and stituted by morpholinyl. Z represents N. R. R' suitably represents 1 H-benzod 0204. In one embodiment, R represents - Calkyl(phe imidazolyl or 1H-imidazo[1,2-alpyridinyl. nyl substituted by an O-carbocyclyl group). When R rep 0214) When X represents CRR, Y represents C=O and resents —Calkyl(phenyl Substituted by an —O-carbocy Z represents —N R, R suitably represents: clyl group), R suitably represents benzyl substituted by an 0215 Cls alkyl (such as t-butyl); —O-carbocyclyl group (i.e. —O-cyclohexyl). 0216 carbocyclyl (such as cyclohexyl); US 2011/00925O1 A1 Apr. 21, 2011 15

0217 phenyl optionally substituted by one or more C. 0235 optionally substituted phenyl substituted by alkyl (e.g. methyl), C alkoxy (such as methoxy, optionally substituted heterocyclyl (such as phenyl sub ethoxy, propoxy, butoxy, pentoxy or isopropoxy), halo stituted by —O-(CH2)-piperazinyl or —O-(CH2)- gen (such as fluorine orchlorine), haloC alkyl (Such as morpholinyl); trifluoromethyl) or haloC alkoxy groups (such as tri 0236 optionally substituted phenyl substituted by fluoromethoxy); optionally substituted phenyl; or 0218 optionally substituted phenyl fused to optionally 0237 optionally substituted phenyl substituted by substituted heterocyclyl (such as 4-methoxybenzod1, optionally Substituted heterocyclyl (such as optionally 3dioxol-6-y1, 2,2-difluorobenzod1.3dioxol-5-yl or substituted phenyl substituted by piperazinyl substituted 2,3-dihydrobenzob 14-dioxin-6-yl); by phenyl or optionally substituted phenyl substituted by piperazinyl substituted by methyl). 0219 optionally substituted phenyl substituted by 0238. When X represents CRR, Y represents C=O and optionally substituted heterocyclyl (such as phenyl sub Z represents O, R suitably represents hydrogen. stituted by —O—(CH)-morpholinyl or phenyl substi 0239. In an alternative embodiment, X represents CRR, tuted by —O—(CH-)-morpholinyl); Y represents CHR and Z represents CHR'. In a further 0220 optionally substituted phenyl substituted by embodiment, X represents CH, Y represents CH and Z optionally substituted phenyl; or represents CH2. 0221 optionally substituted phenyl substituted by 0240. When X represents CRR, Y represents CHR and optionally Substituted heterocyclyl (such as optionally Z represents CHR'. R' suitably represents 1H-benzodimi substituted phenyl substituted by morpholinyl, option dazolyl. ally substituted phenyl substituted by piperazinyl sub 0241 When X represents CRR, Y represents CHR and stituted by phenyl or optionally substituted phenyl sub Z represents CHR'. R suitably represents: stituted by piperazinyl substituted by ethyl). 0242 hydrogen; 0222. When X represents CRR, Y represents C=O and 0243 phenyl optionally substituted by one or more Z represents - N R, R suitably represents hydrogen. halogen (such as fluorine or chlorine), C alkoxy (such 0223. When X represents CRR, Y represents C=O and as methoxy); or Z represents N. R. R. R7 and Reach suitably represent 0244 optionally substituted —C alkylaryl (such as hydrogen. unsubstituted benzyl and benzyl substituted a halogen 0224. In one embodiment, X represents C—O, Y repre atom, such as fluorine or chlorine or a C alkoxy, such sents CHR and Z represents N. R. In a further embodi as methoxy). ment, X represents C—O, Y represents CH and Z represents 0245. When X represents CRR, Y represents CHR and NH. Z represents CHR'. R suitably represents hydrogen. 0225. When X represents C—O.Y represents CHR and Z 0246. In an alternative embodiment, X represents S. Y represents - N. R. R' suitably represents 1H-benzodimi represents C=O and Z represents CHR'. In a further dazolyl. embodiment, X represents S, Y represents C=O and Z rep 0226. When X represents C—O.Y represents CHR and Z resents CH. In a further embodiment, X represents S. Y represents —N-R, R suitably represents phenyloptionally represents C=O and Z represents CH-methyl. Substituted by one or more halogen atoms (such as unsubsti 0247. When X represents S, Y represents C=O and Z tuted phenyl or 2,3,5-trifluorophenyl). represents CHR'. R' suitably represents 1H-benzodimida Zolyl. 0227. When X represents C=O.Y represents CHR and Z 0248. When X represents S, Y represents C=O and Z represents - N R, R suitably represents hydrogen. represents CHR'. R suitably represents: 0228. In an alternative embodiment, X represents CRR, Y represents C=O and Z represents O. In a further embodi 0249 phenyl optionally substituted by one or more ment, X represents CHY represents C=O and Z represents halogen (such as fluorine or chlorine); O. In a further embodiment, X represents C(Me), Y repre 0250 optionally substituted naphthyl (such as unsub sents C=O and Z represents O. In a further embodiment, X stituted naphthyl); represents CH-phenyl, Y represents C=O and Z represents 0251 optionally substituted phenyl substituted by O optionally Substituted phenoxy; or 0229 When X represents CRR, Y represents C=O and 0252 optionally substituted heteroaryl (such as unsub Z represents O. R' suitably represents 1H-benzodimida stituted thiophenyl). (0253) When X represents S, Y represents C=O and Z Zolyl or 1H-imidazo 1,2-alpyridinyl. represents CHR', R suitably represents hydrogen. 0230. When X represents CRR, Y represents C=O and 0254. In an alternative embodiment, X represents S. Y Z represents O, R suitably represents: represents C=S and Z represents CHR'. In a further 0231 Cs alkyl (such as i-propyl); embodiment, X represents S, Y represents C—S and Z rep 0232 phenyl optionally substituted by one or more resents CH. halogen (Such as fluorine or chlorine), Calkoxy (such (0255. When X represents S, Y represents C—S and Z as propoxy) or haloC alkyl groups (such as trifluo represents CHR'. R' suitably represents 1H-benzodimida romethyl); Zolyl. 0233 —C alkylaryl (such as benzyl); (0256. When X represents S, Y represents C—S and Z 0234 optionally substituted phenyl fused to optionally represents CHR'. R suitably represents optionally substi substituted heterocyclyl (such as 2,3-dihydrobenzob tuted phenyl or optionally substituted phenyl substituted by 1,4-dioxin-6-yl or benzod1.3dioxol-6-yl); optionally substituted phenoxy. US 2011/00925O1 A1 Apr. 21, 2011

0257. When X represents S, Y represents C—S and Z 0278. When X represents —CH2—CH2—, Y represents represents CHR'. R suitably represents hydrogen. CO and Z represents O, R suitably represents phenyloption ally substituted by a C- alkoxy (such as propoxy). 0258. In an alternative embodiment, X represents CRR, (0279. When X represents - CH-CH , Y represents Y represents C=O and Z represents CHR'. In a further CO and Z represents O, R suitably represents hydrogen. embodiment, X represents CH, Y represents C=O and Z 0280. In one embodiment, the compound of formula (I) is represents CH2. a compound selected from Examples 1 to 235. In a further 0259. When X represents CRR, Y represents C=O and embodiment, the compound of formula (I) is a compound Z represents CHR'. R' suitably represents 1H-benzodimi selected from Examples 1 to 147. In a yet further embodi dazolyl. ment, the compound of formula (I) is a compound selected 0260. When X represents CRR, Y represents C=O and from Examples 12 to 14. Z represents CHR'. R suitably represents: Processes 0261 phenyl optionally substituted by one or more 0281. According to a further aspect of the invention there halogen (Such as fluorine), Calkoxy (such as methoxy is provided a process for preparing a compound of formula (I) or propoxy); or which comprises: 0262 optionally substituted phenyl fused to optionally (a) preparing a compound of formula (I) from a compound of substituted heterocyclyl (such as 2,3-dihydrobenzob formula (II): 1,4-dioxin-6-yl). 0263. When X represents CRR, Y represents C=O and (II) Z represents CHR'. R suitably represents hydrogen. R3 X 0264. In an alternative embodiment, X and Z represent two R2 Z adjacent carbon atoms of a phenyl ring which is fused in that > yM position and Y represents C—O. In a further embodiment, X 1:NS NY and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position and is substituted by one or wherein R. R. X, Y and Z are as defined above for com more halogen or C-alkyl groups such as 2.5-dichlorophenyl pounds of formula (I). The process typically involves reacting or 3,4-dichlorophenyl and Y represents C—O. a compound of formula (II) with a compound of formula R'-L 0265. When X and Z represent two adjacent carbon atoms in which L represents a leaving group e.g. a halogen atom of a phenyl ring which is fused in that position and Y repre Such as iodine. A non-limiting example of the methodology of sents C=O, R' suitably represents 1H-benzodimidazolyl. process (a) is described in Methods 5-8 and 12 herein. 0266. When X and Z represent two adjacent carbon atoms (b) preparing a compound of formula (I) wherein R repre of a phenyl ring which is fused in that position and Y repre sents hydrogen, Y represents CO, Z represents —N Rand sents C=O, R suitably represents: X represents CRR and R represents hydrogen by hydroge 0267 phenyl optionally substituted by one or more nation of a compound of formula (III): halogen (such as fluorine or chlorine), Calkoxy (such as methoxy or propoxy); (III) 0268 optionally substituted phenyl substituted by optionally substituted phenyl: 0269 optionally substituted phenyl fused to optionally substituted heterocyclyl (such as benzod1.3dioxol 6-yl); or 0270 optionally substituted phenyl substituted by optionally substituted phenoxy. 0271 When X and Z represent two adjacent carbon atoms wherein R', R, R and R are as defined above for com of a phenyl ring which is fused in that position and Y repre pounds of formula (I). Process (b) typically comprises hydro sents C=O, R suitably represents hydrogen. genation under suitable conditions, such as PdC, 10% on 0272. In an alternative embodiment, X represents charcoal at 4bar at 40°C. for 4 hours. A non-limiting example —O CH Y represents CO and Z represents CHR'. In a of the methodology of process (b) is described in Method 1 further embodiment, X represents —O—CH2—, Y repre herein. sents CO and Z represents CH (see e.g. Example 93). (c) preparing a compound of formula (I) wherein R repre (0273 When X represents - O CH-Y represents CO sents hydrogen, Y represents CO, Z represents CH and X and Z represents CHR'. R' suitably represents 1 H-benzod represents CH by hydrogenation of a compound of formula imidazolyl. (IV): (0274. When X represents - O CH-Y represents CO and Z represents CHR'. R suitably represents phenyl optionally substituted by a C- alkoxy (such as propoxy). (IV) (0275. When X represents - O CH-Y represents CO and Z represents CHR'. R suitably represents hydrogen. 0276. In an alternative embodiment, X represents —CH2—CH2—, Y represents CO and Z represents O. (0277. When X represents —CH-CH , Y represents CO and Z represents O. R' suitably represents 1 H-benzod imidazolyl or 1H-imidazo[1,2-alpyridinyl. US 2011/00925O1 A1 Apr. 21, 2011 wherein R' and Rare as defined above for compounds of wherein R is as defined above for compounds of formula (I) formula (I). Process (c) typically comprises hydrogenation and P' represents a suitable protecting group, such as p-meth under suitable conditions, such as PdC, 10% on charcoal at oxybenzyl. Process (f) typically comprises treatment of the 1-2 bar at room temperature overnight. A non-limiting compound of formula (IV) with an activated formic acid example of the methodology of process (c) is described in derivative, such as triethyl orthoformate. A non-limiting Method 10 herein. example of the methodology of process (f) is described in (d) preparing a compound of formula (I) wherein R repre Method 3 herein. sents hydrogen, Y represents CO, Z represents - N Rand (g) preparing a compound of formula (I) wherein R repre X represents CH from a compound of formula (V): sents hydrogen, Y represents CO and X and Z are joined to form a carbocyclic ring or else X and Z represent two adjacent carbon atoms of a phenyl ring which is fused in that position (V) and is optionally Substituted by one or more halogen or Calkyl groups, from a compound of formula (VIII): '' (VIII) Oals. NH wherein R, R and Rare as defined above for compounds of formula (I). Process (d) typically comprises reaction with a Suitable reagent, such as a compound of formula LCOL' in which Land L' represent leaving groups. An example reagent is carbonyldiimidazole which may be employed in the pres wherein R', R, X and Zare as defined above for compounds ence of a suitable solvent such as dichloromethane. A non of formula (I). Process (g) is essentially a dehydration reac limiting example of the methodology of process (d) is tion which typically comprises the use of Suitable reagents, Such as trifluoroacetic acid, triethylsilane and sodium bicar described in Method 2 herein. bonate. A non-limiting example of the methodology of pro (e) preparing a compound of formula (I) wherein R repre cess (g) is described in Method 11 herein. sents hydrogen, Y represents CH, Zrepresents - N Rand (h) preparing a compound of formula (I) wherein X repre X represents CO from a compound of formula (VI): sents S, for example a compound of formula (I) wherein R represents hydrogen, Y represents CO, Z represents —CH2 and X represents S from a corresponding compound in which (VI) X represents O. Process (h) typically comprises the use of Suitable reagents such as Lawesson's Reagent. A non-limiting example of the methodology of process (h) is described in Method 9 herein. (i) preparing a compound of formula (I) wherein R repre sents —NH from a corresponding compound of formula (I) wherein R represents H by treatment with nitrite followed by reduction. Typically the compound of formula (I) wherein R' wherein R', RandR'areas defined above for compounds of represents H is treated with sodium (or potassium) nitrite in formula (I). Process (e) typically comprises the use of a the presence of acid (e.g. glacial acetic acid) and then reduced Suitable reagent, such as an activated formic acid derivative by treatment with Zinc powder. A non-limiting example of the e.g. triethyl-Ortho formate under Suitable conditions. Such as methodology of process (i) is described in Example 65 herein. reflux followed by reduction e.g. with sodium borohydride. A (j) preparing a compound of formula (I) wherein R repre non-limiting example of the methodology of process (e) is sents —C-alkyl or —C(O)Calkyl from a corresponding described in Method 4 herein. compound of formula (I) wherein R represents H by treat (f) preparing a compound of formula (I) wherein R' repre ment with an alkylating or alkanoylating agent. Typical alky sents 1H-benzodimidazol-5-yl, R represents hydrogen, Y lating agents include compounds of formula R-L wherein L represents CO, Z represents - NH and X represents CH is a leaving group Such as iodine and typical alkanoylating from a compound of formula (VII): agents include activated acids such as compounds of formula R-L wherein L is a leaving group such as halogen (e.g. chlorine) or a corresponding acid anhydride. (VII) (k) interconversion of compounds of formula (I). Examples of Such an interconversion includes interconversion of a com pound of formula (I) whereinY represents CO to a compound of formula (I) wherein Y represents CS. Such an interconver sion may typically comprise the use of suitable reagents. Such HN as toluol and Lawesson's Reagent. A non-limiting example of the methodology of process (k) is described in Method 9 herein; and (1) deprotecting a compound of formula (I) which is pro tected. US 2011/00925O1 A1 Apr. 21, 2011 18

0282 Compounds of formula (I) and intermediate com- (11-42), ABri, ADan, Gastrin, Neurotensin, FPP, CCL 2. pounds may also be prepared using techniques analogous to CCL 7, CCL 8, CCL 16, CCL 18, Fractalkine, Orexin A, those known to a skilled person, or described herein. Gln)-glucagon(3-29), Gln)-substance P(5-11) and the 0283 Novel intermediates are claimed as an aspect of the peptide QYNAD. For further details see table 1. The com present invention. pounds and/or combinations according to the present inven Therapeutic Uses tion and pharmaceutical compositions comprising at least one 0284 Physiological substrates of QC (EC) in mammals inhibitor of QC (EC) are useful for the treatment of conditions are, e.g. amyloid beta-peptides (3-40), (3-42), (11-40 and that can be treated by modulation of QC activity.

TABLE 1. Amino acid sequences of physiological active peptides with an N-terminal glutamine residue, which are prone to be cyclized to final pClu Peptide Amino acid sequence Function Abeta(1-42) Asp-Ala-Glu-Phe-Arg-His-Asp-Ser- Plays a role in (SEQ ID NO: 1) 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 (SEQ ID NO: 2) 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 (SEQ ID NO : 3) 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-Ile-Ala Danish Dementia, Down Syndrome Abeta (3-40) Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr- Plays a role in (SEQ ID NO : 4) 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 Abeta (11-42) Glu-Val-His-His-Gln-Lys-Leu-Val- Plays a role in (SEQ ID NO: 16) 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 (SEO ID NO : 17) 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 (SEQ ID NO: 18) SRTWKKNIIEEN role in Familial British Dementia

ADan EASNCFA IRHFENKFAW ETLIC Pyroglutamated form plays a (SEQ ID NO: 19) FNLFLNSOEKHY role in Familial Danish Dementia

Gastrin 17 OGPWL EEEEEAYGWM DF Gastrin stimulates the stomach Swiss-Prot: PO1350 (amide) mucosa to produce and secrete (SEO ID NO. 5) hydrochloric acid and the pancreas to secrete its digestive enzymes. It also stimulates Smooth muscle contraction and increases blood circulation and water secretion in the stomach and intestine. US 2011/00925O1 A1 Apr. 21, 2011 19

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

Neurotensin OLYENKPRRP YIL Neurotensin plays an endocrine Swiss-Prot: P3O990 or paracrine role in the (SEQ ID NO : 6) regulation of fat metabolism. It causes contraction of Smooth muscle.

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

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

GnRH OHWSYGL RP (G) amide Stimulates the Secretion of Swiss-Prot: PO1148 gonadotropins; it stimulates the (SEO ID NO : 7 secretion of both luteinizing and follicle-stimulating hormones.

CCL16 (Small QPKVPEW VNTPSTCCLK Shows chemotactic activity for inducible cytokine YYEKWLPRRL WWGYRKALNC lymphocytes and monocytes A16) HLPAIIFWTK RNREWCTNPN but not neutrophills. Also shows Swiss-Prot: O15467 DDWVOEYIKD PNLPLLPTRN potent myelosuppressive (SEQ ID NO: 8) LSTWKIITAK NGOPOLLNSQ activity, suppresses proliferation of myeloid progenitor cells. Recombinant SCYA16 shows chemotactic activity for monocytes and THP-1 monocytes, but not for resting lymphocytes and neutrophills. Induces a calcium flux in THP-1 cells that were desensitized by prior expression to RANTES.

CCL8 (Small QPDSVSI PITCCFNVIN Chemotactic factor that attracts inducible cytokine RKIPIORLES YTRITNIOCP monocytes, lymphocytes, A8) KEAWIFKTKR GKEWCADPKE basophills and eosinophills. May Swiss-Prot: P8 OO75 RWVRDSMKHL DOIFONLKP play a role in neoplasia and (SEO ID NO: 9) inflammatory host responses. This protein can bind heparin.

CCL2 (MCP-1, small QPDAINA PVTCCYNFTN Chemotactic factor that attracts inducible cytokine RKISWORLAS YRRITSSKCP monocytes and basophills but A2) KEAVIFKTIV AKEICADPKO not neutrophills or eosinophills. Swiss-Prot: P13500 KWVODSMDHL DKOTOTPKT Augments monocyte anti-tumor (SEQ ID NO: 10) activity. Has been implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis or atherosclerosis. May be involved in the recruitment of monocytes into the arterial wall during the disease process of atherosclerosis. Binds to CCR2 and CCR4.

CCL18 (Small OVGTNKELC CLVYTSWOIP Chemotactic factor that attracts inducible cytokine OKFIVDYSET SPOCPKPGVI lymphocytes but not monocytes A18) LLTKRGROIC ADPNKKWVOK or granulocytes. May be Swiss-Prot: P55774 YISDLKLNA involved in B cell migration into US 2011/00925O1 A1 Apr. 21, 2011 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 (SEQ ID NO: 11) 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 OHHGVT KCNITCSKMT The soluble form is chemotactic (neurotactin) SKIPWALLIH YOONOASCGK for T cells and monocytes, but Swiss-Prot: P78423 RAIILETROH RLFCADPKEO not for neutrophills. The (SEQ ID NO: 12) WWKDAMOHLD ROAAALTRNG membrane-bound form GTFEKOIGEV KPRTTPAAGG promotes adhesion of those MDESWWLEPE ATGESSSLEP leukocytes to endothelial cells. TPSSQEAQRA LGTSPELPTG May play a role in regulating WTGSSGTRLP PTPKAODGGP leukocyte adhesion and VGTELFRVPP VSTAATWOSS migration processes at the APHOPGPSLW AEAKTSEAPS endothelium binds to CX3CR1. TODPSTOAST ASSPAPEENA PSEGORVWGO GOSPRPENSL EREEMGPWPA HTDAFODWGP GSMAHWSWWP WSSEGTPSRE PWASGSWTPK AEEPIHATMD PORLGVLITP VPDAOAATRR QAVGLLAFLG LLFCLGVAMF TYQSLQGCPR KMAGEMAEGL RYIPRSCGSN SYWLWPW

CCL7 (Small QPVGINT STTCCYRFIN Chemotactic factor that attracts inducible cytokine KKIPKORLES YRRTTSSHCP monocytes and eosinophills, but A7) REAVIFKTKL DKEICADPTO not neutrophills. Augments Swiss-Prot: P80098 KWVODFMKHL DKKTOTPKL monocyte anti-tumor activity. (SEQ ID NO: 13) Also induces the release of gelatinase B. This protein can bind heparin. Binds to CCR1, CCR2 and CCR3. Orexin A (Hypocretin-1) QPLPDCCRQK TCSCRLYELL Neuropeptide that plays a Swiss-Prot O43 612 HGAGNHAAGI LTL significant role in the regulation (SEQ ID NO: 14) of food intake and sleep Wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. It plays also a broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids. Orexin-A binds to both OX1R and OX2R with a high affinity. Substance P RPK POOFFGLM Belongs to the tachykinins. (SEQ ID NO: 15) 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 (SEQ ID NO: 2O) channels. US 2011/00925O1 A1 Apr. 21, 2011

0285) Glutamate is found in positions 3, 11 and 22 of the biochemical effects of centrally administered NT remarkably amyloid B-peptide. Among them the mutation from glutamic resemble those of systemically administered antipsychotic acid (E) to glutamine (Q) in position 22 (corresponding to drugs, and antipsychotic drugs increase NT neurotransmis amyloid precursor protein APP 693, Swissprot P05067) has Sion. This concatenation of findings led to the hypothesis that been described as the so called Dutch type cerebroarterial NT functions as an endogenous antipsychotic. Moreover, amyloidosis mutation. typical and atypical antipsychotic drugs differentially alter 0286 The B-amyloid peptides with a pyroglutamic acid NT neurotransmission in nigrostriatal and mesolimbic residue in position 3, 11 and/or 22 have been described to be dopamine terminal regions, and these effects are predictive of more cytotoxic and hydrophobic than the amyloid 0-peptides side effect liability and efficacy, respectively (Binder, E. B. et 1-40(42/43) (Saido T. C. 2000 Medical Hypotheses 54(3): al. 2001 Biol Psychiatry 50 856-872). 427-429). 0291 Fertilization promoting peptide (FPP), a tripeptide 0287. The multiple N-terminal variations, e.g. Abeta(3- related to thyrotrophin releasing hormone (TRH), is found in 40), Abeta(3-42), Abeta(11-40) and Abeta (11-42) can be seminal plasma. Recent evidence obtained in vitro and in vivo generated by the B-secretase enzyme B-site amyloid precur showed that FPP plays an important role in regulating sperm sor protein-cleaving enzyme (BACE) at different sites (Huse fertility. Specifically, FPP initially stimulates nonfertilizing J.T. et al. 2002.J. Biol. Chem. 277 (18): 16278-16284), and/or (uncapacitated) spermatozoa to "switch on and become fer by aminopeptidase or dipeptidylaminopeptidase processing tile more quickly, but then arrests capacitation so that sper from the full length peptides Abeta(1-40) and Abeta(1-42). In matozoa do not undergo spontaneous acrosome loss and all cases, cyclization of the then N-terminal occurring therefore do not lose fertilizing potential. These responses are glutamic acid residue is catalyzed by QC. mimicked, and indeed augmented, by adenosine, known to 0288 Transepithelial transducing cells, particularly the regulate the adenylyl cyclase (AC)/cAMP signal transduction gastrin (G) cell, co-ordinate gastric acid secretion with the pathway. Both FPP and adenosine have been shown to stimu arrival of food in the stomach. Recent work showed that late cAMP production in uncapacitated cells but inhibit it in multiple active products are generated from the gastrin pre capacitated cells, with FPP receptors somehow interacting cursor, and that there are multiple control points in gastrin with adenosine receptors and G proteins to achieve regulation biosynthesis. Biosynthetic precursors and intermediates (pro of AC. These events affect the tyrosine phosphorylation state gastrin and Gly-gastrins) are putative growth factors; their of various proteins. Some being important in the initial products, the amidated gastrins, regulate epithelial cell pro “switching on, others possibly being involved in the liferation, the differentiation of acid-producing parietal cells acrosome reaction itself. Calcitonin and angiotensin II, also and histamine-secreting enterochromaffin-like (ECL) cells, found in seminal plasma, have similar effects in vitro on and the expression of genes associated with histamine Syn uncapacitated spermatozoa and can augment responses to thesis and storage in ECL cells, as well as acutely stimulating FPP. These molecules have similar effects in vivo, affecting acid secretion. Gastrin also stimulates the production of fertility by stimulating and then maintaining fertilizing poten members of the epidermal growth factor (EGF) family, which tial. Either reductions in the availability of FPP, adenosine, in turn inhibit parietal cell function but stimulate the growth calcitonin, and angiotensin II or defects in their receptors of Surface epithelial cells. Plasma gastrin concentrations are contribute to male infertility (Fraser, L. R. and Adeoya elevated in subjects with Helicobacter pylori, who are known Osiguwa, S.A. 2001 Vitam Horm 63, 1-28). to have increased risk of duodenal ulcer disease and gastric 0292. CCL2 (MCP-1), CCL7, CCL8, CCL16, CCL18 and cancer (Dockray, G.J. 1999 J Physiol 15315-324). fractalkine play an important role in pathophysiological con 0289. The peptide hormone gastrin, released from antral G ditions, such as Suppression of proliferation of myeloid pro cells, is known to stimulate the synthesis and release of his genitor cells, neoplasia, inflammatory host responses, cancer, tamine from ECL cells in the oxyntic mucosa via CCK-2 psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, receptors. The mobilized histamine induces acid secretion by humoral and cell-mediated immunity responses, leukocyte binding to the H(2) receptors located on parietal cells. Recent adhesion and migration processes at the endothelium, inflam studies Suggest that gastrin, in both its fully amidated and less matory bowel disease, restenosis, pulmonary fibrosis, pulmo processed forms (progastrin and glycine-extended gastrin), is nary hypertension, liver fibrosis, liver cirrhosis, nephroscle also a growth factor for the gastrointestinal tract. It has been rosis, Ventricular remodeling, heart failure, arteriopathy after established that the major trophic effect of amidated gastrin is organ transplantations and failure of vein grafts. for the oxyntic mucosa of stomach, where it causes increased 0293. A number of studies have underlined in particular proliferation of gastric stem cells and ECL cells, resulting in the crucial role of MCP-1 for the development of atheroscle increased parietal and ECL cell mass. On the other hand, the rosis (Gu, L., et al., (1998) Mol. Cell 2, 275-281; Gosling, J., major trophic target of the less processed gastrin (e.g. gly et al., (1999).J. Clin. Invest 103,773-778); rheumatoid arthri cine-extended gastrin) appears to be the colonic mucosa tis (Gong, J. H., et al., (1997) J Exp. Med 186, 131-137; (Koh, T.J. and Chen, D. 2000 Regul Pept 9337–44). Ogata, H., et al., (1997).J. Pathol. 182, 106-114); pancreatitis 0290 Neurotensin (NT) is a neuropeptide implicated in (Bhatia, M., et al., (2005) Am. J Physiol Gastrointest. Liver the pathophysiology of schizophrenia that specifically modu Physiol 288, G1259-G1265); Alzheimer's disease (Yama lates neurotransmitter systems previously demonstrated to be moto, M., et al., (2005) Am. J Pathol. 166, 1475-1485); lung misregulated in this disorder. Clinical studies in which cere fibrosis (Inoshima, I., et al., (2004) Am. J Physiol Lung Cell brospinal fluid (CSF) NT concentrations have been measured Mol. Physiol 286, L1038-L1044); renal fibrosis (Wada, T., et revealed a subset of schizophrenic patients with decreased al., (2004).JAm. Soc. Nephrol. 15.940-948), and graft rejec CSFNT concentrations that are restored by effective antip tion (Saiura, A., et al., (2004) Arterioscler: Thromb. Vasc. sychotic drug treatment. Considerable evidence also exists Biol. 24, 1886-1890). Furthermore, MCP-1 might also play a concordant with the involvement of NT systems in the mecha role in gestosis (Katabuchi, H., et al., (2003) Med Electron nism of action of antipsychotic drugs. The behavioral and Microsc. 36, 253-262), as a paracrine factor in tumor devel US 2011/00925O1 A1 Apr. 21, 2011 22 opment (Ohta, M., et al., (2003) Int. J Oncol. 22,773-778; Li, especially multiple sclerosis, the Guillain-Barré syndrome S., et al., (2005).J Exp. Med 202, 617-624), neuropathic pain and chronic inflammatory demyelinizing polyradiculoneur (White, F. A., et al., (2005) Proc. Natl. Acad. Sci. U.S.A) and opathy. AIDS (Park, I. W., Wang, J. F., and Groopman, J. E. (2001) 0298. Furthermore, QYNAD is a substrate of the enzyme Blood 97, 352-358; Coll, B., et al., (2006) Cytokine 34, glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in 51-55). the brain of mammals, especially in human brain. Glutaminyl cyclase catalyzes effectively the formation of plYNAD from 0294 MCP-1 levels are increased in CSF of AD patients its precursor QYNAD. and patients showing mild cognitive impairment (MCI) (Gal 0299. Accordingly, the present invention provides the use imberti, D., et al., (2006) Arch. Neurol. 63,538-543). Further of the compounds of formula (I) for the preparation of a more, MCP-1 shows an increased level in serum of patients medicament for the prevention or alleviation or treatment of a with MCI and early AD (Clerici, F., et al., (2006) Neurobiol. disease selected from the group consisting of mild cognitive Aging 27, 1763-1768). impairment, Alzheimer's disease, Familial British Dementia, 0295) Several cytotoxic T lymphocyte peptide-based vac Familial Danish Dementia, neurodegeneration in Down Syn cines against hepatitis B. human immunodeficiency virus and drome, Huntington's disease, Kennedy's disease, ulcer dis melanoma were recently studied in clinical trials. One inter ease, duodenal cancer with or w/o Helicobacter pylori infec esting melanoma vaccine candidate alone or in combination tions, colorectal cancer, Zolliger-Ellison syndrome, gastric with other tumor antigens, is the decapeptide ELA. This cancer with or without Helicobacter pylori infections, patho peptide is a Melan-A/MART-1 antigen immunodominant genic psychotic conditions, Schizophrenia, infertility, neopla peptide analog, with an N-terminal glutamic acid. It has been sia, inflammatory host responses, cancer, malign metastasis, reported that the amino group and gamma-carboxylic group melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, impaired humoral and cell-mediated of glutamic acids, as well as the amino group and gamma immune responses, leukocyte adhesion and migration pro carboxamide group of glutamines, condense easily to form cesses in the endothelium, impaired food intake, impaired pyroglutamic derivatives. To overcome this stability problem, sleep-wakefulness, impaired homeostatic regulation of several peptides of pharmaceutical interest have been devel energy metabolism, impaired autonomic function, impaired oped with a pyroglutamic acid instead of N-terminal hormonal balance or impaired regulation of body fluids, mul glutamine or glutamic acid, without loss of pharmacological tiple sclerosis, the Guillain-Barré syndrome and chronic properties. Unfortunately compared with ELA, the pyro inflammatory demyelinizing polyradiculoneuropathy. glutamic acid derivative (PyrELA) and also the N-terminal 0300 Furthermore, by administration of a compound acetyl-capped derivative (AcELA) failed to elicit cytotoxic T according to the present invention to a mammal it can be lymphocyte (CTL) activity. Despite the apparent minor modi possible to stimulate the proliferation of myeloid progenitor fications introduced in PyrELA and AchELA, these two cells. derivatives probably have lower affinity than ELA for the 0301 In addition, the administration of a QC inhibitor specific class I major histocompatibility complex. Conse according to the present invention can lead to Suppression of quently, in order to conserve full activity of ELA, the forma male fertility. tion of PyrELA must be avoided (Beck A. et al. 2001, J Pept 0302) In a preferred embodiment, the present invention Res 57(6):528-38.). provides the use of inhibitors of QC (EC) activity in combi 0296 Orexin A is a neuropeptide that plays a significant nation with other agents, especially for the treatment of neu role in the regulation of food intake and sleep-wakefulness, ronal diseases, artherosclerosis and multiple Sclerosis. possibly by coordinating the complex behavioral and physi 0303. The present invention also provides a method of ologic responses of these complementary homeostatic func treatment of the aforementioned diseases comprising the tions. It plays also a role in the homeostatic regulation of administration of a therapeutically active amount of at least energy metabolism, autonomic function, hormonal balance one compound of formula (I) to a mammal, preferably a and the regulation of body fluids. human. 0304 Most preferably, said method and corresponding 0297 Recently, increased levels of the pentapeptide uses are for the treatment of a disease selected from the group QYNAD were identified in the cerebrospinal fluid (CSF) of consisting of mild cognitive impairment, Alzheimer's dis patients suffering from multiple sclerosis or Guillain-Barré ease, Familial British Dementia, Familial Danish Dementia, syndrome compared to healthy individuals (Brinkmeier H. et neurodegeneration in Down Syndrome, Parkinson's disease al. 2000, Nature Medicine 6,808–811). There is a big contro versy in the literature about the mechanism of action of the and Chorea Huntington, comprising the administration of a pentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), especially its therapeutically active amount of at least one compound of efficacy to interact with and block Sodium channels resulting formula (I) to a mammal, preferably a human. in the promotion of axonal dysfunction, which are involved in 0305 Even preferably, the present invention provides a inflammatory autoimmune diseases of the central nervous method of treatment and corresponding uses for the treatment system. But recently, it could be demonstrated that not of rheumatoid arthritis, atherosclerosis, pancreatitis and res QYNAD, but its cyclized, pyroglutamated form, pEYNAD, is tenosis. the active form, which blocks Sodium channels resulting in the promotion of axonal dysfunction. Sodium channels are Pharmaceutical Combinations expressed at high density in myelinated axons and play an 0306 In a preferred embodiment, the present invention obligatory role in conducting action potentials along axons provides a composition, preferably a pharmaceutical compo within the mammalian brain and spinal cord. Therefore, it is sition, comprising at least one QC inhibitor optionally in speculated that they are involved in several aspects of the combination with at least one other agent selected from the pathophysiology of inflammatory autoimmune diseases, group consisting of nootropic agents, neuroprotectants, anti US 2011/00925O1 A1 Apr. 21, 2011 23 parkinsonian drugs, amyloid protein deposition inhibitors, iximab (syn. to Centara, CEN-000029, cM-T412), beta amyloid synthesis inhibitors, antidepressants, anxiolytic MRA, Dantes, anti-IL-12-antibody, drugs, antipsychotic drugs and anti-multiple Sclerosis drugs. 0327 e) peptide nucleic acid (PNA) preparations, e.g. 0307 Most preferably, said QC inhibitor is a compound of reticulose, formula (I) of the present invention. 0328 f) interferon alpha, e.g. Alfaferone, human alpha 0308 More specifically, the aforementioned other agent is interferon (syn. to Omniferon, Alpha Leukoferon), selected from the group consisting of beta-amyloid antibod 0329 g) interferon beta, e.g. Frone, interferon beta-1a ies, vaccines, cysteine protease inhibitors, PEP-inhibitors, like Avonex, Betron (Rebif), interferon beta analogs, LiCl, acetylcholinesterase (AChE) inhibitors, PIMT enhanc interferon beta-transferrin fusion protein, recombinant ers, inhibitors of beta secretases, inhibitors of gamma secre interferon beta-1 b like Betaseron, tases, inhibitors of aminopeptidases, preferably inhibitors of 0330 h) interferon tau, dipeptidyl peptidases, most preferably DP IV inhibitors: 0331 i) peptides, e.g. AT-008, AnergiX.MS, Immunok inhibitors of neutral endopeptidase, inhibitors of Phosphodi ine (alpha-Immunokine-NNSO3), cyclic peptides like esterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 ZD-7349, receptor antagonists, NMDA receptor antagonists, sigma-1 0332 j) therapeutic enzymes, e.g. soluble CD8 (SCD8), receptor inhibitors, histamine H3 antagonists, immunomodu 0333 k) multiple sclerosis-specific autoantigen-encod latory agents, immunosuppressive agents, MCP-1 antago ing plasmid and cytokine-encoding plasmid, e.g. BHT nists or an agent selected from the group consisting of ante 3009; gren (natalizumab), Neurelan (fampiridine-SR), campath 0334 l) inhibitor of TNF-alpha, e.g. BLX-1002, thali (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), domide, SH-636, paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, 0335 m) TNF antagonists, e.g. solimastat, lenercept adapalene), BAY 361677 (interleukin-4), matrix-metallopro (syn. to R 45-2081, Tenefuse), onercept (sTNFR1), teinase-inhibitors (e.g. BB 76163), interferon-tau (tropho CC-1069, blastin) and SAIK-MS. 0336 n) TNF alpha, e.g. etanercept (syn. to Enbrel, 0309 Furthermore, the other agent may be, for example, TNR-001) an anti-anxiety drug or antidepressant selected from the 0337 o) CD28 antagonists, e.g. abatacept, group consisting of 0338 p) Lck tyrosine kinase inhibitors, 0310 (a) Benzodiazepines, e.g. alprazolam, chlordiaz 0339) q) cathepsin Kinhibitors, epoxide, clobazam, clonazepam, clorazepate, diaz 0340 r) analogs of the neuron-targeting membrane epam, fludiazepam, loflazepate, lorazepam, methaqua transporter protein taurine and the plant-derived calpain lone, oxazepam, prazepam, tranxene, inhibitor leupeptin, e.g. Neurodur, 0311 (b) Selective serotonin re-uptake inhibitors (SS 0341 s) chemokine receptor-1 (CCR1) antagonist, e.g. RI's), e.g. citalopram, fluoxetine, fluvoxamine, escitalo BX-471, pram, Sertraline, paroxetine, 0342 t) CCR2 antagonists, 0312 (c) Tricyclic antidepressants, e.g. amitryptiline, 0343 u) AMPA receptor antagonists, e.g. ER-167288 clomipramine, desipramine, doxepin, imipramine 01 and ER-099487, E-2007, talampanel, 0313 (d) Monoamine oxidase (MAO) inhibitors, 0344 V) potassium channel blockers, e.g. fampiridine, 0314 (e) AZapirones, e.g. buspirone, tandopsirone, 0345 w) tosyl-proline-phenylalanine small-molecule 0315 (f) Serotonin-norepinephrine reuptake inhibitors antagonists of the VLA-4/VCAM interaction, e.g. TBC 3342, (SNRIs), e.g. Venlafaxine, dulloxetine, 0346 x) cell adhesion molecule inhibitors, e.g. TBC 0316 (g) Mirtazapine, 772, 0317 (h) Norepinephrine reuptake inhibitors (NRI's), 0347 y) antisense oligonucleotides, e.g. EN-101, e.g. reboxetine, 0348 Z) antagonists of free immunoglobulin light chain 0318 (i) Bupropione, (Ig|LC) binding to mast cell receptors, e.g. F-991, 0319 (i) Nefazodone, 0349 aa) apoptosis inducing antigens, e.g. Apogen MS, 0320 (k) beta-blockers, 0350 bb) alpha-2 adrenoceptor agonist, e.g. tizanidine 0321 (1) NPY-receptor ligands: NPY agonists or (syn. to Zanaflex, Ternelin, Sirdalvo, Sirdalud, Mioni antagonists. dine), 0322. In a further embodiment, the other agent may be, for 0351 cc) copolymer of L-tyrosine, L-lysine, example, an anti-multiple Sclerosis drug selected from the L-glutamic acid and L-alanine, e.g. glatiramer acetate group consisting of (syn. to Copaxone, COP-1, copolymer-1), 0323 a) dihydroorotate dehydrogenase inhibitors, e.g. 0352 dd) topoisomerase II modulators, e.g. mitox SC-12267, teriflunomide, MNA-715, HMR-1279 (syn. antrone hydrochloride, to HMR-1715, MNA-279), 0353 ee)adenosine deaminase inhibitor, e.g. cladribine 0324 b) autoimmune Suppressant, e.g. laquinimod, (syn. to Leustatin, Mylinax, RWJ-26251), 0325 c) paclitaxel, 0354 ff) interleukin-10, e.g. ilodecakin (syn. to Ten 0326 d) antibodies, e.g. AGT-1, anti-granulocyte-mac ovil, Sch-52000, CSIF), rophage colony-stimulating factor (GM-CSF) mono 0355 gg) interleukin-12 antagonists, e.g. lisofylline clonal antibody, Nogo receptor modulators, ABT-874, (syn. to CT-1501 R, LSF, lysofylline), alemtuzumab (CAMPATH), anti-OX40 antibody, 0356 hh) Ethanaminum, e.g. SRI-62-834 (syn. to CNTO-1275, DN-1921, natalizumab (syn. to CRC-8605, NSC-614383), AN-100226, Antegren, VLA-4 Mab), daclizumab (syn. 0357 ii) immunomodulators, e.g. SAIK-MS, PNU to Zenepax, Ro-34-7375, SMART anti-Tac), J-695, pril 156804, alpha-fetoprotein peptide (AFP), IPDS, US 2011/00925O1 A1 Apr. 21, 2011 24

0358 i) retinoid receptoragonists, e.g. adapalene (syn. WO 2003/077858, WO 2003/074081, WO 2003/070760, to Differin, CD-271), WO 2003/063760, WO 2003/055514, WO 2003/051374, 0359 kk) TGF-beta, e.g. GDF-1 (growth and differen WO 2003/048204, WO 2003/045128, WO 2003/040183, tiation factor 1), WO 2003/039467, WO 2003/016466, WO 2003/015691, 0360 l) TGF-beta-2, e.g. BetaKine, WO 2003/014162, WO 2003/012141, WO 2002/088307, 0361 mm) MMP inhibitors, e.g. glycomed, WO 2002/088306, WO 2002/074240, WO 2002/046237, 0362 inn)phosphodiesterase 4 (PDE4) inhibitors, e.g. WO 2002/046222, WO 2002/041842, WO 2001/062801, RPR-122818, WO 2001/012598, WO 2000/077178, WO 2000/072880, 0363 oo) purine nucleoside phosphorylase inhibitors, WO 2000/063250, WO 1999/060024, WO 1999/027944, e.g. 9-(3-pyridylmethyl)-9-deazaguanine, peldesine WO 1998/044955, WO 1996/025435, WO 1994/017197, (syn. to BCX-34, TO-200), WO 1990/014840, WO 1990/O12871, WO 1990/O12870, 0364 pp) alpha-4/beta-1 integrin antagonists, e.g. ISIS WO 1989/OO6242. 104278, 0378. The beta-amyloid antibodies may be selected from, 0365) qq) antisense alpha-4 integrin (CD49d), e.g. ISIS for example, polyclonal, monoclonal, chimenic or human 17044, ISIS-27104, ized antibodies. Furthermore, said antibodies may be useful 0366 rr) cytokine-inducing agents, e.g. nucleosides, to develop active and passive immune therapies, i.e. Vaccines ICN-17261, and monoclonal antibodies. Suitable examples of beta-amy 0367 ss) cytokine inhibitors, loid antibodies are ACU-5A5, huC091 (Acumen/Merck); 0368 tt) heat shock protein vaccines, e.g. HSPPC-96, PF-4360365, RI-1014, RI-1219, RI-409, RN-1219 (Rinat 0369 uul) neuregulin growth factors, e.g. GGF-2 (syn. Neuroscience Corp (Pfizer Inc)); the nanobody therapeutics to neuregulin, glial growth factor 2), of Ablynx/Boehringer Ingelheim; beta-amyloid-specific 0370 vv) cathepsin S-inhibitors, humanized monoclonal antibodies of Intellect Neuro 0371 ww) bropirimine analogs, e.g. PNU-56169, sciences/IBL: m266, m266.2 (Eli Lilly & Co.); AAB-02 PNU-63693, (Elan); bapineuzumab (Elan); BAN-2401 (Bioarctic Neuro 0372 xx) Monocyte chemoattractant protein-1 inhibi science AB); ABP-102 (Abiogen Pharma SpA); BA-27, tors, e.g. benzimidazoles like MCP-1 inhibitors, LKS BC-05 (Takeda); R-1450 (Roche); ESBA-212 (ESBATech 1456, PD-064036, PD-064126, PD-084486, AG); AZD-3102 (AstraZeneca) and beta-amyloid antibodies PD-172084, PD-172386. of Mindset BioPharmaceuticals Inc. 0373. Further, the present invention provides pharmaceu 0379 Especially preferred are antibodies, which recog tical compositions e.g. for parenteral, enteral or oral admin nize the N-terminus of the AB peptide. A suitable antibody, istration, comprising at least one QC inhibitor, optionally in which recognizes the AB-N-Terminus is, for example Acl-24 combination with at least one of the other aforementioned (ACImmune SA). agents. 0380 Monoclonal antibodies against beta-amyloid pep 0374. These combinations provide a particularly benefi tide are disclosed in WO 2007/068412, WO/2008/156621 cial effect. Such combinations are therefore shown to be and WO/2010/012004. Respective chimeric and humanized effective and useful for the treatment of the aforementioned antibodies are disclosed in WO 2008/011348 and WO/2008/ diseases. Accordingly, the invention provides a method for 060364. Vaccine composition for treating an amyloid-associ the treatment of these conditions. ated disease is disclosed in WO/2002/096937, WO/2005/ 0375. The method comprises either co-administration of 014041, WO 2007/068411, WO/2007/097251, WO/2009/ at least one QC inhibitor and at least one of the other agents or 029272, WO/2009/054537, WO/2009/090650 WO/2009/ the sequential administration thereof. 095857, WO/2010/016912, WO/2010/01 1947, WO/2010/ 0376 Co-administration includes administration of a for 01 1999, WO/2010/044464. mulation, which comprises at least one QC inhibitor and at 0381 Suitable vaccines for treating an amyloid-associated least one of the other agents or the essentially simultaneous disease are, e.g. Affitopes AD-01 and AD-02 (GlaxoSmith administration of separate formulations of each agent. Kline), ACC-01 and ACC-02 (Elan/Wyeth), CAD-106 (No 0377 Beta-amyloid antibodies and compositions contain vartis/Cytos Biotechnology), ing the same are described, e.g. in WO/2009/065054, 0382 Suitable cysteine protease inhibitors are inhibitors WO/2009/056490, WO/2009/053696, WO/2009/033743, of cathepsin B. Inhibitors of cathepsin B and compositions WO/2007/113172, WO/2007/022416, WO 2006/137354, containing such inhibitors are described, e.g. in WO/2008/ WO 2006/118959, WO 2006/103116, WO 2006/095041, 077109, WO/2007/038772, WO 2006/060473, WO 2006/ WO 2006/081171, WO 2006/066233, WO 2006/066171, 042103, WO 2006/0398.07, WO 2006/021413, WO 2006/ WO 2006/066089, WO 2006/066049, WO 2006/055178, 021409, WO 2005/097103, WO 2005/007199, WO2004/ WO 2006/046644, WO 2006/039470, WO 2006/036291, 084830, WO 2004/078908, WO 2004/026851, WO 2002/ WO 2006/026408, WO 2006/016644, WO 2006/014638, 094881, WO 2002/027418, WO 2002/021509, WO 1998/ WO 2006/014.478, WO 2006/008661, WO 2005/123775, 046559, WO 1996/021655. WO 2005/120571, WO 2005/105998, WO 2005/081872, 0383 Examples of suitable PIMT enhancers are 10-ami WO 2005/080435, WO 2005/028511, WO 2005/025616, noaliphatyl-dibenzb, foxepines described in WO 98/15647 WO 2005/025516, WO 2005/023858, WO 2005/018424, and WO 03/057204, respectively. Further useful according to WO 2005/011599, WO 2005/000193, WO 2004/108895, the present invention are modulators of PIMT activity WO 2004/098631, WO 2004/080419, WO 2004/071408, described in WO 2004/039773. WO 2004/069182, WO 2004/067561, WO 2004/044204, 0384 Inhibitors of beta secretase and compositions con WO 2004/032868, WO 2004/031400, WO 2004/029630, taining such inhibitors are described, e.g. in WO/2010/ WO 2004/029629, WO 2004/024770, WO 2004/024090, 094242, WO/2010/058333, WO/2010/021680, WO/2009/ WO 2003/104437, WO 2003/089460, WO 2003/086310, 108550, WO/2009/042694, WO/2008/054698, WO/2007/ US 2011/00925O1 A1 Apr. 21, 2011 25

051333, WO/2007/021793, WO/2007/019080, WO/2007/ 035067, WO03/037327, WO03/04.0174, WO03/045977, 019078, WO/2007/011810, WO03/059346, WO2OO67 WO03/055881, WO03/057144, WO03/057666, WO03/ 099352, WO2006/078576, WO2006/060109, WO2OO67 068748, WO03/068757, WO03/082817, WO03/101449, 057983, WO2006/057945, WO2006/055434, WO2OO67 WO03/101958, WO03/104229, WO03/74500, WO2004/ 044497, WO2006/034296, WO2006/034277, WO2OO67 007446, WO2004/007468, WO2004/018467, WO2004/ 029850, WO2006/026204, WO2006/014944, WO2006/ 018468, WO2004/018469, WO2004/026822, WO2004/ 0.14762, WO2006/002004, U.S. Pat. No. 7,109,217, 032836, WO2004/033455, WO2004/037169, WO2004/ WO2005/113484, WO2005/103043, WO2005/103020, 041795, WO2004/043940, WO2004/048352, WO2004/ WO2005/065195, WO2005/051914, WO2005/044830, 05.0022, WO2004/052850, WO2004/058266, WO2004/ WO2005/032471, WO2005/018545, WO2005/004803, 064778, WO2004/069162, WO2004/071454, WO2004/ WO2005/004802, WO2004/062625, WO2004/043916, 076433, WO2004/076434, WO2004/087053, WO2004/ WO2004/013098, WO03/099202, WO03/043987, WO03/ 089362, WO2004/099185, WO2004/103276, WO2004/ 039454, U.S. Pat. No. 6,562,783, WO02/098849 and WO02/ 103993, WO2004/108730, WO2004/110436, WO2004/ O96897. 111041, WO2004/112701, WO2005/000846, WO2005/ 0385 Suitable examples of beta secretase inhibitors for 000848, WO2005/011581, WO2005/016911, WO2005/ the purpose of the present invention are WY-25105 (Wyeth); 023762, WO2005/025554, WO2005/026148, WO2005/ Posiphen, (+)-phenserine (Torrey Pines/NIH); LSN 030751, WO2005/033106, WO2005/037828, WO2005/ 2434074, LY-2070275, LY-2070273, LY-2070102 (Eli Lilly 040095, WO2005/044195, WO2005/047297, WO2005/ & Co.); PNU-159775A, PNU-178025A, PNU-17820A, 051950, WO2005/056003, WO2005/056013, WO2005/ PNU-33312, PNU-38773, PNU-90530 (Elan/Pfizer); KMI 058849, WO2005/075426, WO2005/082348, WO2005/ 370, KMI-358, kmi-008 (Kyoto University); OM-99-2, 085246, WO2005/087235, WO2005/095339, WO2005/ OM-003 (Athenagen Inc.); AZ-12304146 (AstraZeneca/AS 095343, WO2005/095381, WO2005/108382, WO2005/ tex); GW-840736X (GlaxoSmithKline plc.), DNP-004089 113510, WO2005/116014, WO2005/116029, WO2005/ (De Novo Pharmaceuticals Ltd.) and CT-21166 (CoMentis 118555, WO2005/120494, WO2005/121089, WO2005/ Inc.). 121131, WO2005/123685, WO2006/995613; WO2006/ 0386 Inhibitors of gamma secretase and compositions 009886: WO2006/013104; WO2006/017292; WO2006/ containing such inhibitors are described, e.g. in WO/2010/ 019965; WO2006/020017; WO2006/023750; WO2006/ 090954, WO/2009/011851, WO/2009/008980, WO/2008/ 039325; WO2006/041976: WO2006/047248: WO2006/ 147800, WO/2007/084595, WO2005/008250, WO2006/ 058.064; WO2006/058628: WO2006/066747; WO2006/ 004880, U.S. Pat. No. 7,122,675, U.S. Pat. No. 7,030,239, O6677O and WO2O06/068978. U.S. Pat. No. 6,992,081, U.S. Pat. No. 6,982,264, WO2005/ (0388 Suitable DP IV-inhibitors for the purpose of the 097768, WO2005/028440, WO2004/101562, U.S. Pat. No. present invention are for example Sitagliptin, des-fluoro-sita 6,756,511, U.S. Pat. No. 6,683,091, WO03/066592, WO03/ gliptin (Merck & Co. Inc.); Vildagliptin, DPP-728, SDZ-272 014075, WO03/013527, WO02/36555, WO01/.53255, U.S. 070 (Novartis); ABT-279, ABT-341 (Abbott Laboratories): Pat. No. 7,109,217, U.S. Pat. No. 7, 101,895, U.S. Pat. No. denagliptin, TA-6666 (GlaxoSmithKline plc.); SYR-322 7,049,296, U.S. Pat. No. 7,034,182, U.S. Pat. No. 6,984,626, (Takeda San Diego Inc.); tallabostat (Point Therapeutics Inc.); WO2005/040126, WO2005/030731, WO2005/014553, U.S. Ro-0730699, R-1499, R-1438 (Roche Holding AG): Pat. No. 6,890,956, EP 1334085, EP 1263774, WO2004/ FE-999011 (Ferring Pharmaceuticals);TS-021 (Taisho Phar 101538, WO2004/00958, WO2004/089911, WO2004/ maceutical Co. Ltd.); GRC-8200 (Glenmark Pharmaceuti 073630, WO2004/069826, WO2004/039370, WO2004/ cals Ltd.); ALS-2-0426 (Alantos Pharmaceuticals Holding 03.1139, WO2004/031137, U.S. Pat. No. 6,713,276, U.S. Pat. Inc.); ARI-2243 (Arisaph Pharmaceuticals Inc.); No. 6,686,449, WO03/091278, U.S. Pat. No. 6,649,196, U.S. SSR-162369 (Sanofi-Synthelabo); MP-513 (Mitsubishi Pat. No. 6,448,229, WOO1/77144 and WOO1/66564. Suitable Pharma Corp.); DP-893, CP-867534-01 (Pfizer Inc.); TSL gamma secretase inhibitors for the purpose of the present 225, TMC-2A (Tanabe Seiyaku Co. Ltd.); PHX-1149 (Phe invention are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); nomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.); MK-0752, MRK-560, L-852505, L-685-458, L-852631, PSN-9301 ((OSI) Prosidion), S-40755 (Servier); KRP-104 L-852646 (Merck & Co. Inc.); LY-450139, LY-411575, (ActivX Biosciences Inc.); sulphostin (Zaidan Hojin); AN-37124 (Eli Lilly & Co.); BMS-299897, BMS-433796 KR-62436 (Korea Research Institute of Chemical Technol (Bristol-Myers Squibb Co.); E-2012 (Eisai Co. Ltd.); EHT ogy); P32/98 (Probiodrug AG); BI-A, BI-B (Boehringer 0206, EHT-206 (Exon Hit Therapeutics SA); NGX-555 (Tor Ingelheim Corp.); SK-0403 (Sanwa Kagaku Kenkyusho Co. reyPines Therapeutics Inc.) and Semagacestat (Eli Lilly). Ltd.); and NNC-72-2138 (Novo Nordisk A/S). 0387 DPIV-inhibitors and compositions containing such (0389. Other preferred DPIV-inhibitors are inhibitors are described, e.g. in U.S. Pat. No. 6,011, 155; U.S. (i) dipeptide-like compounds, disclosed in WO99/61431, e.g. Pat. No. 6,107,317; U.S. Pat. No. 6,110,949; U.S. Pat. No. N-Valyl prolyl, O-benzoyl hydroxylamine, alanyl pyrroli 6,124,305; U.S. Pat. No. 6,172,081; WO99/61431, WO99/ dine, isoleucyl thiazolidine like L-allo-isoleucyl thiazolidine, 67278, WO99/67279, DE 1983.4591, WO97/40832, WO95/ L-threo-isoleucyl pyrrolidine and salts thereof, especially the 15309, WO98/19998, WO00/07617, WO99/38501, WO99/ fumaric salts, and L-allo-isoleucyl pyrrolidine and salts 46272, WO99/38501, WO01/68603, WO01/40180, WO01/ thereof; 81337, WO01/81304, WO01/55105, WO02/02560, WO01/ (ii) peptide structures, disclosed in WO 03/002593, e.g. trip 34594, WO02/38541, WO02/083128, WO03/072556, eptides; WO03/002593, WO03/000250, WO03/000180, WO03/ (iii) peptidylketones, disclosed in WO 03/033524: 000181, EP1258476, WO03/002553, WO03/002531, WO03/ (vi) substituted aminoketones, disclosed in WO 03/04.0174: 002530, WO03/004496, WO03/004498, WO03/024942, (v) topically active DP IV-inhibitors, disclosed in WO WO03/024965, WO03/033524, WO03/035057, WO03/ 01/14318; US 2011/00925O1 A1 Apr. 21, 2011 26

(vi) prodrugs of DPIV-inhibitors, disclosed in WO99/67278 land); isocarboxazid; phenelzine; tranylcypromine; indanta and WO99/67279; and dol (Chiesi Farmaceutici SpA.); moclobemide (Roche Hold (v) glutaminyl based DP IV-inhibitors, disclosed in WO ing AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370 O3/072556 and WO 2004/099.134. (Burroughs Wellcome Co.); CX-157 (Krenitsky Pharmaceu 0390 Suitable beta amyloid synthesis inhibitors for the ticals Inc.); desoxypeganine (HF Arzneimittelforschung purpose of the present invention are for example Bisnorcym GmbH & Co. KG); bifemelane (Mitsubishi-Tokyo Pharma serine (Axonyx Inc.); (R)-flurbiprofen (MCP-7869: Flurizan) ceuticals Inc.); RS-1636 (Sankyo Co. Ltd.); esuprone (BASF (Myriad Genetics): nitroflurbiprofen (NicOx); BGC-20-0406 AG); rasagiline (Teva Pharmaceutical Industries Ltd.); lados (Sankyo Co. Ltd.) and BGC-20-0466 (BTG plc.), tigil (Hebrew University of Jerusalem); safinamide (Pfizer), RQ-00000009 (RaCualia Pharma Inc). NW-1048 (Newron Pharmaceuticals SpA.), EVT-302 (Evo 0391 Suitable amyloid protein deposition inhibitors for tec). the purpose of the present invention are for example SP-233 (Samaritan Pharmaceuticals); AZD-103 (Ellipsis Neuro 0395 Suitable histamine H3 antagonists for the purpose of therapeutics Inc.); AAB-001 (BapineuZumab), AAB-002, the present invention are, e.g. ABT-239, ABT-834 (Abbott ACC-001 (Elan Corp plc.); Colostrinin (ReCien Therapeutics Laboratories): 3874-H1 (Aventis Pharma); UCL-2173 (Ber plc.); Tramiprosate (Neurochem); AdPEDI-(amyloid-beta1 lin Free University), UCL-1470 (BioProjet, Societe Civile de 6)11) (Vaxin Inc.); MPI-127585, MPI-423948 (Mayo Foun Recherche); DWP-302 (Daewoong Pharmaceutical Co Ltd); dation); SP-08 (Georgetown University); ACU-5A5 (Acu GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); men/Merck); Transthyretin (State University of New York); cipralisant, GT-2203 (Gliatech Inc.); Ciproxifan (INSERM), PTI-777, DP-74, DP 68, Exebryl (ProteoTech Inc.); m266 1S,2S-2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (Eli Lilly & Co.); EGb-761 (Dr. Willmar Schwabe GmbH): (Hokkaido University); JNJ-17216498, JNJ-5207852 SPI-014 (Satori Pharmaceuticals Inc.); ALS-633, ALS-499 (Johnson & Johnson); NNC-0038-0000-1049 (Novo Nordisk (Advanced Life Sciences Inc.); AGT-160 (ArmaCien Tech A/S); and Sch-79687 (Schering-Plough). nologies Inc.); TAK-070 (Takeda Pharmaceutical Co. Ltd.); 0396 PEP inhibitors and compositions containing such CHF-5022, CHF-5074, CHF-5096 and CHF-5105 (Chiesi inhibitors are described, e.g. in JP 01042465, JP 03031298, Farmaceutici SpA.), SEN-1176 and SEN-1329 (Senexis JP 04208299, WO 00/71144, U.S. Pat. No. 5,847,155; JP Ltd.), AGT-160 (ArmaCien Technologies), Davunetide (Al 09040693, JP 10077300, JP 05331072, JP 05015314, WO lon Therapeutics), ELND-005 (Elan Corp/Transition Thera 95/15310, WO 93/00361, EP 0556482, JP 06234693, JP peutics) and nilvadipine (Archer Pharmaceuticals). 01068396, EP 0709373, U.S. Pat. No. 5,965,556, U.S. Pat. 0392 Suitable PDE-4 inhibitors for the purpose of the present invention are for example Doxofylline (Instituto Bio No. 5,756,763, U.S. Pat. No. 6,121,311, JP 63264454, JP logico Chemioterapica ABC SpA.); idudilast eye drops, tipe 64000069, JP 63162672, EP 0268190, EP 0277588, EP lukast, ibudilast (Kyorin Pharmaceutical Co. Ltd.); theophyl 0275482, U.S. Pat. No. 4,977, 180, U.S. Pat. No. 5,091,406, line (Elan Corp.); cilomilast (GlaxoSmithKline plc.); Atopik U.S. Pat. No. 4,983,624, U.S. Pat. No. 5,112,847, U.S. Pat. (Barrier Therapeutics Inc.); tofimilast, CI-1044, PD-189659, No. 5,100,904, U.S. Pat. No. 5,254,550, U.S. Pat. No. 5,262, CP-220629, PDE 4d inhibitor BHN (Pfizer Inc.); arofylline, 431, U.S. Pat. No. 5,340,832, U.S. Pat. No. 4,956,380, EP LAS-37779 (Almirall Prodesfarma S.A.); roflumilast, 0303434, JP 03056486, JP 01143897, JP 1226880, EP hydroxypumafentrine (Altana AG), tetomilast (Otska Phar 0280956, U.S. Pat. No. 4,857,537, EP 0461677, EP 0345428, maceutical Co. Ltd.); tipelukast, ibudilast (Kyorin Pharma JP 02275858, U.S. Pat. No. 5,506,256, JP 061922.98, EP ceutical), CC-10004 (Celgene Corp.); HT-0712, IPL-4088 0618.193, JP 03255080, EP 0468469, U.S. Pat. No. 5,118, (Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917 811, JP 05025125, WO 93 13065, JP 05201970, WO (Memory Pharmaceuticals Corp.); oglemilast, GRC-4039 9412474, EP 0670309, EP 0451547, JP 06339390, U.S. Pat. (Glenmark Pharmaceuticals Ltd.); AWD-12-281, ELB-353, No. 5,073,549, U.S. Pat. No. 4,999,349, EP 0268281, U.S. ELB-526 (Elbion AG); EHT-0202 (Exon Hit Therapeutics Pat. No. 4,743,616, EP 0232849, EP 022.4272, JP 621 14978, S.A.); ND-1251 (Neuro3d S.A.); 4AZA-PDE4 (4 AZA Bio JP 621 14957, U.S. Pat. No. 4,757,083, U.S. Pat. No. 4,810, science NV.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottap 721, U.S. Pat. No. 5,198.458, U.S. Pat. No. 4,826,870, EP harm SpA.); GP-0203, NCS-613 (Centre National de la 0201742, EP 0201741, U.S. Pat. No. 4,873,342, EP 0172458, Recherche Scientifique); KF-19514 (Kyowa Hakko Kogyo JP 61037764, EP 0201743, U.S. Pat. No. 4,772,587, EP Co. Ltd.); ONO-6126 (Ono Pharmaceutical Co. Ltd.); 0372484, U.S. Pat. No. 5,028,604, WO 91/18877, JP OS-0217 (Dainippon Pharmaceutical Co. Ltd.); IBFB 04009367, JP 04235162, U.S. Pat. No. 5,407,950, WO 130011, IBFB-150007, IBFB-130020, IBFB-140301 (IBFB 95/01352, JP 01250370, JP 02207070, U.S. Pat. No. 5,221, Pharma GmbH); IC-485 (ICOS Corp.); RBX-14016 and 752, EP 0468339, JP 04211648, WO 99/46272, WO 2006/ RBX-11082 (Ranbaxy Laboratories Ltd.). A preferred PDE O5872O and PCTAEP2006/061428. 4-inhibitor is Rolipram. 0397 Suitable prolyl endopeptidase inhibitors for the pur 0393 MAO inhibitors and compositions containing such pose of the present invention are, e.g. Fmoc-Ala-Pyrr-CN. inhibitors are described, e.g. in WO2006/091988, WO2005/ Z-Phe-Pro-Benzothiazole (Probiodrug), Z-321 (Zeria Phar 007614, WO2004/089351, WO01/26656, WO01/12176, maceutical Co Ltd.); ONO-1603 (Ono Pharmaceutical Co WO99/57120, WO99/57119, WO99/13878, WO98/4.0102, Ltd); JTP-4819 (Japan Tobacco Inc.) and S-17092 (Servier). WO98/01157, WO96/20946, WO94/07890 and WO92/ 0398. Other suitable compounds that can be used accord 21333. ing to the present invention in combination with QC-inhibi 0394 Suitable MAO-inhibitors for the purpose of the tors are NPY, an NPY mimetic or an NPYagonist or antago present invention are for example Linezolid (Pharmacia nist or a ligand of the NPY receptors. Corp.); RWJ-416457 (RWJohnson Pharmaceutical Research 0399 Preferred according to the present invention are Institute); budipine (Altana AG); GPX-325 (BioResearch Ire antagonists of the NPY receptors. US 2011/00925O1 A1 Apr. 21, 2011 27

0400 Suitable ligands orantagonists of the NPY receptors 032929, WO03/101458, WO03/091220, WO03/082820, are 3a,4,5,9b-tetrahydro-1h-benzeindol-2-yl amine-de WO03/020289, WO02/32412, WO01/85145, WO01/78728, rived compounds as disclosed in WO 00/68197. WO01/66096, WO00/02549, WO01/00215, WO00/15205, 0401 NPY receptor antagonists which may be mentioned WO00/23057, WO00/33840, WO00/30446, WO00/23057, include those disclosed in European patent applications EP 0 WO00/15205, WO00/09483, WO00/07600, WO00/02549, 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378: WO99/47131, WO99/07359, WO98/30243, WO97/38993, international patent applications WO 94/17035, WO WO97/13754, WO94/29255, WO94/20476, WO94/19356, 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO WO93/03034 and WO92/19238. 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 0406 Suitable acetylcholinesterase inhibitors for the pur 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO pose of the present invention are for example Donepezil (Ei 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO sai Co. Ltd.); rivastigmine (Novartis AG). (-)-phenserine 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; (Torrey Pines Therapeutics); ladostigil (Hebrew University of WO 00/30674, U.S. Pat. Nos. 5,552,411, 5,663,192 and Jerusalem); huperzine A (Mayo Foundation); galantamine 5,567,714; 6,114.336, Japanese patent application JP (Johnson & Johnson); Memoquin (Universita di Bologna); 09157253; international patent applications WO 94/00486, SP-004 (Samaritan Pharmaceuticals Inc.); BGC-20-1259 WO 93/12139, WO95/00161 and WO 99/15498: U.S. Pat. (Sankyo Co. Ltd.); physostigmine (Forest Laboratories Inc.); No. 5,328,899; German patent application DE 393 9797; NP-0361 (Neuropharma SA); ZT-1 (Debiopharm); tacrine European patent applications EP 355 794 and EP 355 793; (Warner-Lambert Co.); metrifonate (Bayer Corp.), INM-176 and Japanese patent applications JP 06116284 and JP (Whanlin), huperzine A (Neuro-Hitech/Xel Pharmaceutical), 07267988. Preferred NPY antagonists include those com mimopezil (Debiopharm) and Dimebon (Medivation/Pfizer). pounds that are specifically disclosed in these patent docu 04.07 NMDA receptor antagonists and compositions con ments. More preferred compounds include amino acid and taining such inhibitors are described, e.g. in WO2006/ non-peptide-based NPY antagonists. Amino acid and non 094674, WO2006/058236, WO2006/058059, WO2006/ peptide-based NPY antagonists which may be mentioned 010965, WO2005/000216, WO2005/102390, WO2005/ include those disclosed in European patent applications EP 0 079779, WO2005/079756, WO2005/072705, WO2005/ 614 911, EP 0 747 357, EP 0 747 356 and EP 0 747 378: 070429, WO2005/055996, WO2005/035522, WO2005/ international patent applications WO 94/17035, WO 009421, WO2005/000216, WO2004/09218.9, WO2004/ 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 039371, WO2004/028522, WO2004/009062, WO03/ 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 010159, WO02/072542, WO02/34718, WO01/98262, 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO WO01/94321, WO01/92204, WO01/81295, WOO1/32640, 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO WO01/10833, WO01/10831, WO00/56711, WO00/29023, 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO00/001.97, WO99/53922, WO99/48891, WO99/45963, WO 99/15498: U.S. Pat. Nos. 5,552,411, 5,663,192 and WO99/01416, WO99/07413, WO99/01416, WO98/50075, 5,567,714; and Japanese patent application JP 09157253. WO98/50044, WO98/10757, WO98/05337, WO97/32873, Preferred amino acid and non-peptide-based NPY antago WO97/23216, WO97/23215, WO97/23214, WO96/14318, nists include those compounds that are specifically disclosed WO96/08485, WO95/3 1986, WO95/26352, WO95/26350, in these patent documents. WO95/26349, WO95/26342, WO95/12594, WO95/02602, 0402 Particularly preferred compounds include amino WO95/02601, WO94/20109, WO94/13641, WO94/09016 acid-based NPY antagonists. Amino acid-based compounds, and WO93/25534. which may be mentioned include those disclosed in interna 0408 Suitable NMDA receptor antagonists for the pur tional patent applications WO 94/17035, WO 97/19911, WO pose of the present invention are for example Memantine 97/19913, WO 97/19914 or, preferably, WO 99/15498. Pre (Merz & Co. GmbH); topiramate (Johnson & Johnson); AVP ferred amino acid-based NPY antagonists include those that 923 (Neurodex) (Center for Neurologic Study); EN-3231 are specifically disclosed in these patent documents, for (Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ example BIBP3226 and, especially, (R) N-2-(dipheny 2/579) (Merz and Forest); CNS-5161 (CeNeS Pharmaceuti lacetyl)-(R) N-1-(4-hydroxy-phenyl)ethyl arginine cals Inc.); dexanabinol (HU-211: Sinnabidol: PA-50211) amide (Example 4 of international patent application WO (Pharmos); EpiCept NP-1 (Dalhousie University); indantadol 99/15498). (V-3381; CNP-3381) (Vernalis); perzinfotel (EAA-090, 0403 M1 receptor agonists and compositions containing WAY-126090, EAA-129) (Wyeth); RGH-896 (Gedeon Rich such inhibitors are described, e.g. in WO2004/087158, ter Ltd.); traxoprodil (CP-101606), besonprodil (PD-196860, WO91f10664. CI-1041) (Pfizer Inc.); CGX-1007 (Cognetix Inc.); delucem 04.04 Suitable M1 receptor antagonists for the purpose of ine (NPS-1506) (NPS Pharmaceuticals Inc.); EVT-101 the present invention are for example CDD-0102 (Cognitive (Roche Holding AG); acamprosate (Synchroneuron LLC.); Pharmaceuticals); Cevimeline (Evoxac) (Snow Brand Milk CR-3991, CR-2249, CR-3394 (Rottapharm SpA.); AV-101 Products Co. Ltd.); NGX-267 (TorreyPines Therapeutics): (4-Cl-kynurenine (4-Cl-KYN)), 7-chloro-kynurenic acid sabcomeline (GlaxoSmithKline); alvameline (H Lundbeck (7-Cl-KYNA) (VistaGen); NPS-1407 (NPS Pharmaceuticals A/S); LY-593093 (Eli Lilly & Co.); VRTX-3 (Vertex Phar Inc.); YT-1006 (Yaupon Therapeutics Inc.); ED-1812 (Sosei maceuticals Inc.); WAY-132983 (Wyeth), CI-101 7/(PD R&D Ltd.); himantane (hydrochloride N-2-(adamantly)-hex 151832) (Pfizer Inc.) and MCD-386 (Mitridion Inc.). amethylen-imine) (RAMS); Lancicemine (AR-R-15896) 04.05 Acetylcholinesterase inhibitors and compositions (AstraZeneca); EVT-102, Ro-25-6981 and Ro-63-1908 containing such inhibitors are described, e.g. in WO2006/ (Hoffmann-La Roche AG/Evotec), neramexane (Merz). 071274, WO2006/070394, WO2006/040688, WO2005/ 04.09 Furthermore, the present invention relates to com 092009, WO2005/079789, WO2005/0395.80, WO2005/ bination therapies useful for the treatment of atherosclerosis, 027975, WO2004/084884, WO2004/037234, WO2004/ restenosis or arthritis, administering a QC inhibitor in com US 2011/00925O1 A1 Apr. 21, 2011 28 bination with another therapeutic agent selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibi tors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors: MCP-1 antagonists and tyrosine kinase inhibitors or, in each case, a pharmaceutically acceptable salt thereof. providing beneficial or synergistic therapeutic effects over 0412 Preferred AT1-receptor antagonists are those agents each monotherapy component alone. that have been approved and reached the market, most pre ferred is Valsartan, or a pharmaceutically acceptable salt 0410 Angiotensin II receptor blockers are understood to thereof. be those active agents that bind to the AT1-receptor subtype of 0413. The interruption of the enzymatic degradation of angiotensin II receptor but do not result in activation of the angiotensin to angiotensin II with ACE inhibitors is a Suc receptor. As a consequence of the blockade of the AT1 recep cessful variant for the regulation of blood pressure and thus tor, these antagonists can, e.g. be employed as antihyperten also makes availableatherapeutic method for the treatment of sive agents. hypertension. 0411 Suitable angiotensin II receptor blockers which may 0414. A suitable ACE inhibitor to be employed in the combination of the present invention is, e.g. a compound be employed in the combination of the present invention selected from the group consisting alacepril, benazepril, include AT receptor antagonists having differing structural benazeprilat, captopril, ceronapril, cilaZapril, delapril, enala features, preferred are those with non-peptidic structures. For pril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, example, mention may be made of the compounds that are perindopril, quinapril, ramipril, spirapril, temocapril and selected from the group consisting of Valsartan (EP 443983), trandolapril, or in each case, a pharmaceutically acceptable losartan (EP 253310), candesartan (EP 459136), eprosartan salt thereof. (EP 403159), irbesartan (EP 454511), olmesartan (EP 0415 Preferred ACE inhibitors are those agents that have 503785), tasosartan (EP 539086), telmisartan (EP522314), been marketed, most preferred are benazepril and enalapril. the compound with the designation E-41 77 of the formula 0416 A diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydro chlorothiazide, methylclothiazide, and chlorothalidon. The most preferred diuretic is hydrochlorothiazide. A diuretic furthermore comprises a potassium sparing diuretic Such as - OH amiloride or triameterine, or a pharmaceutically acceptable 1\-N O salt thereof. 0417. The class of CCBs essentially comprises dihydro pyridines (DHPs) and non-DHPs, such as diltiazem-type and Verapamil-type CCBs. N ( ) ( ) 0418 ACCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, the compound with the designation SC-52458 of the follow nisoldipine, nitrendipine and nivaldipine, and is preferably a ing formula non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and Verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti angina pectoris or anti-arrhythmic drugs. N H 0419 Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and Verapamil or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof. Especially preferred as DHP is amlodipine or a pharmaceutically accept able salt thereof, especially the besylate. An especially pre ferred representative of non-DHPs is verapamil or a pharma ceutically acceptable salt, especially the hydrochloride, thereof. 0420 Beta-blockers suitable for use in the present inven and the compound with the designation the compound tion include beta-adrenergic blocking agents (beta-blockers), ZD-8731 of the formula which compete with epinephrine for beta-adrenergic recep US 2011/00925O1 A1 Apr. 21, 2011 29 tors and interfere with the action of epinephrine. Preferably, 0430. A suitable inhibitor of extracellular matrix synthesis the beta-blockers are selective for the beta-adrenergic recep is halofuginone. tor as compared to the alpha-adrenergic receptors, and so do 0431. A suitable growth factor or cytokine signal trans not have a significant alpha-blocking effect. Suitable beta duction inhibitor is, e.g. the ras inhibitor R115777. blockers include compounds selected from acebutolol. 0432 A suitable tyrosine kinase inhibitor is tyrphostin. atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, 0433 Suitable renin inhibitors are described, e.g. in WO labetalol, metoprolol, nadolol, oXprenolol, penbutolol, pin 2006/116435. A preferred renin inhibitor is aliskiren, prefer dolol, propranolol, Sotalol and timolol. Where the beta ably in the form of the hemi-fumarate salt thereof. blocker is an acid or base or otherwise capable of forming 0434 MCP-1 antagonists may, e.g. be selected from anti pharmaceutically acceptable salts or prodrugs, these forms MCP-1 antibodies, preferably monoclonal or humanized are considered to be encompassed herein, and it is understood monoclonal antibodies, MCP-1 expression inhibitors, CCR2 that the compounds may be administered in free form or in the antagonists, TNF-alpha inhibitors, VCAM-1 gene expression form of a pharmaceutically acceptable salt or a prodrug. Such inhibitors and anti-C5a monoclonal antibodies. as a physiologically hydrolyzable and acceptable ester. For 0435 MCP-1 antagonists and compositions containing example, metoprolol is suitably administered as its tartrate such inhibitors are described, e.g. in WO02/070509, WO02/ salt, propranolol is suitably administered as the hydrochlo 081463, WO02/060900, US2006/670364, US2006/677365, ride salt, and so forth. WO2006/097624, US2006/316449, WO2004/056727, 0421 Platelet aggregation inhibitors include PLAVIX(R) WO03/053368, WO00/198289, WO00/157226, WO00/ (clopidogrel bisulfate), PLETAL(R) (cilostazol) and aspirin. 046195, WO00/0461.96, WO00/046199, WO00/046198, 0422 Cholesterol absorption modulators include WO00/046197, WO99/046991, WO99/007351, WO98/ ZETIAR (ezetimibe) and KT6-971 (Kotobuki Pharmaceuti 006703, WO97/012615, WO2005/105133, WO03/037376, cal Co. Japan). WO2006/125202, WO2006/085961, WO2004/024921, 0423 HMG-Co-A reductase inhibitors (also called beta WO2006/074265. hydroxy-beta-methylglutaryl-co-enzyme-A reductase 0436 Suitable MCP-1 antagonists are, for instance, C-243 inhibitors or statins) are understood to be those active agents (Telik Inc.); NOX-E36 (Noxxon Pharma AG); AP-761 (Acti which may be used to lower lipid levels including cholesterol mis Pharmaceuticals Inc.); ABN-912, NIBR-177 (Novartis in blood. AG); CC-1 1006 (Celgene Corp.); SSR-150106 (Sanofi 0424 The class of HMG-Co-A reductase inhibitors com Aventis); MLN-1202 (Millenium Pharmaceuticals Inc.); prises compounds having differing structural features. For AGI-1067, AGIX-4207, AGI-1096 (AtherioGenics Inc.); example, mention may be made of the compounds, which are PRS-211095, PRS-211092 (Pharmos Corp.); anti-C5amono selected from the group consisting of atorvastatin, cerivasta clonal antibodies, e.g. neutraZumab (G2 Therapies Ltd.); tin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvas AZD-6942 (AstraZeneca plc.); 2-mercaptoimidazoles tatin and simvastatin, or in each case, a pharmaceutically (Johnson & Johnson); TE 1-E00526, TEI-6122 (Deltagen); acceptable salt thereof. RS-504393 (Roche Holding AG); SB-282241, SB-380732, 0425 Preferred HMG-Co-Areductase inhibitors are those ADR-7 (GlaxoSmithKline); anti-MCP-1 monoclonal anti agents, which have been marketed, most preferred is atorv bodies (Johnson & Johnson). astatin, pitavastatin or simvastatin, or a pharmaceutically 0437 Combinations of QC-inhibitors with MCP-1 acceptable salt thereof. antagonists may be useful for the treatment of inflammatory 0426 HDL-increasing compounds include, but are not diseases in general, including neurodegenerative diseases. limited to, cholesterol ester transfer protein (CETP) inhibi 0438 Combinations of QC-inhibitors with MCP-1 tors. Examples of CETP inhibitors include JTT7O5 disclosed antagonists are preferred for the treatment of Alzheimer's in Example 26 of U.S. Pat. No. 6,426,365 issued Jul.30, 2002, disease. and pharmaceutically acceptable salts thereof. 0439 Most preferably the QC inhibitor is combined with 0427. Inhibition of interleukin 6 mediated inflammation one or more compounds selected from the following group: may beachieved indirectly through regulation of endogenous PF-43603.65, m266, bapineuzumab, R-1450, Posiphen, (+)- cholesterol synthesis and isoprenoid depletion or by direct phenserine, MK-0752, LY-450139, E-2012, (R)-flurbiprofen, inhibition of the signal transduction pathway utilizing inter AZD-103, AAB-001 (Bapineuzumab), Tramiprosate, EGb leukin-6 inhibitor/antibody, interleukin-6 receptor inhibitor/ 761, TAK-070, Doxofylline, theophylline, cilomilast, tofimi antibody, interleukin-6 antisense oligonucleotide (ASON). last, roflumilast, tetomilast, tipelukast, ibudilast, HT-0712, gp130 protein inhibitor/antibody, tyrosine kinase inhibitors/ MEM-1414, oglemilast, Linezolid, budipine, isocarboxazid, antibodies, serine/threonine kinase inhibitors/antibodies, phenelZine, tranylcypromine, indantadol, moclobemide, mitogen-activated protein (MAP) kinase inhibitors/antibod rasagiline, ladostigil, safinamide, ABT-239, ABT-834, GSK ies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibod 189254A, Ciproxifan, JNJ-17216498, Fmoc-Ala-Pyrr-CN, ies, Nuclear factor kappaB (NF-kB) inhibitors/antibodies, Z-Phe-Pro-Benzothiazole, Z-321, ONO-1603, JTP-4819, IKB kinase (IKK) inhibitors/antibodies, activator protein-1 S-17092, BIBP3226; (R) N-2-(diphenylacetyl)-(R) N (AP-1) inhibitors/antibodies, STAT transcription factors 1-(4-hydroxyphenyl)ethyl arginine amide, Cevimeline, inhibitors/antibodies, altered IL-6, partial peptides of IL-6 or sabcomeline, (PD-151832), Donepezil, rivastigmine, (-)- IL-6 receptor, or SOCS (Suppressors of cytokine signaling) phenserine, ladostigil, galantamine, tacrine, metrifonate, protein, PPARgamma and/or PPAR beta/delta activators/ Memantine, topiramate, AVP-923. EN-3231, neramexane, ligands or a functional fragment thereof. Valsartan, benazepril, enalapril, hydrochlorothiazide, amlo 0428. A suitable antiinflammatory corticosteroid is dex dipine, diltiazem, isradipine, nicardipine, nifedipine, nimo amethasone. dipine, nisoldipine, nitrendipine, Verapamil, amlodipine, ace 0429 Suitable antiproliferative agents are cladribine, butolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, rapamycin, Vincristine and taxol. esmolol, labetalol, metoprolol, nadolol, oXprenolol, penb US 2011/00925O1 A1 Apr. 21, 2011 30 utolol, pindolol, propranolol, Sotalol, timolol, PLAVIX(R) 0452) a QC inhibitor, preferably a QC inhibitor of for (clopidogrel bisulfate), PLETAL(R) (cilostazol), aspirin, mula (I), more preferably a QC inhibitor selected from ZETIAR (ezetimibe) and KT6-971, statins, atorvastatin, any one of examples 1-235, in combination with HMG pitavastatin or simvastatin; dexamethasone, cladribine, rapa Co-A-reductase inhibitors, for the prevention and/or mycin, Vincristine, taxol, alliskiren, C-243, ABN-912, SSR treatment of restenosis, wherein the HMG-Co-A-reduc 150106, MLN-1202 and betaferon. tase inhibitor is selected from atorvastatin, cerivastatin, 0440. In particular, the following combinations are con fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvas sidered: tatin and simvastatin, 0441 a QC inhibitor, preferably a QC inhibitor of for 0453 a QC inhibitor, preferably a QC inhibitor of for mula (I), more preferably a QC inhibitor selected from mula (I), more preferably a QC inhibitor selected from any one of examples 1-235, in combination with Atorv any one of examples 1-235, in combination with HMG astatin for the treatment and/or prevention of arthero Co-A reductase inhibitors, for the prevention and/or Sclerosis, treatment of atherosclerosis wherein the HMG-Co-A- 0442 a QC inhibitor, preferably a QC inhibitor of for reductase inhibitor is selected from atorvastatin, ceriv mula (I), more preferably a QC inhibitor selected from astatin, fluvastatin, lovastatin, pitavastatin, pravastatin, any one of examples 1-235, in combination with immu rosuvastatin and simvastatin, nosuppressive agents, preferably rapamycin for the pre 0454) a QC inhibitor, preferably a QC inhibitor of for vention and/or treatment of restenosis, mula (I), more preferably a QC inhibitor selected from 0443) a QC inhibitor, preferably a QC inhibitor of for any one of examples 1-235, in combination with HMG mula (I), more preferably a QC inhibitor selected from Co-A reductase inhibitors, for the prevention and/or any one of examples 1-235, in combination with immu treatment of rheumatoid arthritis wherein the HMG-Co nosuppressive agents, preferably paclitaxel for the pre A-reductase inhibitor is selected from atorvastatin, vention and/or treatment of restenosis, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravas 0444 a QC inhibitor, preferably a QC inhibitor of for tatin, rosuvastatin and simvastatin, mula (I), more preferably a QC inhibitor selected from 0455 a QC inhibitor, preferably a QC inhibitor of for any one of examples 1-235, in combination with AChE mula (I), more preferably a QC inhibitor selected from inhibitors, preferably Donepezil, for the prevention and/ any one of examples 1-235, in combination with amy or treatment of Alzheimer's disease, loid-beta antibodies for the prevention and/or treatment 0445 a QC inhibitor, preferably a QC inhibitor of for of mild cognitive impairment, wherein the amyloid-beta mula (I), more preferably a QC inhibitor selected from antibody is Act-24, any one of examples 1-235, in combination with inter 0456) a QC inhibitor, preferably a QC inhibitor of for ferones, preferably Aronex, for the prevention and/or mula (I), more preferably a QC inhibitor selected from treatment of multiple Sclerosis, any one of examples 1-235, in combination with amy 0446 a QC inhibitor, preferably a QC inhibitor of for loid-beta antibodies for the prevention and/or treatment mula (I), more preferably a QC inhibitor selected from of Alzheimer's disease, wherein the amyloid-beta anti any one of examples 1-235, in combination with inter body is Act-24, ferones, preferably betaferon, for the prevention and/or 0457 a QC inhibitor, preferably a QC inhibitor of for treatment of multiple Sclerosis, mula (I), more preferably a QC inhibitor selected from 0447 a QC inhibitor, preferably a QC inhibitor of for any one of examples 1-235, in combination with amy mula (I), more preferably a QC inhibitor selected from loid-beta antibodies for the prevention and/or treatment any one of examples 1-235, in combination with inter of neurodegeneration in Down Syndrome, wherein the ferones, preferably Rebif, for the prevention and/or amyloid-beta antibody is Act-24, treatment of multiple sclerosis 0458 a QC inhibitor, preferably a QC inhibitor of for 0448 a QC inhibitor, preferably a QC inhibitor of for mula (I), more preferably a QC inhibitor selected from mula (I), more preferably a QC inhibitor selected from any one of examples 1-235, in combination with beta any one of examples 1-235, in combination with Copax secretase inhibitors for the prevention and/or treatment one, for the prevention and/or treatment of multiple scle of mild cognitive impairment, wherein the beta-secre rOS1S, tase inhibitor is selected from WY-25105, GW-840736x 0449 a QC inhibitor, preferably a QC inhibitor of for and CTS-21166, mula (I), more preferably a QC inhibitor selected from 0459 a QC inhibitor, preferably a QC inhibitor of for any one of examples 1-235, in combination with dexam mula (I), more preferably a QC inhibitor selected from ethasone, for the prevention and/or treatment of resteno any one of examples 1-235, in combination with beta S1S, secretase inhibitors for the prevention and/or treatment 0450 a QC inhibitor, preferably a QC inhibitor of for of Alzheimer's disease, wherein the beta-secretase mula (I), more preferably a QC inhibitor selected from inhibitor is selected from WY-25105, GW-840736x and any one of examples 1-235, in combination with dexam CTS-21166, ethasone, for the prevention and/or treatment of athero 0460) a QC inhibitor, preferably a QC inhibitor of for Sclerosis, mula (I), more preferably a QC inhibitor selected from 0451 a QC inhibitor, preferably a QC inhibitor of for any one of examples 1-235, in combination with beta mula (I), more preferably a QC inhibitor selected from secretase inhibitors for the prevention and/or treatment any one of examples 1-235, in combination with dexam of neurodegeneration in Down Syndrome, wherein the ethasone, for the prevention and/or treatment of rheu beta-secretase inhibitor is selected from WY-25105, matid arthritis, GW-840736x and CTS-21166, US 2011/00925O1 A1 Apr. 21, 2011 31

0461) a QC inhibitor, preferably a QC inhibitor of for powder, injection, teaspoonful and the like, an amount of the mula (I), more preferably a QC inhibitor selected from active ingredient(s) necessary to deliver an effective dose as any one of examples 1-235, in combination with described above. The pharmaceutical compositions herein gamma-secretase inhibitors for the prevention and/or will contain, per dosage unit, e.g., tablet, capsule, powder, treatment of mild cognitive impairment, wherein the injection, Suppository, teaspoonful and the like, from about gamma-secretase inhibitor is selected from LY-450139, 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be LY-41 1575 and AN-37124, given at a dosage of from about 0.1-300 mg/kg per day (pre 0462) a QC inhibitor, preferably a QC inhibitor of for ferred 1-50 mg/kg per day) of each active ingredient or com mula (I), more preferably a QC inhibitor selected from bination thereof. The dosages, however, may be varied any one of examples 1-235, in combination with depending upon the requirement of the patients, the severity gamma-secretase inhibitors for the prevention and/or of the condition being treated and the compound being treatment of Alzheimer's disease, wherein the gamma employed. The use of either daily administration or post secretase inhibitor is selected from LY-450139, periodic dosing may be employed. LY-41 1575 and AN-37124, 0469 Preferably these compositions are in unit dosage 0463 a QC inhibitor, preferably a QC inhibitor of for forms from Such as tablets, pills, capsules, powders, granules, mula (I), more preferably a QC inhibitor selected from sterile parenteral Solutions or Suspensions, metered aerosol or any one of examples 1-235, in combination with liquid sprays, drops, ampoules, autoinjector devices or Sup gamma-secretase inhibitors for the prevention and/or positories; for oral parenteral, intranasal, Sublingual or rectal treatment of neurodegeneration in Down Syndrome, administration, or for administration by inhalation or insuf wherein the gamma-secretase inhibitor is selected from flation. Alternatively, the composition may be presented in a LY-450139, LY-411575 and AN-37124. form Suitable for once-weekly or once-monthly administra 0464 Such a combination therapy is in particular useful tion; for example, an insoluble salt of the active compound, for AD, FAD, FDD and neurodegeneration in Down syn Such as the decanoate salt, may be adapted to provide a depot drome as well as atherosclerosis, rheumatoid arthritis, rest preparation for intramuscular injection. For preparing Solid enosis and pancreatitis. compositions such as tablets, the principal active ingredientis mixed with a pharmaceutical carrier, e.g. conventional tablet 0465 Such combination therapies might result in a better ing ingredients such as corn starch, lactose, Sucrose, Sorbitol, therapeutic effect (less proliferation as well as less inflamma talc, Stearic acid, magnesium Stearate, dicalcium phosphate tion, a stimulus for proliferation) than would occur with either or gums, and other pharmaceutical diluents, e.g. water, to agent alone. form a solid preformulation composition containing a homo 0466. With regard to the specific combination of inhibitors geneous mixture of a compound of the present invention, or a of QC and further compounds it is referred in particular to pharmaceutically acceptable salt thereof. When referring to WO 2004/098.625 in this regard, which is incorporated herein these preformulation compositions as homogeneous, it is by reference. meant that the active ingredient is dispersed evenly through out the composition so that the composition may be readily Pharmaceutical Compositions Subdivided into equally effective dosage forms such as tab 0467 To prepare the pharmaceutical compositions of this lets, pills and capsules. This solid preformulation composi invention, at least one compound of formula (I) optionally in tion is then subdivided into unit dosage forms of the type combination with at least one of the other aforementioned described above containing from 0.1 to about 500 mg of each agents can be used as the active ingredient(s). The active active ingredient or combinations thereof of the present ingredient(s) is intimately admixed with a pharmaceutical invention. carrier according to conventional pharmaceutical compound 0470 The tablets or pills of the compositions of the ing techniques, which carrier may take a wide variety of present invention can be coated or otherwise compounded to forms depending of the form of preparation desired for provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner administration, e.g., oral or parenteral Such as intramuscular. dosage and an outer dosage component, the latter being in the In preparing the compositions in oral dosage form, any of the form of an envelope over the former. The two components can usual pharmaceutical media may be employed. Thus, for be separated by an enteric layer which serves to resist disin liquid oral preparations, such as for example, Suspensions, tegration in the stomach and permits the inner component to elixirs and solutions, Suitable carriers and additives include pass intact into the duodenum or to be delayed in release. A water, glycols, oils, alcohols, flavoring agents, preservatives, variety of material can be used for such enteric layers or coloring agents and the like; for Solid oral preparations such coatings, such materials including a number of polymeric as, for example, powders, capsules, gelcaps and tablets, Suit acids with Such materials as shellac, cetyl alcohol and cellu able carriers and additives include starches, Sugars, diluents, lose acetate. granulating agents, lubricants, binders, disintegrating agents 0471. This liquid forms in which the compositions of the and the like. Because of their ease in administration, tablets present invention may be incorporated for administration and capsules represent the most advantageous oral dosage orally or by injection include, aqueous solutions, Suitably unit form, in which case solid pharmaceutical carriers are flavoured syrups, aqueous or oil suspensions, and flavoured obviously employed. If desired, tablets may be Sugar coated emulsions with edible oils such as cottonseed oil, Sesame oil, or enteric coated by standard techniques. For parenterals, the coconut oil or peanut oil, as well as elixirs and similar phar carrier will usually comprise sterile water, though otheringre maceutical vehicles. Suitable dispersing or Suspending dients, for example, for purposes such as aiding solubility or agents for aqueous Suspensions, include synthetic and natural for preservation, may be included. gums such as tragacanth, acacia, alginate, dextran, Sodium 0468. Injectable suspensions may also prepared, in which carboxymethylcellulose, methylcellulose, polyvinylpyrroli case appropriate liquid carriers, Suspending agents and the done or gelatin. like may be employed. The pharmaceutical compositions 0472. The pharmaceutical composition may contain herein will contain, per dosage unit, e.g., tablet, capsule, between about 0.01 mg and 100 mg, preferably about 5 to 50 US 2011/00925O1 A1 Apr. 21, 2011 32 mg, of each compound, and may be constituted into any form according to dosage regimens established in the art whenever suitable for the mode of administration selected. Carriers treatment of the addressed disorders is required. include necessary and inert pharmaceutical excipients, 0479. The daily dosage of the products may be varied over including, but not limited to, binders, Suspending agents, a wide range from 0.01 to 1.000 mg per mammal per day. For lubricants, flavorants, Sweeteners, preservatives, dyes, and oral administration, the compositions are preferably provided coatings. Compositions Suitable for oral administration in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, include solid forms, such as pills, tablets, caplets, capsules 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milli (each including immediate release, timed release and Sus grams of each active ingredient or combinations thereof for tained release formulations), granules, and powders, and liq the symptomatic adjustment of the dosage to the patient to be uid forms, such as Solutions, syrups, elixirs, emulsions, and treated. An effective amount of the drug is ordinarily supplied Suspensions. Forms useful for parenteral administration at a dosage level of from about 0.1 mg/kg to about 300 mg/kg include sterile solutions, emulsions and Suspensions. of body weight per day. Preferably, the range is from about 1 0473 Advantageously, compounds of the present inven to about 50 mg/kg of body weight per day. The compounds or tion may be administered in a single daily dose, or the total combinations may be administered on a regimen of 1 to 4 daily dosage may be administered in divided doses of two, times per day. three or four times daily. Furthermore, compounds for the 0480 Optimal dosages to be administered may be readily present invention can be administered in intranasal form via determined by those skilled in the art, and will vary with the topical use of Suitable intranasal vehicles, or via transdermal particular compound used, the mode of administration, the skin patches well known to those of ordinary skill in that art. strength of the preparation, the mode of administration, and To be administered in the form of transdermal delivery sys the advancement of disease condition. In addition, factors tem, the dosage administration will, of course, be continuous associated with the particular patient being treated, including rather than intermittent throughout the dosage regimen. patient age, weight, diet and time of administration, will 0474 For instance, for oral administration in the form of a result in the need to adjust dosages. tablet or capsule, the active drug component can be combined 0481. In a further aspect, the invention also provides a with an oral, non-toxic pharmaceutically acceptable inert car process for preparing a pharmaceutical composition compris rier Such as ethanol, glycerol, water and the like. Moreover, ing at least one compound of formula (I), optionally in com when desired or necessary, Suitable binders; lubricants, dis bination with at least one of the other aforementioned agents integrating agents and coloring agents can also be incorpo and a pharmaceutically acceptable carrier. The compositions rated into the mixture. Suitable binders include, without limi are preferably in a unit dosage form in an amount appropriate tation, starch, gelatin, natural Sugars such as glucose or for the relevant daily dosage. betalactose, corn Sweeteners, natural and synthetic gums such 0482 Suitable dosages, including especially unit dosages, as acacia, tragacanth or Sodium oleate, sodium Stearate, mag of the compounds of the present invention include the known nesium Stearate, Sodium benzoate, Sodium acetate, sodium dosages including unit doses for these compounds as chloride and the like. Disintegrators include, without limita described or referred to in reference text such as the British tion, starch, methyl cellulose, agar, bentonite, Xanthan gum and US Pharmacopoeias, Remington's Pharmaceutical Sci and the like. ences (Mack Publishing Co.), Martindale The Extra Pharma 0475. The liquid forms in suitable flavored suspending or copoeia (London, The Pharmaceutical Press) (for example dispersing agents such as the synthetic and natural gums, for see the 31st Edition page 341 and pages cited therein) or the example, tragacanth, acacia, methyl-cellulose and the like. above mentioned publications. For parenteral administration, sterile Suspensions and Solu 0483 Compounds and combinations of the invention may tions are desired. Isotonic preparations which generally con have the advantage that they are, for example, more potent, tain Suitable preservatives are employed when intravenous more selective, have fewer side-effects, have better formula administration is desired. tion and stability properties, have better pharmacokinetic 0476. The compounds or combinations of the present properties, be more bioavailable, be able to cross blood brain invention can also be administered in the form of liposome barrier and are more effective in the brain of mammals, are delivery systems, such as Small unilamellar vesicles, large more compatible or effective in combination with other drugs unilamellar vesicles, and multilamellar vesicles. Liposomes or be more readily synthesized than other compounds of the can be formed from a variety of phospholipids, such as cho prior art. lesterol, Stearylamine or phosphatidylcholines. 0484 Definitions and methods described herein are pro 0477 Compounds or combinations of the present inven vided to better define the present invention and to guide those tion may also be delivered by the use of monoclonal antibod of ordinary skill in the art in the practice of the present ies as individual carriers to which the compound molecules invention. Unless otherwise noted, terms are to be understood are coupled. The compounds of the present invention may according to conventional usage by those of ordinary skill in also be coupled with soluble polymers as targetable drug the relevant art. carriers. Such polymers can include polyvinylpyrrolidone, 0485. In some embodiments, numbers expressing quanti pyran copolymer, polyhydroxypropylmethacryla ties of ingredients, properties Such as molecular weight, reac midephenol, polyhydroxyethylaspartamid-ephenol, or poly tion conditions, and so forth, used to describe and claim ethyleneoxidepolyllysine substituted with palmitoyl residue. certain embodiments of the invention are to be understood as Furthermore, the compounds of the present invention may be being modified in some instances by the term “about.” In coupled to a class of biodegradable polymers useful in some embodiments, the term “about is used to indicate that achieving controlled release of a drug, for example, polyactic a value includes the standard deviation of the mean for the acid, polyepsilon caprolactone, polyhydroxybutyeric acid, device or method being employed to determine the value. In polyorthoesters, polyacetals, polydihydropyrians, polycy Some embodiments, the numerical parameters set forth in the anoacrylates and cross-linked or amphipathic block copoly written description and attached claims are approximations mers of hydrogels. that can vary depending upon the desired properties sought to 0478 Compounds or combinations of this invention may be obtained by a particular embodiment. In some embodi be administered in any of the foregoing compositions and ments, the numerical parameters should be construed in light US 2011/00925O1 A1 Apr. 21, 2011

of the number of reported significant digits and by applying limitation on the scope of the invention otherwise claimed. ordinary rounding techniques. Notwithstanding that the No language in the specification should be construed as indi numerical ranges and parameters setting forth the broad cating any non-claimed element essential to the practice of Scope of some embodiments of the invention are approxima the invention. tions, the numerical values set forth in the specific examples 0490 Groupings of alternative elements or embodiments are reported as precisely as practicable. The numerical values of the invention disclosed herein are not to be construed as presented in some embodiments of the invention may contain limitations. Each group member can be referred to and certain errors necessarily resulting from the standard devia claimed individually or in any combination with other mem tion found in their respective testing measurements. The reci bers of the group or other elements found herein. One or more tation of ranges of values herein is merely intended to serve as members of a group can be included in, or deleted from, a a shorthand method of referring individually to each separate group for reasons of convenience or patentability. When any value falling within the range. Unless otherwise indicated Such inclusion or deletion occurs, the specification is herein herein, each individual value is incorporated into the specifi deemed to contain the group as modified thus fulfilling the cation as if it were individually recited herein. written description of all Markush groups used in the 0486 In some embodiments, the terms “a” and “an and appended claims. “the and similar references used in the context of describing 0491. The invention embraces all combinations of pre a particular embodiment (especially in the context of certain ferred and more preferred groups and embodiments of groups of the following claims) can be construed to cover both the recited herein. singular and the plural, unless specifically noted otherwise. In 0492 All publications, patents, patent applications, and Some embodiments, the term 'or' as used herein, including other references cited in this application are incorporated the claims, is used to mean “and/or unless explicitly indi herein by reference in their entirety for all purposes to the cated to refer to alternatives only or the alternatives are mutu same extent as if each individual publication, patent, patent ally exclusive. application or other reference was specifically and individu 0487. The terms “comprise.” “have” and “include” are ally indicated to be incorporated by reference in its entirety open-ended linking verbs. Any forms or tenses of one or more for all purposes. Citation of a reference herein shall not be of these verbs, such as “comprises.” “comprising.” “has.” construed as an admission that Such is prior art to the present “having.” “includes” and “including.” are also open-ended. invention. For example, any method that “comprises.” “has or 0493 Having described the invention in detail, it will be “includes one or more steps is not limited to possessing only apparent that modifications, variations, and equivalent those one or more steps and can also cover other unlisted embodiments are possible without departing the scope of the steps. Similarly, any composition or device that “comprises.” invention defined in the appended claims. Furthermore, it “has' or “includes one or more features is not limited to should be appreciated that all examples in the present disclo possessing only those one or more features and can cover Sure are provided as non-limiting examples. other unlisted features. 0488 Throughout the specification and the claims which EXAMPLES follow, unless the context requires otherwise, the word com prise, and variations such as comprises and comprising, 0494 The following non-limiting examples are provided will be understood to imply the inclusion of a stated integer, to further illustrate the present invention. It should be appre step, group of integers or group of steps but not to the exclu ciated by those of skill in the art that the techniques disclosed sion of any other integer, step, group of integers or group of in the examples that follow represent approaches the inven steps. tors have found function well in the practice of the invention, 0489 All methods described herein can be performed in and thus can be considered to constitute examples of modes any suitable order unless otherwise indicated herein or oth for its practice. However, those of skill in the art should, in erwise clearly contradicted by context. The use of any and all light of the present disclosure, appreciate that many changes examples, or exemplary language (e.g. "Such as') provided can be made in the specific embodiments that are disclosed with respect to certain embodiments herein is intended and still obtain a like or similar result without departing from merely to better illuminate the invention and does not pose a the spirit and scope of the invention.

Mol Example Chemical Name Structure Formula Weight

1 5-tert-butyl-1-(1H CHNO 258.319 benzodimidazol-5- yl)imidazolidin-2-one

N

US 2011/00925O1 A1 Apr. 21, 2011 87

-continued

Mol Example Chemical Name Structure Formula Weight 235 (S)-3-(3,4- C2HNO 399.44 dimethoxyphenyl)-2-(3- methylH-imidazo[1,2-a pyridin-7-yl)isoindolin-1- Ole 'it O 1)N

General Synthesis Description: 0495

Method 1 O

NH,2 - N. N R1 R1 R O R4

R4 R4 R R2 e NH -- NH R1 N Sk R1 N N O O 0498. 1 equivalent of the aldehyde was dissolved in AcOH (5 mL in case of 4 mmol starting material) and 1.1 equivalents 0496 The amine (1 equivalent) was dissolved in CHCl, of the amine were added. 1 equivalent of TMSCN was then and TEA (3 equivalents) were added. Di(1H-imidazol-1-yl) added to the mixture. The mixture was then stirred for 1.5 hat methanone (1 equivalent), dissolved in a small amount of rt. CHCl, was then added. The mixture was stirred at r.t. for 2 0499. The mixture was then poured on ice/ammonia (con h, then the corresponding aminoalkyl ketone hydrochloride taining 12 mL of a 25% NH solution in case of 4 mmol (1 eq), Suspended in a small amount of CH2Cl containing 2 starting material). The aqueous layer was extracted 3 times by equivalents of TEA, was added. The mixture was stirred for means of CH2Cl the organic phases were combined and 2-3 huntil the formation of the urea was complete. The urea dried. The solvent was removed and remains were taken up in was isolated by means of preparative HPLC. MeOH and 1-2% of conc. HCl were added. The solution was 0497. The urea was taken up in a mixture of AcOH and subjected to hydrogenation (PdC 10%, H 4 bar, 3 h, RT). conc. aqueous HCl (40/1, V/v) and kept under reflux for 1 h. After filtration, the solvent was evaporated and the remaining The solvent was removed and the remains were re-dissolved oil was dissolved in CHC1 and TEA (2.2 equivalents) were in MeOH and little HCl was added (1-2%). The solution was added. After addition of carbonyldiimidazole (1.2 eq) the subjected to hydrogenation (PdC, 10% on charcoal, 4 bar, 40° mixture was kept under reflux for 18 h. The solvent was C.) for 4 h. The catalyst was removed by filtration through a removed and the remaining oil was taken up in CHCl, pad of CELITE(R). The solvent was removed and purified by washed with water two times and subjected to column chro means of preparative HPLC. matography using a CHCl/MeOH gradient. US 2011/00925O1 A1 Apr. 21, 2011 88

Method 3

O R ul H StepP A - R1J Step"P- B RS N-ol Step C - R al- STs 'P-Step D Ry N Step f O o1 o1 -N Step H Step G Step F HN O a- -a- -a- O X-sh HN O O NH NH

vu HN XN N X N O R / R vu "Nu

Step A: Step C: 0500) 1.34 equivalents of a 1M-solution of potassium tert- 0502. The product (1 equiv.) obtained from step B was butoxide or 2 equivalents of n-butyl lithium in THF was added dissolved in dichloromethane and the solution was cooled to a Suspension of 1.34 equivalents of methyltriphenylphos down to 0°C. Tosylchloride (1.05 equiv.) and triethylamine phonium bromide in THF at 0°C. under argon atmosphere. (1.4 equiv.) were added to the solution. The reaction was The reaction was allowed to warm up to ambient temperature allowed to adopt ambient temperature and was stirred for 14 and was stirred for 10 minutes. The reaction was then cooled hours before the reaction mixture was transferred into water. down to 0° C. again, a solution of 1 equivalent 4-propoxy The mixture was extracted three times by means of dichlo benzaldehyde in THF was added. The reaction was stirred at romethane. The combined organic layers were washed with ambient temperature until the TLC control (heptane/chloro brine, dried (NaSO), filtered and the solvent was removed form 1:1) indicated a complete consumption of the aldehyde. under reduced pressure. The product was purified by FPLC The reaction mixture was filtered and the filtrate was concen using a hexane-ethyl acetate gradient (0->30%). trated under vacuum. The product was purified via flash chromatography (hexane/chloroform 8:2). Step D: Step B: 0503. The product obtained from step C (1 equiv.) was dissolved in DMF and sodium azide (1.5 equiv.) was added. 0501 Tert-butyl carbamate (3.1 equiv.) was dissolved in The reaction was stirred for 2 hours at 70°C. The reaction was 1-propanol and 0.38 M aqueous NaOH (3.1 eq) was added. cooled downto ambient temperature, before water was added The reaction was stirred for 5 minutes at ambient temperature and the mixture was extracted three times with 60 mL ethyl and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione acetate. The combined organic layer was washed with brine, (1.535 equiv.) was added and the reaction was stirred for 10 dried over sodium sulfate, filtered and concentrated under minutes at ambient temperature. The reaction was cooled reduced pressure. The product was purified via FPLC using down to 0°C. and (DHQ),PHAL (0.06 equiv.) dissolved in hexane-ethyl acetate gradient (0->30%). 1-propanol was added. After that 1 equiv. of the correspond ing styrene dissolved in 1-propanol was added followed by Step E: potassium osmate dihydrate (0.04 equiv.) Suspended in a small amount of aqueous NaOH. The reaction was stirred at 0504 The product obtained from step D was dissolved in 0° C. until complete consumption of the styrene (TLC con ethanol. The mixture was purged with argon, loaded with trol). Water was added and the reaction mixture was extracted palladium on activated carbon (10%) and the mixture was three times by means of ethyl acetate. Saturated aqueous hydrogenated using an autoclave for 14 hours at ambient Sodium chloride Solution had to be added until phase separa temperature and 4 bar hydrogen pressure. The catalyst was tion was observed. The combined organic layer was washed filtered off through a pad of CELITE(R) and the filtrate was with brine, dried over sodium sulfate, filtered and the solvents concentrated under reduced pressure. The product firstly were removed under reduced pressure. The product was puri appears as a colorless oil and crystallizes after a few minutes. fied by flash chromatography using a heptane-ethyl acetate 0505. The crude product obtained from the hydrogenation gradient (0->30%). was dissolved in ethanol and p-anisaldehyde (1.2 equiv.) was US 2011/00925O1 A1 Apr. 21, 2011

added to the solution. The reaction was stirred for 5 hours at ambient temperature, before the reaction was cooled down to 0° C. and sodium borohydride (2.4 equiv.) was added. The Method 4 mixture was stirred at ambient temperature for 14 hours. The NH2 + -- solvent was removed under reduced pressure. The residue R 1 an R2 was suspended in Saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The NH2 combined organic layers were washed with brine, dried 2 -e- (NaSO), filtered and concentrated under reduced pressure. R1 R1 O R R Step F:

0506. The crude material obtained from step E was dis H solved in dichloromethane and trifluoroacetic acid (20% N V/V) was added. The reaction was stirred until the complete ?y-o consumption of the starting material (TLC control). Toluol N was added and the solvents and the trifluoroacetic acid were R1 removed under reduced pressure. R 0507. The crude material obtained from the Boc-deprotec tion was dissolved in dichloromethane and triethylamine (2.2 0510 1 equivalent of the aldehyde was dissolved in AcOH equiv.) was added. To the stirred solution di(1H-imidazol-1- (5 mL in case of 4 mmol starting material) and 1.1 equivalents yl)methanone (1.2 equiv.) was added and the reaction was of the amine were added. 1 equivalent of TMSCN was then stirred for 1 hour at reflux. After cooling down the reaction added to the mixture. The mixture was stirred for 1.5 h at r,t. mixture, the solvent was removed and water was added. The 0511. The mixture was then poured on ice/ammonia (con aqueous layer was extracted with ethyl acetate three times. taining 12 mL of a 25% NH solution in case of 4 mmol The combined organic layer was washed with brine, dried starting material). The aqueous layer was extracted 3 times by over Sodium Sulfate, filtered and the solvent was removed means of CHCl the organic phases were combined, dried, under reduced pressure. The product was purified by FPLC filtrated and the solvent was removed. The remains were (hexane-ethyl acetate 0->100%). re-dissolved in concentrated HCl and kept at 40° C. over night. Water was added and the solution was neutralized by Step G: adding NaOH. The aqueous phase was extracted three times 0508. The imidazolidin-2-one (1 equiv.), 4-iodobenzene by means of CHCl2, thereafter the organic phases were com 1.2-diamine (1 equiv.), copper(I) iodide (0.1 equiv.) and bined and dried. The solvent was removed and the remains cesium fluoride (2 equiv.) were added in a reaction flask were taken up intriethyl-Ortho formate. The mixture was kept purged with argon. Cyclohexane-1,2-diamine (mixture of cis under reflux for 1 h. The orthoester was removed and the and trans 0.1 equiv.) was dissolved in dry dioxane and was remaining oil was dissolved in MeOH and NaBH (1.5 given to the solids and the mixture was heated at 95°C. under equivalents) were added. The mixture was kept at ambient argon atmosphere until TLC indicated consumption of the temperature for 1 h, followed by 60° C. for 1 h and the starting material. The reaction mixture was cooled down to reaction was quenched by addition of an aqueous Solution of 45° C. and filtered through a pad of CELITE(R). The pad was ammonia (12%). The aqueous layer was extracted three times washed with warm dichloromethane several times. The fil by means of CH2Cl2, thereafter the organic phases were com trate was concentrated under reduced pressure. The product bined and dried. The solvent was removed and the remaining was purified by FPLC using a chloroform-methanol gradient mixture was subjected to preparative HPLC. (0%->10%).

Step H: Method 5 0509. The product obtained from step G was dissolved in triethyl orthoformate and the reaction was stirred for 30 min utes at reflux. After cooling the excess of triethyl orthofor mate was removed under reduced pressure and the remains were dissolved in trifluoroacetic acid. The reaction was stirred for 14 hours at ambient temperature. The TFA was removed under reduced pressure and the residue was re dissolved in buffer (pH7) and three times extracted by means of dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The final prod uct was purified by means of FPLC using a methanol-chlo roform gradient (0->10%). US 2011/00925O1 A1 Apr. 21, 2011 90

The reaction mixture was quenched into Saturated Sodium -continued sulphite solution and extracted with ethyl acetate (3x40 mL). The combined organic layer was washed with water, brine, dried over anhydrous Sodium Sulfate and concentrated under reduced pressure to afford crude product. Purification by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate in petroleum ether as eluent to afford the product Step C: Step A: 0515. The product obtained from step B was dissolved in 0512 1.34 equivalents of a 1M-solution of potassium tert a 0.2 M solution of sodium hydroxide in methanol. The reac butoxide or 2.0 equivalents of n-butyl-lithium in THF were tion was stirred at reflux until the TLC control indicated added to a Suspension of 1.34 equivalents of methyltriph complete consumption. The solvent was removed under enylphosphonium bromide in THF at 0°C. under argon atmo reduced pressure and ethyl acetate was added. The organic sphere. The reaction was allowed to warm up to ambient layer was washed with brine, dried over sodium sulfate, fil temperature and was stirred for 10 minutes. The reaction was tered and the solvent was removed under reduced pressure. then cooled down to 0°C. again, a solution of 1 equivalent of The product was purified via FPLC using a heptane-ethyl the aldehyde in THF was added. The reaction was stirred at acetate gradient (0->100%). ambient temperature until the TLC control (heptane/chloro form 1:1) indicated a complete consumption of the aldehyde. Step D: The reaction mixture was filtered and the filtrate was concen trated under vacuum. The product was purified via flash 3-(1H-benzodimidazol-5-yl)oxazolidin-2-ones chromatography (hexane/chloroform 8:2). 0516. 1 equiv. of the oxazolidin-2-one was given together with 4-iodobenzene-1,2-diamine (1 equiv.), cesium fluoride Step B: (2 equiv.) and copper(I) iodide (0.1 equiv.) in a flask. The flask 0513 Ethyl carbamate (3 equiv.) was dissolved in 1-pro was purged with argon and a solution of cyclohexane-1,2- panol and 0.5 M aqueous NaOH (3 equiv.) was added. The diamine (0.1 equiv.) in dioxane was added. The reaction was reaction was stirred for 5 minutes at ambient temperature and stirred at 95° C. until TLC indicated consumption of the 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.5 oxazolidin-2-one. After cooling to 45° C. the reaction mixture equiv.) were added and the reaction was stirred for 10 minutes was filtered through a pad of CELITE(R), the pad was washed at ambient temperature. (DHQ),PHAL (0.06 equiv.) dis with warm dichloromethane and the Solution was concen solved in 1-propanol were added. After that 1 eq of the cor trated under reduced pressure. The product was purified via responding styrene obtained from step A dissolved in 1-pro FPLC using a chloroform-methanol gradient (0->10%). panol were added followed by potassium osmate dihydrate 0517. The product obtained from the copper(I)-catalyzed (0.04 equiv.) suspended in small amount of 0.5 M aqueous coupling was dissolved in triethyl orthoformate and the reac NaOH. The reaction was stirred at ambient temperature until tion was stirred at reflux for 1 h. After cooling the excess of complete consumption of the styrene. (TLC control) Water triethyl orthoformate was removed under reduced pressure. was added and the reaction mixture was extracted three times The final product was purified via FPLC using a chloroform by means of ethyl acetate. The combined organic layer was methanol gradient (0->10%). washed with brine, dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The product 3-(imidazol-2-alpyridin-7-yl)oxazolidin-2-ones was purified via flash-chromatography using a heptane-ethyl 0518) 1 equiv. of the oxazolidin-2-one was given together acetate gradient. with 7-bromoimidazol-2-alpyridine (1 equiv.), cesium fluo ride (2 equiv.) and copper(I) iodide (0.1 equiv.) in a flask. The Alternative: flask was purged with argon and a solution of cyclohexane 051.4 T-butyl hypochlorite (3 eq) was added to a stirred 1.2-diamine (0.1 equiv.) in dioxane was added. The reaction Solution of benzyl carbamate (3 eq) 0.4M aqueous sodium was stirred at 95°C. until TLC indicated consumption of the hydroxide in 1-propanol at 0° C. and stirred for 15 min. A oxazolidin-2-one. After cooling to 45° C. the reaction mixture solution of (DHQ)PHAL (0.05 eq) in 1-propanol was added. was filtered through a pad of CELITE(R), the pad was washed Then the corresponding olefine (1 eq)) in 1-propanol fol with warm dichloromethane and the Solution was concen lowed by potassium osmate dihydrate (100 mg, 0.025 eq) and trated under reduced pressure. The final product was purified the reaction mixture was stirred for 2 hat room temperature. via FPLC using a chloroform-methanol gradient (0->10%).

Method 6 O O NH O OH O O ul Step A Step B Step C N R H --> O He- -- R N R2 NH2 R NH2 s D US 2011/00925O1 A1 Apr. 21, 2011 91

-continued

O O --Step - G R.1. NH R N

Step A: (75 mL) at 0°C. and stirred for 6 hat room temperature. The 0519 Potassium cyanide (1.2 eq) was added to a stirred reaction mixture was concentrated under reduced pressure to Solution of the corresponding aldehyde (1 eq), ammonium give crude compound. The crude product was purified by carbonate (3 eq)) in ethanol and water. The reaction mixture washing with n-pentane. was heated at 60°C. overnight. Then the reaction mixture was cooled to 0°C., precipitated solid was filtered and washed Step G: with water and petroleum ether. The residue was dried in WaClO. 0525. A mixture of the product of step F (1 eq), 1,2- diamino 4-iodo benzene (1 eq), cesium fluoride (1.5 eq) in Step B: 1,4-dioxane were purged with argon gas for 15 min. 1.2- 0520. A mixture of the product of step A (1 eq) and 10% diaminocyclohexane (0.1 eq) and copper iodide (0.1 eq) was NaOH was refluxed overnight. The reaction mixture was added to the reaction mixture, purging continued for another extracted with ethyl acetate (3x30 mL) and the aqueous layer 5 min and stirred over night at 120°C. in a sealed tube. The was acidified with concentrated HCl up to pH-2. The aqueous reaction mixture was quenched with water and extracted with layer was extracted with ethyl acetate and the aqueous layer ethyl acetate. The organic layer was washed with brine solu was concentrated under vacuo and co-distilled with toluene. tion, dried over anhydrous sodium Sulphate and concentrated This crude product was taken as Such for the next step. under vacuo to give crude compound. The crude product was purified by column chromatography using neutral alumina Step C: using 2% methanol in dichloromethane as eluent. 0521. Thionyl chloride was added to a stirred solution of 0526. A mixture of the product of step G (1 eq) and formic the product of step B (1 eq)) in methanol and refluxed over acid was heated at 70° C. for 1 h. The reaction mixture was night. The reaction mixture was concentrated in vacuo and the residue was dissolved in water and extracted with ethyl cooled to 0°C. and basified using saturated sodium bicarbon acetate. The aqueous layer was basified with solid sodium ate solution. The aqueous layer was extracted with ethyl bicarbonate and extracted with ethyl acetate. The combined acetate, washed with brine solution and dried over anhydrous organic layer was washed with brine solution, dried over Sodium sulfate. The compound was purified by preparative anhydrous sodium Sulphate and concentrated in vacuo. TLC or HPLC 1 M ether-HCl (0.57 mL, 0.57 mmol) was added to a stirred solution of the product (150 mg, 0.47 mmol) Step D: in dichloromethane (10 mL) at 0°C. and stirred for 30 minat 0522 Product of step C (1 eq) was added portion wise to a room temperature. The reaction mixture was filtered and suspension of sodium borohydride (3 eq) in ethanol (100 mL) washed with pentane. at 0° C. and stirred at room temperature for 5 h. Excess ethanol was removed in vacuo and the residue was partitioned between water and ethyl acetate. Separated organic layer was Method 7 washed with water, brine, dried over anhydrous sodium sul O phate and concentrated in vacuo. Step E: R step A OH step B OH -e- -e- 0523 Triethylamine (2 eq), Boc anhydride (1.5 eq) was 2 added successively to a stirred solution of the product of step O R NH2 R NH2 D (1 eq) in dry dichloromethane and stirred for 4 hat room temperature. The reaction mixture was poured into water and s C extracted with dichloromethane. The combined organic layer was washed with brine solution, dried over anhydrous sodium Sulphate and concentrated in vacuo. This was purified by uC O re step D O Super fluid chromatography to obtain the R. Senantiomers. R N -NO R N 1sO 2 2 H Step F: R 0524. Thionyl chloride (8 eq) was added to a stirred solu tion of compound product of step E (1 eq) in tetrahydrofuran US 2011/00925O1 A1 Apr. 21, 2011 92

Step A: pressure. The final product was purified via FPLC using a 0527 Malonic acid (1 equiv.) and ammonium acetate (2 chloroform-methanol gradient (0->10%). equiv.) were dissolved in methanol. To the stirred solution the corresponding aldehyde (1 equiv.) was added and the reaction Method 8 was stirred at reflux for 18 hours. The reaction was cooled to 0° C. and the precipitate was filtered off and washed with cold ethanol. Br Cys N R Step B: 0528. To a suspension of the 3-aminopropionic acid obtained from step A in THF, a 2M solution of lithium alu minium hydride (1.5 equiv.) in THF was added slowly. The stirred solution was stirred at 50° C. for 2 hours. The reaction was cooled to 0°C. and the reaction was quenched by addition of water. The solution was extracted with ethyl acetate three times, the organic layers were combined, washed with brine, 0533 5(6)-Bromobenzimidazole (200 mg; 1 mmol; 1 eq.), filtered and the solvents were removed under reduced pres the respective pyrrolidine derivative (1.2 mmol; 1.2 eq.), 2-di SUC. cyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 Step C: mg; 0.024 mmol; 0.024 eq.; 2.4 mol%) and Pd dba (9 mg: 0.01 mmol; 0.01 eq.; 1 mol%) were dissolved in THF (1 ml). 0529 Product obtained from step B was dissolved in After addition of lithiumbis(trimethylsilyl)amide (1 M solu dichloromethane and di(1H-imidazol-1-yl)methanone (1.2 tion in THF: 2.2 ml; 2.2 mmol; 2.2 eq.) the mixture was stirred equiv.) was added to the Solution. The reaction was heated at under argon-atmosphere at 65° C. for 24 h. After cooling to reflux for 1 hour. The reaction was cooled down to ambient room temperature, 2 NHCl was added until acidic pH and temperature and washed with water. The organic layer was stirred for additional 10 min. The mixture was poured into dried over sodium sulphate, filtered and the solvent was saturated sodium bicarbonate solution (20 ml) and extracted removed under reduced pressure. The product was purified with EtOAc (3x25 ml). The combined organic layers were via FPLC using a heptane-ethyl acetate gradient (0->100%). dried over NaSO and evaporated. The remaining residue was purified by flash-chromatography using Al-O and a Step D: CHCl/MeOH gradient. 3-(1H-benzodimidazol-5-yl)-1,3-oxazinan-2-one 0530 1 equiv. of the 1.3-oxazinan-2-one was given Method 9 together with 4-iodobenzene-1,2-diamine (1 equiv.), potas sium carbonate (2 equiv.) and copper(I) iodide (0.1 equiv.) in a flask. The flask was purged with argon and a solution of cyclohexane-1,2-diamine (0.1 equiv.) in dioxane was added. NH2 RI - N X.O The reaction was stirred at 95°C. until TLC indicated con sumption of the 1.3-oxazinan-2-one. After cooling to 45° C. the reaction mixture was filtered through a pad of CELITER, Step A Step B the pad was washed with warm dichloromethane and the Solution was concentrated under reduced pressure. The prod N N uct was purified via FPLC using a chloroform-methanol gra \- NH \- NH dient (0->10%). 0531. The product obtained from the copper(I)-catalyzed S > coupling was dissolved in triethyl orthoformate and the reac --> tion was stirred at reflux for 1 h. After cooling the excess of triethyl orthoformate was removed under reduced pressure. The final product was purified via FPLC using a chloroform methanol gradient (0->10%). N 3-(imidazol-2-alpyridin-7-yl)-1,3-oxazinan-2-one 0532. 1 equiv. of the 1.3-oxazinan-2-one was given together with 7-bromoimidazol-2-alpyridine (1 equiv.). potassium carbonate (2 equiv.) and copper(I) iodide (0.1 Step A: equiv.) in a flask. The flask was purged with argon and a Solution of cyclohexane-1,2-diamine (0.1 equiv.) in dioxane 0534 5-Aminobenzimidazole (1 eq) was dissolved in was added. The reaction was stirred at 95° C. until TLC EtOH then the corresponding aldehyde (3 eq) and piperidine indicated consumption of the 1.3-oxazinan-2-one. After cool (catalytic amounts) was added. The solution was stirred at 80° ing to 45° C. the reaction mixture was filtered through a pad C. in a sealed tube overnight and further at reflux for 1.5 h. of CELITE(R), the pad was washed with warm dichlo Then the solvent was removed and the remains were taken up romethane and the Solution was concentrated under reduced in toluol and mercapto acetic acid (1.5 eq) or 2-mercapto US 2011/00925O1 A1 Apr. 21, 2011

propionic acid (1.5 eq) was added. The solvent was removed and the product was purified by means of preparative HPLC. Method 11 Step B: 0535. The product of step B (1.0 eq) was dissolved in toluol and Lawessons Reagent (5.0 eq) was added. The mix O ture was kept under reflux for 6 h. The solvent was removed NH2 O NH and the remains were taken up in CHCl then washed by means of a saturated solution of NaHCO. The solvent was Step A removed and the product was purified by means of prepara -- Ho tive HPLC. R2

NH HO O Method 10 s B

NH2 O (SNH OH O Step R. A O N R2 O N R2 | HO Her Step C N O N a

s B N\-h N\-h

R2 Step A, B and C: 0538. The respective 2-oxo benzoic acid (1 eq.) was dis solved in THF (5 ml in case of 1 mmol) and DCC (1 eq.) was added. After stirring at r.t. for 1 h, benzimidazol-5(6)-amine (1 eq.) was added and stirring at r.t. was continued for 24 h. The mixture was put into the fridge for 2 hand afterwards the precipitated solid was filtered off. The filtrate was concen trated in vacuo, re-dissolved in a mixture of AcOH and toluol 22NH NH (3 ml and 7 ml in case of 1 mmol batch) and refluxed over night. After cooling the solvents were evaporated. The result ing residue was dissolved in CHCl (10 ml in case of 1 mmol batch), cooled to 0°C. and treated with TFA (1 ml (4 ml) per Step A: mmol). After stirring at rit. for 10 min, triethylsilane (2 eq. (4 0536 The respective 4-oxo-butanoic acid (1 eq.) was dis eq.)) was added. The reaction was allowed to warm up to solved in dichlormethane (10 ml). Carbonyldiimidazole (1 room temperature and stirred for 3 h. After that time, the eq.) was added and the mixture was stirred at room tempera mixture was quenched with Saturated Sodium bicarbonate ture for 1 h. After the addition of benzimidazol-5(6)-amine (1 Solution. The organic layer was separated and the aqueous eq.) the mixture was stirred overnight. The precipitated Solid layer was extracted with EtOAc (3x25 ml). The combined was collected by filtration and washed with dichlormethane organic layers were dried over NaSO, concentrated in to give the title compounds that were used without further vacuo and the remaining residue was purified by flash-chro purification. matography using silica gel and a CHCl/MeOH gradient. Method 12 Step B and C: 0537. The respective 4-oxo-butanoicacidamide was dis solved in a mixture of AcOH (3 ml) and toluol (7 ml) and refluxed overnight. After that the solvents were removed by O NH Step A O evaporation. The resulting residue was dissolved in AcOH -- -> (10 ml) and was hydrogenated over night (PdC 10%; 1-2 bar; \, O Ts 2 \ O r.t.). After filtration through Celite the solvent was evapo \ / \ rated. The remaining residue was taken up with water, brought to basic pH by means of 2 N NaOH and extracted with EtOAc (3x25 ml). The combined organic layers were dried over NaSO, evaporated and the residue was purified by flash-chromatography on silica gel using a CHCl/MeOH gradient. US 2011/00925O1 A1 Apr. 21, 2011 94

diaminocyclohexane (0.1 eq.) and cesium fluoride (2 eq.) -continued were dissolved in dioxan (5 ml) and heated to 95°C. under R2 R argon atmosphere over night. After cooling to room tempera ture the reaction was quenched with Saturated sodium bicar bonate solution and extracted with EtOAc (3x25 ml). The N N combined organic layers were dried over NaSO and con T1 T1 centrated in vacuo. The remaining residue was dissolved in formic acid orthoethylester (5 ml) and heated to reflux for 2 h. O O The solvent was evaporated and the residue was purified by s C r C semi-preparative HPLC. R2 R SYNTHESIS OF THE EXAMPLES Example 1 5-tert-butyl-1-(1H-benzodimidazol-5-yl)imidazoli HN HN din-2-one 0542. The compound was synthesized as hydrochloride O O salt by the following procedure. (0543 Phenylchloroformate (0.98 mL, 7.8 mmol) was dis s D Step D solved in CHCl, cooled down to 0°C. and 5-aminobenz imidazole (0.865 g. 6.5 mmol) was added slowly. The mixture R2 R2 was kept at 0°C. for 30 min and then the mixture was allowed N N e. to adapt ambient temperature. The mixture was stirred at N N ambient temperature for 2 h. The resulting solid was with HN HN drawn by Suction, dried and taken up in a small amount of O O DMF. To the solution, 1-amino-3,3-dimethylbutan-2-one (0.986, 6.5 mmol) and TEA (2.73 mL, 19.5 mmol) were added. The mixture was kept at 40°C. for 2h. The solvent was Step A: removed and purified by means of preparative HPLC. The 0539 Methyl-2-formylbenzoate (3.28 g; 20 mmol; 1 eq.) remains were re-dissolved in MeOH and a small amount of and para-toluenesulfonamide (3.42 g; 20 mmol; 1 eq.) were HCl was added (1-2%). The solution was subjected to hydro genation (PdC, 10% on charcoal, 4 bar, 60° C.) for 4 h. The suspended in tetraethylorthosilicate (4.69 ml, 21 mmol; 1.05 catalyst was removed by filtration through a pad of CELITE(R) eq.) and heated to reflux for 6 h. Upon cooling the mixture and the residue was washed with water. The organic layer was was diluted with warm EtOAc (70 ml). After treating with dried, filtrated and the solvent was removed to result in the n-pentane (250 ml) the mixture was put into a fridge over final product. Yield: 0.087 g (6.3%); MS m/z 259.4 (M+H)"; night. The precipitate was collected by filtration and washed H NMR (DMSO, 400 MHz): 8 0.72 (s, 9H); 3.23-3.27 (m, with n-pentane. Yield: 4.83 g (76.2%); MS m/z. 318.2 H); 3.46-3.50 (m, H); 4.37-4.41 (m, H); 6.84 (bs, H): 7.56 (dd. M+H" H, J=9.1 Hz, J=1.7 Hz); 7.70 (d, H, J=9.1 Hz); 7.81 (d, H, Step B, C: J=1.7 Hz); 9.27 (s, H), HPLC (214 nm, B: rt 6.83 min (99%). 0540. The respective boronic acid (2 eq.), RhCl(CH), (0.031 eq.) and (3aS,6aS)-3,6-diphenyl-1,3a,4,6a-tetra-hy Example 2 dropentalen (0.066 eq.), for the preparation of 3S-enanti 1-(1H-benzodimidazol-5-yl)-5-cyclohexylimidazo omers, or (3aR, 6aR)-3,6-diphenyl-1,3a,4,6a-tetrahydropen lidin-2-one talen (0.066 eq.), for the preparation of 3R-enantiomers, were 0544 The compound was synthesized as trifluoroacetate dissolved in toluol (2.5 ml) and heated to 55° C. under argon salt starting from 5-aminobenzimidazole (0.59 g, 4.4 mmol), atmosphere. After 1 h, methyl-2-(tosylimino-methyl)ben cyclohexanecarbaldehyde (0.45 g, 0.485 mL, 4 mmol), Zoate (1 eq.), toluol (6 ml) and TEA (2 eq.) were added TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.05 g), di-(imidazol sequentially and stirring was continued for 5 h. The mixture 1-yl)methanone (0.64g, 3.92 mmol), as described in method was quenched with saturated NaHCO-solution and extracted 2. The product was purified via preparative HPLC using a with EtOAc (3x25 ml). The combined organic layers were water-acetonitrile gradient with 0.04% trifluoroacetic acid. dried over NaSO and evaporated. The resulting residue was (0545 Yield: 0.089 g (5.6%); MS m/z 285.1 (M+H)"; "H dissolved in THF (10 ml). After cooling to 0°C. the solution NMR (DMSO,400 MHz): 8 0.82-0.91 (m, H): 0.97-1.16 (m, was treated with Sml (1 M solution in THF) until the dark 4H); 1.39-142 (m, H); 1.52-1.69 (m, 5H); 3.24-327 (m, H): blue color persisted. Stirring was continued for 1 h then the 3.42-3.46 (m, H); 4.48-4.52 (m, H); 6.92 (s, H); 7.56-7.59 reaction was quenched with Saturated Sodium bicarbonate (dd, H, J=9.1 Hz, J-2.1 Hz); 7.73-7.75 (d, H, J=9.1 Hz); solution and extracted with CHCl (3x25ml). The combined 7.94-7.95 (d, H, J=2.1 Hz); 9.24 (s, H), HPLC (=214 nm, organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by flash-chromatography B:rt 8.64 min (99%). using silica gel and a heptane/EtaOAc gradient. Example 3 1-(1H-benzodimidazol-5-yl)-5-phenylimidazolidin Step D: 2-one 0541. 4-lodbenzen-1,2-diamine (1 eq.), the respective 0546. The compound was synthesized starting from 3-phenylisoindolinone (1.1 eq.), copper(I) iodide (0.1 eq.), 5-aminobenzimidazole (1.46 g. 10 mmol), benzaldehyde US 2011/00925O1 A1 Apr. 21, 2011

(1.06 g. 10 mmol), TMSCN (1.25 mL, 10 mmol), PdC (10%, di(1H-imidazol-1-yl)methanone (0.052 g, 2 mmol), TEA 0.05 g). di-(imidazol-1-yl)methanone (1.73, 12 mmol), as (0.799 mL, 6 mmol), aminomethyl-(4-methoxy)phenyl described in method 2. ketone hydrochloride (0.403 g, 2 mmol), TEA (0.558 mL, 4 (0547. Yield: 0.303 g (10.9%); MS m/z 279.3 (M+H); H mmol), PdC (10%, 0.02 g) as described in method 1. NMR (DMSO,400 MHz): 83.08-3.11 (m, H); 3.85-3.89 (m, 0551. Yield: 0.234 g (37.8%); MS m/z 309.3 (M+H); H H); 5.54–5.58 (m, H); 7.19-7.33 (m, 6H): 7.51-7.54 (m, H): NMR (DMSO, 400 MHz): 83.09-3.12 (m, H); 3.67 (s, 3H): 7.60 (d, H, J=8.7 Hz); 7.84 (d, H, J=1.7 Hz); 9.15 (s, H), 3.84-3.88 (m, H); 5.52-5.55 (m, H); 6.84-6.88 (m, 2H): 7.23 HPLC (214 nm, B:rt 7.36 min (96%). (s, H): 7.25-7.29 (m, 2H): 7.58 (dd, H, J=9.1 Hz, J=2.1 Hz); Example 4 7.65 (d, H, J=9.1 Hz); 7.90 (s, H): 9.39 (s. H), HPLC (-214 1-(1H-benzodimidazol-5-yl)-5-m-tolylimidazoli nm, B:rt 7.84 min (94%). din-2-one 0548. The compound was synthesized as hydrochloride Example 6 salt by the following procedure. 4-Nitrophenyl chloroformate (0.564g, 3.5 mmol) was dissolved CHCl, cooled down to 0° 1-(1H-benzodimidazol-5-yl)-5-(4-methoxyphenyl) C. and 5-aminobenzimidazole (0.466 g, 3.5 mmol) was added imidazolidin-2-one slowly. The mixture was kept at 0°C. for 30 min and then the mixture was allowed to adapt ambient temperature. The mix Enantiomer 1 ture was stirred at ambient temperature for 2 h. The resulted Solid was withdrawn by Suction, dried and taken up in a small 0552 Separation of example 12 by chiral HPLC, column: amount of DMF. To the solution aminomethyl-(4-chloro-3- Nucleocel Alpha RP-S, 250*21 mm (5 um), eluent: 50/50 methylphenyl)ketone (0.774, 3.5 mmol) and TEA (1.46 ml, acetonitrile/water 30/70, flow 10 mL/min, second eluting 10.5 mmol) was added. The mixture was kept at 40°C. for 2 enantiomer rt: 20.2 min (99.35)%. h. The solvent was removed and purified by means of pre parative HPLC. The remains were re-dissolved in MeOH and Example 7 a small amount of HCl was added (1-2%). The solution was subjected to hydrogenation (PdC, 10% on charcoal, 4 bar, 60° 1-(1H-benzodimidazol-5-yl)-5-(4-methoxyphenyl) C.) for 4 h. The catalyst was removed by filtration through a imidazolidin-2-one pad of CELITER) and the solvent was removed and purified by means of preparative HPLC. Enantiomer 2 (0549. Yield: 0.008 g (0.6%); MS m/z 293.4 (M+H)"; "H NMR (DMSO, 400 MHz): 8 2.21 (s.3H); 3.05-3.09 (m, H): 0553 Separation of example 12 by chiral HPLC, column: 3.83-3.87 (m, H); 5.49-5.53 (m, H): 701-7.10 (m, 2H); 7.15 Nucleocel Alpha RP-S, 250*21 mm (5 um), eluent: 50/50 (d, H, J=7.9 Hz); 7.19 (s. H); 7.52-7.55 (m, H), 7.60 (d, H, acetonitrile/water 30/70, flow 10 mL/min, first eluting enan J=8.7 Hz); 7.84 (s, H); 9.16 (s, H), HPLC (214 nm, B:rt tiomer rt: 16.5 min (99.75)% 8.05 min (100%). Example 5 Example 8 1-(1H-benzodimidazol-5-yl)-5-(4-methoxyphenyl) (4R,5S)-1-(1H-benzodimidazol-6-yl)-5-(4-methox imidazolidin-2-one yphenyl)-4-methylimidazolidin-2-one 0550 The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.266 g, 2 mmol), 0554 US 2011/00925O1 A1 Apr. 21, 2011 96

HO Z

US 2011/00925O1 A1 Apr. 21, 2011 97

Step A: centrated under reduced pressure. The product firstly appears as a colorless oil and crystallizes after a few minutes. Yield: 0555 Tert-butyl carbamate (3.1 equiv., 4.54 g., 38.75 0.629 g (91.9%) mmol) was dissolved in 50 mL of 1-propanol and 99 mL of a 0.38 Maqueous NaOH was added. The reaction was stirred Step CL: for 5 minutes at ambient temperature and 1,3-dichloro-5,5- 0558 2.24 mmol of the crude tert-butyl (1S,2R)-2-amino dimethylimidazolidine-2,4-dione (1.535 equiv., 3.78 g. 19.2 1-(4-methoxyphenyl)propylcarbamate (1 equiv., 0.629 g) mmol) were added and the reaction was stirred for 10 minutes obtained from the hydrogenation was dissolved in 14 mL of at ambient temperature. The reaction was cooled down to 0° ethanol and p-anisaldehyde (1.2 equiv., 0.366 g., 0.326 ml, C. and (DHQ), PHAL (0.06 equiv., 0.585 g, 0.75 mmol) dis 2.69 mmol) was added to the solution. The reaction was solved in 50 mL 1-propanol were added. After that 1 equiv. of stirred for 4 hours at ambient temperature before the reaction the trans-anethole (1.85g, 1.875 mL, 12.5 mmol) dissolved in was cooled down to 0°C. and 5.38 mmol of sodium borohy 100 mL of 1-propanol were added followed by potassium dride (2.4 equiv., 0.203 g) were added. The mixture was osmate dihydrate (0.04 equiv., 0.184g, 0.5 mmol) suspended stirred at ambient temperature for 14 hours before the solvent in 1 mL 0.38 Maqueous NaOH. The reaction was stirred at 0° was removed under reduced pressure. The residue was Sus C. until complete consumption of the trans-anethole (TLC pended in 20 mL Saturated aqueous ammonium chloride solu control). 85 mL of water was added and the reaction mixture tion and extracted three times with 40 mL ethyl acetate. The was extracted three times by means of 150 mL ethyl acetate. combined organic layers were washed with brine, dried Saturated aqueous sodium chloride solution had to be added (NaSO), filtered and concentrated under reduced pressure. until phase separation was observed. The combined organic Yield: 0.97g layer was washed with brine, dried over sodium sulfate, fil trated and the solvents were removed under reduced pressure. Step D: The product was purified by FPLC using a heptane-ethyl 0559) 0.97g of crude tert-butyl (1S,2R)-2-(4-methoxy acetate gradient (0->30%). The product elutes at about 25% benzylamino)-1-(4-methoxyphenyl) propylcarbamate (2.4 of ethyl acetate. Yield: 1.54 g (43.8%) mmol) was dissolved in 25 mL of dichloromethane and 5 mL of trifluoroacetic acid was added. The reaction was stirred at Step B: room temperature until the complete consumption of the starting material (TLC control). Toluol was added and the 0556 tert-butyl (1S,2S)-2-hydroxy-1-(4-methoxyphenyl) solvents and the trifluoroacetic acid were removed under propylcarbamate (1 equiv., 5.5 mmol. 1.54 g) obtained from reduced pressure. Yield: 1.78 g step B was dissolved in 20 mL of dichloromethane and the solution was cooled down to 0°C. Tosylchloride (1.05 equiv., Step E: 1.10g, 5.75 mmol) and triethylamine (1.4 equiv., 0.78g, 1.07 0560. The crude (1S,2R)- N2-(4-methoxybenzyl)-1-(4- mL, 7.7 mmol) were added to the solution. The reaction was methoxyphenyl)propane-1,2-diamine obtained from the allowed to adopt ambient temperature and was stirred for 18 Boc-deprotection (step D) was dissolved in 30 mL dichlo hours, before the reaction mixture was transferred into 100 romethane and triethylamine (2.2 equiv., 1.04 mL, 7.5 mmol) mL water. The mixture was extracted three times by means of was added. To the stirred solution di(1H-imidazol-1-yl) 100 mL dichloromethane. The combined organic layers were methanone (1.2 equiv., 0.662 g, 4.08 mmol) was added and washed with brine, dried (NaSO), filtered and the solvent the reaction was stirred for 1 hour at reflux. After cooling was removed under reduced pressure. The product was puri down the reaction mixture, the solvent was removed and 60 fied by FPLC using a heptane-ethyl acetate gradient mL water was added. The aqueous layer was extracted with (0->40%). The product elutes at 25% of ethyl acetate. Yield: 70 mL of ethyl acetate three times. The combined organic 1.79g (74.7%); MS m/z. 436.4 (M+H)" (1S,2S)-1-(tert-bu layer was washed with brine, dried over sodium sulfate, fil toxycarbonylamino)-1-(4-methoxyphenyl)propan-2-yl trated and the solvent was removed under reduced pressure. 4-methylbenzene-Sulfonate (1 equiv., 1.79g. 4.1 mmol) was The product was purified by FPLC (heptane/ethyl acetate dissolved in 20 mL DMF and sodium azide (1.5 equiv., 0.4g, 0->100%). The product elutes at about 80 percent of ethyl 6.2 mmol) was added. The reaction was stirred for 2 hours at acetate. Yield: 0.29 g; MS m/z 327.4 (M+H)" 70° C. The reaction was cooled down to ambient temperature Step F: before 50 mL water was added and the mixture was extracted three times with 50 mL ethyl acetate. The combined organic 0561. The (4S.5R)-1-(4-methoxybenzyl)-4-(4-methox layer was washed with brine, dried over sodium sulfate, fil yphenyl)-5-methylimidazolidin-2-one (1 equiv., 0.29 g, 0.89 trated and concentrated under reduced pressure. The product mmol), 4-iodobenzene-1,2-diamine (1 equiv., 0.208 g. 0.89 was purified via FPLC using heptane-ethyl acetate gradient mmol), copper(I) iodide (0.1 equiv., 0.017 g., 0.089 mmol) and cesium fluoride (2 equiv., 0.27g, 1.78 mmol) were added (0->30%). The product elutes at about 15% ethyl acetate. in a reaction flask and purged with argon. Cyclohexane-1,2- Yield: 0.75 g (59.6%) diamine (mixture of cis and trans 0.1 equiv., 0.01 g, 0.011 0557. 1 equiv. tert-butyl (1S,2R)-2-azido-1-(4-methox mL) was dissolved in 4 mL of dry dioxane was given to the yphenyl)propylcarbamate (0.75g, 2.45 mmol) was dissolved solids and the mixture was heated for 3 days at 95°C. under in 20 mL ethanol. The mixture was purged with argon, loaded argon atmosphere. The reaction mixture was cooled down to with palladium on activated carbon (10%) and the mixture 45° C. and filtered through a pad of celite. The pad was was hydrogenated using an autoclave for 24 hours at ambient washed with warm dichloromethane several times. The fil temperature and 4 bar hydrogen pressure. The catalyst was trate was concentrated under reduced pressure. The product filtered off through a pad of celite and the filtrate was con was purified by FPLC using a chloroform-methanol gradient US 2011/00925O1 A1 Apr. 21, 2011

(0%->10%). The product elutes at about 4% methanol. Yield: dehyde (0.601 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC 0.105 g (27.3%); MS m/z. 433.5 (M+H)" (10%, 0.02 g), TEA (0.98 mL, 7.0 mmol), di-(imidazol-1-yl) methanone (0.622, 3.84 mmol) as described in method 2. Step G: 0569. Yield: 0.126 g (9.8%); MS m/z 323.3 (M+H)"; "H 0562 (4R,5S)-1-(3,4-diaminophenyl)-3-(4-methoxyben NMR (DMSO,400MHz): 81.21-1.24 (m,3H);3.03-3.07 (m, Zyl)-5-(4-methoxyphenyl)-4-methylimidazolidin-2-one H); 3.75-3.79 (m, H); 3.87-3.92 (m, 2H): 5.37-5.41 (m, H): (0.105 g, 0.24 mmol) obtained from step F was dissolved in 3 6.79 (d. 2H, J=8.7 Hz); 6.86 (s, H); 7.19-7.23 (m,3H); 7.35 (d. mL triethyl orthoformate. The reaction was stirred for 30 H, J=8.7 Hz); 7.49 (s. H); 8.04 (s, H); 12.19 (bs, H), HPLC minutes at reflux. After cooling the solvent was removed and (214 nm, B:rt 8.40 min (93%). the remains were dissolved in 8 mL trifluoroacetic acid. The reaction was stirred for 14 hours at ambient temperature. The Example 12 TFA was removed under reduced pressure and the residue 1-(1H-benzodimidazol-5-yl)-5-(4-propoxyphenyl) was re-dissolved in 20 mL of buffer (pH7) and three times imidazolidin-2-one extracted by means of 25 mL dichloromethane. The com bined organic layers were washed with brine, dried over 0570. The compound was synthesized starting from sodium sulfate, filtrated and the solvent was removed under 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-propoxyben reduced pressure. The final product was purified by FPLC Zaldehyde (0.632 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA 0.558 mL, 4 mmol), di-(imidazol using a chloroform-methanol gradient (0->10%). The prod 1-yl)methanone (0.648, 4 mmol) as described in method 2. uct elutes at about 5% methanol. Yield: 0.135 g (10.0%); MS m/z 337.0 (M+H)"; H NMR 0563 Yield: 0.048 g (62%); MS m/z 323.3 (M+H); H (DMSO,400 MHz): 8 0.90-0.93 (m,3H); 1.61-1.70 (m, 2H): NMR (DMSO, 400 MHz): 8 0.65-0.67 (m, H); 3.67 (s, 3H): 3.08-3.12 (m, H); 3.81-3.87 (im, 3H); 5.49-5.53 (m, H); 6.85 406-4.13 (m,3H);5.43-5.45 (m, H); 6.83-6.85 (m, 2H); 6.97 (d. 2H, J=8.3 Hz); 7.19 (s. H); 7.25 (d. 2H, J=8.7 Hz): 7.55 (bs, H); 7.12-7.14 (m, 2H); 7.19-7.25 (m, H); 7.30-7.47 (m, (dd, H, J=9.1 Hz, J-2.1 Hz): 7.62 (d, H, J=9.1 Hz); 7.86 (d. H): 7.50-7.69 (m, H); 8.05 (s, H); 12.19-12.24 (m, H), HPLC H. J=2.1 Hz); 9.21 (s, H), HPLC (214 nm, B:rt 9.00 min (214 nm, B:rt 8.45 min (98.7%). (99%). Example 9 Example 13 1-(1H-benzodimidazol-5-yl)-5-(3-methoxyphenyl) (R)-1-(1H-benzodimidazol-5-yl)-5-(4-propoxyphe imidazolidin-2-one nyl)imidazolidin-2-one 0564. The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (0.532 g, 4 mmol), (0571 Separation of example 12 by chiral HPLC, column: di(1H-imidazol-1-yl)methanone (0.713 g, 4.4 mmol), TEA Nucleocel Alpha RP-S, 250*21 mm (5 um), eluent: 50/50 (1.67 mL, 12 mmol), aminomethyl-(3-methoxyphenyl)ke acetonitrile/water 50/50, flow 10 mL/min, second eluting tone hydrochloride (0.807 g., 4 mmol), TEA (1.12 mL, 8 enantiomer rt: 12.8 min (98.35)%. mmol), PdC (10%, 0.02 g) as described in method 1. 0565 Yield: 0.087 g (6.3%); MS m/z 309.1 (M+H)"; "H Example 14 NMR (DMSO, 400 MHz): 83.07-3.11 (m, H); 3.66 (s, 3H): (S)-1-(1H-benzodimidazol-5-yl)-5-(4-propoxyphe 3.83-3.88 (m, H); 5.51-5.55 (m, H, 6.76-6.78 (m, H); 6.85-6. nyl)imidazolidin-2-one 88 (m,2H); 7.17-7.21 (m, H): 7.24 (bs, H); 7.57 (dd, H, J=9.2 Hz J=1.8 Hz): 7.64 (d, H, J=9.2 Hz); 7.89 (d, H, J=1.8 Hz); Variant 1 9.36 (s, H), HPLC (=214 nm, B:rt 7.79 min (99%). 0572 The compound was synthesized according to method 3 Example 10 1-(1H-benzodimidazol-5-yl)-5-(2-methoxyphenyl) Step A: imidazolidin-2-one (0573 Potassium tert-butoxide (41.7 mL, 41.7 mmol), 0566. The compound was synthesized starting from methyltriphenylphosphonium bromide (14.89 g, 41.7 mmol), 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2-methoxyben 4-propoxybenzaldehyde (4.915 mL, 31.1 mmol), yield: 4.77 Zaldehyde (0.484 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), g (94.6%) PdC (10%, 0.02g), TEA (1.05 mL, 7.55 mmol), di-(imidazol 1-yl)methanone (0.667, 4.12 mmol) as described in method 2. Step B: 0567. Yield: 0.184 g (14.9%); MS m/z 309.3 (M+H)"; "H (0574 tert-butyl carbamate (9.08 g., 77.5 mmol), 0.38 M NMR (DMSO,400 MHz): 8 2.99-3.03 (m, H); 3.84-3.89 (m, aqueous NaOH (200 mL, 76 mmol), 1,3-dichloro-5,5-dim 4H); 5.66-5.69 (m, H); 6.79-6.83 (m, H); 6.91 (s, H); 7.02-7. ethylimidazolidine-2,4-dione (7.56 g. 38.4 mmol), (DHQ) 07 (m,2H); 7.18-7.22 (m,2H); 7.40(bs, H); 7.56 (bs, H); 8.06 PHAL (1.17 g, 1.5 mmol), 1-propoxy-4-vinylbenzene (s, H); 12.21 (bs, H), HPLC (214 nm, B: rt 7.81 min (4.055g, 25 mmol), potassium osmate dihydrate (0.368 g. 1 (96%). mmol) Example 11 (0575 Yield: 5.49 g (74.4%); MS m/z 296.3 (M+H)" 1-(1H-benzodimidazol-5-yl)-5-(4-ethoxyphenyl) Step C: imidazolidin-2-one (0576 Product obtained from step B (2.95 g, 10 mmol), 0568. The compound was synthesized starting from 4-methylbenzene-1-sulfonyl chloride (2 g, 10.5 mmol), tri 5-aminobenzimidazole (0.585g, 4.4 mmol), 4-ethoxybenzal ethylamine (1.95 mL, 14 mmol) US 2011/00925O1 A1 Apr. 21, 2011 99

0577. Yield: 2.59 g (57.6%); MS m/z 450.3 (M+H)" -continued Step D: NH2 0578 Product obtained from step C (2.59 g, 5.76 mmol), OEt Step E sodium azide (0.562 g, 8.64 mmol) -e- 0579. Yield: 1.25 g (67.8%); MS m/z 321.3 (M+H)" N-1N O O Step E: NH2 OH 0580 Product obtained from step D (1.25 g, 3.9 mmol), Step F PdC (10%, 0.02 g), p-anisaldehyde (0.598 mL, 4.92 mmol), -e- sodium borohydride (0.372g, 9.84 mmol) 0581. Yield: 1.68 g (crude material) Step F: - NHBoc 0582 Crude material obtained from step E (1.63 g, 3.94 mmol), trifluoroacetic acid (9.6 mL), triethylamine (1.52 mL, OH Step G 10.9 mmol), di(1H-imidazol-1-yl)methanone (0.963 g, 5.94 -e- mmol) N-1 no 0583. Yield: 1.05 g (81.6%); MS m/z 341.1 (M+H)" NHBOc further as Step G: w OH -- described in 0584 (S)-1-(4-methoxybenzyl)-4-(4-propoxyphenyl) s method 3 imidazolidin-2-one obtained from step F (0.28g, 0.82 mmol), 4-iodobenzene-1,2-diamine (0.192 g, 0.82 mmol), copper(I) N-1\o iodide (0.016 g., 0.08 mmol), cesium fluoride (0.249 g, 1.64 mmol), cyclohexane-1,2-diamine (mixture of cis and trans 0.01 mL, 0.08 mmol) Step A 0585. Yield: 82 mg (22.4%); MS m/z 447.5 (M+H)" 0590. Phenol (10g, 106.1 mmol) was added to a solution Step H: of powdered aluminium chloride (28.3 g, 212.2 mmol) over a period of 15 minin dichloromethane (100 mL) at 0°C., stirred 0586 Product obtained from step G (0.082g, 0.18 mmol), for 30 min and ethyl oxalyl chloride (14.2 mL, 127.5 mmol) triethyl orthoformate (5 mL), trifluoroacetic acid (10 mL) was added to the above reaction mass drop wise over a period 0587 Yield: 35 mg (57.9%); of 30 min keeping the temperature at 0°C. Warmed to room 0588 Overall yield: 2.9%; MS m/z 337.2 (M+H)"; HPLC temperature and stirred for 15 h. The reaction mass was (214 nm, B:rt 9.00 min (97.4%) quenched into coldwater and the organic layer separated. The aqueous layer was extracted with dichloromethane. The com Variant 2 bined organic layer was washed with water followed by brine Solution, dried over anhydrous Sodium Sulphate and concen 0589 trated under reduced pressure to afford crude product. Puri fication by column chromatography over silica gel (60-120 mesh) using 20-22% ethyl acetate in petroleum ether afforded OH O 7 g (34%) of the product as pale yellow solid. OEt Step A Step B Step B He- -> O 0591 1-propyl bromide (4.9 mL, 53.73 mmol) was added HO to a mixture of the product of step A (6.9 g, 35.82 mmol) and O potassium carbonate (9.9 g, 71.65 mmol) in acetonitrile (100 mL) and refluxed for 18 h. The reaction mass was filtered and OEt washed with acetonitrile. The filtrate was concentrated under Step C -e- reduced pressure. The resulting residue was taken in ethyl N1N O acetate and washed with water followed by brine solution. O Dried over anhydrous sodium Sulphate and concentrated NOH under reduced pressure to afford 6 g (71%) of the product as OEt brown oil. Step D He Step C O O 0592 Hydroxylamine hydrochloride (1.6 g. 22.98 mmol) was added to a mixture of the product of step B (3.6 g. 15.25 mmol) and sodium acetate (2.5 g. 30.50 mmol) in absolute ethanol (50 mL) and refluxed for 18 h. The reaction mass was