NZ618456B2

NZ618456B2 - NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H-PYRROLO[1,2-a][1,4]BENZO- DIAZEPINES AND 6H-PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH HETEROCYCLIC DERIVATIVES

Info

Publication number: NZ618456B2
Application number: NZ618456A
Authority: NZ
Inventors: Koen Jan Ludovicus Augustyns; Wit Kelly De; Louis Jules Roger Marie Maes; Lieven Meerpoel
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2011-05-05
Filing date: 2012-05-03
Publication date: 2015-09-01

Abstract

Disclosed are 5,6-dihydro-4-(heteroaryl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine derivatives as represented by the general formula (I), or a stereoisomeric form thereof, wherein, R1 is hydrogen, halo, alkyl or alkoxy; R2 is hydrogen, halo, alkyl or alkoxy; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical as defined herein. Representative compounds include 7-chloro-5,6-dihydro-4-(2-pyridinyl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 5,6-dihydro-4-(2-trifluoromethylpyridin-4-yl)-7-methyl-4H-pyrrolo[1,2-a][1,4]benzodiazepine hydrochloride, 5,6-dihydro-4-(benzofuran-2-yl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 5,6-dihydro-4-(benzothiazol-2-yl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 7-chloro-4-(1-ethylpyrazol-4-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine, 7,9-dichloro-4-(5-ethylthiazol-2-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepin. Further disclosed is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined above, for use in the treatment or prevention of a fungal infection. ether form a bond; Het is a monocyclic or bicyclic heterocyclic radical as defined herein. Representative compounds include 7-chloro-5,6-dihydro-4-(2-pyridinyl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 5,6-dihydro-4-(2-trifluoromethylpyridin-4-yl)-7-methyl-4H-pyrrolo[1,2-a][1,4]benzodiazepine hydrochloride, 5,6-dihydro-4-(benzofuran-2-yl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 5,6-dihydro-4-(benzothiazol-2-yl)-4H-pyrrolo[1,2-a][1,4]benzodiazepine, 7-chloro-4-(1-ethylpyrazol-4-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine, 7,9-dichloro-4-(5-ethylthiazol-2-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepin. Further disclosed is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined above, for use in the treatment or prevention of a fungal infection.

Description

NOVEL ANTIFUNGAL 5,6-DIHYDRO-4H—PYRROLO[l,2-a][1,4]BENZO- DIAZEPINES AND 6H—PYRROLO[1,2-a][1,4]BENZODIAZEPINES SUBSTITUTED WITH CYCLIC DERIVATIVES Field of the Invention The present invention is ned with novel antifungal 5,6-dihydro—4H—pyrrolo— [l,2-a][l ,4]benzodiazepines and 6H—pyrrolo[1,2—a][1,4]benzodiazepines, both substituted with cyclic derivatives, active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Background ofthe ion Dermatophyte is a common label for a group of 3 types of ﬁmgi that commonly causes skin disease in animals and . These anamorphic (asexual or imperfect fungi) genera are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these 3 genera.

Dermatophytes cause infections of the skin, hair and nails due to their ability to obtain nts from keratinized material. The organisms colonize the keratin tissues and inﬂammation is caused by host response to metabolic by—products. They are usually restricted to the corniﬁed layer of the mis because of their inability to penetrate Viable tissue of an immunocompetent host. However, occasionally the organisms do invade subcutaneous tissues, resulting in kerion pment. Invasion does elicit a host response ranging from mild to . Acid proteinases, elastase, keratinases, and other proteinases reportedly act as nce factors.

Systemic fungal infections (SFI) are life—threatening conditions that most commonly affect patients with reduced immunity often resulting from therapeutic interventions to treat malignant diseases. The number of SFI’s in modern hospitals keeps increasing, and the number of different fungi that have been involved in SFI is large and still growing. Despite many cases of invasive candidiasis and aspergillosis there has been an increased incidence of infections due to other molds like Scedosporz‘um apiospermum, Fusarium spp., and Zygomycetes, Rhizopus and Mucor spp.. Effective therapeutic agents treating all these infections very well therefore need to have very broad spectrum of ty. In the past few decades itraconazole, ﬂuconazole, ketoconazole, and enous or liposomal amphotericin B have been used in SF1, and all ofthese agents have their limitations with regard to spectrum, safety or ease of administration.

WC 2012/150305 More recently a third generation of azoles have been investigated and introduced to the market, improving the treatment options in intensive care units. Voriconazole (erndTM) and posaconazole (NoxafilTM) show much improvement oftreatment towards life threatening invasive SFI such as iasis, aspergillosis, and infections due to Fusarz'um species at clinical relevant dosages. Moreover posaconazole shows efﬁcacy t infections caused by the emerging Zygomycetes spp. Echinocandins, such as anidulafungin, ungin, and micafungin, which are non-competitive inhibitors of 1,3-B-glucan sis in fungal cell walls, display high efﬁcacy t Candida spp. and Aspergillus spp., but no activity against coccus, Fusarium, or Zygomycetes spp.. Of all antimycotic agents, azoles still represent a unique class of compounds displaying the broadest antifungal spectrum via inhibition of 14 demethylase, an enzyme being essential for ergosterol biosynthesis in fungi.

Onychomycosisis the most common disease ofthe nails and constitutes about a half of all nail abnormalities. The prevalence ofonychomyCOSis1Sabout 6-8 %in the adult population. The causative pathogens of onychomycosis include dermatophytes, Candida, and non-dermatophytic moulds. Dermatophytesare the fungi most commonly responsible for mycosisin the temperate western countries; meanwhile, Candida and non-dermatophytic moulds are more frequently involvedin the tropics and subtropics. TIichophyton rabram is the most coriimOn dermathophyte involvedin ony’chomycosis. Other derrnatophytes that may be involved are Trzchophyton . interdigitale, mophytonﬂoccosum Trichophyton violaceam, Microsporum gypseum,Trichophyton ns phyton soudanense and phyron V61rucosum Other causative pathogens include Candida and non—dermatophytic moulds,in ular members of the mould generation Scytalidium (also Neoscytalz'dium), Scopulalzopsis, andAspergillus. ' ,6-Dihydro-4H—pyrrolo[1,2—a][1,4]benzodiazepines have been described in J. Chem.

Soc.(C), 2732-2734 (1971); J. Heterocyclic Chem, _1_§, 711-716 (1976); and J.

Heterocyclic Chem, 16, 241-244 (1979). The compounds disclosed in these references all have a phenyl moiety in the 4-position and no biological activities were reported in any of these nces.

A new synthetic route to aryl(heteroaryl)-annulated pyrrolo[ l ,2-a][l ,4]diazepines has been described in Org. Biomol. Chem, 8, 3316-3327 (2010).

W002/34752 describes 4—substituted 5,6-dihydro—4H—pyrrolo[1,2-a][1,4]benzo- diazepines as a new class of antiﬁingal compounds. However, 4752 only discloses compounds with a phenyl moiety in the 4-position.

The PhD thesis of De Wit K. describes the implementation of an in vitro and in viva mycological evaluation platform and ty proﬁling of antifungal pyrrolobenzodiazepines (PhD Thesis; University of Antwerp, Belgium; Faculty of Pharmaceutical, ical and Veterinary Sciences; Department of Biomedical Sciences; 2011; 220 p.).

The antifungal compounds of the present invention or part of the compounds of the present invention are structurally different and may have improved potency, improved metabolic stability properties, improved solubility, ed plasma binding, reduced hERG channel inhibition, reduced cytochrome P450 liabilities, or improved bioavailability compared with compounds disclosed in the prior art. Preferably said compounds have a broad ngal spectrum, and maintain adequately high thereapeutic efﬁcacy and adequately low toxicity or other side effects.

The compounds of the present invention are useful as squalene ase inhibitors.

It is accordingly an object of the present invention to provide novel compounds with antifungal activity to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide the public with useful alternative compounds.

Summary of the invention It has been found that the compounds of the present invention are useful as antifungal compounds.

The t invention concerns novel compounds of a (I): R4 \ N Het \m (I) and stereoisomeric forms thereof, wherein R1 is hydrogen, halo, C1_4a1ky1 or kyloxy; R2 is hydrogen, halo, C1_4a1kyl or C1_4all<yloxy; R3 and R4 are en; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical selected from HN _b \zN Ix /b \\ X3¢X4 I’ C ‘\ II b \ (d-1) (d-2) (d-3) (d-4) (d-5) a I a / ,X9 ’ X / ’ )(14 ’ Xe” I X13 \ i )|(7 >|(|10 \>‘ ‘- ’ 15 o o b‘ ~ 0 b‘ ~ §X8 \X“ (d-7) (d~8) ((1-6) (d-9) 19 5 1 8 , , [X X\ , a I /N\ ’ / ’ X17 l a X20 \\ \ / I 16 / 6 \ X \ x b \ N b \ (d-10) (ct-11) (d-12) (d-l) and (d-2) are attached to the remainder of the molecule with a bond in position a, b or c; (d-4), (d—6), (d-7), (d-lO) and (d-12) are attached to the remainder of the molecule with a bond in position a or b; X1 is O, S or NH; X2 is O or S; X3, X4 and X5 each independently are CH or N; provided that exactly two ofX3, X4 and X5 are N, the other being CH; X6, X7, X8 and X9 each ndently are CH or N; provided that one or two ofX6, X7, X8 and X9 are N, the other being CH; X10, Xl 1, X12 and X13 each independently are CH or N; provided that maximum one of X10, Xl 1, X12 and X13 is N, the other being CH; X14 is CH or N; X15 is NH, O or S; X16 is CH or N; X17 is CH or N; X18 is NH, S or O; X19 is CH or N; X20 is NH or S; R5 and R6 taken together form a bivalent radical —R5—R6—, having a: ~(CH2)m(CH2)n-m— (a), —(CH2)n_m—O—(CH2)m— (b), —(CH2)s— (0)» 0T —CH=CH—CH=CH— ((1); wherein the bivalent radical —R5—R6— may, Where possible, be substituted with one or more substituents selected from the group ting of halo, C14alkyl, yl, Cqualkyloxy and oxo; m represents 0, 1 or 2; n represents 2, 3 or 4; represents 3, 4 or 5; wherein radicals (d-1)—(d-11) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, C14a1kylthio, C14alkylsulphonyl, CMalkylsulphinyl, and l optionally substituted with one or more halo substituents; provided that radicals (d—l)—(d-l 1) are not substituted in the a-positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the es thereof; provided that the compound is not 5,6-dihydro-4—(2—pyridinyl)-4H—pyrrolo[1,2-a][1,4] benzodiazepine .HCl.

The t invention also concerns methods for the ation of compounds of Formula (I) and pharmaceutical compositions comprising them.

The present compounds are useful agents for combating fungi in vivo.

The novel compounds described in the present ion may be useful in the treatment or prevention of ions caused by dermatophytes, systemic fungal infections and onychomycosis; in particular infections caused by ophytes.

The novel compounds described in the present invention may be active against a wide variety of ﬁmgi, such as Candida spp., e.g. Candida albicans, a glabrata, Candida krucei; Candida parapsilosis, Candida keﬁzr, Candida tropicalis; Aspergillus spp., e.g. Aspergillusfumigatas, Aspergillus niger, Aspergillusﬂavus; Cryptococcus neoformans; Sporothrz'x kz‘i; Epidermophytonﬂoccosum; Microsporam spp., e. g.

Microsporum canis, Microsporam gypseum; Trichophyton spp., e. g. Trichophyz‘on mentagrophyz‘es, Trichophyton rubram, phyton quinckeanam, phyton tonsarans, Trichophyton verrucosum, Trichophyton violaceam, Trichophyton interdigitale, Trichophyion soudanense; Fusarium spp., e.g. Fasarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelioides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malasseziafuifur; Acremonz’um W0 2012/150305 spp.; Paecz‘lomyces; Scopularz'opsz's; Arthrographis spp.; z’dium; Scea’osporz'um spp., e.g. Scedosporz'um permum, porz'um ﬁcans; Trichoderma spp., Penicillium spp. ; Penicillium marneffez'; Blastoschizomyces.

In view of the aforementioned pharmacology ofthe present compounds, it follows that they are suitable for use as a medicament.

The invention also relates to a compound according to the general Formula (I), the isomeric forms thereof and the pharmaceutically acceptable addition salts and the solvates thereof, for use in the treatment or tion of fungal infections.

One advantage of the compounds or a part of the compounds of the present invention may lie in their ed bioavailability, improved metabolic stability properties, improved PK properties, reduced hERG channel inhibition, or reduced cytochrome P450 ities compared with the compounds disclosed in the prior art.

The present ion will now be further described. In the ing passages, different aspects of the invention are deﬁned in more detail. Each aspect so deﬁned may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Detailed description 2O When describing the compounds of the invention, the terms used are to be construed in accordance with the following deﬁnitions, unless a context dictates otherwise.

Whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from I to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution s in a chemically stable compound, i.e. a compound that is ently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

The term “halo” or “halogen” as a group or part of a group is generic for ﬂuoro, chloro, bromo, iodo unless ise is indicated or is clear from the t.

The term "CMakal" as a group or part of a group (e.g. in CMalkylcarbonyl, CMalkylthio, CMalkylsulphonyl, CMalkylsulphinyl) refers to a hydrocarbyl radical of Formula CnH2n+1 wherein n is a number ranging from 1 to 4. CMalkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein ing a carbon atom, the ipt refers to the number of carbon atoms that the named group may contain.

Thus, for example, CMalkyl es all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, n—propyl, i- propyl, 2—methyl—ethyl, butyl and its isomers (e.g. n-butyl, isobutyl and ten-butyl), and the like.

The term “C14alkyloxy” as a group or part of a group refers to a radical having the Formula ~0Ra wherein Ra is CMalkyl. Non—limiting examples of suitable CMalkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, xy, isobutyloxy, sec—butyloxy and tert—butyloxy.

The chemical names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service, using Advanced Chemical Development, Inc., nomenclature software abs Release 1200 Product version 12.01; Build 33104, 27 May 2009).

In case of tautomeric forms, it should be clear that the other non-depicted tautomeric form is also included within the scope of the present invention.

The atoms in the tricyclic system are numbered as shown in the following formula (Q): 9 7 (Q) 2 When any variable occurs more than one time in any tuent, each deﬁnition is independent.

Whenever radicals (d—1)—(d-1 1) are substituted with one or more substituents, those substituents may e any hydrogen atom bound to a carbon or nitrogen atom, including NH and CH groups in the deﬁnition of X1, X3-X14, O, provided however that NH and CH groups in the or-positions to the carbon atom of attachment are not substituted.

For example, (d-l 1) W0 2012/150305 b_.) / \ x20 (d-1 1) may be substituted on the CH group in position a), but also on the NH group in position b) in case X20 represents NH.

It will be appreciated that some of the compounds of Formula (I) and their pharmaceutically acceptable addition salts and so lvates may n one or more centers of ity and exist as stereoisomeric forms.

Hereinbefore and hereinafter, the term “compound(s) of formula (1)” is meant to include the addition salts, the solvates and the stereoisomers thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

The term “stereoisomeric forms” as used hereinbefore deﬁnes all the possible ic forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible chemically isomeric forms. The invention es all stereoisomers of the compound ofFormula (I) either as a pure stereoisomer or as a e of two or more stereoisomers. The deﬁnition of “compound of formula (1)” inherently includes all stereoisomers of the compound of formula (I) either as a pure stereoisomer or as a e oftwo or more stereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 e of a pair of enantiomers is a racemate or racemic mixture. More in particular, stereogenic s may have the R— or S—conﬁguration. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the tuents may be in the E or the Z conﬁguration at said double bond. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans—conﬁguration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans conﬁguration. Stereoisomeric forms of the compounds of Formula (I) are embraced within the scope of this invention. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z s, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

The absolute conﬁguration is speciﬁed according to the ngold-Prelog system.

The conﬁguration at an asymmetric atom is speciﬁed by either R or S. Resolved W0 2012/150305 compounds whose absolute conﬁguration is not known can be ated by (+) or (—) depending on the direction in which they rotate plane polarized light.

When a speciﬁc isomer is identiﬁed, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, ofthe other isomers. Thus, when a nd of formula (I) is for instance speciﬁed as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance speciﬁed as E, this means that the nd is substantially free ofthe Z ; when a compound of formula (I) is for instance speciﬁed as cis, this means that the compound is substantially free of the trans isomer.

Some ofthe nds according to formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present ion.

For therapeutic use, salts of the compounds of Formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also ﬁnd use, for example, in the preparation or puriﬁcation of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned above or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for e, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, esulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, ic, salicylic, p-amino-salicylic, pamoic and the like acids. Conversely said salt forms can be ted by treatment with an appropriate base into the free base form.

The compounds of Formula (1) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with riate organic and inorganic bases. Appropriate base salt forms comprise, for example, the WC 2012/150305 ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and ry aliphatic and aromatic amines such as methylamine, mine, propylamine, isopropylamine, the four butylamine s, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di—n— butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N— methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term solvate comprises the es and solvent addition forms which the compounds of Formula (I) are able to form, as well as the salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.

The compounds of Formula (I) as prepared in the processes described below may be sized in the form ofmixtures of enantiomers, in particular racemic mixtures of omers that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (1) es liquid chromatography using a chiral stationary phase. Said pure stereochemically ic forms may also be derived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occurs stereospeciﬁcally. Preferably if a c stereoisomer is desired, said compound would be synthesized by stereospeciﬁc methods of preparation. These methods will advantageously employ omerically pure ng materials.

In the framework of this ation, a compound according to the invention is ntly intended to comprise all isotopic combinations of its chemical ts. In the framework of this application, a chemical element, in particular when mentioned in relation to a compound according to Formula (1), comprises all isotopes and isotopic mixtures of this element. For example, when hydrogen is mentioned, it is understood to refer to 1H, 2H, 3H and mixtures thereof.

A compound according to the invention therefore inherently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, ing a ctive compound, also called radiolabelled compound, wherein one or more nonradioactive atoms has been replaced by one of its radioactive isotopes. By the term "radiolabelled nd" is meant any compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which contains at least one radioactive atom.

W0 2012/150305 For example, a compound can be labelled with positron or with gamma emitting radioactive isotopes. For radio -binding techniques, the 3H-atom or the 125I-atom is the atom of choice to be replaced. For imaging, the most commonly used positron emitting (PET) radioactive isotopes are ”C, 18F, 15O and 13N, all ofwhich are accelerator produced and have half—lives of 20, 100, 2 and 10 minutes respectively.

Since the half—lives of these radioactive es are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus ng their use. The most widely used of these are 18F, 99mTc, 201T1 and 123I. The ng of these radioactive isotopes, their production, isolation and incorporation in a molecule are known to the skilled person.

In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular, the radioactive isotope is ed from the group of 3H, 11C, 18F, 1221’ 123I, 1251, ml, 75Br, 76Br, 77Br and 82Br.

As used in the speciﬁcation and the appended claims, the singular forms "a", "an," and "the" also include plural referents unless the context y es otherwise. By way of example, "a compound" means one compound or more than one compound.

The terms described above and others used in the speciﬁcation are well understood to those in the art.

Preferred features of the compounds ofthis invention are now set forth.

In an embodiment, the present invention concerns novel compounds of Formula (I): R4\ R1 tiet a) / R2 and stereoisomeric forms thereof, wherein R1 is hydrogen, halo, CMalkyl or CMalkyloxy; R2 is en, halo, Claalkyl or CMalkyloxy; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical selected from X=N HN —b » / \ /b \ \ Xa‘x4 I, C ‘\ I b \ (d-1) (d-Z) ((1-3) (OI-4) ((1-5) 9 12 a ’ a ’ / I z Xe’rx I x13‘X\ xii: I l7 £10 > — _ X§X8 I O O b‘~ o b\~ \X“ X15 (d-7) (d—8) (d-9) (d—6) 19 5 lx18 X\ // /N\ , a , I / z X17 l a X20 I X \ b \ N b \ (d-10) (d-11) (d-12) (d—l) and (d—2) are attached to the remainder of the molecule with a bond in position a, b or c; (d-4), (d—6), (d-7), (d-lO) and (d-12) are attached to the remainder of the molecule with a bond in on a or b; X1 is O, S or NH; X2 is O or S; X3, X4 and X5 each independently are CH or N; provided that exactly two ofX3 , X4 and X5 are N, the other being CH; X6, X7, X8 and X9 each independently are CH or N; provided that exactly one of X6, X7, X8 and X9 is N, the other being CH; X10, X1 1, X12 and XI3 each independently are CH or N; provided that maximum one of X10, Xl 1, X12 and X13 is N, the other being CH; X14 is CH or N; X15 is O or S; X16 is CH or N; X17 is CH or N; x18 is NH, 8 or o; X19 is CH or N; x20 is NH or s; R5 and R6 taken together form a bivalent radical —, having formula: —(CH2)m—O—(CH2)n_m— (a), —(CH2)n-m—O—(CH2)m— (b), or “(CH2)S_ (C), wherein the bivalent radical —R5—R6— may, where possible, be substituted with one or more substituents selected from the group consisting of halo, CMalkyl, hydroxyl, yloxy and 0x0; m represents 0, l or 2; n represents 2, 3 or 4; 8 represents 3, 4 or 5; n radicals (d—1)-(d—l 1) may be substituted with one or more substituents each ndently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, CMalkylthio, Clhalkylsulphonyl, Clhalkylsulphinyl, and CMalkyl optionally substituted with one or more halo substituents; provided that radicals (d-1)- (d-l 1) are not substituted in the a—positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the solvates thereof.

In an embodiment, the present ion concerns novel compounds of Formula (I): R4 \ N Flet ‘\d;:[::::i (n / R2 and stereoisomeric forms thereof, wherein R1 is hydrogen, halo, CMalkyl or Clhalkyloxy; R2 is hydrogen, halo, yl or CMalkyloxy; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical selected from ._ b XZN HN /\\ /b \ \ x3¢X4 I, C \\ I, b \ (d—1) (d—2) (d—3) (d-4) (d-5) 9 12 a I a I / I X14 z X6¢X ’ x13‘x\ I l7 £10 \> ' " X§X8 , \X” X15 O O b\ o b‘~ (d-7) (d-8) (d_6) (d-9) (d-10) (d-11) (d-12) (d-l) and (d-2) are attached to the remainder of the molecule with a bond in position a, b or c; (d-4), (d-6), (d-7), (d-lO) and (d-12) are attached to the remainder of the molecule with a bond in position a or b; X1 is O, S or NH; X2 is O or S; X3, X4 and X5 each independently are CH or N; provided that exactly two ofX3, X4 and X5 are N, the other being CH; X6, X7, X8 and X9 each independently are CH or N; provided that exactly one ofX6, X7, X8 and X9 is N, the other being CH; X”, X1 1, X12 and X13 each independently are CH or N; provided that maximum one of X”, X“, X12 and X13’ is N, the other being CH; X14 is CH or N; X15 is O or S; X16 is CH or N; X17 is CH or N; x18 is NH, 3 or o; X19 is CH or N; X20 is NH or S; R5 and R6 taken together form a bivalent l ~R5—R6—, having formula: m—0—(CH2)n—m* (a), —(CH2)n-m—O—(CH2)m— (b), or -(CH2)s— (0); n the bivalent radical —R5—R6— may, where le, be substituted with one or more substituents ed from the group consisting of halo, l, hydroxyl, CMalkyloxy and oxo; m represents 0, l or 2; n represents 2, 3 or 4; 3 represents 3, 4 or 5; wherein radicals (d—1)-(d-11) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, CMalkylthio, CMalkylsulphonyl, CMalkylsulphinyl, and CMalkyl optionally substituted with one or more halo substituents; provided that radicals (d-1)— (d—l 1) are not substituted in the u—positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the es thereof; provided that the compound is not hydro—4—(2-pyridinyl)-4H-pyrrolo[1,2-a][1,4] benzodiazepine .HCl.

In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein R1 is hydrogen, halo or CMalkyl; R2 is hydrogen, halo or CMalkyl; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical selected from C O a // ” X1’N\a ” sz/ \N \ it, l X's/\[ L—Na /\d k 3’ b \ x I, c \\ ,’ b \\ (d-1) (d-2) (d-3) (d-4) (d-5) 9 12 Xa’zx / 14 / X13X\ X\ l7 )|(l10 > _ _ X§X8 / \X“ X15 (d-8) (d-Q) (d-l) and (d-2) are attached to the remainder of the molecule with a bond in position a, b or c; (d-4), (d-lO) and (d-12) are attached to the remainder of the molecule with a bond in position a or b; X1 is O or NH; X2 is S; X3, X4 and X5 each ndently are CH or N; provided that exactly two ofX3, X4 and X5 are N, the other being CH; X6, X7, X8 and X9 each independently are CH or N; provided that one or two ofX6, X7, X8 and X9 are N, the other being CH; X10, Xl 1, X12 and X13 each ndently are CH or N; provided that maximum one of X10, X”, X12 and X13 is N, the other being CH; X14 is CH or N; X15 is 0 or s; X16 is CH or N; X17 is CH or N; X18 is NH, 3 or o; X19 is CH or N; X20 is NH or S; R5 and R6 taken together form a bivalent radical 6—, having formula: ~(CH2)s— (0): 0T —CH=CH—CH=CH— (d); s ents 3, 4 or 5; wherein radicals (d-1)—(d-5) and (d—8)—(d—l 1) may be substituted with one or more tuents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, and CMalkyl optionally substituted with one or more halo tuents; provided that radicals (d—l)-(d-5) and (d—8)—(d—l l) are not substituted in the u—positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the solvates thereof; provided that the compound is not 5,6-dihydro~4—(2—pyridinyl)-4H-pyrrolo[l,2-a][l,4] benzodiazepine .HCl.

In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein R1 is hydrogen, halo or yl; R2 is hydrogen, halo or CMalkyl; R3 and R4 are hydrogen; W0 2012/150305 or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical ed from C O a z r X1’N\a ” \ / 5 I x2 \ , a I )(|/\1/4 —b _N /\\/J HN I \ /b \\ |\X3”X I C \ I b \ , \ (d-l) (d-2) (cl-3) (d-4) ((1-5) 9 12 X6¢X , 14 , X13‘X\ X\ 17 Jim > - " (d-8) (d-9) 19 5 18 / I /X X\ a ’z , /N\ I / X17 I a X20 \\ \ / I x16 /b\\ 6 \ N \ N b \ (d-10) (d-11) (d-12) (d-l) and (d-2) are attached to the remainder of the molecule with a bond in position a, b or c; (d-4), (d-10) and (d-12) are ed to the remainder of the molecule with a bond in position a or b; X1 is O or NH; x2 is s; X3, X4 and X5 each independently are CH or N; provided that exactly two ofX3 , X4 and X5 are N, the other being CH; X6, X7, X8 and X9 each ndently are CH or N; provided that exactly one ofX6, X7, X8 and X9 is N, the other being CH; X10, X1 l, X12 and X13 each independently are CH or N; provided that maximum one of X10, X] 1, X12 and X13 is N, the other being CH; X14 is CH or N; X15 is O or S; X16 is CH or N; X17 is CH or N; X18 is NH, S or O; X19 is CH or N; X20 is NH or S; R5 and R6 taken together form a bivalent radical —R5—R6—, having formula: W0 2012/150305 -(CH2)s— (C); s represents 3, 4 or 5; wherein radicals (d-l)-(d—5) and (d-8)-(d-1 1) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, and CMalkyl optionally substituted With one or more halo substituents; provided that radicals (d-l)—(d-5) and (d-8)—(d—l 1) are not substituted in the a—pOSitiOIlS to the carbon atom of attachment; and the pharmaceutically able addition salts, and the solvates thereof; ed that the compound is not 5,6-dihydro—4—(2-pyridinyl)—4H-pyrrolo[l,2-a][l ,4] benzodiazepine .HCl.

In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms f, wherein R1 is en, chloro, ﬂuoro or methyl; R2 is hydrogen, chloro, ﬂuoro or methyl; R3 and R4 are en; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic heterocyclic radical selected from o a ,a X’s/\[/ X1’N\a v’ xz§ax \N §=N )«J HN k ,x“ __ b /b \ 3/ x ,’ b \ X (d-1a) (d-2a) (d-3) (d4) (d-5) X9 , X12 54 r 13 \ X14 x )l(l )l(7 \>_ _ _ X10 / §Xg \X11 x15 (d—8) (d~9) X18 I N ,’ / \ / \ / X17 a X20 \\ 1 \ / l X /b g N 6 \ x \ N b \ (d-10) (d-11) (d-12) (d-la), (d—2a), (d-4), (d-lO) and (d-l2) are attached to the remainder of the molecule with a bond in position a or b; X1 is O or NH; X2 is S; W0 2012/150305 X3, X4 and X5 each independently are CH or N; provided that exactly two ofX3, X4 and X5 are N, the other being CH; X6, X7 and X9 are CH; X8 is N; X10, Xl 1, X12 and X13 each independently are CH or N; provided that maximum one of X10, X”, X12 and X13 is N, the other being CH; X14 is CH or N; X15 is O or S; X16 is CH or N; X17 is CH or N; X18 is NH, S or O; X19 is CH or N; X20 is NH or S; R5 and R6 taken er form a bivalent radical —R5-R6—, having formula: —(CH2)s- (C); s represents 3; wherein radicals (d-l a)-(d-5) and (d-8)—(d—l 1) may be substituted with one or more substituents each independently selected ﬁom the group consisting of methoxy, chloro, ﬂuoro, methylcarbonyl, and CMalkyl optionally substituted with one or more ﬂuoro substituents; provided that radicals (d-la)-(d-5) and (d—1 1) are not substituted in the (I-pOSitiOIlS to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the solvates thereof; provided that the compound is not hydro—4-(2-pyridinyl)—4H~pyrrolo[l,2-a][l ,4] benzodiazepine .HCl.

In an embodiment, the invention relates to compounds ula (I) and stereoisomeric forms thereof, wherein R1 is hydrogen, halo or CMalkyl; R2 is hydrogen, halo or CMalkyl; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; Het is a monocyclic or bicyclic cyclic l selected from (d-l), (d—2), (d-3), (d—5), (d—8), (d—9), (d—lO) and (d-l 1); (d-l) and (d-2) are attached to the remainder of the molecule with a bond in position a, b or c; (d-lO) is attached to the der of the molecule with a bond in position a or b; X1 is O or NH; X:2 is S; X3, X4 and X5 each independently are CH or N; provided that exactly two ofX3 , X4 and X5 are N, the other being CH; X6, X7, X8 and X9 each independently are CH or N; ed that exactly one of X6, X7, X8 and X9 is N, the other being CH; X10, X1 1, X12 and X13 each independently are CH or N; provided that maximum one of X10, X”, X12 and X13 is N, the other being CH; X14 is CH or N; X15 is O or S; X16 is CH or N; X17 is CH or N; X18 is NH, S or O; X19 is CH or N; X20 is NH or S; wherein radicals (d-l), (d-2), (d—3), (d-S), (d—8), (d—9), (d-lO) and (d—l 1) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, and CHalkyl optionally substituted with one or more halo tuents; provided that radicals (d-l), (d-2), (d-3), (d-5), (d-8), (d—9), (d-l 0) and (d—l l) are not substituted in the (nu-positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the solvates f; provided that the nd is not hydro-4—(2-pyridinyl)—4H—pyrrolo[1,2—a][l ,4] benzodiazepine .HCl.

In an embodiment, the invention s to compounds of Formula (I) and stereoisomeric forms thereof, wherein R1 is hydrogen, halo or CMalkyl; R2 is hydrogen, halo or CMalkyl; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; Het is @-X15 (d-9a) X15 is O or S; in particular 0; wherein radical (d-9a) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, W0 2012/150305 CMalkylcarbonyl, and CMalkyl optionally substituted with one or more halo substituents; ed that l (d-9a) is not substituted in the a—positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the solvates thereof.

In an embodiment, the invention s to compounds ofFormula (I) and stereoisomeric forms thereof, wherein R] is hydrogen, halo or CMalkyl; R2 is hydrogen, halo or CMalkyl; R3 and R4 are en; or R3 and R4 taken er form a bond; Het is selected from X18 8 “ and < X15 \Xl:9\ (d-Qa) (d-1Oa) (d- 10a) is attached to the remainder of the molecule with a bond in position a or b; X15 is O or S; in particular 0; X16 is CH or N; in particular CH; X18 is NH, S or O; in particular S or 0; more in ular 0; wherein ls (d-9a) and (d-10a) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, Clnalkylcarbonyl, and CMalkyl optionally substituted with one or more halo substituents; provided that radicals (d-9a) and (d—lOa) are not substituted in the (X.- positions to the carbon atom of attachment; and the pharmaceutically acceptable addition salts, and the solvates thereof.

In an embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments, wherein Het is (d-9b) In an embodiment, the invention s to any of the other embodiments or any combination of the other embodiments, wherein Het is quinolinyl.

W0 2012/150305 In an embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments, wherein R1 is hydrogen; R2 is hydrogen; R3 and R4 are taken together to form a bond; and Het is quinolinyl.

In another embodiment, the ion relates to any of the other embodiments or any combination ofthe other embodiments, wherein R3 and R4 are hydrogen.

In another ment, the invention relates to any of the other embodiments or any combination of the other embodiments, wherein R3 and R4 are taken together to form a bond.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments, n radicals (d-1)~(d-1 1) may be substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, C1.4alkylcarbonyl, CMalkylsulphonyl, CMalkylsulphinyl, and CMalkyl optionally substituted with one or more halo substituents; in particular CMalkyloxy, halo, lcarbonyl, and l ally substituted with one or more halo substituents; provided that radicals (d-1)-(d-11) are not substituted in the (l-pOSIthIlS to the carbon atom of attachment.

In another embodiment, the invention relates to any of the other ments or any combination ofthe other embodiments, wherein radicals (d-l)—(d—2) and (d—4)—(d-1 1) may be substituted with one or more tuents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, CMalkylthio, CMalkylsulphonyl, CMalkylsulphinyl, and CMalkyl optionally substituted with one or more halo substituents; wherein radical (d—3) is substituted with one or more substituents each independently ed from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, CMaIkylthio, C1.4alkylsulphonyl, CMalkylsulphinyl, and CMalkyl optionally substituted with one or more halo substituents; provided that radicals (d—1)—(d-l 1) are not substituted in the tions to the carbon atom of attachment.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments, wherein Het is a monocyclic or bicyclic heterocyclic radical ed from the group consisting of pyrazolyl, nyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzoxazolyl, quinolinyl, furo[3,2-c]pyridinyl, ﬁ1r0[2,3-b]pyridinyl, W0 2012/150305 furo[2,3—c]pyridinyl, b]thiophenyl, benzothiazolyl, quinoxalinyl, isoxazolyl, thiazolyl, indolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, lH-1,2,3- benzotriazolyl, 2H—l ,2,3—benzotriazolyl, 6,7-dihydro-5H-cyclopenta[b]pyridin-3 -yl, hydro—2—oxo-pyridinyl and benzimidazolyl; in ular wherein Het is a monocyclic or bicyclic heterocyclic radical selected from the group consisting ofpyridinyl, benzofuranyl and benzo[b]thiophenyl; more in particular wherein Het is a monocyclic or bicyclic heterocyclic radical selected from the group ting of uranyl and benzo[b]thiophenyl; wherein said radicals may be substituted with one or more substituents each independently selected from the group consisting of Claalkyloxy, halo, CHalkylcarbonyl, and CMalkyl optionally substituted with one or more halo substituents; provided that said radicals are not substituted in the a—positions to the carbon atom of attachment.

In another embodiment, the invention s to any ofthe other embodiments or any combination of the other embodiments, wherein Het is a monocyclic or bicyclic heterocyclic l selected from the group consisting ofpyridinyl, benzo l and benzo[b]thiophenyl; n benzoﬁiranyl and benzo[b]thiophenyl may be tuted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, and CMalkyl optionally substituted with one or more halo substituents; wherein pyridinyl is substituted with one or more substituents each independently selected from the group consisting of CMalkyloxy, halo, CMalkylcarbonyl, and CMalkyl optionally substituted with one or more halo substituents; ed that said radicals are not substituted in the (I-pOSi’EiOIlS to the carbon atom of attachment.

In another embodiment, the invention s to any ofthe other embodiments or any combination of the other embodiments, 3O wherein Het being nyl is substituted with one or more substituents deﬁned in the other embodiment; provided that pyridinyl is not substituted in the d-positions to the carbon atom of attachment.

In another embodiment, the invention relates to any of the other embodiments or any combination ofthe other embodiments, wherein at least one of R1 and R2 is other than hydrogen.

WO 50305 In a particular embodiment, the invention s to any of the other embodiments or any combination ofthe other embodiments, wherein R2 is hydrogen, chloro or ﬂuoro.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments, wherein R1 or R2 is in the 7-position and is other than en.

In r embodiment, the invention relates to any ofthe other embodiments or any combination of the other embodiments, wherein R1 is in the 7-position and is chloro or ﬂuoro; in particular R1 is in the 7-position and is chloro.

In another ment, the invention relates to any of the other embodiments or any IO ation ofthe other embodiments, n R1 is in the 7-position and is chloro, ﬂuoro or methyl; in particular R1 is in the 7— position and is chloro or ﬂuoro; more in particular R1 is in the 7—position and is chloro; and R2 is in any of the other positions and is hydrogen, chloro, ﬂuoro or ; in particular chloro, fluoro or methyl; more in particular chloro or ﬂuoro; even more in particular chloro.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments, wherein R2 is in the 7-position and is chloro, fluoro or methyl.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other ments, wherein R2 is in the 7—position and is chloro, ﬂuoro or methyl; and R1 is in any of the other positions and is en, chloro or ﬂuoro; in particular chloro or ﬂuoro; more in particular chloro.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein R1 is halo.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein R2 is hydrogen.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein R1 is halo and R2 is hydrogen.

In r embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein Het is selected from (d-3), (d-9) and (d-lO); in particular Het is ed from (d-9) and (d-IO); more in particular Het is wherein said heterocyclic radicals may be substituted as deﬁned in any of the other embodiments.

W0 2012/150305 In another embodiment, the ion s to any of the other ments or any combination of the other embodiments wherein Het is selected from (d—3), (d—9) and (d-lO); wherein radicals (d-3), (d-9) and (d-IO) may be substituted with one or more substituents each independently selected from the group consisting of Cmalkyloxy, halo, CMalkylcarbonyl, CMalkylthio, Clnalkylsulphonyl, CMalkylsulphinyl, and CMalkyl optionally substituted with one or more halo substituents; provided that radicals (d—3), (d—9) and (d-IO) are not substituted in the (it-positions to the carbon atom of ment.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein Het is selected from (d—9) and (d-lO); n radicals (d-9) and (d- l 0) may be substituted with one or more substituents each independently selected from the group consisting of Cmalkyloxy, halo, CMalkylcarbonyl, CMalkylthio, CMalkylsulphonyl, Cmalkylsulphinyl, and CMalkyl optionally substituted with one or more halo tuents; provided that radicals (d-9) and (d-lO) are not substituted in the a—pOSlthIlS to the carbon atom of attachment.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein Het is selected from (d-8), (d-9), (d-IO) and (d-l 1); wherein radicals (d—8), (d—9), (d-lO) and (d—l 1) may be substituted as deﬁned in any ofthe other embodiments.

In another embodiment, the invention relates to any ofthe other ments or any combination of the other embodiments wherein Het is selected from (d—6), (d—7), (d-8), (d—9), (d—lO), (d—l l) and (d—l2); in ular Het is ed from (d-6), (d-7), (d-8), (d—9), (d—lO) and (d-l 1); wherein said bicyclic heterocyclic radicals may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the invention relates to any of the other embodiments or any combination ofthe other embodiments wherein Het is selected from (d—l), (d-2), (d-3), (d-4) and (d-S); in ular Het is selected from (d—3) and (d-S); more in particular Het is (d-3); wherein said monocyclic heterocyclic radicals may be substituted as deﬁned in any of the other ments.

In r embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein Het is selected from (d—l) and (d-2); in particular Het is (d-l); WO 50305 wherein said monocyclic heterocyclic radicals may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the invention s to any of the other embodiments or any combination of the other embodiments n Het is (d-2); wherein (d-2) may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein Het is (d-S); wherein (d-5) may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the ion relates to any of the other ments or any combination of the other embodiments wherein Het is (d-4); wherein (d—4) may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other embodiments wherein Het is (d-8); wherein (d-8) may be substituted as deﬁned in any of the other ments.

In another embodiment, the invention relates to any ofthe other embodiments or any combination of the other embodiments n Het is (d-lO); wherein (d-lO) may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the ion relates to any of the other embodiments or any combination of the other ments wherein Het is (d—l 1); wherein (d-l 1) may be substituted as deﬁned in any of the other embodiments.

In another embodiment, the invention relates to any of the other embodiments or any combination of the other ments wherein Het is (d—12).

In another embodiment, the invention relates to any ofthe other embodiments or any combination of the other embodiments wherein Het is (d-93) wherein X15 is O or S; in particular 0; wherein (d-9a) may be substituted as deﬁned in any ofthe other embodiments.

In another embodiment, the invention relates to any ofthe other embodiments or any combination of the other embodiments wherein Het is selected from 2012/058142 X18 / "' and < x15 \x“:©9\ (d-Qa) (d-10a) ) is attached to the der of the molecule with a bond in position a or b; wherein X15 is O or S; in particular 0; wherein X16 is CH or N; in particular CH; n X18 is NH, S or O; in particular S or 0; more in particular 0; n radicals (d-9a) and (d—lOa) may be substituted as deﬁned in any ofthe other embodiments.

In another embodiment, the invention relates to any of the other embodiments or any combination ofthe other embodiments, wherein R5 and R6 taken together form a bivalent radical —R5—R6—, having formula: —(CH2)S— (c), or —CH=CH—CH=CH—— (d).

In another embodiment, the invention relates to any of the other ments or any combination ofthe other embodiments, wherein R5 and R6 taken together form a bivalent radical —R5—R6—, having a: —CH=CH—CH=CH— (d).

In another embodiment, the ion relates to any of the other embodiments or any combination ofthe other embodiments wherein Het is (d—12), and RS and R6 taken together form a bivalent radical ~R5—R6—, having formula: -CH=CH~CH=CH— (d).

In a next embodiment the compound of Formula (I) is selected from the group consisting of: 7—chloro—5,6-dihydro(6—methylpyridiny1)~4H-py1rolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro-5,6-dihydro-4—(2-pyridinyl)—4H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(2—benzoﬁiranyl)-7—chloro-5,6-dihydro-4H—pyrrolo[1,2-a][1,4]benzodiazepine . HCl, 7-chloro—5,6-dihydro(4-pyridinyl)-4H—pyrrolo [ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro—5,6—dihydro—4-(4-pyridinyl)—4H-pyrro10[1 ,2—a] [1 ,4]benzodiazepine . HBr, -chloro-5,6-dihydro(4-pyridinyl)-4H-pyrrolo[1 ,2-a] [1 ,4]benzodiazepine . HBr, 9-chloro-5,6-dihydro(4-pyridiny1)-4H—pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine . HBr, 8-chloro-5,6-dihydro(4-pyridiny1)-4H-pyrrolo[1,2-a][1,4]benzodiazepine . HBr, 7-chloro—5,6—dihydro[6—(triﬂuoromethy1)—3-pyridinyl]—4H—pyrro lo[ 1 ,2-a][1,4] benzodiazepine . HCl, ydro—4-[6—(triﬂuoromethy1)-3—pyridinyl]—4H-pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine HCl, 4-(2-benzofurany1)-5,6—dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine . HCl, 4-benzo[b]thienylchloro-5,6—dihydro-4H-pyrrolo[ 1 ,Z-a] [1 ,4]benzodiazepine . HCI, o[b]thien—2-y1—5,6-dihydro—4H—pyrrolo [1 ,2—a][1,4]benzodiazepine . HCl, 7-ch10r0—4—(6—ethyl-3 iny1)—5 ,6-dihydro—4H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepine . HCI, 4-(2-benzoﬁ1rany1)-5,6-dihydro—7-methy1—4H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine . HCl, 4—(2—benzothiazo1y1)chloro-5,6-dihydro-4H~pyrrolo[1 ,2-a] [1 ,4]benzodiazepine . HC 1, 7—ch10r0—5,6-dihydro-4—[2-(triﬂuoromethy1)pyrimidiny1]-4H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCI, 4-benzo[b]thien—2-y1—5,6-dihydro~7—methy1—4H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine . HCl, ,6—d1'hydr0methy1—4-[6-(triﬂu0romethy1)—3-pyridiny1]-4H-pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCl, ro(5—ethy1~2-pyridinyl)-5,6—dihydro-4H-pyrrolo[ 1 ,2-a] [1 zodiazepine . HCl, 7-ch10r0(5-ch10robenzofurany1)—5,6-dihydr0-4H-pyrrolo[ 1 ,2-a][1 ,4] benzodiazepine . HCl, 4—(5—ch10ro—2—benzofuranyD-S ,6—dihydromethy1—4H—pyrro 10 [1 ,2-a] [1 ,4] benzodiazepine . HCl, 7~chloro-5,6—dihydro—4-[6-(triﬂuoromethyl)-3—pyridaziny1]—4H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCl, 7~chloro-5,6—dihydro—4-(6-methylbenzoﬁ1ranyl)-4H—pyrr0 10 [ 1 ,2—a][1,4] benzodiazepine . HCI, ,6—dihydro(6-methy1—2—benzofuranyl)—4H—pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine . HCl, ,6-dihydro—7-methy1—4-(6-methy1—2~benzofurany1)-4H-pyrrolo[ 1 ,2—a] [1 ,4] benzodiazepine . HCl, 7-chlor0-5,6-dihydro(2—methy1—5-pyrimidiny1)~4H-pyrrolo[ 1 ,2-a] [1 ,4] iazepine . HCl, 7-ch10r0(1 -ethyl— 1 H—pyrazo1—3-y1)—5 ,6—dihydro-4H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HBr, 4-benzo[b]thien—2-ylchloro—5,6-dihydro-4H—pyrrolo[1,2-a][1 ,4]benzodiazepine . HCl, 7,9—dichloro—5,6-dihydro—4—(6—methy1—2-benzofurany1)-4H-pyrrolo[1,2-a][1,4] benzodiazepine . HCl, W0 2012/150305 9-ch10ro-5,6-dihydro—4-(7-methoxy—2-benzofurany1)-4H-pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCl, 4-benzo[b]thieny1—5,6-dihydro- 1 0-methy1-4H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine . HCI, 9—chloro-5,6—dihydro(4-methyl—2—benzoﬁ1ranyl)-4H-pyrro 10 [ 1 ,2-a][1,4] benzodiazepine . HCl, chloro—4—(5—ﬂuorobenzofurany1)-5,6-dihydro—4H-pyrrolo[1,2—a][1 ,4] benzodiazepine . HCl, 4-benzo[b]thien—2-y1—7,9-dichloro-5,6-dihydro-4H-pyrr010[ 1 ,2-a] [1 zodiazepine . HCl, 7—chloro—4—(5-ﬂuorobenzoﬁ1ranyl)-5,6-dihydro-4H-pyrrolo[1 ,Z—a] [1 ,4] benzodiazepine, 4-(2—benzofuranyl)-5,6-dihydro— 1 0—methy1—4H—pyrro10[ 1 ,2—a] [1 ,4]benzodiazepine . HCI, 7,9-dich10ro-5,6—dihydro(5-methoxy—2-benzofurany1)-4H—pyrro10[ 1 ,2-a] [1 ,4] benzodiazepine . HCI, 9-ch10ro-5,6—dihydro~4-(5-methoxy—2-benzofurany1)-4H—pyrro10[ 1 ,2-a][1,4] iazepine . HCl, 7—ch10r0—5,6—dihydro(5-methoxybenzofurany1)-4H-pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCI, 4-(2—benzoﬁlrany1)-7,9-dichloro-5 ,6—dihydro—4H-pyrrolo[ 1 2-21] [1 ,4]benzodiazepine . HCI 4-benzo[b]thien—2~yl—7-ch10ro-5,6-dihydromethy1—4H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCI, 7,9—dichlor0-5,6—dihydro(7-methoxy-2~benzofurany1)—4H-pyrrolo[ 1 ,2—a] [1 ,4] benzodiazepine . HCl, 7-chloro—5,6-dihydro-4—(4-methy1—2-benzofurany1)~4H~pyrro 10 [ 1 ,2-a] [1 ,4] benzodiazepine . HCl, 7—chloro—5,6-dihydro- 1 0-methyl—4—[2-(triﬂuoromethyl)-5—pyrimidinyl]-4H— pyrrolo[1,2-a][1,4]benzodiazepine . HCl, 7-ﬂuoro—5,6-dihydro-4—[6-(triﬂuoromethy1)—3-pyridiny1]—4H—pyrro10[ 1 ,2-a] [1 ,4] iazepine . HCl, 7,9-dich10ro-5 ,6-dihydr0[6-(triﬂuoromethy1)pyridinyl]-4H-pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCl, 9—ch10r0—4—(5—ﬂuorobenzofurany1)—5,6-dihydro—4H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCl, 7—ch10r0-5,6-dihydr0—4-(2-methy1—6-benzoxazo 1y1)—4H—pyrr010 [ 1 ,Z-a] [ 1 ,4] W0 2012/150305 2012/058142 benzodiazepine . HCl, 7-ch10ro(6-chlorofuro[3 ,2-c]pyridiny1)-5 ,6-dihydro-4H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine . HCl, 7—ch10ro—4—(3—ch10robenzo[b]thienyl)—5,6-dihydro-4H-pyrrolo[1 ,2-a] [1 ,4] benzodiazepine . HCl, 4-(2—benzoﬁJranyl)- 1 0-ch10ro—5 ,6-dihydro—4H~pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro—5,6-dihydr0(7-methy1benzofurany1)~4H-pyrrolo[1 ,2-a] [1 ,4] benzodiazepine, ro(1—ethy1—1H—pyrazo1-4—y1)-6H-pyrrolo[1,2-a][1 ,4]benzodiazepine, enzoﬁu‘anyl)—7—chlor0-6H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepine, 8, 10—dichloro(1—ethy1-1H—pyrazol—4-y1)—6H-pyrrolo[1,2-a][1,4]benzodiazepine, 7,10-dich10ro(1-ethy1—1H-pyrazol—4-yl)—6H—pyrrolo[ 1,2—a][1,4]benzodiazepine, 7-chloro[6-(triﬂuoromethy1)—3-pyridinyl]-6H—pyrrolo[ 1 ,2—a] [ 1 ,4]benzodiazepine, 4—benzo[b]thien—2—y1—7-chloro—6H—pyrr010[1 ,2-a] [1 ,4]benzodiazepine, 4—benzo[b]thien—2-y1—6H-pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 4~[6-(triﬂuoromethy1)—3-pyridiny1]-6H~pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(2—benzoﬁJrany1)-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro-4—[2-(triﬂuoromethy1)-5—pyrimidiny1]-6H-pyrrolo [ 1 ,2-a] [1 zodiazepine, 7-methyl[6-(triﬂuoromethy1)-3—pyridiny1]—6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(5-chloro~2~benzoﬁxrany1)-7—methy1—6H—pyrro lo [1 ,2-a] [1 ,4]benzodiazepine, 4—(2-benzofuranyl)—7-methy1—6H-pyrro10[ 1 ,2—a] [1 ,4]benzodiazepine, 4-benzo[b]thien-2—y1methy1—6H-pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 7,8-dichloro-4—(6—ethy1—3—pyridiny1)—6H—pyrro10[ 1 ,2—a] [1 ,4]benzodiazepine, enzothiazo1y1)chloro—6H-pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 4-(2-benzothiazo1y1)ch10ro-6H~pyrrolo[1 ,2-a] [1 ,4]benzodiazepine, . HCl 7-methy1—4-(2-methy1—5-pyrimidiny1)-6H—pyrrolo [ 1 ,2~a] [1 ,4]benzodiazepine, 7-chloro—4—(2-methy1—4~pyridiny1)-6H-pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 7-chloro(6-methy1—2-benzofurany1)-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(6—methyl—2-benzofurany1)~6H—pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, ro—4—(2~methy1—5-pyrimidiny1)-6H~pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10r0(5-chlorobenzofurany1)-6H-pyrro10[ 1 ,2-a] [1 zodiazepine, 4—(6-benzofuranyl)—7—ch10ro-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-methy1(6-methy1—2-benzofurany1)-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-benzo[b]thieny1chloro-6H-pyrrolo[1 ,2-a] [1 ,4]benzodiazepine, 7-chloro(5-methy1—2-benzofuranyl)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4—(6—benzofurany1)—7,10—dichloro-6H—pyrrolo[1,2-a][1,4]benzodiazepine, 9-chloro~4-(5-methy1—2-benzofuranyl)-6H-pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine, 4-benzo[b]thien—2-y1ch10ro-6H—pyrrolo[1,2—a][1,4]benzodiazepine, 4-(2-benzofurany1)chloro—6H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepine, 4-(2-benzofuranyl)chloro-6H-pyrrolo[1,2-a][1,4]benzodiazepine, 7,9-dichloro—4-(5—ethy1-2—pyridinyl)—6H—pyrro10[ 1 ,2—a] [1 ,4]benzodiazepine, 7—chloro—4-(5—ethylpyridiny1)—6H-pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 4—(2-methylpyfidinyl)—6H—pyrr0lo[ 1 ,Z—a] [1 ,4]benzodiazepine, 7-methyl—4-(2-methy1—4-pyridiny1)-6H—pyrr010[ 1 ,2~a] [1 ,4]benzodiazepine, 4-(6—benzothiazo1y1)methy1-6H-pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(7-methoxy—2—benzofurany1)—6H—pyrrolo[ 1 ,2—a][1 ,4]benzodiazepine, 7—methy1-4—(7—methy1—2-benzoﬁ1rany1)-6H—pytro10[ 1 ,2-a] [1 zodiazepine, 4-(6—benzothiazo1y1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(7-methy1benzofurany1)—6H—pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine, 7-chloro-4—(7—methy1—2—benzoﬁJranyl)-6H-pyrr010[ 1 ,2-a] [1 ,4]benzodiazepine, eth0xybenzofurany1)—7—methyl-6H~pyrrolo[ 1 2-21] [1 ,4]benzodiazepine, 4-(6-benzothiazo1y1)—7-chloro-6H-pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 4—[2-(triﬂuoromethy1)—5-pyrimidiny1]—6H~pyrro10[1 ,2-a][1,4]benzodiazepine, 7-ch10ro(2—ethy1~4-thiazo1y1)-6H—py1“rolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro(7-methoxybenzofurany1)-6H-py1rolo [1 ,2-a] [1 ,4]benzodiazepine, 7-chloro(1-methy1- 1 H-indoly1)—6H—pyrrolo[ 1,2-a][1 ,4]benzodiazepine, ro(1—methyl-1H-indol—S-yl)—6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, ch10ro(5-methy1benzofurany1)—6H—pyrro10[ 1 ,Z—a] [1 ,4]benzodiazepine, 7,9—dichloro—4—(6—methy1—2—benzoﬁ1ranyl)—6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, ro—4-(3-ethy1—5-isoxazo1y1)-6H-pyrrolo[ 1 1,4]benzodiazepine, 4-benzo[b]thien—2-yl- l 0—methyl~6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 9-ch10r0-4—(7-methoxy—2-benzofuranyl)—6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9-dichloro—4—(2-ethy1—4-thiazo1y1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10ro-4—(6—ethy1—3-pyridiny1)-6H—pyrrolo[ 1 ,2-a] [1 zodiazepine, 4-benzo[b]thien—2-y1—7,9—dichloro-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9-dichloro(1-methy1—1H—ind01y1)-6H-pyrr010[ 1 ,2—a] [1 ,4]benzodiazepine, 7,9-dich10ro(6-ethyl—3-pyridiny1)—6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(2-benzofuranyl)—10-methy1-6H~pyrr010[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10r0(5-methoxy—2—benzoﬁ1rany1)—6H—pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 4-(2-benzofuranyl)—7,9-dich10ro-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10ro(5-ﬂuorobenzoﬁ1rany1)—6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9-dichlor0(5-methoxy—2—benzofuranyl)-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, chloro—4—(5-ﬂuorobenzofurany1)-6H—pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine, 9—chlor0(4—methy1benzofurany1)—6H—pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, W0 2012/150305 7-rnethyl—4-[2-(triﬂuoromethy1)—5-pyrimidinyl]~6H-pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, -chloro(7-methoxybenzofurany1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 9-chloro(5-methoxybenzofurany1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(6-benzothiazo1y1)-9—Chloro—6H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepine, 4-(6-benzothiazoly1)—10—ch10r0-6H-pyrrolo[ 1 ,2-a] [1 zodiazepine, 7-chloro-4—(4—methy1benzofurany1)—6H-pyrrolo[ 1 ,2-a] [1 zodiazepine, 7—chloro-4—(4—ethy1—2-thiazo 1y1)—6H-pyrr010[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9—dich10ro-4—(4-ethy1-2—thiazo1y1)-6H-pyrrolo[1 ,2—a] [1 ,4]benzodiazepine, ro(5—ethy1—2-thiazo1y1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4—benzo[b]thien—2-y1—7-chloromethy1—6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9-dichloro(7—methoxy—2-benzofuranyl)-6H—pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine, 7,9-dichloro—4-(5—ethy1thiazoly1)-6H~pyrrolo[1,2-a][1 ,4]benzodiazepine, 7-ﬂuoro[6—(triﬂuoromethy1)pyridiny1]-6H—pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 4—(6-benzothiazo1y1)-7,9—dich10r0-6H-pyrr010[1,2—a][1,4]benzodiazepine, ro(5,7-diﬂuorobenzoﬁlrany1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9-dichloro(7—ﬂuoro-2—benzoﬁlrany1)-6H-pyrrolo[ 1 ,2-a][1 ,4]benzodiazepine, 4-(2,1,3—benzothiadiazol—5-y1)chloro-6H—pyrrolo[1 ,2-a] [1 ,4]benzodiazepine, 7,9-dichloro[2-(triﬂuoromethy1)—5-pyrimidiny1]-6H-pyrrolo[1,2-a][1,4] benzodiazepine, 7,9—dichloro[6-(triﬂuoromethy1)-3—pyridinyl]-6H—pyrro10[ 1 ,2—a] [1 ,4] benzodiazepine, 9-ch10ro-4—(5—ﬂuoro—2—benzoﬁ1rany1)-6H~pyrr010[ 1 ,2-a][1,4]benzodiazepine, 7,9-dichloro—4-(5,7—diﬂuoro—2—benzofurany1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7,9—dich10ro(2-methy1—2H— 1 ,2,3~benzotriazo 1—5—y1)—6H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine, 7-ch10r0(7-chlorobenzofurany1)-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10ro—4-(7-ﬂuorobenzoﬁ1rany1)—6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10r0—4-(2-methy1—2H~ 1 ,2,3-benzotriazo 1~5—y1)-6H—pyrro10[ 1 ,2-a] [1 ,4] benzodiazepine, 7-chlor0(7-ﬂuorobenzo[b]thien—2-yl)-6H—pyrrolo[1,2-a][1,4]benzodiazepine, 7,9-dichloro(7—ﬂuorobenzo[b]thien-2~y1)—6H-pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 7-chloro(1-methy1—1H—1,2,3-benzotriazo1—6-y1)-6H-pyrro10[1,2-a][1,4] benzodiazepine, 7,9-dichloro(1-methy1-1H-1,2,3-benzotriazo1y1)-6H-pyrrolo[1,2-a][1,4] iazepine, 4-(5~benzofurany1)—7-chloro-6H—pyrrolo[1,2-a][1,4]benzodiazepine, ro—4—(6—ch10ro-3—pyridiny1)-6H—pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(1 ,2,3-benzothiadiazoly1)ch10ro-6H-pyrr010[1 ,2-a] [1 ,4]benzodiazepine, 7-ch10ro-4—(2-methy1benzothiazoly1)-6H—pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro(5 hloropyridiny1)-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4-benzo[b]thienyl—7-ch10ro-6H—pyrr010[1,2-a][1,4]benzodiazepine, 4—(7-chloro—6H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepin—4-y1)-1—(1-methylethyl)-2(1H)- pyridinone, 7-ﬂuoro(2—methy1—6—quinoliny1)—6H-pyrro10[ 1 ,2~a] [1 zodiazepine, 7-chlor0(2-methy1—6-quinoliny1)-6H—pyrr010[ 1 ,2-a] [1 ,4]benzodiazepine, 4-(5 ,6-dichloro-3—pyridiny1)-7—ﬂuoro-6H—pyrro10 [ 1 ,2-a] [1 ,4]benzodiazepine, 4-(5 ,6-dichloro—3—pyridiny1)—7,9—diﬂuoro-6H—pyrrolo[ 1 ,2—a] [ 1 ,4]benzodiazepine, 7-chloro-4~(6-ch10r0pyridiny1)-9~ﬂuoro-6H—pyrrolo[ 1 ,Z-a] [1 ,4]benzodiazepine, 7-chloro[6-(1,1-diﬂuoroethy1)~3 -pyridiny1]—6H—pyrrolo[ 1 ,2—a][1,4]benzodiazepine, 1-[5-(7-chlor0~6H—pyrro10 [1 ,2-a] [1 ,4]benzodiazepin—4-y1)—2-pyridinyl]-ethanone, 4—[6—(1,1-diﬂuoroethyl)~3-pyridiny1]ﬂuoro—6H—pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 4~[6-(1,1-diﬂu0roethy1)-3—pyridiny1]-7,9-diﬂuoro-6H—p3n‘rolo[1,2-a][1,4] benzodiazepine, 4-(5-ch10rofuro[2,3—b]pyridin—2-y1)-7,9-diﬂuoro-6H—pyrr010[1,2-a][1,4] iazepine, ﬂuoro-4—(2-methy1—6-quino1iny1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro(6,7—dihydro-5H—cyc10penta[b]pyridiny1)—6H-pyrrolo[ 1 ,2-a][1,4] iazepine, 7,9-dichloro—4-[6—(1 ,1 roethy1)~3~pyridinyl] -6H—pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine, 1—[5-(7,9-diﬂuoro-6H—pyrrolo[1,2—a][1 ,4]benzodiazepin—4~y1)-2—pyridiny1]—ethanone, 4-benzo[b]thien—5-y1— 1 O—chloro-6H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepine, 7—chloro-4—[6-(1,1~diﬂuoroethy1)-3~pyridiny1]ﬂuoro-6H-pyrrolo[1,2-a][1,4] benzodiazepine, 4-benzo[b]thien—5-y1-7—ﬂuoro—6H—pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 4-benzo[b]thien—5 —y1chloro-6H-pyrrolo[1 ,2-a] [1 ,4]benzodiazepine, 4-benzo[b]thien—5—y1-7,9-diﬂu0r0-6H—pyrrolo[1 ,2-a] [1 ,4]benzodiazepine, 1-[5-(7-ﬂu0ro-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepiny1)pyridinyl]-ethanone, 4-benzo[b]thien—6-y1chloro—6H-pyrrolo [1 ,2-a] [1 ,4]benzodiazepine, 7-ch10r0furo[2,3-b]pyridiny1-6H—pyrrolo[ 1 ,2-a] [1 zodiazepine, 7-ch10ro(2-methy1—6-benzoxazo1yl)-6H-pyrro10[ 1 ,2-a] [1 ,4]benzodiazepine, 7-chloro—4-[2-(triﬂuor0methyl)-4—pyridiny1]-6H—pyrrolo[ 1 ,2-a] [ 1 ,4]benzodiazepine, 4-(5 —benzothiazo1y1)ch10ro—6H—pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine, 7-chloro—4-(6-chlorofuro[3,2—c]pyridin-2—y1)-6H-pyrro10[ 1 2—21] [1 ,4]benzodiazepine, 7-chloro(5-ch10romethy1furo[2,3-c]pyridin—2-y1)-6H-pyrro 10[ 1 ,2—a] [1 ,4] benzodiazepine, 4-(5-benzothiazo1y1)ﬂuoro-6H-pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7—ch10r0—4—(3-ch10ro—5-benzoﬁ1ranyI)-6H-pyrrolo[1,2-a][1,4]benzodiazepine, 4-(5-benzothiazo1y1)-7,9-diﬂuoro-6H—pyrr010 [1 ,2—a] [1 ,4]benzodiazepine, 7-ﬂuor0—4-[2—(triﬂuoromethy1)benzothiazo lyl]-6H—pyrro10[ 1 ,2—a] [1 ,4] benzodiazepine, 7-ch10r0[2-(triﬂuoromethy1)—5—benzothiazo1y1]—6H-pyrrolo[ 1 ,2-a] [1 ,4] benzodiazepine, 9-chloro[2—(triﬂuoromethyl)-4—pyridiny1]-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 7-ch10r0—4—(3-chlorobenzo[b]thien—5~y1)-6H-pyrrolo[1,2-a][1,4]benzodiazepine, 7—ch10ro-4—(3-chlorobenzofurany1)—6H—pyrrolo[ 1 ,Z—a] [1 ,4]benzodiazepine, 4-(3-ch10robenzofuranyl)—7,9-diﬂu0ro—6H~pyrrolo [1 ,Z-a] [1 ,4]benzodiazepine, 4-(3-chloro-5—benzofurany1)~7-ﬂuoro-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, 4—( 1 O-chloro-6H-pyrr010[ 1 ,2-a] [1 ,4]benzodiazepin-4—yl)(1 -methylethy1)-2(1H)- none, 7-chloro-4—(2~ch10robenzofuranyl)—6H—pyrr010[ 1 ,2—a] [1 ,4]benzodiazepine, 9-ch10r0(3-chlorobenzo[b]thien—5-yl)-6H—pyrrolo[1 ,2-a] [1 ,4]benzodiazepine, -chloro-4—(3—chlorobenzo[b]thieny1)-6H-pyrro10[1,2-a][1 ,4]benzodiazepine, 7-chloro-4—(3—quinoliny1)-6H—pyrro10[ 1 ,2—a] [1 ,4]benzodiazepine, 4-(3-quinoliny1)-6H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine, ro-4—(4-pyridiny1)-6H—pyrrolo[1 1,4]benzodiazepine, 4-(1H-benzimidazo1-6—y1)ch10ro—6H—pyrrolo[1,2-a][1,4]benzodiazepine, 4-(1H—benzimidazo1—6-y1)ch10ro—6H~pyrr010[1,2-a][1,4]benzodiazepine, 9-ch10ro-4—(3—quinoliny1)-6H-pyrr010[1,2-a][1,4]benzodiazepine, 7-chloro(6-quinoxalinyl)-6H-pyrro10[ 1 ,2-a][1 ,4]benzodiazepine, ro-5,6-dihydro(6-quin0xaliny1)~4H-pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine .HC1, 9-chloro(3-ch10robenzo[b]thien—5 -y1)-5 ,6—dihydro-4H-pyrrolo[1,2-a][1,4] benzodiazepine, -ch10ro-5,6—dihydro(7-methoxybenzofuranyl)-4H—pyrro10[ 1 ,2-a] [1 ,4] benzodiazepine, 7-ch10r0-5,6-dihydro(7-methoxybenzofurany1)-4H—pyrrolo[ 1 ,2-a][1 ,4] iazepine .HCl, ydro(7-methoxybenzofuranyl)—7-methy1-4H-pyrrolo[ 1 ,2-a][1,4] benzodiazepine .HCl, ,6-dihydro—4—(7-methy1—2—benzofurany1)-4H-pyrro10[ 1 ,2—a] [1 ,4]benzodiazepine .HCl, ,6—dihydro-7—methy1—4-(7-methy1—2—benzofurany1)-4H-pyrrolo[ 1 ,2-a] [1 ,4] W0 2012/150305 benzodiazepine .HCl, 7—chloro( 1 - l H-pyrazol—4-yl)-5 ,6-dihydro-4H—pyrrolo[ 1 ,2-a][1,4] benzodiazepine .HCl, 7, l O-dichloro-4—( l -ethyl- l zol—4-yl)-5 ,6-dihydro—4H—pyrrolo[ l ,2-a] [ l ,4] benzodiazepine .HCl, 8,10-dichloro-4—(l-ethyl-lH—pyrazol—4-yl)—5,6-dihydro-4H-pyrrolo[l ,2-a][1,4] benzodiazepine .HCl, 4-(2-benzofuranyl)chloro~5,6-dihydro-4H—pyrrolo[ 1 ,2—a] [1 ,4]benzodiazepine .HCl, 4-benzo[b]thien—2-yl-9—chloro—5,6-dihydro-4H—pyrrolo[ 1 ,2-a] [1 ,4]benzodiazepine .HCl, 7-chloro(3-pyridinyl)-6H-pyrrolo[ 1 ,2—a] [l zodiazepine, 7—chloro—4—(2-quinolinyl)-6H~pyrrolo[ 1 ,2-a] [l ,4]benzodiazepine, and 7—chloro~4—(4-pyridinyl)-6H-pyrrolo[ l ,2-a] [ l ,4]benzodiazepine, including stereoisomeric forms thereof, and the free bases, the pharmaceutically acceptable on salts and the so lvates thereof.

The present invention also encompasses processes for the preparation of compounds of Formula (I) and subgroups thereof.

The compounds of Formula (I) and the ups thereof can be prepared by a succession of steps as described hereunder. They are generally ed from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art. The compounds of the present invention can be also prepared using standard synthetic processes commonly used by those skilled in the art of organic chemistry.

The person skilled in the art will realize that for some reactions anhydrous conditions need to be d and/or an inert protecting atmosphere such as, for example, N2 or argon, must be used.

The compounds of the present invention, can be prepared according to Scheme 1: ~36- R1 R2 I I R1 R2 I I o 0 0 o 0 0+ l + OH NH2 0 (IX) — NHz (VI) — \ /N,I—ICI, or \ /N.chor \ /'\I CH3COOH, 1,4—dioxane R1 R2 R1 R2 OH NH2 N O Q(VIII) R1 R2 : CH2 Het-COOH (XIII) R1 R2 N Het \H/ \ N O \ R1 ; (H) N \ /; l |ntr§mqlecular Het cychzatIon oxidation H R2 \ (I a)— \ N R1 6' reduction Het \ (I-b) W0 50305 The compounds of Formula (I) wherein R3 and R4 together form an extra bond, said compounds being represented by formula (I-b), can be prepared from the compounds represented by the formula (I-a), following art-known amine to imine oxidation reactions. These oxidation reactions may be conducted by reacting a compound of formula (I—a) with an oxidant such as, for example, lead tetra—acetate or ese dioxide, in a reaction inert solvent such as a halogenated hydrocarbon e.g. dichloromethane (DCM) or trichloromethane. The reaction rate can be enhanced by stirring and optionally heating the reaction mixture.

Alternatively, a compound of formula (I-b) can be prepared by an intramolecular cyclization ofan intermediate of formula (II). In the presence of an acid such as, for example, POC13, the amide in the intermediate of a (II) can function as a C-electrophile, resulting in a ring closure. The reaction may be med in a le solvents such as, for example, DCM (CHZClz). Stirring and heating may enhance the rate of the reaction.

A compound of formula (I-a) can be prepared from an intermediate of formula (IV) by converting it in a salt (III) by reaction with an acid H+X' of formula (XI), and reacting said salt of formula (III) with an aldehyde of formula (XII) in an riate solvent such as an alcohol, e. g. methanol (MeOH), ethanol (EtOH), isopropanol, at an elevated temperature, preferably at reﬂux temperature.

Alternatively, the ediate of formula (IV) may be reacted ﬁrst with the aldehyde of a (X11) and the thus formed imine may be cyclized in the presence of an acid H+X' of formula (XI) to a nd of formula (l-a).

Alternatively, a compound of a (I—a) may be obtained by the reduction of a compound of formula (I-b) by using methods well-known to those skilled in the art.

Some compounds of formula (I-b) can be converted to other compounds of formula (I—b). For e, compounds of formula (I-b) wherein Het is selected from (d-l)—(d—l l) and n Het is substituted with Claalkylsulphonyl can be prepared by oxidation ofthe sulphur group in a compound of formula (I—b) n Het is selected from (d-1)—(d-l l) and wherein Het is substituted with lthio. Typically, this 3O reaction can be carried out in the presence of an oxidizing agent such as oxone and a suitable solvent such as, for example, THF.

An intermediate of formula (11) may be prepared by a coupling reaction between an intermediate of formula (III) and (XIII). Said reaction may be performed in the presence of coupling agents such as typically 1-hydroxy—lH-benzotriazo 1e (HOBT) and N—(ethylcarbonimidoyl)—N,N—dimethyl- l ,3-propanediamine monohydrochloride ~38- (EDCI). The reaction may be performed in the presence of a base such as triethylamine (Eth) and a suitable solvent such as, for e, DCM. Alternatively, an acid chloride derivative of (XIII) or a reactive ester derivative of (XIII) can also be used in this type of reaction to prepare an intermediate of formula (II).

An intermediate of a (XIII) or its acid chloride or ester derivative, can be easily prepared by those skilled in the art. ediates of formula (III) and (IV) are ed by reducing a l-(2-cyano- phenyl)pyrrole derivative of a (V). Several procedures well-known to those skilled in the art may be used to reduce the nitrile function such as, for example: 1. LiAlH4/THF [S. Raines, S.Y. Chai and F.P. Palopoli; J. Heterocyclic Chem., _l_3_, 711—716 (1976)] 2. i. sodium bis(2—methoxyethoxy)aluminate (Red-A1®) 70% w/w Toluene, RT : ii. NaOH 10%, RT . Cheeseman and S.G. Greenberg; J. Heterocyclic Chem, 16, 241-244(1979)] 3a. i. KBH4/CF3COOH, THF; ii. H20; iii. HCl [P. Trinka, P. Slégel and J. Reiter; J. Prakt. Chem, 338, 675-678(1996)] 3b. Borane—dimethyl sulﬁde (1:1), THF 4a. RaNi (Raney Nickel) / H2 4b. RaNi / thiophene solution / (MCOH/NHg) Even other well—known methods for reducing the nitrile function may also be used.

An intermediate of formula (V) in turn is commercially available or alternatively can be easily prepared by, for example, treating a 2~aminobenzonitrile derivative of formula (VI) with tetrahydro—2,5—dimethoxyfuran in an inert solvent such as dioxane or tetrahydroﬁ1ran(THF) in the presence of an acid such as 4~chloropyridine hydrochloride, or in an acidic t such as l acetic acid, at an ed temperature, preferably at reﬂux temperature. Alternatively, an intermediate of formula (V) can also be prepared from an intermediate of a (X). Typically, an intermediate of formula (X) wherein Halo is deﬁned as Br, 1, C1 or F, is reacted with pyrrole in the presence of a base such as, for example, C32C03 or NaH, in a suitable solvent such as typically N,N—dimethylformamide (DMF).

Alternatively, an intermediate of formula (IV) may be prepared by ng an intermediate of formula (VII) with borane-dimethyl sulﬁde (1:1) in a suitable solvent such as, for example, THF. The reaction typically can be med in the presence of an acid such as HCl. After the reaction has ded, the reaction mixture can be basiﬁed with a suitable base such as NaOH. The reaction can be performed at an elevated temperature, preferably at reﬂux temperature.

An ediate of formula (VII) can be prepared from an intermediate of formula (VIII). An intermediate of formula (VIII) can be reacted with a nitrogen source such as, NH3.H20 in the presence ofHOBT and EDCI. This type of on typically can be performed in a suitable t like DMF. Stirring of the reaction mixture may enhance the rate of reaction.

An intermediate of formula (VIII) can be easily prepared by treating an intermediate of formula (IX) with tetrahydro-2,5—dimethoxyfuran in an inert solvent such as dioxane in the presence of an acid such as pyridine hydrochloride (1:1) at an elevated temperature, preferably at reﬂux temperature. atively, a reactive ester derivative of (IX) can also be used in this type of reaction to prepare an ediate of formula (VIII).

All starting materials are cially available or can be easily prepared by those skilled in the art. The synthesis of some of the starting materials is exempliﬁed in the experimental part.

In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, ﬁirther puriﬁed according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. In ular, isomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethylphenyl carbamate) or Chiralpak® AS, both purchased from Daicel al ries, Ltd, in Japan.

Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be ted by chromatographic techniques using chiral stationary . Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms ofthe appropriate starting materials, provided that the reaction occurs stereoselectively or stereospeciﬁcally. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospeciﬁc methods of preparation. These methods will advantageously employ ly pure starting materials. Stereoisomeric forms of the compounds of Formula (I) are obviously intended to be included within the scope of the invention.

The chirally pure forms ofthe compounds of a (1) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the preparation of nds of Formula (I) with the corresponding conﬁguration.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dematiaceous ycetes, dimorphic ens, dermatophytes, zygomycetes, hyaline hyphomycetes, yeasts and yeastlike organisms.

The compounds of Formula (I) and isomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dimorphic pathogens, yeasts and yeastlike organisms.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates f, may be active against moulds.

The compounds of a (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida krucei‘, a ilosis, Candida kejjzr, Candida tropicalis; Aspergillus spp., e.g. Aspergillusfumigatus, Aspergillus niger, Aspergillusﬂavus; Ciyptococcus neoformans; Sporothrix schenckz‘i; Epidermophytonﬂoccosum; porum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e. g. Trichophylon mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, phyton verrucosum, Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanense', Fusarium spp., e.g. Fusarz'um solani, Fusarium oxysporum, um proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circz'nelloides; Rhizopus spp., e. g. Rhizopus Oiyzae, us microspores; Malasseziafulfur; Acremonium spp., Paecz’lomyces; Scopalariopsis; Arthrographis spp; Scytalidium; porium spp., e.g. Scedosporium apiospermum, Scedosporium proli loans; Trichoderma spp., Penz’cillium spp., llium marneﬁh‘; Blastoschizomyces.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates f, may be active against a wide variety of fungi, such as Candida parapsilosis; Aspergillus spp., e.g.

Aspergillusfumigatus, Aspergillus niger, Aspergillusﬂavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophytonﬂoccosum; Microsporum spp., e.g.

Microsporum canis, Microsporum m; Trichophyton spp., e.g. Trichophyton mentagrophyies, Trichophyz‘on rubrum, phyton quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton igz‘tale, Trichophyton soudanense; Fusarz‘um spp., e.g. Fusarium solam', Fusarz'um oxysporum, Fusarz’um prolz'feratum, Fusarz'um verticillioides; Rhizomucor spp., e.g. Rhizomucor i, Rhizomucorpusz'llus; Mucor 'nelloides; Rhizopus spp., e.g. Rhizopus org/me, Rhizopus microspores; Acremonz’um spp.; Paecz'lomyces; Scopulariopsz's; Arthrographis spp., Scytalz'dz'um; Scedosporz'um spp., e.g.

Scedosporium ermum, Scedosporz'um ﬁcans; Trz'choderma spp.; llium spp., llium mameﬁz’; Blastoschizomyces.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable on salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsz’losz’s; Aspergillus spp., e.g. illusfumz’gatus, Aspergillus niger, Aspergillusﬂavus; Cryptococcus neoformans; mophytonﬂoccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton mbrum, Trichophyton quinckeanum, Trichophyton tonsurans, phyton verrucosum, Trichophyton violaceum, Trz'chophyton interdigz‘tale, Trz'chophyton soudanense; Fusarium spp., e.g. Fusarz'um solam', Fusarz'um oxysporum, 'um prolz'feratum, Fusarz’um verticz'llioz'des; ucor spp., e.g. ucor miehez’, Rhizomucorpusz’llus; Mucor cz'rcz'nelloz'des; Rhizopus spp., e.g. Rhizopus Olyzae, Rhizopus microspores; Acremom'um spp.; Paecz'lomyces; Scapulariopsis; Arthrographz‘s spp.; Scytalz'dz'um; Scedosporl'um spp., e.g. Scedosporium apiospermum, Scea’osporz'um cans; Trichoderma spp.; Penicillium spp.; Penicillium mameﬂez‘; Blastoschz'zomyces; in ular Aspergillus spp., e.g. Aspergillusfumigatus, Aspergz'llus niger, Aspergillusﬂavus; Cryptococcus neoformans; Epidermophyton ﬂoccosum; Microsporum spp., e.g. Microsporum canis, Microspomm gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trz'chophyton , Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton vermcosum, Trichophyton violaceum, Trichophyton interdigz’tale, Trichophyton soudanense; Fusarium spp., e. g. Fusarz'um salami, Fusarz'um oxysporum, um proliferatum, Fusarium verticz'llz'oides; Rhizomucor spp., e.g. Rhizomucor mz'ehez‘, Rhizomucor pusillus; Mucor Circinelloz'des; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonz'um spp.; Paecz'lomyces; Scopularz'opsz's; Arthrographz's spp., Scytalia’z'um; sporz'um spp., e.g. Scedosporium apiospermum, Scedosporium proliﬁcans; Trichoderma spp., Penicillium spp.; Penicillium mameﬁ’ez’; Blastoschizomyces. The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsilosis; illus spp.; Cryptococcus neoformans; Sporothrz’x schenckz'z'; porum spp.; Fusarium spp.; Scedosporz‘um spp.; in particular Candida z'losis; Aspergillus spp.; Cryptococcus neoformans; Microsporum spp.; Fusarz'um spp.; Scedosporz'um spp.; more in particular Aspergz'llus spp.; Cryptococcus mans; Microsporum spp.; Fusarium spp.; Scedosporz'um spp.

The compounds ofFormula (I) and stereoisomeric forms thereof, and the pharmaceutically able addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as Candida parapsz'losz's; Aspergillus spp.; Clyptococcus neoformans; Trichophyton spp.; Sporothrz'x schenckz'i; porum spp.; Fusarz'um spp.; Scedosporium spp.; in particular Aspergillus spp.; Microsporum spp.; Trichophyton spp.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against fungi such as Candida parapsz'losz‘s, Aspergillus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against fungi such as Candida parapsz‘losz's; Aspergz'llus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillusﬂavus; Cryptococcus neoformans; Sporothrz'x schenckii; Epidermophytonfloccosum; porum canis; Trichophyton spp., cg. ophyton mentagrophytes, Trichophyton rubrum, phyton quinckeanum; in particular a parapsz‘losz’s; Aspergillus spp., e.g. Aspergz'llusfumigatus, Aspergz'llus niger, z'llusﬂavus; Cryptococcus neoformans; Epidermophyton ﬂoccosum; Microsporum canis; Trichophyton. spp., e.g. Trichophyton mentagrophytes, Trz'chophyton rubram, Trichophyton quinckeanum; more in particular Aspergillus spp., e.g. Aspergz'llusfumigatus, Aspergillus niger, Aspergillusﬂavus; Cryptococcus neoformans; Epidelmophytonﬂoccosum; .Mz'crosporum canis; Trz'chophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum.

The compounds of a (I) and stereoisomeric forms f, and the pharmaceutically able addition salts, and the solvates thereof, may be active against Candida parapsz'losz's, Aspergz'llusfumigaz‘us, Cryptococcus neoformans, Sporothrz'x schenckiz', Microsporam canis, Trichophyton mentagrophytes, Trichophyton , Scedosporium apiospermum and Scedosporz'um proliﬁcans; in particular Aspergillusfumigatus, Microsporum canis, Trichophyton mentagrophytes, phyton rubrum, Scedosporium apz'ospermum and Scedosporium prolz‘ zcans.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against fungi such as Candida ilosz’s; Aspergillus spp.; Cryptococcus neoformans; Microsporum spp.; Trichophyton spp.; Scedosporium spp..

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsilosis, Aspergillusfumigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium proliﬁcans; in particular Candida ilosis, Aspergillusfumz‘gatus, Cryptococcus neoformans, porum canis, Trichophyton mentagrophytes, ﬁichophyton rubrum, porium apiospermum, Scedosporium proli zcans; more in particular z'llusﬁtmigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, porz'um proli zcans.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsz'losis, Aspergillasfumz’gatus, Cryptococcus neoformans, Sporothrix schenckz'i, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium proliﬁcans, Rhizopus oryzae, Rhizomucor miehei.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates f, may be active against a parapsz'losis B66126, illusfumigaz‘us B42928, Cryptococcus mans B66663, Sporothrix schenckz'i B62482, porum canis B68128, Trichophyton mentagrophytes , Trichophyton rubrum , Scedosporium apiospermum IHEM381 7, Scedosporium ﬁcans IHEM2115 7.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsz‘losis B66126, Aspergz'llusfumigatus B42928, Clyptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophytes B70554, phyton rubrum B68183, Scedosporium apiospermum IHEM381 7, Scedosporz'um proliﬁcans IHEM21 15 7, Rhizopus oryzae IHEM5223 and Rhizomucor miehez’ 1HEM13391.

The compounds of a (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Candida parapsz'losz‘s, Aspérgz’llusfumz'gatus, Cryptocaccus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum; in particular Aspergillusfumz'gatus, Cryptococcus mans, Microsporum canis, Trichophylon. mentagrophytes, Trichophyton rubrum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the ceutically acceptable addition salts, and the solvates f, may be active t Microsporum canis, Trichophyton rubrum, Aspergz'llusfumigatus, Cryptococcus neoformans and Trichophyton mentagrophytes; in particular Microspomm canis B68128, Trichophyton rubrum , Aspergillus fumigatus B42928, Cryptococcus neoformans B66663 and phyton mentagrophytes B70554.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable on salts, and the solvates thereof, may be active t Candida parapsz'losz‘s B66126, Aspergillusfumigatus B42928, Ciypz‘ococcus neoformans B66663, Microsporum canz’s B68128, Trichophyton mentagrophytes B70554, Trichophyton rubrum B68183, Rhizopus oryzae 1HEM5223, Rhizomucor miehei 391 .

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active t Candida parapsz'losz's B66126, Aspergz‘llusfumz'gatus B42928, Cryptococcus neoformans B66663, Microsporum cam’s B68128, Trz'chophyton. mentagrophytes B70554, Trichophyton rubrum B68183; in particular Aspergillusfumz’gatus B42928, Cryptococcus neoformans B66663, Microspomm canis B68128, Trichophyton mentagrophytes B70554, Trichophyton rubrum B68183.

The compounds of Formula (I) and isomeric forms thereof, and the ceutically acceptable addition salts, and the solvates thereof, may be active against a variety of ﬁmgi that infect the skin, hair and nails, as well as subcutaneous and systemic fungal pathogens.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates f, may be active against a wide variety of fungi, such as Aspergillus spp.; Microsporam spp.; W0 2012/150305 Trichophyton spp.; Scedosporz'um spp.; a parapsz’losz's; and Cryptococcus neoformans; in particular Aspergillus spp.; Microsporum spp.; and Trichophyz‘on spp..

The nds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a Wide variety of fungi, such as illus spp.; Microspomm spp.; Trichophyton spp.; Scedosporz'um spp.; in particular Trichophyton spp. and Microsporum spp..

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against a wide variety of fungi, such as z’llusfumigatus, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporz‘um apiospermum and Scedosporz'um prolz'ﬁcans; in particular Microsporum canis, Trichophyton mentagrophytes and phyton rubrum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the ceutically acceptable addition salts, and the solvates thereof, may be active against the 3 dermatophyte genera: Trichophyton, Microsporum and Epidermophyton; in particular against Trichophyton and Microsporum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dermatophytes and Aspergillus spp.; in ular dermatophytes and Aspergz'llusfumz‘gatus; more in ular porum canis, Trichophyton mentagrophytes, Trichophyton. rubrum and Aspergz'llusfumz'gatus; even more in particular Microsporum canis, Trichophyton mentagrophytes and Trz'chophyton rubrum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus spp.; in particular ophyton mentagrophytes, Trichophyton rubrum and Aspergz'llus fumigatus.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton rophytes; Trichophyton rubrum; Aspergillus spp., e.g. illusfumigatus; Fusarz’um spp.; Mucor Spp.; Zygomycetes spp.; Scedosporz'um spp.; Microsporum canis; hrz'x schenckz'z'; Cryptococcus neoformans; Candida parapsilosis. —46— The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against dermatophytes.

The compounds of Formula (I) and stereoisomeric forms f, and the ceutically acceptable addition salts, and the solvates thereof, may be active against Aspergz’llusfumigatus.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Microsporum canis, in particular Microsporum canis B68128.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, may be active against Trichophyton rubrum, in particular Trichophyton rubrum B68183.

The nds of Formula (I) and isomeric forms thereof, and the pharmaceutically acceptable addition salts, and the es thereof, are potent antifungals when administered orally or topically.

The compounds of the present invention may be useful as ergosterol synthesis inhibitors.

In View of the utility of the compound of Formula (I), there is provided a method of treating warm-blooded animals, including humans, ing from, or a method of preventing warm-blooded animals, including humans, to suffer from any one ofthe diseases mentioned hereinbefore. Hence, compounds of Formula (I) are provided for use as a medicine. Also the use of a compound of Formula (I) in the manufacture of a medicament useful in treating fungal infections is ed. Further compounds of Formula (I) are provided for use in the treatment of fungal infections As used herein, the term "treatment" is intended to refer to all ses, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of an infection, but does not necessarily te a total elimination of all symptoms.

The invention relates to a compound ing to the l Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use as a medicament.

The invention also relates to a compound ing to the general Formula (I), the stereoisomeric forms f and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the treatment or prevention of fungal ions; in ular fungal infections caused by one or more of the fungi mentioned hereinbefore.

W0 2012/150305 The invention also relates to a compound according to the general Formula (I), the isomeric forms thereof and the ceutically acceptable acid or base addition salts and the solvates thereof, for the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.

The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.

The invention also relates to a compound ing to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base on salts and the solvates thereof, for use in the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned before.

The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment or prevention, in particular ent, of fungal infections; in particular fungal ions caused by one or more of the fungi selected from a group consisting of fungi mentioned hereinbefore.

The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms f and the pharmaceutically acceptable acid or base addition salts and the solvates f, for use in the treatment or prevention of a fungal infection, in particular a fungal infection caused by one or more of the fungi mentioned hereinbefore.

The invention also relates to nds according to the general Formula (I), the stereoisomeric forms thereof and the ceutically able acid or base addition salts and the solvates thereof, for use in the treatment or prevention of a ﬁmgal infection, wherein the fungal ion is caused by one or more ofthe fungi selected from the group consisting of Candida spp.; Aspergz'llus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophytonfloccosum; Microsporum spp.; Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor cz‘rcz'nelloz‘des; Rhizopus spp.; Malassezz‘afuifur; Acremom’um spp.; Paecz'lomyces; Scopulariopsis; Arthrographis spp.; Scytalz'dz’um; Scedosporz'um spp.; Trichoderma spp.; Penicillium spp.; Penicillium mameﬂez’; and schz'zomyces; in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida parapsz’losz‘s; Aspergillus spp.; Cryptococcus ~48- neoformans; Sporothrix schenckz'z'; Epidermophytonfloccosum; Microsporum spp.; Trichophyton spp.; Fusarz'um spp.; Rhizomucor spp.; Mucor circz'nelloz'des; Rhizopus spp.; Acremonz'um spp.; Paecz'lomyces; Scopularz’opsz‘s; Arthrographz‘s spp.; Scytalz’dz'um; Scedosporium spp.; Trichoderma spp.; Penicz'llz’um spp.; Penicillium marneﬂei; and schz'zomyces; even more in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting ofMicrosporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergz'llusfumz'gatus. The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the so lvates thereof, for use in the treatment or prevention of a ﬁingal infection, wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp.; Aspergillus spp.; CIj/pz‘ococcus neoformans; Sporothrz'x schenckz'z‘; Epidermophytonﬂoccosum; Microsporum spp.; Trichophyton spp; Fusarz‘um spp.; ucor spp.; Mucor circz'nelloz'des; Rhizopus spp.; Malassezz‘afmfur; Acremonium spp.; lomyces; Scopularz'opsz’s; Arthrographz‘s spp.; Scytalz'dz'um; sporz‘um spp.; Trichoa'enna spp.; Penicillium spp.; Penicillium mameﬁez‘; Blastoschizomyces; in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting ofAspergz'llus spp.; Microsporum spp.; Trichophyton spp.; and Scedosporz'um spp.; more in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting ofMicrosporum canis, Trichophyton mentagrophytes and Trz'chophyton rubrum.

The compounds ofFormula (I) and isomeric forms thereof, and the pharmaceutically acceptable addition salts, and the es thereof, may be active t a wide variety of fungi, such as one or more of the fungi ned hereinbefore.

The novel compounds described in the present invention may be useful in the treatment or prevention of diseases or ions ed from the group consisting of infections caused by derrnatophytes, systemic fungal ions and onychomycosis.

The novel compounds bed in the present invention may be useful in the treatment or prevention of diseases or conditions such as for example infections caused by dermatophytes, systemic fungal infections or onychomycosis.

The invention also relates to the use of a compound according to the general a (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the manufacture of a medicament.

The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvates f, for the manufacture of a medicament for the treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned before.

The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.

In view of the utility ofthe compound of Formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing looded animals, including , to suffer from fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.

Said s comprise the administration, i.e. the systemic or topical administration, preferably oral stration, of an effective amount of a compound of Formula (I), a stereoisomeric form thereof or a pharmaceutically acceptable addition salt or solvate thereof, to warm-blooded s, including .

Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I), to warm-blooded animals, including humans.

Those of skill in the treatment of such diseases could ine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in ular from 0.01 mg/kg to 25 mg/kg body weight, preferably ﬁom about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a compound according to the present ion, also referred to here as the active ient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and ion of the recipient, and the particular er or disease being treated.

A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably ated prior to administration. As described herein below, le pharmaceutical formulations are prepared by known ures using well known and readily available ingredients.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.

The present invention also provides compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of a (I) and a pharmaceutically able r or diluent.

The r or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the ition and not deleterious to the recipients thereof.

The compounds ofthe present invention,that are suitable to treat or prevent fungal infections, may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and each additional therapeutic agents in its own separate pharmaceutical dosage formulation. For e, a compound of Formula (I) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

In View of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form f, or any subgroup or combination thereofmay be formulated into s pharmaceutical forms for administration es. As riate compositions there may be cited all compositions usually employed for systemically administering drugs.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical itions are desirable in unitary dosage W0 2012/150305 form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, , elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, ants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease in administration, tablets and es represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.

For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for e, to aid solubility, may be ed. able solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of Formula (I) may be formulated in an oil for prolonged .

Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, n oil, synthetic ol esters of long chain fatty acids and es ofthese and other oils. Inj ectable sions may also be prepared in which case appropriate liquid carriers, ding agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, ally combined with suitable additives of any nature in minor proportions, which additives do not introduce a signiﬁcant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These itions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

Acid or base addition salts of compounds of Formula (1) due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.

Transungual compositions are in the form of a solution and the carrier optionally comprises a ation enhancing agent which s the penetration of the ngal into and through the keratinized ungual layer of the nail. The solvent medium comprises water mixed with a co-solvent such as an alcohol having from 2 to 6 carbon atoms, e.g. ethanol.

WO 50305 ‘ In order to enhance the solubility and/or the stability of the compounds of Formula (I) in pharmaceutical compositions, it can be advantageous to employ a-, [3— or “y- extrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropy1—B-cyclodextrin or sulfobutyl-B—cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the ion in pharmaceutical itions.

The ratio of active ingredient over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of active ingredient over cyclodextrin range from about 1/10 to 10/ 1. More interesting ratios of active ingredient over cyclodextrin range from about 1/5 to 5/1.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight ofthe compound of Formula (I), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the ition.

For parenteral compositions, also other ingredients, to aid solubility for example, e. g. cyclodextrins, may be included. Appropriate cyclodextrins are 0L-, [3-, y—cyclodextrins or ethers and mixed ethers thereofwherein one or more of the hydroxy groups ofthe anhydroglucose units of the cyclodextrin are substituted with C1_6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated B-CD; hydroxyC1_6alkyl, particularly hydroxyethyl, y-propyl or hydroxybutyl; carboxyC1_6alkyl, particularly carboxymethyl or carboxy—ethyl; C1-6alkylcarbony1, particularly acetyl.

Especially noteworthy as complexants and/or solubilizers are B-CD, ly methylated B—CD, methyl-[3-CD, 2-hydroxyethyl-B-CD, 2-hydroxyethyl—y—CD, 2-hydroxypropyl-y-CD and (2-carboxymethoxy)propyl—B-CD, and in particular 2-hydroxypropyl—B-CD (2-HP-B~CD).

The term mixed ether denotes cyclodextrin derivatives n at least two cyclodextrin hydroxy groups are etheriﬁed with different groups such as, for e, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average tution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit.

The M.S. and D.S. value can be determined by various analytical ques such as nuclear magnetic resonance WMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration comprise particles consisting of a solid dispersion comprising a compound of Formula (I) and one or more appropriate pharmaceutically acceptable water—soluble rs.

The term ”a solid dispersion” deﬁnes a system in a solid state (as opposed to a liquid or s state) comprising at least two components, in casu the compound of Formula (I) and the water—soluble r, wherein one component is dispersed more or less evenly throughout the other component or components ( in case additional pharmaceutically able formulating agents, generally known in the art, are included, such as plasticizers, preservatives and the like). When said dispersion of the components is such that the system is chemically and physically m or nous throughout or consists of one phase as deﬁned in thermo-dynamics, such a solid dispersion will be called “a solid solution”. Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This age can probably be explained by the ease with which said solid solutions can form liquid solutions when contacted with a liquid medium such as the gastro-intestinal juices. The ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase.

The term “a solid dispersion” also comprises dispersions which are less homogenous throughout than solid ons. Such dispersions are not ally and physically m throughout or comprise more than one phase. For example, the term “a solid dispersion” also relates to a system having domains or small regions wherein amorphous, microcrystalline or crystalline compound of Formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer, or both, are dispersed more or less evenly in another phase comprising water~soluble polymer, or compound of a (I), or a solid solution comprising compound of Formula (I) and soluble polymer. Said domains are regions within the solid dispersion distinctively marked by some physical e, small in size, and evenly and randomly distributed throughout the solid dispersion.

It may ﬁirther be convenient to formulate the t ngal compounds in the form ofnanoparticles which have a surface modiﬁer adsorbed on the surface thereof in an W0 2012/150305 amount sufﬁcient to maintain an effective average particle size of less than 1000 nm.

Useful surface rs are believed to include those which physically adhere to the e of the antifungal agent but do not chemically bond to the ngal agent.

Suitable surface modiﬁers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients e various polymers, low molecular weight oligomers, natural ts and surfactants. Preferred surface modiﬁers include nonionic and anionic surfactants.

Yet another interesting way of formulating the present nds involves a pharmaceutical composition whereby the present antifungals are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus ng a composition which can conveniently be manufactured and which is suitable for preparing ceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating ﬁlm of a hydrophilic polymer and an antifungal agent and a seal-coating layer.

Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have riate dimensions and ﬁrmness. Examples of such als are polymers, inorganic nces, organic substances, and saccharides and derivatives thereof.

It is especially advantageous to formulate the entioned pharmaceutical itions in unit dosage form for ease of administration and uniformity of dosage.

Unit dosage form as used in the speciﬁcation and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, itories, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Since the compounds according to the invention are potent orally administrable compounds, pharmaceutical compositions comprising said compounds for administration orally are especially advantageous.

The following examples illustrate the t invention.

Experimental part after, the term “DCM” means dichloromethane; “LCMS” means Liquid Chromatography/Mass spectrometry; “Et3N” means triethylamine; “PE” means W0 2012/150305 petroleum ether; “TFA” means triﬂuoroacetic acid; “HPLC” means erformance liquid chromatography; “rt.” means room temperature; “mp.” means melting point; “min” means minute(s); “h” means hour(s); “EtOAc” means ethyl acetate; “EtOH” means ethanol; “MeOH” means methanol; “rm.” means reaction mixture(s); “q.s.” quantum sufﬁcit; “THF” means tetrahydrofuran; “HOAc” means acetic acid; “HBTU” means 1-[bis(dimethylamino)methylene]—1H-benzotriazol—1-ium 3-oxide hexaﬂuoro- phosphate, “HOBT” means 1—hydroxy—1H—benzotriazole; “MeZS” means dimethyl sulﬁde; and “EDCI” means N—(ethylcarbonimidoyl)—N,N-dimethyl—1,3-propanediamine monohydrochloride.

The person skilled in the art will realize that for some reactions in the examples anhydrous conditions need to be applied and/or an inert ting atmosphere such as, for example, N2 or argon, must be used.

A. ation ofthe intermediates Example A1 a) Preparation of intermediatel A solution of 2-aminomethylbenzonitrile (25.0 g, 0.189 mo 1) and ydro-2,5- dimethoxyfuran (25.0 g, 0.189 mo 1) in HOAc (200 ml) was reﬂuxed for 4 h. After reaction, the solvent was evaporated and the product was dried in vacuo and directly used as such in the next reaction step. Yield: 33.0 g of intermediate 1. aration intermediate2 A solution of intermediate 1 (33.0 g, approximately 0.181 mol) and borane-dimethyl sulphide (1:1) (20 ml of a 10 N solution of BH3 in Megs, 0.20 mol) in THF (100 ml) was reﬂuxed for 16 h. Subsequently, HCl (6 N; 50 ml) was added at 0 °C. The mixture was heated under reﬂux again for 30 min. The solution was cooled to 0 °C (ice-water bath) and NaOH (solid; q.s.) was added until pH>10. The mixture was ted with DCM (3x) and the separated c layer was dried (MgSO4), d, and the solvent was evaporated. The residue was treated with HCl/dioxane (q.s.) to obtain 27 g of intermediate 2 (67.5 % yield; .HCl).

W0 2012/150305 Example A2 a) Preparation of ediate 3 CI CN {$0\/ A e of 2-amino—6—chlorobenzonitrile (17.72 g, 0.116 mo 1) and tetrahydro-2,5— dimethoxyfuran (0.116 mol) in HOAc (100 ml) was stirred and reﬂuxed for 30 min.

Subsequently, the mixture was cooled and evaporated. The residue was puriﬁed over silica gel on a glass ﬁlter (eluent: DCM). The product fractions were collected and the solvent was evaporated. The residue was llized from EtOH. Yield: 18.83 g of intermediate 3 (80 % yield). bPrearation of intermediate4 Borane-dimethyl sulphide (1:1) (2.5 ml of a 10 N solution ofBH3 in Megs, 0.0247 mol) was added at r.t. under N2 atmosphere to a solution of intermediate 3 (5.0 g, 0.0247 mol) in THF (20 ml). The mixture was heated to reﬂux for 10 h. After cooling to r.t., HCl (6 N; 15 ml) was added dropwise. Subsequently the mixture was heated under reﬂux for 30 min. The solution was cooled to 0 °C and then NaOH (6 N; q.s.) was added. The mixture was extracted with DCM (50 ml x 3) and the separated c layer was dried (Na2SO4), ﬁltered, and the solvent was ated to yield an oil.

HCl/dioxane (5 ml) and THF (20 ml) were added and the precipitate was collected by ﬁltration and dried Yield: 5.14 g of intermediate 4 (86 % yield; .HCl). ediate61was prepared by an analogous protocol as5%: described for the synthesis of intermediate 4. 0 Pre aration of intermediate 5 2-(Triﬂuoromethyl)pyridinecarboxylic acid (0.28 g, 1.45 mrnol) was ved in DCM (20 ml). Et3N (1.5 ml, 9.2 mmol), HOBT (0.20 g, 1.45 mmol), EDCI (0.28 g, 1.45 mmol) and intermediate 4 (0.32 g, 1.32 mmol) were added to the solution. The r.m. was stirred overnight at r.t. Water (q.s.) was added and the mixture was extracted with DCM. The separated organic layer was dried (NaZSO4), d and the solvent was evaporated. The crude product was puriﬁed by preparative HPLC (Synergy column 150 X 30 mm; mobile phase: 55%~85% CH3CN (0.1 % TFA)/H20 (0.1 % TFA); ﬂow rate 25 ml/min; 19 min). The product fractions were collected and the t was evaporated in vacuo. The residue was neutralized with a saturated NaHC03 solution and extracted with DCM. The organic layer was dried (NaZSO4), ﬁltered and the solvent was evaporated, yielding intermediate 5 (38 % yield).

Example A3 Preparation of intermediate 7 N \ Q o -Benzofurancarboxylic acid (0.285 g, 1.76 mmol) was dissolved in DCM (20 ml).

Et3N (1.3 ml, 8.8 mmol), HOBT (0.237 g, 1.76 mmol), EDCI (0.337 g, 1.76 mmol) and intermediate 4 (0.427 g, 1.76 mmol) were added to the solution. The r.m. was d overnight at r.t. Subsequently, the mixture was concentrated and water (q.s.) was added. The aqueous mixture was extracted with DCM. The ted organic layer was dried (Na2SO4), ﬁltered and the t was evaporated. The crude product was puriﬁed by HPLC (YMC column 150 x 25 mm; mobile phase: 52%-72% CH3CN (0.1 % TFA)/H20 (0.1 % TFA); ﬂow rate 20 ml/min; 20 min). The product fractions were collected and the solvent was evaporated in. vacuo. The residue was neutralized with a saturated NaHC03 solution and extracted with DCM. The organic layer was dried (Na2804), d and the solvent was evaporated, yielding 0.190 g of intermediate 7 (32 % yield).

WC 2012/150305 Example A4 intermediate8Pre aration of A mixture of othiophenecarboxylic acid (1.01 g, 5.68 mmol), DCM (20 ml), Et3N (3 ml), HOBT (0.76 g, 5.68 mmol), HBTU (2.12 g, 5.68 mmol) and intermediate 4 (1.26 g, 5.16 mmol) was stirred overnight at r.t. Subsequently, the mixture was washed with water (3 x 100 ml), dried (MgSO4), d, and the solvent was evaporated under reduced pressure. The residue was puriﬁed by column chromatography over silica ge1(e1uent: PE/EtOAc from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in. vacuo. Yield: 1.5 g of ediate 8 (79 %).

Example A5 a) Preparation of intermediate 9 NH2 NH + ©:\ .HCi \ .HCI \ intermediate 9 (mixture) LiAlH4 (54.3 ml, 109 mmol) in anhydrous THF (20 ml) was added over a period of 2 minutes to a stirring solution of 2-chloro(1H—pyrrol—1—y1)benzonitrile (20 g, 99 mmol) in anhydrous THF (200 ml) while cooling the reaction mixture with ice. After addition, the r.m. was cooled with an ice-bath and was stirred for 1 hour. Subsequently, the on mixture was reﬂuxed for 1 hour.

Then, water (100 ml) was added to 500 ml of a saturated solution of (2R,3R)—2,3— dihydroxybutanedioic acid monopotassium monosodium salt tetrahydrate (84 g, 296 mmol) (Rochelle salt). First the rm. and then EtOAc (1 1) were added to this solution under vigorously ng and ice cooling. The mixture was stirred for 2 hours while the e was allowed to reach room temperature.

W0 2012/150305 2012/058142 The layers were separated and the aqueous layer was extracted with EtOAc (500 ml).

The combined organic layers were washed with water (50 ml), dried (Na2S04) and d. The ﬁltrate was evaporated under reduced pressure to yield a yellow translucent oil. This oil was dissolved in 320 (2 l) and HCl in dioxane (4 M, q.s.) was added to this solution. The suspension was ﬁltered and washed with 320, to yield 12.4 g of intermediate 9 (mixture 2 products). b Pre aration of intermediate 10 CI 0 O N /N /N H 1 +©:\HN \| ©\ 0 intermediate 10 (mixture) O-(Benzo triazol-1~yl)—N,N,N',N'-tetramethy1uronium tetraﬂuoroborate (TBTU) (1.709 g, 5.32 mmol) was added to a solution of 3-quinolinecarboxylic acid (0.838 g, 4.84 mmol) and N,N-di-iso-propylethylamine (DIPEA) (3.20 ml, 19.35 mol) in anhydrous DMF (20 ml). This mixture was stirred for 10 minutes. Subsequently, intermediate 9 (1 g) was added and the reaction mixture was left ght at room temperature. The t was evaporated under reduced pressure (co—evaporated with xylene/toluene).

Water (100 ml) and EtOAc (100 ml) were added to the crude oil). Both layers were separated and the organic layer was washed twice with an aqueous solution of 1 N HCl (2x25 ml). The water layer was extracted with EtOAc (100 ml). The combined organic layers were washed with a saturated solution Og, dried (Na2S04), ﬁltered and evaporated under reduced pressure to yield a dark residue. The crude residue was puriﬁed using ﬂash chromatography (100 % hexane to 100 % EtOAc) to yield 0.9 g of intermediate 10 as a beige solid (mixture of 2 ts).

Example A6 Preparation of intermediate 11 HZN <1] LiAlH4 (125 ml, 250 mmol) in anhydrous THF (20 ml) was added over a period of 2 minutes to a stirring solution of 4-chloro—2-(lH—pyrrol—1-yl)benzonitrile (23 g, 114 —60- mmol) in anhydrous THF (200 ml) while g the reaction mixture with ice. After addition, the r.rn. was stirred for 1 hour at 0 °C.

Ice water (100 ml) was added to 200 ml of a saturated solution of (2R,3R)-2,3- dihydroxybutanedioic acid monopotassium monosodium salt tetrahydrate (96 g, 341 mmol) (Rochelle salt). Subsequently, ﬁrst the rm. and then EtOAc (300 ml) were added to this solution under vigorously stirring and ice cooling. The e was stirred for 2 hours while the reaction mixture was allowed to reach room temperature.

The layers were separated and the aqueous layer was extracted with EtOAc (300 ml).

The combined organic layers were washed with water (50 ml), dried (NaZSO4) and ﬁltered. The ﬁltrate was evaporated under reduced pressure to yield a yellow translucent oil. This oil was dissolved in EtzO (800 ml) and HCl in dioxane (q.s.) was added to this solution. The precipitating salts were ﬁltered and washed with EtZO. The ﬁlter e was dried ght in vacuo to yield 18 g of intermediate 11 as a yellow solid. .15 B. ation of the compounds Example B] a) Preparation of compound 1 NH 3 \ .HCl A mixture of ediate 2 (1.5 g, 0.0067 mo l) and benzo[b]thiophene—2- carboxaldehyde (1.42 g, 0.0088 mol) in EtOH (15 ml) was stirred and d for 4 h.

The mixture was cooled off, and was then recrystallized overnight. The product was ﬁltered off, and dried in vacuo. Yield: 1.45 g of compound 1 (59.2 % yield; .HCl). b) Preparation of compound 2 N S Compound 1 (1.4 g, 0.0038 mol) was treated with NH3.H20 (10 ml), and extracted with DCM (50 ml). The layers were separated and dried (Na2804), ﬁltered and MnOz (6.5 g, 0.074 mo 1) was added. This mixture was stirred for 4 days. The precipitate was ﬁltered off and the ﬁltrate was ated. The residue was puriﬁed by column chromatography over silica gel (eluent: PE/EtOAc 5/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.550 g of compound 2 (44.3 % yield).

W0 2012/150305 Example B2 Preparation of compound 3 N/ \ Cl \ Intermediate 5 (0.22 g, 0.58 mmol) was dissolved in POC13 (4.5 ml). The mixture was stirred and reﬂuxed overnight. Subsequently, the mixture was cooled and poured into water. NaOH was added to pH 7. The mixture was extracted with DCM. The separated organic layer was dried (NaZSO4), ﬁltered and the ﬁltrate was evaporated in vacuo. The residue was puriﬁed by ative HPLC (Synergy column 150 x 33 mm; mobile phase: 33%-65% CH3CN (0.1 % 20 (0.1 % TFA); ﬂow rate 25 mein; 18 min). The desired fractions were collected and the solvent was evaporated in vacuo.

The residue was neutralized with a saturated NaHCO3 solution. The mixture was ted with DCM. The organic layers were dried (NaZSO4), ﬁltered and the t was evaporated. Yield: 0.060 g of compound 3 (30 % yield).

Example B3 a) Preparation of compound 4 \ CI \ .HCl 2-Benzofurancarboxaldehyde (0.541 g, 3.7 mmol) was added to a solution of intermediate 6 (0.75 g, 3.08 mmol) in EtOH (5 ml). The r.m. was stirred and reﬂuxed for 4 h, and was then . After standing ght, the mixture was concentrated.

The residue was puriﬁed by ﬂash column chromatography over silica gel (eluent: PE/EtOAc 20/1). The product fractions were collected and the solvent was evaporated to yield 1.0 g of compound 4 (88 % yield; .HCl). b Pre aration ofcom ound 5 \ CI Compound 4 (1.0 g, 2.6 mmol) was treated with 0 (15 ml), and extracted with DCM (50 ml). The layers were separated and dried (NaZSO4), ﬁltered and MnOz (2.8 g, 32.3 mmol) was added. This mixture was stirred for 2 days. The itate was ﬁltered —62- off and the ﬁltrate was evaporated. The residue was dried in vacuo. Yield: 0.720 g of compound 5 (83 % yield).

Example B4 a) Preparation of compound 6 \ .HCl 0 HN 7-Methyl—2-benzofurancarboxaldehyde (1.18 g, 7.4 mmol) was added to a solution of intermediate 4 (1.5 g, 6.1 mmol) in EtOH (10 ml). The r.m. was d and reﬂuxed for 4 h, and was then cooled. After standing overnight, the crystals were ﬁltered off and dried in vacuo. Yield: 1.5 g of compound 6 (65 % yield; .HCl). b Pre n of com ound 7 Compound 6 (1.5 g, 3.9 mmol) was d with NH3.H20 (15 ml), and extracted with DCM (50 ml). The layers were separated and dried (NaZSO4), ﬁltered and MnOz (4.07 g, 46.8 mmol) was added. This mixture was stirred for 2 days. The precipitate was ﬁltered off and the ﬁltrate was evaporated. The residue was puriﬁed by ﬂash column chromatography over silica gel (eluent: PE/EtOAc 4/1). The desired ons were collected and the solvent was evaporated. Yield: 0.380 g of compound 7 (28 % yield).

Example B5 Preparation of compound 8 \ N o \ go Intermediate 7 (0.19 g, 0.541 mmol) was dissolved in POC13 (5 ml). The mixture was stirred and d overnight. Subsequently, the mixture was cooled and poured into water. NaOH was added to pH 7. The mixture was extracted with DCM. The separated organic layer was dried (MgSO4), ﬁltered and the ﬁltrate was ated. Yield: 0.164 g ofcompound 8 (91 % yield). —63- Example B6 Preparation of compound 9 S \ A mixture of intermediate 8 (1.5 g, 4.09 mmol) and POC13 (4 ml) was d overnight. Subsequently, the mixture was cooled and poured into water. NaOH was added to pH 8—9. The mixture was extracted with EtOAc. The separated organic layer was dried, ﬁltered and the ﬁltrate was evaporated. The e was puriﬁed by column chromatography t: PE/EtOAc 30/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.67 g of compound 9 (47 % yield).

Example B7 Compounds 10, 21, 22, 23 and 24 were obtained as HBr salt forms. These compounds were prepared by using ous on ures as bed in W002/34752.

Example B8 Preparation of compounds 201 and 202 Qtw mm Compound 201 Compound 202 POC13 (9274 ul, 99 mmol) was added to intermediate 10 (900 mg). The reaction mixture was reﬂuxed for 5 hours. The excess of POC13 was evaporated under reduced pressure. MeOH was added to the resulting oil. The exces MeOH was evaporated.

EtOAc (q.s.) and a 2M aqueous solution ofNaOH were added to the resulting crude.

The two layers were separated and the water layer was extracted with EtOAc. The combined organic layers were dried over anhydrous NaZSO4, ﬁltered and evaporated under reduced pressure to yield a crude which was puriﬁed over silica (100 % Hexane to 100 % EtOAc) to yield two pure fractions. Both fractions were triturated in EtOz resulting in fraction 1: 412 mg of compound 201; fraction 2: 99.4 mg of compound 202.

By using analogous reaction protocols as described in the foregoing examples, the compounds in Table 1a en Table 1b have been prepared. ‘Co. No.’ means compound number. ‘Pr.’ refers to the Example number ing to which protocol the compound was synthesized. In case no salt form is indicated, the compound was ed as a ﬁee base.

Compounds wherein R3 and R4 are hydrogen and for which no speciﬁc stereochemistry is ted in Table 1a were ed as racemic mixtures of R and S enantiomers.

In order to obtain the HCl salt forms of the compounds, several procedures known to those skilled in the art were used. In a typical procedure, the compound was dissolved in a solvent such as, for example, 2-propanol, and subsequently a HCl solution in a solvent such as, for example, 2-propanol was added dropwise. Stirring for a certain period oftime, typically about 10 minutes, could enhance the rate of the reactions.

Table 1a: \ 10 R1 WO 50305 —65— g2: Pr. Salt Form l9 B1.a .HCl B3.a 21 B7 22 B7 [\J u» w\1 27 .HCl B1.a B3.a 31 B1.a 32 B1.a 33 B1.a 34 B1.a 7—CH3 .HCl W0 50305 Het Salt Form 36 B1.a 37 B1.a 38 B1.a UB].a 40 B1.a 41 Bl.a B4.a 42 B].a 43 Bl.a 44 B].a 45 B1.a 46 B1.a 7-C1 47 B4.a 7-Cl W0 50305 -67— £3: Pr 48 B1. 49 B1. 50 B1. 51 B] .a 52 B].a B].a 53 B].a 54 B].a 55 B].a 56 B].a 57 B].a 58 B].a 59 B].a 207 B1.a 2012/058142 Pr. Salt Form 208 B].a 209 B4.a 210 B4.a 211 B4.a 212 B4.a 213 B4.a 7-CH3 H .HCl 214 B].a 7—01 H If \ ..... .HCl 215 B1.a 7—01 10—(31—I If \ _____ .HCl 216 B].a 8-C1 10~c1 1? \ ..... .HCl 217 B3.a 9—c1 H @----- .HCl 218 B].a 9—Cl H @----- .HCl WO 50305 Table 1b: Salt Form / Comment 2012/058142 Salt Form / Comment 88 B1.b 7-CH3 WO 50305 Salt Form / Comment 103 B6 W0 20121’150305 2012/058142 Salt Form / Comment W0 201215150305 2012/058142 Salt Form / Comment 122 B3.b 123 B3.b 7—C1 124 B3.b 9—CI 125 B3.b 7-C1 9-6 m..... 126 B6 7—01 .1 C1 l:27 \ .....

B6 7-Cl H \ ..... 128 B6 7-C1 H 2012/058142 Salt Form / Comment W0 20121150305 2012/058142 Salt Form / Comment WO 50305 Salt Form / Comment W0 2012I'150305 _C*0 1 2 Salt Form/ Pr. R R Het No. t 2 B1.b 7-0H3 H @..... 164 B1.b 10—0113 H @..... _l_ s 165 B1.b 701 H @..... 166 B1.b 9—01 1—1 ©E\>.....s 167 B1.b 10-01 H @..... _[__ 168 B1.b 7—01 9—01 \ ..... 169 B1.b 701 10—01113 @..... \ ..... 170 B6 7-01 H \ ..... 171 B6 7-01 901 f F 172 B6 7-01 H [Q..... 9 B6 701 H s 173 B6 9-01 H s 174 B6 175 B6 WO 50305 C0. Salt Form / Pr. R1 2 R Het No. Comment 176 B6 177 B1.b 178 B1.b 179 B1.b 180 B1.b 181 B6 182 B6 183 B6 184 B6 185 B6 186 B6 187 B6 7-c1 9-01 IEQ""" Salt Form / Pr. 1 2 R R Het 188 B6 7-c1 H K5/9""" 189 B6 7-F H K3/9""" 190 B6 7-F 9—1T gSQ'''' 191 B6 7—c1 H A3/9"""N 192 B6 7-F H A5/9 F3C N 193 B6 70 H i/Q" 194 B6 195 B6 197 B8 198 B8 199 B8 200 B1.b 201 B8 7—Cl Salt Form / Comment 80 % pure, containing 20 % dehalogenated product C. Analﬂical results LCMS — Generalprocedure A The HPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode—array detector (DAD) (wavelength used 220 nm), a column heater and a column as ed in the respective methods below. Flow from the column was split to a Agilent MSD Series G1946C and G1956A. MS detector was conﬁgured with API- ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by ng from 100 to 1000. The capillary needle voltage was 2500 V for positive and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas ature was maintained at 350 °C at a ﬂow of 10 l/min.

LCMS — Generalprocedure B The HPLC measurement was performed using an ce HT 2790 (Waters) system sing a quaternary pump with degasser, an autosampler, a column oven (set at 40 °C, unless otherwise indicated), a diode-array detector (DAD) and a column as speciﬁed in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was conﬁgured with an electrospray ionization source.

Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature was maintained at 140 °C. Nitrogen was used as the zer gas. Data acquisition was performed with a Waters—Micromass MassLynx-Openlynx data system.

W0 2012/150305 ~81- LCMS — Generalprocedure C The LC measurement was performed using an Acquity UPLC s) system comprising a binary pump, a sample organizer, a column heater (set at 55 °C), a diode- array detector (DAD) and a column as speciﬁed in the respective s below. Flow from the column was split to a MS spectrometer. The MS detector was conﬁgured with an electrospray ionization source. Mass a were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 s. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 °C. Nitrogen was used as the zer gas. Data acquisition was performed with a Waters—Micromass MassLynx—Openlynx data system.

LCMS — Generalprocedure D The HPLC measurement was performed using a Waters acquity H-class UPLC system comprising a quaternary pump with degasser, an autosampler, a column oven with a column heater. This was coupled to a waters TUV (Tunable UV) detector and waters TQD ESI (electrospray ionization) mass spectrometer. The MS detector was conﬁgured with an ospray ionization source. A waters acquity UPLC BEH C18 1.7um 2.1 x 50 mm column was used. Column temperature was 30°C and ﬂow rate 0.7mL/min unless otherwise noted. Mass ES positive mode spectra were acquired by scanning from 151 to 1000 in 0.1 second. ES negative mode spectra were acquired by seaming from 151 to 1000 in 0.1 second. The capillary needle voltage was 2 kV and the source temperature was maintained at 140 °C. en was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

LCMSMethod 1 In addition to general procedure A: Reversed phase HPLC was carried out on a YMC- Pack ODS—AQ, 50x20 mm 5pm column with a ﬂow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used. First, 100 % A was hold for 1 minute. Then a nt was applied to 40 % A and 60 % B in 4 minutes and hold for 2.5 minutes. Typical injection volumes of2 n1 were used. Oven temperature was 50 °C. (MS polarity: positive) LCMSMethod 2 In addition to general procedure A: Reversed phase HPLC was d out on a YMC- Pack ODS-AQ, 50x20 mm 5 pm column with a ﬂow rate of 0.8 ml/min. 2 mobile phases e phase A: water with 0.1 % TFA; mobile phase B: CH3CN with 0.05 % TFA) were used. First, 90 % A and 10 % B was hold for 0.8 min. Then a gradient was applied to 20 % A and 80 % B in 3.7 min and hold for 3 min. Typical injection volumes of 2 n1 were used. Oven temperature was 50 °C. (MS polarity: positive) ~82- LCMSMethod 3 In addition to general procedure A: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50x21 mm 5um column with a ﬂow rate of 0.8 ml/min. Two mobile phases e phase C: 10 mmol/l NH4HC03; mobile phase D: CH3CN) were used.

First, 100 % C was hold for 1 minute. Then a nt was applied to 40 % C and 60 % D in 4 minutes and hold for 2.5 min. Typical ion volumes of2 ul were used. Oven temperature was 50 oC. (MS polarity: positive) LCMSMethod 4 In addition to general procedure B: Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 nm, 4.6 x 100 mm) with a ﬂow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and 99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 ul was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

LCMSMethod 5 In addition to general procedure A: Reversed phase HPLC was d out on a YMC- Pack ODS-AQ, 50x20 mm 5nm column with a ﬂow rate 01°08 ml/min. Two mobile phases (mobile phase A: water with 0.1 % TFA; mobile phase B: acetonitrile with 0.05 % TFA) were used. First, 70 % A and 30 % B was hold for 0.8 s. Then a gradient was applied to 10 % A and 90 % B in 3.2 minutes and hold for 3.5 minutes.

Typical injection volumes of 2 n1 were used. Oven temperature was 50 °C. (MS polarity: ve) LCMSMethod 6 In addition to general procedure A: Reversed phase HPLC was carried out on an Ultimate , 50x21 mm 5urn column with a ﬂow rate of 0.8 . Two mobile phases (mobile phase C: 10 mmol/L NH4HC03; mobile phase D: acetonitrile) were used. First, 90 % C and 10 % D was hold for 0.8 minutes. Then a gradient was applied to 20 % C and 80 % D in 3.7 minutes and hold for 3 s. Typical injection volumes of 2 ul were used. Oven temperature was 50 °C. (MS polarity: positive) WC 2012/150305 2012/058142 -83— LCMSMethod 7 In addition to general procedure C: Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 um, 2.1 x 50 mm; Waters Acquity) with a ﬂow rate of 0.8 ml/min. Two mobile phases (10 mM um acetate in HzO/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 s and hold for 0.3 minutes. An injection volume of 0.5 ul was used. Cone voltage was 10 V for positive ionization mode and 20 V for ve ionization mode.

LCMSMethod 8 In addition to general ure D: Solvent A: water with 0.1% formic acid; Solvent B: acetonitrile with 0.1% formic acid. In 1.75 min from 95% A, 5%B to 95%B, 5% A, then 0.25min 95% B, 5% A. with 0.75 min reequilibration towards 5% B. UV detection wavelength: 254nm, MS polarity: positive and negative. Cone e was 10 V for positive and negative ionization mode. Typical injection volumes of 1 ul were used.

Melting Points For a number of compounds, melting points (m.p.) were determined with a WRS-2A melting point apparatus purchased from ai Precision and Scientiﬁc Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2—5.0 °C/min The reported values are melt ranges. The maximum temperature was 300 °C.

For compound 20, the m.p. was determined with a DSC823e (Mettler-Toledo). The mp. was measured with a temperature gradient of 30 °C/minute. Maximum temperature was 400 °C. The value is ted as a peak value.

The results of the analytical measurements are shown in table 2.

W0 2012/150305 ~84- Table 2: Retention time (R) in min, [M+H]+ peak (protonated molecule), and mp. (melting point in °C). (“n.d.” means not determined; “dec” means decomposed).

-[M+H]+I\I:I:‘11l1/Iosd C) 2 2424—2477 . 2289—2293 2 3.79 329 2 1089—1815 49 3.83 387 l 2 2348—2354 3 3.27 362 2 1582—1606 50 2.80 350 l 2 - 3.63 333 2 1599—1608 51 2.86 370 2 - 7 3.76 W 2 1752—1773 52 3.80 317 1-94.44949 8 3.26 333 2 163.9-164.1 53 3.87 351 -189.9-1908 1:369 349 2 1825—1549 55 3.78 331 2 dec _1_3_ 3.52 324 2 dec 56 3.93 385 2 386 14 3.78 324 l 1 — 57 3.80 365 2 2535—2551 4.50 330 1 2408-2413 58 4.02 385 2 206.0-208.0 364 2 2001—2019 59 3.58 352 2 314 17 4.25- 1 2389—2404 60 3.95-154.3-156.6 18 3.47 344 2 244.7—246.5 61 3.36 2444—2464 1855-1874 n.d.-_156.0-156.9 21 4.89 64 -—119.4-123.5 3.75 311 1 1937—2001 65 3.47 — 365 1 2490—2520 66 3.45 1428—1448 365 1 780 67 3.96 - 29 3.70 301 2 327 68 3.50 1420—1431 3.69 335 2 2336—2350 69 _4_.1_2~ 362 -144.7—145.4 __3_1_ 3.78 369 2 234.6-237.1 _7_0_—4£ 352 - 32 3.69 315 2 - 71 5.00 352 1 — 33 L3.56 315 2 dec _7_2__3_.3_4_ 322 2 1980—1995 34 3.85 349 2 2453—2485 _7_3_ 3.63 356 2 _ 369 2 2082—2140 74 6.00 36 3.49 349 2 24182432 .338 356 37 3.96 349 2 2324-2329 76 3.21 356 2 38 3.68- 2 2481—2526 77 3.03 328 2 349 2 176.2-176.8 78 2.72 346 40 3.80 329 2 244.4—245.8 j_9_ 3.74 362 383 2 267.1-268.2 80 3.26 2 2389-2402 81 3.47 45 6.51 365 3 2256—2309 84 3.46 46 3.69 399 2 2413—2438 85 — .357 353 2 1153—1164 86 4.07 —85- .22: R. 87 4.40 328 1 — 131--— 88 3.42 342 2 135.1—136.6 132 3.65 347 89 3.58 362 2 175.3—176.6 133 3.79 347 90 4.22 346 1 - 134 3.80 347 91 3.79 396 2 147.8-149.1 135 3.82 347156.5-157.1 92 3.92 336 1 186.1-187.7 1_3§_4_.97_ 381 -192.9-193.2 94 3.75 338 1 2142—2159 137 3.51 313 -232.0—2379 95 5.37 274 3 328 138 _3_.84_ 347 -197.0-1982 96 4.05 308: 1 1884-1900 1_32_4£:/_ 381-198.2-201.3 9713—92 288 1 1785—1800 1492-331 327 -138.1-138.3 98 3.77 362 2 _ 1413.76 363 2 180.7-1822 99 3.87 289 1 1770—1779 142 3.85 363 2 1862-1879 100 3.92 309 1 2286—2301 143 6.41 363 3 — 101 4.54 329 1 1332—1342] 144 3.80 343 2 190.1 102 5.59 363 1 1424—1450 145 5.33 397 6 — 103 4.40 343 1 1514—1539 146 3.45 363 2 1511—1523 104 4.44 397 2 180.5-181.9 147- 363 2 215.1-216.7 105 2.73 334 2 182.7-184.4 148- 397 2 1086—1099 106 3.83 346 2 - 149 3.85 385 2 2072-2091 107 3.65 380 2 2109-2115 150 3.50 - 108 3.02 348 2 520 151 7.62 206.4—207.7 109 3.26 382 2 213.4-216.0 152 3.312093—2104 110 3.90 348 1 2224—2237 153- 351 2 111 3.03 382 2 224.1-224.6 154- 369 2 773 112 5.97 358 3 - 155 3.89 367 2 — 113 5.75 342 3 _ 156 3.91 367 2 — 114 5.86 360 3 2095—2100 157 3.59 329 2 115 3.58 299 2 - 158 3.24 370 116 3.54 313 2 133.6-136.0 159 3.00 368 -219.0—219.9 117 3.40 313 2 1456—1465 160 3.37 382 2 — 118 3.57 333 2 1801—1825 161-_- p19 3.65 333 2 2063—2089 162 2.84 348 2 244.8-246.4 120 3.76 367 2 2289—2301 1_63 3.73 315 2 121 2.41 367 5 2044-2070 164 3.77 329 2 122 3.83 347 2 2004—2027 165 3.95 349 123 3.55 351 2 186.6-186.7 166 3.95 349 2 124 3.66 351 2 173.6-175.1 167 3.98 349 2 1783—1788 125 3.88 385 2 173.6-175.4 168- 383 2 126 3.70 367 2 190.3-192.6 169 3.96—— 127 3.54 351 2 198.6-199.4 170 4.39 128 3.64 369 2 1820—1843 1_71 5.01 129 4.03 403 2 023 172 3.07 130 3.63 313 2 1263-1285 173--_ ~86- Co. + LCMS mp. (°C) Method . t 1350-1395 176-- 2 176.4—178.1 177-- 2 dec 178- 2 179- 2 180-- 2 177.4-177.8 181- 350 2 174.3-176.0 182- 316 3 179.1-181.1 183- 330 6 2325—2354 184- 350 2 2315-2328 185- 350 186- ”1:1 1968—1980 350 187.8—1890 384 2240-2256 188 172.5—173.8 189- 334 HLpN 190- 352 3 1499—1534 1HNMR For a number of compounds, 1H NMR spectra were recorded on a Bruker DPX-300 or on a Bruker DPX-400 spectrometer with rd pulse sequences, operating at 300 MHz and 400 MHz respectively, using FORM—d rated chloroform, CDC13) or DMSO-d5 (deuterated DMSO, yl-d6 sulfoxide) as solvents.

Co. No. 118 :(300 MHz, CDC13) 5 ppm 4.26 (d, J=12.1 Hz, 1 H) 5.65 (d, J=12.3 Hz, 1 H) 6.46-6.57 (m, 1 H) 6.94 (dd, J=4.0, 1.3 Hz, 1 H) 7.20 (s, 1 H) 7.21—7.43 (m, 6 H) 7.56-7.65 (m, 2 H).

Co. No. 115 :(400 MHz, CDC13)5 ppm 4.49 (br. s., 1 H) 5.01 (br. s., 1 H) 6.47-6.58 (m, 1 H) 6.86-7.02 (m, 1 H) 7.15-745 (111,7 H) 7.52 (d, J=7.3 Hz, 1 H) 7.56—7.61 (m, 2 CO. No. 116 :(300 MHz, CDC13) 5 ppm 2.66 (s, 3 H) 4.23 (d, J=11.3 Hz, 1 H) 5.35 (d, J=12.4 Hz, 1 H) 6.55 (br. s., 1 H) 7.03 (br. s., 1 H) 7.19—7.52 (m, 7 H) 7.58-7.68 (m, 2 Co. No. 1 :(300 MHz, DMSO—a’s) 8 ppm 2.59 (s, 3 H) 3.69 (d, J=13.6 Hz, 1 H) 4.39 (d, J=13.9 Hz, 1 H) 5.64 (br. s., 1 H) 6.15-6.28 (m, 1 H) 6.28-6.39 (m, 1 H) 7.27-7.57 (m, 7 H) 7.81-8.11 (m, 2 H) 10.31 (br. s., 1H) 10.94 (br. s., 1 H).

Co. No. 82 : (300 MHz, CDC13) 8 ppm 4.20 (br. s., 1 H), 5.52 (br. s., 1 H), 6.42 - 6.54 (m, 2 H), 6.58 (s, 1 H), 7.23 — 7.33 (m, 2 H), 7.33 - 7.46 (m, 3 H), 7.68 (d, J=8.7 Hz, 1 H), 7.87 (s, 1 H). —87- Co. No. 88 :(300 MHz, CDC13) 8 ppm 2.64 (s, 3 H) 4.21 (br. s., 1 H) 5.28 (br. s., 1 H) 6.36-6.63 (m, 2 H) 7.16-7.37 (m, 3 H) 7.44 (br. s., 1 H) 7.71 (d, J=8.1 Hz, 1 H) 8.24 (d, J=7.5 Hz, 1 H) 9.02 (s, 1 H).

Co. No. 150 :(400 MHz, CDC13) 8 ppm 4.23 (br. s., 1 H) 5.58 (br. s., 1 H) 6.49 (br. s., 1 H) 6.58 (br. s., 1 H) 6.80 (br. s., 1 H) 7.28—7.35 (m, 2 H) 7.39 (br. s., 2 H) 7.53-7.66 (m, 1 H) 7.69 (br. s., 2 H) 7.90 (br. s., 1 H).

Co. No. 130 :(300 MHz, CDC13) 8 ppm 2.62 (s, 3 H) 4.49 (br. s., 1 H) 5.02 (br. s., 1 H) 6.39—6.58 (m, 1 H) 6.84—6.98 (m, 1 H) 7.07-7.22 (m, 3 H) 7.29-7.35 (m, 1 H) 7.35—7.47 (m, 4 H) 7.53 (d, J=7.2 Hz, 1 H).

Co. No. 184 :(400 MHz, CDC13) 8 ppm 4.23 (br. s., 1 H) 5.56 (br. s., 1 H) 6.42—6.51 (m, 1 H) 6.53 (dd, J=3.8, 1.5 Hz, 1 H) 7.28-7.35 (m, 2 H) 7.39 (m,J=3.1, 3.1, 2.1 Hz, 2 H) 7.89 (dd, J=8.5, 1.5 Hz, 1 H) 8.11 (d, J=8.5 Hz, 1 H) 8.37 (d, J=1.5 Hz, 1 H) 9.06 (s, 1 H).

Co. No. 7 :(300 MHz, CDCl}) 8 ppm 2.60 (s, 3 H) 4.23 (d, J=8.9 Hz, 1 H) 5.62 (d, J=9.4 Hz, 1 H) 6.50 (br. s., 1 H) 6.92 (br. s., 1 H) 7.17 (m, J=9.8 Hz, 3 H) 7.23-7.49 (m, 5 H).

Co. No. 117 :(400 MHz, DMSO-d5) 8 ppm 2.32 (s, 3 H) 4.13 (d, J=10.8 Hz, 1 H) 4.82 (d, J=10.8 Hz, 1 H) 6.46 (dd, J=3.6, 2.9 Hz, 1 H) 6.85 (dd, J=3.9, 1.4 Hz, 1 H) 7.23— 7.30 (m, 2 H) 7.31—7.36 (m, 2 H) 7.36-7.45 (m, 2 H) .65 (m, 2 H) 7.70 (d, J=7.8 Hz, 1 H).

Co. No. 175 :(400 MHz, CDC13) 8 ppm 4.29 (br. s., 1 H) 5.17 (br. s., 1 H) 6.48 (m, J=3.3, 3.3 Hz, 1 H) 6.57 (m, J=2.3 Hz, 1 H) 7.09 (t, J=8.5 Hz, 1 H) 7.20 (d, J=8.0 Hz, 1 H) 7.30—7.39 (m, 2 H) 7.40 (br. s., 1 H) 7.47 (d, J=5.5 Hz, 1 H) 7.75 (dd, J=8.5, 1.5 Hz, 1 H) 7.88 (d,J=8.5 Hz, 1 H) 8.18 (d, J=1.5 Hz, 1 H).

Co. No. 3 :(300 MHz, CDC13) 8 ppm 4.26 (br. s, 1 H), 5.55 (br. s, 1 H), .57 (m, 2 H), 7.28 (dd, J=7.9, 1.5 Hz, 1 H), 7.33 (t, J=7.9 Hz, 1 H), 7.38-7.45 (m, 2 H), 7.82 (d, J=5.1 Hz, 1 H), 8.05 (s, 1 H), 8.75 (d, J=5.0 Hz, 1 H).

Co. No. 194 :(400 MHz, CDC13) 8 ppm 4.26 (br. s., 1 H) 5.63 (br. s., 1 H) 6.51 (m, J=2.8 Hz, 1 H) 6.60 (br. s., 1 H) 7.30—7.37 (m, 2 H) 7.38-7.47 (m, 2 H) 8.00 (d, J=9.3 Hz, 1 H) 8.16 (d, J=9.0 Hz, 1 H) 8.30 (s, 1 H).

Co. No. 65 :(400 MHz, CDC13) 8 ppm 1.41 (t, J=7.5 Hz, 3 H) 3.12 (q, J=7.7 Hz, 2 H) 4.16 (br. s., 1 H) 5.52 (br. s., 1 H) 6.48 (m, J=3.4, 3.4 Hz, 1 H) 6.79 (dd, J=3.6, 1.4 Hz, 1 H) 7.25 (d, J=1.8 Hz, 1 H) 7.29-7.33 (m, 1 H) 7.39 (d, J=1.8 Hz, 1 H) 7.57 (s, 1 H).

Co. No. 173 :(300 MHz, CDC13) 8 ppm 4.54 (br. s, 1 H), 4.87 (br. s, 1 H), 6.46-6.57 (m, 1 H), 6.57—6.67 (m, 1 H), 7.30 (dd, J=8.1, 2.1 Hz, 1 H), 7.36 (d, J=5.5 Hz, 1 H), 7.39-7.52 (m, 4 H), 7.74 (dd, J=8.5, 1.6 Hz, 1 H), 7.90 (d, J=8.5 Hz, 1 H), 8.19 (s, l H).

W0 2012/150305 Co. No. 172 :(300 MHz, CDC13) 8 ppm 4.21 (br. s, 1 H), 5.53 (br. s, 1 H), 6.46 (t, J=3.2 Hz, 1 H), 6.54 (dd, J=3.6, 1.5 Hz, 1 H), 7.27-7.32 (m, 2 H), .42 (m, 3 H), 7.51 (d, J=5.4 Hz, 1 H), 7.75 (dd, J=8.3, 1.3 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1 H), 8.24 (s, 1 H).

Co. No. 185 :(300 MHz, CDC13) 8 ppm 4.51 (br. s, 1 H), 4.84 (br. s, 1 H), 6.44-6.51 (m, 1 H), 6.51—6.58 (m, 1 H), 7.28 (dd, J=8.1, 1.9 Hz, 1 H), 7.35-7.47011, 3 H), 7.87 (dd, J=8.6, 1.7 Hz, 1 H), 8.11 (d,J=8.6 Hz, 1 H), 8.33 (s, 1 H), 9.06 (s, 1 H).

Co. No. 85 :(300 MHz, CDC13) 5 ppm 2.01 (t, J=18.6 Hz, 3 H), 4.25 (br. s, 1 H), 5.51 (br. s, 1 H), 6.55 (dd, J=4.0, 2.8 Hz, 1 H), 6.61 (dd, J=3.9, 1.6 Hz, 1 H), 7.06 (dd, J=8.8, 2.5 Hz, 1 H), 7.20 (dd, J=8.2, 2.5 Hz, 1 H), 7.45 (dd, J=2.8, 1.6 Hz, 1 H), 7.69 (d, J=8.2 Hz, 1 H), 8.19 (dd, J=8.2, 2.2 Hz, 1 H), 8.89 (d, J=2.2 Hz, 1 H).

CO. No. 105 : (300 MHz, CDC13) 8 ppm 2.15 (quin, J=7.6 Hz, 2 H), 2.95 (t, J=7.4 Hz, 2 H), 3.04 (t, J=7.7 Hz, 2 H), 4.17 (br. s., 1 H), 5.52 (br. s., 1 H), 6.46 (dd, J=3.8, 2.8 Hz, 1 H), 6.52 (dd, J=3.8, 1.7 Hz, 1 H), 7.25 — 7.43 (m, 4 H), 7.89 (s, 1 H), 8.57 (s, 1 H).

Co. No. 126 : (400 MHz, CDC13) 8 ppm 4.23 (d, J=11.3 Hz, 1 H), 5.65 (d, J=11.5 Hz, 1 H), 6.52 (t, J=3.3 Hz, 1 H), 6.94 (d, J=3.9 Hz, 1 H), 7.19 (t, J=7.8 Hz, 1 H), 7.22 — 7.29 (m, 2 H), 7.31 (t, J=8.0 Hz, 1 H), 7.34 — 7.43 (m, 3 H), 7.50 (d, J=7.8 Hz, 1 H).

Co. No. 131 :(400 MHz, CDC13) 8 ppm 2.61 (s, 3 H), 2.65 (s, 3 H), 4.19 (d, J=11.5 Hz, 1 H), 5.30 (d, J=11.5 Hz, 1 H), 6.45—6.56 (m, 1 H), 6.93 (br. s, 1 H), 7.10-7.29 (m, 6 H), 7.39 (br. s., 1 H), 7.42 (dd, J=6.9, 2.3 Hz, 1 H).

Co. No. 138 : (300 MHz, CDC13) 8 ppm 2.45 (s, 3 H), 4.20 (d, J=11.5 Hz, 1 H), 5.59 (d, J=11.5 Hz, 1 H), 6.47 (t, J=3.4 Hz, 1 H), 6.90 (d, .1138 Hz, 1 H), 7.04 (d, J=8.0 Hz, 1 H), 7.11 (s, 1 H), 7.19 — 7.39 (m, 5 H), 7.43 (d, J=7.9 Hz, 1 H).

Co. No. 174 : (400 MHz, CDC13) 5 ppm 4.32 (d, J=11.1 Hz, 1 H), 4.86 (d, J=11.1 Hz, 1 H), 6.42 — 6.45 (m, 1 H), 6.53 (dd, J=3.8, 1.5 Hz, 1 H), 7.24 (t, J=7.8 Hz, 1 H), 7.36 (d, J=5.1 Hz, 1 H), 7.42 ~ 7.53 (m, 3 H), 7.58 (dd, J=2.9, 1.5 Hz, 1 H), 7.82 (dd, J=8.5, 1.7 Hz, 1 H), 7.88 (d, J=8.4 Hz, 1 H), 8.22 (d, J=1.0 Hz, 1 H).

CO. No. 123 : (400 MHz, DMSO‘dﬁ) 8 ppm 4.14 (br. s, 1 H), 5.36 (br. s, 1 H), 6.58 (dd, J=3.8, 2.9 Hz, 1 H), 7.00 (dd, J=3.8, 1.6 Hz, 1 H), 7.27 (td, J=9.2, 2.7 Hz, 1 H), 7.33 (d, J=0.9 Hz, 1 H), 7.45 - 7.56 (m, 4 H), 7.68 (dd, J=9.0, 4.1 Hz, 1 H), 7.78 (dd, J=2.9, 1.6 Hz, 1 H).

Co. No. 76 : (400 MHz, CDC13) 8 ppm 1.31 (t, J=7.6 Hz, 3 H), 2.87 (q, J=7.6 Hz, 2 H), 4.15 (s, 1 H), 5.47 (s, 1 H), 6.48 (dd, J=3.9, 2.8 Hz, 1 H), 6.53 (dd, J=3.8, 1.6 Hz, 1 H), 7.18 (d, J=8.1 Hz, 1 H), 7.31 (d, J=2.0 Hz, 1 H), 7.35 (dd, J=2.9, 1.6 Hz, 1 H), 7.41 (d, J=2.0 Hz, 1 H), 7.95 (dd, J=8.1, 2.3 Hz, 1 H), 8.78 (d, J=2.3 Hz, 1 H). —89— Co. No. 141 : (400 MHz, CDC13)5 ppm 3.85 (s, 3 H), 4.22 (d, J=11.5 Hz, 1 H), 5.61 (d, J=11.5 Hz, 1 H), 6.50 (t, J=3.3 Hz, 1 H), 6.88 (dd, J=8.5, 1.8 Hz, 1 H), 6.93 (d, J=3.4 Hz, 1 H), 7.08 - 7.16 (m, 2 H), 7.22 - 7.33 (m, 2 H), 7.35 (s, 1 H), 7.39 (CI, J=7.5 Hz, 1 H), 7.45 (d, J=8.6 Hz, 1 H).

Co. No. 119 : (400 MHz, CDClg) 8 ppm 4.44 (br. s, 1 H), 4.99 (br. s, 1 H), 6.53 (dd, J=3.7, 3.0 Hz, 1 H), 6.96 (dd, J=3.8, 1.7 Hz, 1 H), 7.21 (s, 1 H), 7.26 (t, J=7.5 Hz, 1 H), 7.29 (dd, J=8.l, 2.1 Hz, 1 H), 7.33 — 7.42 (m, 3 H), 7.45 (d, J=8.1 Hz, 1 H), 7.60 (t, J=8.6 Hz, 2 H).

Co. No. 121 : (400 MHz, CDC13) 5 ppm 4.24 (br. (1, J=11.5 Hz, 1 H), 5.64 (br. d, J=11.4 Hz, 1 H), 6.53 (t, J=3.3 Hz, 1 H), 6.93 (br. s, 1 H), 7.15 (br. s., 1 H), 7.22 — 7.35 (m, 3 H), 7.35 — 7.44 (m, 2 H), 7.52 (d, J=8.7 Hz, 1 H), 7.57 (s, 1 H).

D. Pharmacological examples Example D.1: Measurement of antifungal ty in vitro The standard susceptibility screen is performed in l plates (U-bottom, Greiner e). Serial dilutions (2-fold or 4-fold) of 20 mM compound stock solutions are made in 100 % DMSO, followed by an intermediate dilution step in water. These serial dilutions (10 ul) are then d onto test-plates that can be stored in the dark at 4°C for a maximum period of 2 weeks. An adequate broad dose-range is included with 64 uM as the highest in—test concentration. The culture medium RPMI-1640 is supplemented with L-glutamine, 2% glucose and buffered with 3-(N—morpholino)— propanesulfonic acid (MOPS) at pH 7.0 :t 0.1.

The different fungal species/isolates (Table 3a) are cryopreserved and l/1000 diluted in medium just prior to use. A standard um of 200 ul containing 103 colony—forming unit (cfu) is then added to each well. A ve control (100 % growth = fungal e without antifungal) and a negative control (0 % growth = RPMI—MOPS medium) are included on each plate. Optimal incubation time and temperature are dependent on the fungal species and vary from 24 h for yeasts (37 °C) to one week or more for dermatophytes (27 °C). Inhibition of ﬁingal growth is measured after adding 10 ul of 0.005% (w/V) resazurin (Sigma Aldrich) to each well, based on the principle that living cells convert the non-ﬂuorescent blue resazurin into the pink and ﬂuorescent resoruﬁn, allowing etric reading (Rex 550 nm and 719m 590 nm) after an additional incubation period (‘resa’ time mentioned in Table 3a). Results are shown in Table 3b as pIC50 values.

Table 3a: tion conditions for the different fungal species. ‘Resa time’ represents the additional incubation time after the addition of rin to the test system.

Resa time Microsporum canis 9 days 24 hours Trichoghxton mentagroghgtes 27 7 da 3 24 hours Trickophyton rubrum 27 7 days Scedosgorium agiosgermum 37 48 hours 17 hours Scedosﬂuﬂprolzﬁcins : 37 48 hours 17 hours Sporothrix schenkz'z' 27 4 days 24 hours Asgergz’llus fumigatus 27 48 hours 17 hours Candida parapsilosz's 37 24 hours 4 hours Crzgtococcus neoformans _1_ 37 24 hours 4 hours Rhizopus orjyzae 37 24 hours 6 hours I Rhizomucor miehez’ 37 48 hours 17 hours Table 3b: Activities of the test compounds in vitro (‘n.d.’ means not determined; ‘Inf.’ means infection; values are pICso values) Inf. ‘A’: Sporothrix schenkz'z' B62482 Inf. ‘G’: Trichophyton mentagrophytes B70554 Inf. ‘B’: Microspomm canis B68128 Inf. ‘H’: porium apiospermum 1HEM381 7 Inf. ‘C’: Trichophyton rubrum B68183 Inf. ‘1’: Scedosporz'um proliﬁcans 1HEM21157 Inf. ‘D’: Candida parapsz'losz's B66126 Inf. ‘J’: Rhizopus oryzae 23 Inf. ‘E’: Aspergillusfumigatus B42928 Inf. ‘K’: Rhizomucor miehez‘ 1HEM13391 Inf. ‘F’: Cryptococcus neoformans B66663 ' Inf.A Inf.B Inf.C Inf. DELF. Inf.F Inf. G Inf.H 1111.1 __.._ w!w~5.52 6.35 7.17 4.34 5.70 <4.19 6.69 <4.19 5.74 6.19 6.48—l—6.78 <4.19 5.70 5.70 6.37 6.28 5.79 <4.19 6.90 7.37_L<4.19 587 <4.19 6.64 5.67 5.52 6.18 6.50 7.16 <4.19i‘57 5.45 6.97 5.22 6.51 .56 6.76 7.19 5.01 6.52 6.12 6.61 6.29 4.85 6.37 7.41 6.10 6.31 5.37 6.75 4.99 6.36 578 6.19 7.01 6.26 7.40 425 <4.19 <4.19-<4.19 <4.19 n..d 4-71 <4-19 4-31 459 <4.49 4.92 <4.49 <4.49 4.82 13 <4.19 5.40 5.70 <4.19 _H.—— [—14‘<4.19 5.30 5.30 <4.19 <4.19 4.28 4.74 n.d. n.d. 2012/058142 _91_ Inf. A Inf. B Inf.C 1111.1) Inf.E 1111.11 Inf.G Inf.H 161.1 <419 <44 <4.19 <4.19 4.64 5.28 n.d. <4.19 <4.19 4.23 <419 nd n.d. 18 <4.19—<4.19 <4.19 <4.19 4.62 d.- n.d. n.d.

E<419 4.95 -<4.19 <4.19 5.02 4.57 n.d. n.d. n.d. <4.19—<4.19 <4.19 <4.19 <4.19 n.d nd. n.d. 21 4.70 5.04 5.52 <4.19 <4.19 4.66 n.d. n..d n.d. 22 <4.19 @510 <4.19 <4.19 4.32 n.d. n.d. n.d. 23 <4.19 4.72 5.00 <4.19]<4.19 4.57 4.39 nd. nd nd n.d. 24 <4.19 4.57 4.74 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d. <4.19 4.43 4.19 <4.19 <4.19 <4.19 <419 n.d. nd. nd. n.d.

Y<4J9 4.92 5.10 <4.19 <4.19 <419 444 nd. n.d. 27 <4.90 <4.90 <4.90 <4.90 <490 <490 <490 28 <4.19 4.29 4.43 <4.19 <W<419 428 29 5.70 <4.19 <4.19 4.80 5.30 4.89 6.27 6.29 5.22 6.32 <4.19 6.15 <4.19 31 <4.19 <4.19 <4.19 4.87 n.d. 32 4-35 --<4419 not 44 4.44 444 44 34 <4.19 6.40 6.72 <4.19 <4.19 <4.19 622 <4.19 <4.19 5.70 6.07 <4.19 <4.19 <4.19 5.70 i<419 5.19 5.10 <4.19 <4.19 <4.19 5.21 . 37 <4.19 4.38 5.31 <4.19 <4.19 5.39 4.41 38 4.40 5.15 5.22 <4.19 4.41 <4.19 5.22 39 5.52 5.52 5.15 <4.19 5.52 <4.19 5.15 40 <4.19 5.52 4.77 <4.19 <4.19 <4.19 4.47 41 <4.19 <4.19 4.80 <4.19 <4.19 <4.19 <4.19 L42 <4.19 4.19 5.06 <4.19 <4.19 4.89 4.49 43 <4.19 4.52 4.30 <4.19 <4.19 <4.19 <4.19 44 <4.19 5.31 5.20 <4.19 <4.19 <4.19 477 45 f4.80 5.32 5.09 <4.19 <419 462 <419 d._- .. 46 <419 5.12 <419 <4.19 <4.19-.11“ n.d. n.d. 47 <419<419481 44 <4 44 44 49 <480 50 <419 456 449 <419 <4.19_—_-— 51 <4.19-'<4.19<4.19 4.45 4.94 WO 50305 Inf. A Inf. C Inf. D Inf. E 54 n.d. —5 5.04 56 <4.19 5.71 58 nd nd nd nd 59 n:d: n.d: l 60 n.d. | n.d. 61 n.d. 1 n.d. 62 n.d. 63 PP? €499 n..d 64 n..d 4.56 5.19 F::O‘ n..d <4.19 4.98 6.18 _:o. n.d <4.19 4.50 :5 Q. n..d <4.19 1'3P- <4 19 4.71 5.09 <4.19 <4.19 <4.19 <4.19 n.d. n.d. PF99* n.d. .17 6.36 6.99 6.00 5.28 6.40 6.38 5.50 4.52 .42 5.83 5.55 <4.19 <4.19 5.00 5.78 n.d.II:11d4 n.d. .61 6.05 <4.49 <4.49 <4.49 <4.49 n.d. nd. n.d. <4.49 5.10 6.09 <4.49 <4.49 <4.49 <4.49 n.d. n.d. n.d. 4.44 5.91 6.31 4.92 5.25 <4.19 6.18 6.88 <4.19 <4.19 75 <4.19 6.45 <4.19 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. 76 4.46 6.34 5.75 <4.19 4.72 4.82 5.00 5.46 <4. 19 4.49 77 452. 5.67 6.22 4.69 6.05 5.03 5.71 4.88 5.57 <4 19 <4. 19 78 <4.19 5.41 6.18 5.07 5.42 <4. 19 4.47 n.d. n.d. n d n.d. 79 5.72 6.33 4.69 6.63 <4.19 5.76 6.12 6.28 <419 <4.19 80 5.42 5.09 5.79 <4.19 5.59 <4.19 5.23 n.d. n.d. n.d. n.d. 81 5.65 <4.19 <4.19 4.19 5.58 <4.19 <4.19 n.d. n.d. 82 <4.19 6.37 6.85 5.285 6.28 <4.19 6.24 6.01 6.24 <419 <4.19 4-97 6.68 <4.19 5.33 <4.19 5.88 <4.19 6.09 <419 <4.19 84 5.65 6.24 6.26 5.44 6.24 5.88 5.31 <4.19 <4.19 <4.19 85 4.63 5.86 <4.19 86 4.94 5.59 4.43 5.77 <4.19 <4.19 87 <4.19 5.97 6.54 <4.19 4.94 5.18 <4.19 5.71 <4.19 88 4.85 6.63 l 7.10 <4.191<4.19 <4.19 5.80 [SE Inf.A 1111.13 Inf. C 1111.1) Inf. E Inf. F .Inf. H Inf. I <419 614 <419 5.33 44. .72 <419 5.28 <4.19 <4.19 <4.19 <4.19 <4.19 <4.19 93 <4.19 5.26 6.16 <4.19 5.02 <4.19 5.63 n.d. n.d. ..d —5.71 6.19 4.59 5.13 4.58 5.92 <4.19 <4.19 <419 <4.19 95 <4.49 <4.49 5.17 <4.49 <4.49 <4.49 4.58 n.d. n.d. 96 <4.19 4.80 5.10Ji419 4.40 <4.19 5.00 n.d. n.d. 97 <4.49 4.87 5.99 <4.49 <4.49 <4.49 4.83 n.d. n.d. n.d. n.d. 98 4.49 <4.19 4.47 5.06 4.49 5.03 4.48 n.d. n.d. n.d. n.d. 99 <4.19 5.10 4.89 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d. 100 <4.19 4.21 <4.19 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d. 101 <4.19 4.56 5.23 <4.19 <4.19 <4.19 557. n.d. n.d. n..d n.d. 102 4.59 6.34 6.84 <4.19 5.05 <4.19 6.01 <4.19 5.18 <419- 103 <4.19 <4.19 4.49 <4.19 <4.19 <419 <419 nd n.d nd n.d. 104 <4.19 <4.19 5.91 <4.19 5.54 <419“ nd n.d. 105 5.70 6.67 6.87 4.91 5.76 5.30 691 --<419 4.23 106 4.90 5.79 6.18 5.09 5.05 5.26 5.51 n.d. n.d. 107 5.16 6.31 5.92 4.87 5.06 5.53 5.44 4.90 5.48 <4.19 108 <4.49 4.98 5.99 <4.49 <4.49 <4.49 5.43 n.d. n.d. 109-<4.19 5.70 <4.19 <4.19 4.34 .. .. 110 4.44 5.30 5.96 4.58 5.50 5.09 5.60 4.77 -<4.49 <4.49 111 4.41 5.69 6.09 <4.19 5.76 5.74 5.31 577 <419 453 112 <4.19 5.18 4.19 <4.19 5.07 <4.19 n..d 113 <4.19 <4.19 5.86 <4.19 <4.19 <4.19 <4.19 n.d 11d 114 <4.19 <4.19 5.75 <4.19L<4.19 <4.19 <4.19 n.d. \ n.d. 115 5.70 7.02 7.47 4.25 6.82 5.70 7.28 <419 5.98 1167.39 7.52 4.70 6.26 5.65 J_6.83 622 117 5.74 6.52 7.07 <4.19—598— 5.77 6.43 118 5.70 7.39 7.01 5.70 7.38 5.30 7.07 <4.19-_— 119 6.00 6.54 6.87 5.61 6.30 6.40 6.62 <4.19 120 4.86 6.16 6.31 <4.19 5.99 5.52 121 6.11 122 5.42 m 6.86 <4.19 5.38 4.69 123 5.04 6.75 6.96 <4.19 124 5.10 5.63 6.22 <4.19 6.25 6.32 125 4.91 5.85 5.72 <4.19 5.70 5.69 WO 50305 Inf. A Inf. B Inf. C Inf. D Inf. E Inf. F Inf. G Inf.H- Inf. J Inf. K D1206. <4 49 6.29 4.49 <449 <4.19 6.94 <4.19 6.31 <4.19 <4.19 <4.19 6.02 7.10 <4. 19 <4.19 129 <4.19 <4.19 n.d. 130 5.50 6.70 4.91 13 1 5.51 4.59 132 <4.49 4.59 n.d. l_133 <4. 19 <4. 19 <4.19 <4.19 <4.19 5.83 <4.19 n.d. 4.50 6.68 <4. 19 <4.19 4.41 n.d. <4.19 4.41 n.d. .52 6.81 4.50 6.99 <4.19 4.46 6.23 6.44 7.50 4.34 5.35 636 <4.19 4.68 6.88 6.86 <4.19 <4.19 <4.19 7.64 <449 <449 <4 49 4.4 4.4. 4-4.815.69 6.49 >8.41 4.57 5.62 9.94 4.44 145 5.11 <4.19 <4.19 <4.19 <4.49-“— 146 <4.19 5.76 6.19 <4.19 <4.19 <4.19 5.44 <4 49 147 <4.19 5.66 5.35 <4.19 <4. 19 19<4. <4.19 -- 148 <4.19 5.82 5.04 <4.19 <4 19_1_<4. 19 4.19 nd 44 149 <4.19 5.35 6.10 124.19 5.47 4. 81 5.61 <449 150 5.52 6.14 8.25 4.68 6.00 4.57 6.15 <4.19 5.93 <4.19 <4.19 151 <4.19 <4.19 4.95 <4.19 <4.19 <4.19 <4.19 n.d. n.d. n.d. n.d. 152 5.11 6.34 6.85 5.59 6.26 5.82 6.46 4.28 5.15 <4.19 153 <4.19 <4.19 <4.19 5.00 <4.19 5.16 <4.19 n.d. 4.4 154 <4.19 <4.19 <4.19 <4.19 <4.19 <4.19 <4.19 n.d. 4.4. 155 5.66 6.82 7.15 4.94 5.88 5.81 6.82 n.d. n.d. n..d n.d 156 <4.19 <4.19 <4.19 <4.19 4.48 4.51 4.49 n.d n.d. n.d n..d 157 <4.49 5.79 6.58 4.61 <4.49 <4.49 s94 44 158 5.72 <4.19 <4.19 _—mil— <449 159 <4.49 6.41 6.46 <4.49 <4.49 <4.49 <449 4.4. 160 <4.49 5.03 5.84 <4.49 5.85 5.61 5.48 n.d. 161 5.02 5.96 6.12 <4.19 5.04 4.56 6.47 6.27 <4.19 162 4.22 5.61 <4.19 4.36 4.49 n.d. 4.4 WO 50305 Inf. A Inf. B 163 5.59 5.12 164 5-40 5.85 6.29 5.66 6.44 <4.19 5.15 165 5.12 _<4.19 5.28 5.81 5.86 <4.19 4.46 <4.19 166 5.52 _<4.19 6.00 6.00 5.52 4.33 5.65 5.37 <4.19 67 4.90 5.38 5.86 5.97 5.72 6.31 <4.19 5.10 168 6.22 4.96 6.18 <4.19 6.73 6.41 6.40 <4.19 6.48 <4.19 <4.19 169 <4.19 5.00 6.01 «@2419 <4.19 <4.19 n.d. n.d. n.d. n.d. 170 5.55 6.23 6.63 <4.19 5.74 6.47 6.18 5.63 6.51 <4.19 <4.19 171 <4.19 <4.19 5.73 <4.19 <4.19 6.50 <4. 19 n.d. n.d. n.d. n.d. 172 5.59 6.90 7.35 5.80 6.29 5.85 6.81 5.15 5.45 4.72 173 5.70 6.54 6.41 5.71—1—630 6.41 6.51 5.08 5.08 174 6.06 6.54 6.87 <4.19 6.30 6.43 6.80 <4.19 4.80 <4.19 <4.19 175 5.70 6.90 7.36W17 6.85 6.41 7.11 5.08 5.56 5.07 5.14 176 5.70 6.89 6.90 6.03 6.49 6.49 6.57 5.54 6.15 <4.19 <4. 19 177 <4.19 <4.19 <4.19 <4.19 <4.19 5.73 <4.19 n.d. n.d. n.d. n.d. 178 <4.19 4.37 <4.19 5.93 6.49 4.26 n.d. n.d. n.d. 179 4.41 4.80 5.03 <4.19 4.49 4.67 4.69 n.d. n.d. 180 <4.19 4.40 6.03 <4.19 <4.19 <4.19 4.39 n.d. n.d. 181 5.69 5.94 <4.19 <4.19 <4.19 4.98 n.d. n.d. n.d. n.d. 182 <4.49 5.52 6.70 4.58 4.94 5.87 n.d. n.d. n.d. n.d. 183 4.77 5.85 6.68 5.31 5.26 4.49 5.99 <4.49 4.96 <4.49 <4.49 184 <4.19 7.32 <4.19 6.27 <4.19 6.51 6.15 <4.19 <4. 19 .28 6.39 6.73 423—1629 6.33 6.04 5.16 <4.19 <4.19 186 5.15 5.95 6.34 <4.19 5.63 5.69 6.06 5.40 <4.19 4.35 187 5.09 5.68 6.77 4.50 5.98 5.46 6.92 4 19 <4.19 188 6.20 6.64 4.90 5.56 6.24 <4.19 4.42 -<4.19 5.29 6.05 <4.19 5.02 n.d. n.d. n.d. 190 <4.19 5.56 6.14 <4.19 n.d n.d. n.d. n.d. 191 4.75 5.69 6.18 <4.19 <4.19 192 <4.19 <4.19 4.29 <4.19 . . n.d. 193 <4.19 <4.19 <4.19 <4.19 194 <4.19 <4.19 6.82 n.d. 195 6.34 <4.19 <4.19 <4.19 196 5.00 6.36 6.77 5.25 5.84 L9]. 5.00 6.00 6.00 4.00 198 <4 4.00 199 <4 4.50 5.00 <4 5.00 <4 <4 <4 W0 2012/150305 IKE! -467— n.d. means not determined E. Composition e e ingredient” as used throughout these examples, relates to a compound of Formula (1), including any stereochemically isomeric form thereof, a pharmaceutically able salt thereof or a solvate thereof; in particular to any one of the exempliﬁed compounds. e El : Injectable on. 1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams sodium hydroxide are dissolved in about 0.5 1 ofboiling water for injection. After g to about 50°C there are added while stirring 0.05 grams propylene glycol and 4 grams of the active ingredient. The solution is cooled to room temperature and supplemented with water for injection q.s. ad 1 1, giving a solution comprising 4 mg/ml of active ingredient. The solution is sterilized by ﬁltration and ﬁlled in sterile containers.

Example E2 : Transungal composition. 0.144 g KHZPO4, 9 g NaCl, 0.528 g NagHPO4.2H20 is added to 800 ml H20 and the mixture is stirred. The pH is adjusted to 7.4 with NaOH and 500 mg NaN3 is added.

Ethanol (42 V/V %) is added and the pH is adjusted to 2.3 with HCl. mg active ingredient is added to 2.25 ml PBS (Phosphate Buffer Saline)/Ethanol (42 %; pH 2.3) and the mixture is d and treated with ultrasound. 0.25 ml PBS/Ethanol (42 %; pH 2.3) is added and the mixture is further stirred and treated with ultrasound until all active ingredient is ved, yielding the desired transungual composition.

Example E3 : Oral drops 500 Grams of the Al. is dissolved in 0.5 l of a sodium hydroxide solution and 1.5 l of the polyethylene glycol at 60~80 °C. After cooling to 30~40°C there are added 35 1 ethylene glycol and the mixture is stirred well. Then there is added a solution of 1750 grams of sodium saccharin in 2.5 1 ofpurified water and while stirring there are added 2.5 l of cocoa ﬂavor and polyethylene glycol q.s. to a volume of 50 1, providing an oral drop solution comprising 10 mg/ml of A.I.. The resulting solution is W0 2012/150305 ﬁlled into suitable containers.

Example E4 : Capsules Grams ofthe Al, 6 grams sodium lauryl sulfate, 56 grams , 56 grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 grams magnesium stearate are vigorously stirred together. The resulting mixture is subsequently ﬁlled into 1000 suitable ed gelatin es, comprising each 20 mg of the active ingredient.

Example E5 : Film-coated tablets Brsparatiqnnitabletcore A mixture of 100 grams ofthe AL, 570 grams lactose and 200 grams starch is mixed well and thereafter ﬁed with a solution of 5 grams sodium dodecyl sulfate and grams polyvinylpyrrolidone in about 200 ml r. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 grams microcrystalline cellulose and 15 grams hydrogenated ble oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ient.

Coating To a solution of 10 grams methyl cellulose in 75 m1 of denaturated ethanol there is added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 grams of magnesium octadecanoate, 5 grams ofpolyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole is nated. The tablet cores are coated with the thus obtained mixture in a coating apparatus.

Example E6 : 2 % Cream Stearyl alcohol (75 mg), cetyl alcohol (20 mg), sorbitan earate (20 mg) and isopropyl myristate (10 mg) are introduced in a doublewall jacketed vessel and heated until the mixture has completely molten. This mixture is added to a seperately prepared mixture ofpuriﬁed water, ene glycol (200 mg) and polysorbate 60 (15 mg) having a temperature of 70 to 75 °C while using a homogenizer for liquids. The resulting mixture is allowed to cool to below 25°C while continuously . A solution ofA.I.(20 mg), polysorbate 80 (1 mg) and puriﬁed water (1.5. ad 1g and a solution of sodium sulﬁte anhydrous (2 mg) in puriﬁed water are next added to the emulsion while continuously mixing. The cream is homogenized and ﬁlled into suitable tubes.

W0 2012/‘150305 Example E7 : 2 % Cream A mixture of Al. (2 g), atidyl e (20 g), cholesterol (5 g) and ethyl alcohol (10 g) is stirred and heated at 55-60 °C until complete solution and is added to a solution of methyl paraben(0.2 g), propyl paraben (0.02 g), disodium edetate (0.15 g) and sodium chloride (0.3 g) in puriﬁed water (ad 100 g) while homogenizing.

Hydroxypropylmethylcellulose (1.5 g) in puriﬁed water is added and the mixing is continued until swelling is complete.

W0 2012/150305 2012/058142

Claims

Claims 1.

1. A compound of formula (I) R4 \ N Het m (I) / R2 5 or a stereoisomeric form thereof, wherein, R1 is hydrogen, halo, CMalkyl or CMalkyloxy; R2 is hydrogen, halo, CMalkyl or CMalkyloxy; R3 and R4 are hydrogen; or R3 and R4 taken together form a bond; 10 Het is a monocyclic or bicyclic heterocyclic radical selected from