OA16408A

OA16408A - Antifungal 5,6-dihydro-4H-pyrrolo[1,2-A][1,4]benzodiazepines and 6H-pyrrolo[1,2-A][1,2-A][1,4] benzodiazepines substituted with phenyl derivatives.

Info

Publication number: OA16408A
Application number: OA1201300194
Authority: OA
Inventors: Lieven Meerpoel; Louis Jules Roger Marie Maes; Kelly De Wit
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2010-11-24
Filing date: 2011-11-18
Publication date: 2015-10-07

Abstract

The present invention is concerned with novel antifungal 5,6-dihydro-4H-pyrrolo-[1,2a][1,4]benzodiazepines and 6H-pyrrolo[1,2a][1,4]benzodiazepines of Formula (I)

Description

The présent invention is concemed witli novel antifungal 5,6-dihydro-4/7-pyrrolo[l,2-a][l,4]benzodiazepines and 6//-pyrrolo[1,2-<7][l,4]benzodiazepines, both substituted with benzene dérivatives, active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel 10 compounds, pharmaceutical compositions comprising said compounds as an active ingrédient as well as the use of said compounds as a médicament.

Background of the invention

Dermatophyte is a common label for a group of 3 types of fungi that commonly causes skin disease in animais and humans. These anamorphic (asexual or imperfect fungi) 15 généra are: Microsporum, Epidermophyton and Trichophyton. There are about 40 species in these 3 généra.

Dermatophytes cause infections of the skin, haïr and nails due to their ability to obtain nutrients from keratinized material. The organisms colonize the keratin tissues and inflammation is caused by host response to metabolic by-products. They are usually 20 restricted to the comified layer of the epidermis because of their inability to penetrate viable tissue of an immunocompétent host. However, occasionally the organisms do invade subcutaneous tissues, resulting in kerion development. Invasion does elicit a host response ranging from mild to severe. Acid protéinases, elastase, keratinases, and other protéinases reportedly act as virulence 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 modem hospitaîs keeps increasing, and the number of different fungi that hâve been involved in SFI is large and still growing. Despite many cases of invasive candidiasis and aspergillosis there has been an 30 increased incidence of infections due to other molds like Scedosporium apiospermum, Fnsarium spp., and Zygomycetes, Rhizoptis and Mucor spp.. Effective therapeutic agents treating ail these infections very well therefore need to hâve very broad spectrum of activity. In the past few décades itraconazole, fluconazole, kétoconazole, and intravenous or liposomal amphotericin B hâve been used in SFI, and ail of these agents hâve their limitations with regard to spectrum, safety or ease of administration.

More recently a third génération of azoles hâve been investigated and introduced to the market, improving the treatment options in intensive care units. Voriconazole (Vfend™) and posaconazole (Noxafïl™) show much improvement of treatment towards life threatening invasive SFI such as candidiasis, aspergillosis, and infections due to Fnsarinm species at clinical relevant dosages. Moreover posaconazole shows efficacy against infections caused by the emerging Zygomycetes spp. Echinocandins, such as anidulafungin, caspofungin, and micafungin, which arenon-competitive inhibitors of 1,3-P-glucan synthesis in fungal cell walls, display high efficacy against Candida spp. and Aspergilhts spp., but no activity against Cryptococctts, Fnsaiïutn, or

Zygomycetes spp.. Of ali antimycotic agents, azoles still represent a unique class of compounds displaying the broadest antifungal spectrum via inhibition of 14-ademethylase, an enzyme being essential for ergosterol biosynthesis in fungi.

Onychomycosis is the most common disease of the nails and constitutes about a half of ali nail abnormalities. The prevalence of onychomycosis is about 6-8 % in the adult population. The causative pathogens of onychomycosis include dermatophytes, Candida, and non-dermatophytic moulds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries, meanwhile, Candida and non-dermatophytic moulds are more frequently involved in the tropics and subtropics.'7>7c^o/jAy/o/ï rnbrum is the most common dermathophyte involved in onychomycosis. Other dermatophytes that may be involved are Trichophyton interdigitale, Epidermophyton floccosttm, Trichophyton violaceitm, Microsporum gypsenm, Trichophyton tonsurans, Trichophyton sondanense and Trichophyton verrucosum. Other causative pathogens include Candida and non-dermatophytic moulds, in particular members of the mould génération Scytalidium (also

Neoscytalidium), Scopulariopsis, and Aspergilhts.

5,6-Dihydro-4//-pynOlo[l,2-a][l,4]benzodiazcpincs hâve been described in J. Chem. Soc.(C), 2732-2734 (1971); J. Hetcrocyclic Client., 711-716 (1976); and J. Hctcrocyclic Chem., 16. 241-244 (1979), The compounds disclosed in these référencés ail hâve a different substitution on the phenyl moiety in the 4-position and moreover no biological activities were reported in any of thèse références.

WO02/34752 describes 4-substitutcd 5,6-dihydro-4//-pyrrolo[l,2-a][l ,4]bcnzodiazepines as a new class of antifungal compounds. However, WO02/34752 docs not disclose the présent substitution pattern on the phenyl moiety in the 4-position.

The PhD thesis of De Wit K. describes the implémentation of an in vitro and in vivo mycological évaluation platform and activity profiling of antifungal

pyrrolobenzodiazepines (PhD Thesis; University of Antwerp, Belgium; Faculty of Pharmaceutical, Biomédical and Veterinary Sciences; Department of Biomédical Sciences; 2011; 220 p.)

The antifungal compounds of the présent invention or part of the compounds ofthe présent invention are structurally different and may bave improved metabolic stability properties, improved PK (pharmacokinetic) properties, împroved plasma binding, reduced hERG channel inhibition, reduced cytochrome P450 liabilities, or improved bioavailability compared with compounds disclosed in the prior art. Preferably satd compounds hâve a broad antifungal spectrum, and maintain adequately hight thereapeutic efficacy and adequately low toxicity or other side effects.

It is accordîngly an object ofthe présent 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 useful alternative compounds

Summary of the invention

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

The présent invention concems novel compounds of Formula (I):

and stereoisomeric forms thereof, wherein

R¹ is hydrogen, halo, Ci-^alkyI or Ci^alkyloxy;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Ci-ialkylcarbonyl, CMalkylsulphonyl, C^alkylsulphinyl, or C|_ialkyl substituted 25 with one hydroxyl moiety;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

The présent invention also concems methods for the préparation of compounds of

Formula (I) and pharmaceutical compositions comprising them.

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

The novel compounds described in the présent invention may be useful in the treatment or prévention of infections caused by dermatophytes, systemic fungal infections and onychomycosis.

The novel compounds described in the présent invention may be active against a wide variety of fungi, such as Candida spp., e,g. Candida athicans, Candidaglabrata, Candida kruceï, Candida parapsi/osis, Candida kefyr, Candida tropicalis; Aspergillus spp, e.g. Aspergillusftunigatns, Aspergillus niger, Aspergillus flavtis; Cryptococcus neoformans; Sporothrix schenckii; Epidermophytonfloccosum; Microsporum spp., e.g. Microsporum canis, Microsporumgypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton cptinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanense; Fusarlum spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium prolifération, Fusarium verticiHioides·, Rhizomucor spp., e.g. Rhizomucor tniehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporiumprolificans; Trichoderma spp.; Pénicillium spp. ; Pénicillium marneffei; Blastoschizomyces.

In view of the aforementioned pharmacology of the présent compounds, it follows that 20 they are suitable for use as a médicament.

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

One advantage of the compounds or a part of the compounds of the présent invention 25 may lie in their enhanced bioavailability, improved metabolic stability properties, improved PK properties, reduced hERG channel inhibition, or reduced cytochrome P450 liabilities compared with the compounds disclosed in the prior art.

The présent invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined 30 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

When describing the compounds of the invention, the tenus used are to be construed in accordance with the following définitions, unless a context dictâtes otlierwise.

The term “halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, 5 bromo, iodo unless otlierwise is indicated or is clear from the context.

The term Ci-talkyl as a group or part of a group refers to a hydrocarbyl radical of Formula C_uH2_tH.| wherein n is a number ranging from 1 to 4 Ci^alkyI 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 following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for exaniple, Ci-talkyl includes ail linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, H-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. u-butyl, Âwbutyl and fô/7-butyl), and the like.

The term “Ci_ialkyloxy” as a group or part of a group refers to a radical having the Formula -0R^a wherein R^a is Cwalkyl. Non-limiting examples of suitable Ci-talkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and ze/7-butyloxy.

The term Cijalkyl sulfonyl refers to a straiglit chain or branched chain alkylsulfonyl group having from 1 to 4 carbon atoms, such as inethylsulfonyl, ethyl sulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.

The term Ci-jalkylcarbonyl refers to a straight chain or branched chain alkylcarbonyl 25 group having from 1 to 5 carbon atoms, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl and the like.

The chemical names of the compounds of the présent invention were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service, using Advanced Chemical Development, Inc., nomenclature software (ACD/Name product version 10.01; Build 15494, 1 Dec 2006).

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

The atoms in the tricyclic System are numbered as shown in the following formula (Q):

°(

N 5 (Q)

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

As used in the description, whenever the term “compound(s) of formula (1)” is used, it is meant to include the stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof.

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

The term “stereoisomeric forms” as used hereinbefore defines ail the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical désignation of compounds dénotés the mixture of ail possible stereochemically isomeric forms.

The définition of “compound of formula (1)” inherently includes ail stereoisomers of the compound of formula (I) either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers diat are not enantiomers, i.e. they are not related as mirror images. More in particular, stereogenic centers may hâve the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may hâve either the cis- or trans-configuration. Compounds encompassing double bonds can hâve an E or Z-stereochemistry at said double bond. Stereoisomeric forms of the compounds of Formula (I) are cmbraccd within the scope ofthis invention. Thereforc, the invention includes enantiomers, diastereomers, racematcs, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

The absolute configuration is specified according to the Cahn-Ingold-Prelog System. The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarîzed light.

When a spécifie stereoisomeric form is indicated, this means that said form 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 %, further preferably less than 2 % and most preferably less than 1 % of the other isomer(s). Thus, when a compound of the présent invention is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of the présent invention is for instance specified as E, this means that the compound ts substantially free of the Z isomer; when a compound of the présent invention is for instance specified as cis, this means that the compound is substantially free of the trans isomer

Some ofthe compounds of 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 présent invention.

The compounds of formula (I) hâve been drawn herein in a single tautomeric form, the different tautomers are équivalent to each other and ail possible tautomeric forms are included within the scope of the invention

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 préparation or purification of a pharmaceutically acceptable compound. AH salts, whether pharmaceutically acceptable or not are included within the ambit of the présent invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxïc acid and base addition sait 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 example, 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, tartane, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids. Conversely said sait forms can be converted by treatment with an appropriate base into the free base form.

The compounds of Formula (I) containing an acidic proton may also be converted into their non-toxic métal or amine addition sait forms by treatment with appropriate

-8organic and inorganic bases. Appropriate base sait forms comprise, for example, the ammonium salts, the alkali and earth alkaline métal salts, e.g. the lithium, sodium, potassium, magnésium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylaniine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, dî-/;-buty lamine, pyrrolidine, piperidine, morpholine, trimethylamine, tri ethyl ami ne, tripropylamïne, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, /V-methyl-D-glucamîne, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the sait form can be converted by treatment with acid into the free acid form.

The terni solvaté comprises the hydrates 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 synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. A manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure 20 stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a spécifie stereoisomer is desired, said compound would be synthesized by stéréo spécifie methods of préparation. These methods will advantageously employ enantiomerically pure starting materials.

In the framework of this application, a compound according to the invention is inherently intended to comprise ail isotopic combinations of its chemical éléments. In the framework of this application, a chemical element, in particular when mentîoned in relation to a compound according to Formula (1), comprises ail isotopes and isotopic mixtures of this element. For example, when hydrogen is mentîoned, it is understood to refer to ’H, ²H, ’H 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, including a radioactive compound, also called radiolabelled compound, wherein one or more nonradioactive atoms has been replaced by one of its radioactive isotopes. By the term radiolabelled compound is meant any compound according to Formula (I), or a

-9pharmaceutically acceptable sait thereof, which contains at least one radioactive atom. For example, a compound can be labelled with positron or with gamma emitting radioactive isotopes. For radioligand-bindïng techniques, the ³H-atom or the ^l2SI-atom is the atom of clioice to be replaced. For tmaging, the most commonly used positron emitting (PET) radioactive isotopes are ^l'C, ^l8F, ^lsO and ¹³N, ail of which are accelerator produced and hâve half-lives of 20, 100, 2 and 10 minutes respectively. Since the half-lives of these radioactive isotopes are so short, it is only feasible to use them at institutions which hâve an accelerator on site for their production, thus lîmiting their use. The most widely used of these are ^1KF, ⁹⁹ⁱⁿTc, ²⁰¹TI and ^l23l. The handling of these radioactive isotopes, their production, isolation and incorporation in a molécule 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 selected

As used in the spécification and the appended daims, the singular forms a, an, and the also include plural referents unless the context clearly dictâtes otherwise. By way of example, a compound means one compound or more than one compound.

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

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

The présent invention concems novel compounds of Formula (1):

(D

R^B R³ and stereoisomeric forms thereof, wherein

R¹ is hydrogen, halo, CMalkyl or Ci^alkyloxy;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen, or R³ and R⁴ taken together form a bond;

R⁵ is C|_.alkylcarbonyl, CMalkylsulphonyl, Ci-jalkylsuiphinyl, or Ci_ialkvI substîtuted with one hydroxyl moiety;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

-lOIn an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein

R¹ is hydrogen, halo, Ci-ialkyl or Ci^alkyloxy;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Ci-ialkylcarbonyl, C)_ialkylsulphonyl, orC^alkyl substituted with one hydroxyl moiety;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

Γη an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein

R* is hydrogen, halo, C]_^alkyl or Ci_;alkyloxy; in particular R¹ is halo;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Cualkylcarbonyl or C|.;a1ky1sulphonyl; in particular Cwalkylcarbonyl;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein

R¹ is hydrogen, halo, CMalkyl or Ci^alkyloxy; in particular R¹ is halo;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Cualkylcarbonyl, or Cnalkyl substituted with one hydroxyl moiety;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof

R¹ is hydrogen, halo, Ci^alkyl or Cwalkyloxy, in particular R¹ is halo;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

R⁵ is Ci-jalkylcarbonyl, Ci-ialkylsulphinyl, Cualkylsulphonyl, or CMalkyl substituted with one hydroxyl moiety; in particular R⁵ is Cmalkylcarbonyl, Cualkylsulphonyl, or

-l lCnalkyl substituted with one hydroxyl moiety; more in particular R^s is Ci_ialkylcarbonyl;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

R¹ is hydrogen, halo, Ci-talkyl or Ci-ialkyloxy; in particular R¹ is halo;

R² is hydrogen or halo;

R³ and R⁴ taken together form a bond;

R^s is Ci-ialkylcarbonyl, Ci_;alkylsulphinyl, Ci_;alkylsulphonyl, or C₁._lalkyl substituted with one hydroxyl moiety; in particular R⁵ is Cualkylcarbonyl, Cmalkylsulphonyl, or Ci_;alkyl substituted with one hydroxyl moiety; more in particular R⁵ is Ci-talkylcarbonyl;

R⁶ is hydrogen or halo; in particular R⁶ is hydrogen;

and the pharmaceutically acceptable addition salts, and the solvatés thereof

R¹ ishalo;

R² is hydrogen or halo;

R³ and R⁴ taken together form a bond;

R⁵ isCMalkylcarbonyl, Ci-talkylsulphonyl, orCmalkyl substituted with one hydroxyl moiety; in particular R⁵ is Ci_ialkylcarbonyl or Cmalkylsulphonyl;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof.

R¹ is halo;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Ci_ialkylcarbonyl, Ci_ialkylsulphinyl, Ci^alkylsulphonyl, orCi_;alkyl substituted with one hydroxyl moiety; in particular R⁵ is Cualkylcarbonyl, Cualkylsulphonyi, or Cmalkyl substituted with one hydroxyl moiety;

R⁶ is hydrogen or halo, and the pharmaceutically acceptable addition salts, and the solvatés thereof.

-12In an embodiment, the invention relates to compounds of Formula (I) and stereoisomeric forms thereof, wherein

R* is halo;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Ci.jalkylcarbonyl;

R⁶ is hydrogen or halo;

and the pharmaceutically acceptable addition salts, and the solvatés thereof

R¹ is halo; in particular chloro or fluoro; more in particular chloro;

Λ

R is hydrogen or halo; in particular hydrogen, chloro of fluoro;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R^s is C]_ia1kylcarbonyl, C_t_ialkylsulphonyl, or Ci.ialkyl substituted with one hydroxyl moiety; in particular methylcarbonyl, methylsulphonyl or 1-hydroxyethyl;

R⁶ is hydrogen or halo; in particular hydrogen or fluoro; more in particular hydrogen; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

An embodiment of the présent invention relates to those compounds of formula (1) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R¹ is halo, Cwalkyl or Cwalkyloxy; and wherein R² is halo; in particularwherein R¹ and R² both are halo.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein at least one of R¹ and R² is other than hydrogen.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R¹ is halo.

An embodiment of the présent invention relates to those compounds of formula (1) or any subgroup thereof as mentioned in any of the other embodiments wherein R² is halo.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R³ and R⁴taken together form a bond.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R⁵ is Ci^alkyicarbonyl; Ci^alkylsulphonyl; or Cj^alkyl substituted with one hydroxyl moiety.

An embodiment of the présent invention reiates to those compounds of formula (I) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R⁵ is Cualkylcarbonyl; in particular methylcarbonyl.

An embodiment ofthe présent invention relates to those compounds offormula (I) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R⁵ is IO Ci-ialkylsulphonyl.

An embodiment ofthe présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R⁵ is methylcarbonyl, methylsulphonyl or l-hydroxyethyl;

An embodiment of the présent invention relates to those compounds of formula (T) or any subgroup thereof as mentioned in any of the other embodiments wherein R⁶ is halo.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R⁶ is hydrogen.

An interesting group of compounds concems novel compounds of Formula (I), having 20 one or more of the Formulae selected from (I-x) and (I-y) and stereoisomeric forms thereof

(i-x) (i-y) wherein ail the substituents hâve the same meaning as defined in any of the embodiments hereinbefore, and the pharmaceutically acceptable addition salts and the solvatés thereof.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof, having Formula (I-x).

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof, having Formula (I-y).

-14In an embodiment, the invention relates to compounds of Formula (I-x) and (I-y) and stereoisomeric forms thereof, wherein

R¹ is halo; in particular chloro or fluoro; more in particular chloro;

R² is hydrogen or halo; in particular hydrogen, chloro of fluoro;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Ci-ιalkylcarbonyl, C|„ialkylsulphonyl, Ci-ialkylsulphinyl, or Ci-talkyl substituted with one hydroxyl moiety; in particular R⁵ is C'i^alkylcarbonyl, Ci-ialkylsulphonyl, or Ci_ialkyI substituted with one hydroxyl moiety; more in particular methylcarbonyl, methylsulphonyl or 1-hydroxyethyl,

In an embodiment, the invention relates to compounds of Formula (T-x) and stereoisomeric forms thereof, wherein

R¹ is halo; in particular chloro or fluoro; more in particular chloro;

R² is hydrogen or halo; in particular hydrogen, chloro of fluoro;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Cj-ialkylcarbonyl, Ci-ialkylsulphonyl, Cijalkylsulphinyl, orÜMalkyl substituted with one hydroxyl moiety; in particular R⁵ is Ci_»alkylcarbonyl, Ci_ialkylsulphony), or C]-ialkyl substituted with one hydroxyl moiety; more in particular methylcarbonyl, methylsulphonyl or 1-hydroxyethyl;

R^fi is hydrogen or halo; in particular hydrogen or fluoro; more in particular hydrogen; and the pharmaceutically acceptable addition salts, and the solvatés thereof.

In an embodiment, the invention relates to compounds of Formula (I-y) and stereoisomeric forms thereof, wherein

R¹ is halo; in particular chloro or fluoro; more in particular chloro,

R² is hydrogen or halo; in particular hydrogen, chloro of fluoro;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R^s is Ci-ialkylcarbonyl, Ci-talkylsulphonyl, Cualkylsulphinyl, or Cualkyl substituted with one hydroxyl moiety; in particular R⁵ is Cualkylcarbonyl, Cualkylsulphonyl, or Ci-talky 1 substituted with one hydroxyl moiety, more in particular methylcarbonyl, methylsulphonyl or 1-hydroxyethyl;

R⁶ is hydrogen or halo, in particular hydrogen or fluoro, more in particular hydrogen, and the pharmaceutically acceptable addition salts, and the solvatés thereof.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R³ and R⁴are always taken together form a bond.

In a next embodiment the compound of Formula (I) is selected from the group consisting of:

l-[4-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodi azepi n-4-yl)phenyl]ethanone HCI, l-[4-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)phenyl]ethanone HBr, l-(4-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodi azepi n-4-yl)phenyl]ethanone, l -[4-(7-chloro-6H-py rrolof l ,2-a] [ l ,4]benzodi azepi n-4-yl )phenyl ]-ethanone, l -(4-(7,8-dichloro-5,6-dihydro-4H-pyrrolo( 1,2-a][l ,4]benzodi azepi n-4-yl)phenyl]ethanone HCl, l -(4-(7,8-dichloro-5,6-dihydro-4H-pyrrolo[ 1,2-a] [l ,4]benzodi azepi n-4-yl)phenyl]ethanone, l -(4-(8, l O-dichl oro-5,6-dîhydro-4H-pyrrolo[ l ,2-a] [ l ,4]benzodiazepi n-4-y I )phenyl ]ethanone .HCl,

1-(4-(8,1 O-dichl oro-5,6-dihydro-4H-pyrrolo[ 1,2-a][ 1,4]benzodiazepin-4-yl)phenyl]ethanone,

1-(4-(8,1 O-dichl oro-6H-pyrrolo[ 1,2-a] f 1,4]benzodiazepin-4-yl)phenyl]-ethanone, 4-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-alpha-methylbenzenemethanol,

1-(4-(7,8-dichloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)phenyl]-ethanone, 1-(4-(7,8-dichloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)phenyl]-ethanone HCI,

4-(7,8-dichloro-5,6-dihydro-4H-pyrrolo( 1,2-a][ 1,4]benzodîazepin-4-yl)-alphamethyl-benzenemethanol .HCl,

4-(7,8-dichloro-5,6-dihydro-4H-pyrrolo(l,2-a][l,4]benzodiazepin-4-yl)-alphamethyl-benzenemethanol,

4-(8,10-dichloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-alphamethyl-benzenemethanol .HCl,

4-(8,10-dichloro-5,6-dihydro-4H-pyrrolo[l,2-a](l,4]benzodiazepin-4-yI)-alphamethyl-benzenemethanol,

-[3-(7-chloro-5,6-dihydro-4H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepi n-4-y l)phenyl]ethanone,

1-(4-(7,9-dichloro-5₎6-dihydro-4H-pyrrolo[l,2-a](l,4]benzodiazepin-4-yl)phenyl]ethanone HCl,

-(4-(7,9-dichloro-5,6-dihydro-4H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepin-4-yl)pbenyl]ethanone,

1-(3-(7,9-dichloro-5,6-dibydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)pbenyl]ethanone HCl,

-(3-(7,9-dichloro-5,6-dihydro-4H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepin-4-yl)phenyl]ethanorte,

-(4-(7,9-dichloro-6H-pyrrol o( 1,2-a] [ 1,4]benzodi azepi n-4-y I )phenyl ]-ethanone, l-[3-(7-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)phenyl]-ethanone, • -(4-(7,10-dichloro-6H-pyrrol o[ 1,2-a] [ 1,4]benzodi azepi n-4-y I )phenyl ]-ethanone, 7-chloro-4-[3-(methylsulfonyl)phenyl 6H-pyrrolo[l,2-a](l,4]benzodiazepine,]-

7.9- dichloro-4-[3-(methylsulfonyi)phenyl]-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-fluoro-4-[4-(metliylsuifonyl)phenyl]-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-[4-(methylsulfonyl)phenyl]-6H-pyrrolo(l,2-a][l,4]benzodiazepine,

I -(5-(7,9-dichloro-5,6-dihydro-4H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepin-4-yl)-2fluorophenyl]-ethanone,

7.9- dichloro-4-[4-(methylsulfonyl)phenyl]-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

-(4-(9-chloro-5,6-dihydro-4H-pyrrolo[ 1,2-a] ( 1,4]benzodiazepi n-4-yl )phenyl]ethanone, l-[5-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a](l,4]benzodiazepin-4-yl)-2fluorophenyl]-ethanone .HCl,

-[5-(7-chloro-5,6-dihydro-4H-pyrrol o( 1,2-a] [ 1,4]benzodiazepin-4-yl)-2fluorophenyl]-ethanone,

1-(5-(7,9-dichloro-6H-pyrrolo(l,2-a][l,4]benzodiazepin-4-yl)-2-fluorophenyl]ethanone,

1-(4-( 10-chloro-6H-pyrrolo[ 1,2-a][ 1,4]benzodiazepin-4-yl)phenyl]-ethanone, l-[5-(7-chtoro-6H-pyrrolo[l,2-a](l,4]benzodiazepin-4-yl)-2-fluorophenyl]etlianone, l-[4-(9-chloro-6H-pyrrolo[l,2-a](l,4]benzodiazepin-4-yl)phenyl]-ethanone,

1-(4-(7,9-difluoro-6H-pyrrolo[l,2-a](l,4]benzodiazepin-4-yl)phenyl]-ethanone,

- [4-( 7-fl uoro-6H-py rrol o[ 1,2-a] [ 1,4]benzodiazepi n-4-y 1 )phenyl ]-ethanone,

4-(7,9-dichloro-5,6-dihydro-4/7-pyrrolo[I,2-a][l,4]benzodiazepin-4-yl)benzeneethanol HCI,

4-(7,9-dichloro-5,6-dihydro-4//-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)benzeneethanol,

4-(7-chloro-5,6-dihydro-4//-pyrrolo[l,2-i»][l,4]benzodiazepin-4-yl)-benzeneethanol

HCl,

4-(7-chloro-5,6-dihydro-4//-pyrrolo[ l ,2-α][ l ,4]benzodiazepin-4-yl)-benzeneethanol,

4-(8,10-dichloro-5,6-dihydro-47/-pyrro1 o[ 1,2-or] [ 1,4]benzodiazepin-4-yl)benzeneethanol HCI,

4-(8,10-dichloro-5,6-dihydro-4//-pyrrol o[ 1,2-a][ 1,4]benzodiazepin-4-yl)benzeneethanol,

4-(7,8-dichloro-5,6-dihydro-4/7-pyrrol o[ 1,2-α][ 1,4]benzodiazepin-4-yl)benzeneethanol HCl,

4-(7,8-dichloro-5,6-dihydro-4//-pyrrolo[1,2-a][l,4]benzodiazepin-4-yl)benzeneethanol,

4-(7,10-dichloro-5,6-dihydro-4//-pyrrol o[ 1,2-a][ 1,4]benzodiazepin-4-yl)benzeneethanol .HCl,

4-(7,10-dichloro-5,6-dibydro-4/7-pyrrolo[ 1 ,2-îï] [ 1,4]benzodiazepin-4-yl)benzeneethanol,

4-(9-chloro-5,6-dihydro-47/-pyrrolo[ I ,2-î/][ 1,4]benzodiazepin-4-yl)-benzeneethanol, l-[4-(7-fluoro-5,6-dihydro-4//-pyrrolo[ 1,2-a][l ,4]benzodiazepin-4-yl)phenyl]ethanone HCl,

-[4-(7-fluoro-5,6-dihydro-4//-py rrolo[ 1,2-ev] [ 1,4]benzodiazepin-4-yl)phenyl]ethanone,

-[4-(7,10-dichloro-5,6-dihydro-4//-pyrrolo[ 1,2-a] [ 1,4]benzodiazepin-4-yl)phenyl]ethanone HCI, l-[4-(7,10-dichloro-5,6-dihydro-4/7-pyrrolo[l,2-àr][l,4]benzodiazepin-4-yl)phenyl]ethanone, l-[4-( 10-chloro-5,6-dihydro-4//-pyrrolo[ 1,2-a] [ 1,4]benzodiazepi n-4-yl)phenyl ]ethanone, l-[4-(7,9-difluoro-5,6-dihydro-4//-pyrrolo[l,2-ûf][l,4]benzodiazepin-4-yl)phenyl]ethanone, and l-[4-(7,9-difluoro-5,6-dihydro-47/-pyrrolo[l,2-i/][l,4]benzodiazepin-4-yl)phenyl]ethanone HCl, including any stereochemically isomeric form thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

Ail possible combinations of the above-indicated interesting embodiments are considered to be embraced within the scope of this invention,

The présent invention also encompasses processes for the préparation of compounds of Formula (I) and subgroups thereof

The compounds of Formula (I) and the subgroups thereof can be prepared by a succession of steps as described hereunder. They are generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art. The compounds of the présent invention can be also 5 prepared using standard synthetic processes commonly used by those skilled in the art of organic chemistry

The compounds of the présent invention wherein R^5a is Ci^alkylcarbonyl and wherein the other substituents are defined as before, can be prepared according to Scheme 1 :

Scheme l

1.4-dtoxane R¹ R^z

-20The 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 manganèse 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 of an intermediate of formula (Π) In the presence of an acid such as, for example, POCIj, the amide in the intermediate of formula (II) can function as a C-electrophile, resulting in a ring closure. The reaction may be performed in a suitable solvents such as, for example, DCM (CH2CI2) 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 sait (III) by reaction with an acid H⁺X' of formula (XI), and reacting said sait of formula (III) with an aldéhyde of formula (XII) in an appropriate solvent such as an alcohol, e.g. methanol (MeOH), éthanol (EtOH), isopropanol, at an elevated température, preferably at reflux température.

Alternatively, the intermediate of formula (IV) may be reacted first with the aldéhyde of formula (XII) and the thus formed imine may be cyclized in the presence of an acid H⁺X’ of formula (XI) to a compound of formula (I-a).

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

An intermediate of formula (II) 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 l -hydroxy-lH-benzotriazole (HOBT) and //-(ethylcarbonimidoyl)-M A-diniethyl-1,3-propanediamine monohydrochloride (EDCI). The reaction may be performed in the presence of a base such as trietylamine (Et₃N) and a suitable solvent such as, for example, DCM. Alternatively, an acid chloride dérivative of (XIII) or a reactive ester dérivative of (XIII) can also be used in this type of reaction to préparé an intermediate of formula (II).

An intermediate of formula (XIII) or its acid chloride or ester dérivative, can be easily prepared by those skilled in the art.

Intermediates of formula (III) and (IV) are prepared by reducing a l-(2-cyanophenyl)pyrrole dérivative of formula (V). Several procedures well-known to those skilled in the art may be used to reduce the nitrile function such as, for example:

1. Li AlHi/THF [S Raines, S.Y. Chai and F.P. Palopoli; J. Heterocyclic Chem., B,

711-7I6 (1976)]

2. t. sodium bis(2-methoxyethoxy)aluminate (Red-AI®) 70% w/w Toluene, RT :

h. NaOH 10%, RT [G.W.H. Cheeseman and S G. Greenberg; J. Heterocyclic Chem., 16, 241-244(1979)]

3a. i. KBH1/CF3COOH, THF; ii. H₂O; 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 / (MeOH/NHa)

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 dérivative of formula (VI) with tetrahydro-2,5-dimethoxyfuran in an inert solvent such as dioxane or tetrahydrofuran (THF) in the presence of an acid such as 4-chloropyridine hydrochloride, or in an acidic solvent such as glacial acetic acid, at an elevated température, preferably at reflux température. Alternatively, an intermediate of formula (V) can also be prepared from an intermediate of formula (X). Typically, an intermediate of formula (X) wherein Halo is defined as Br, I, Cl or F, is reacted with pyrrole in the presence of a base such as, for example, Cs₂CO₃ or NaH, in a suitable solvent such as typically DMF.

Alternatively, an intermediate of formula (IV) may be prepared by treating 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 performed in the presence of an acid such as HCl. After the reaction has proceeded, the reaction mixture can be basified with a suitable base such as NaOH. The réaction can be performed at an elevated température, preferably at reflux température.

An intermediate 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.H₂O in the presence of HOBT and EDCI. This type of reaction typically can be performed in a suitable solvent like DMF. Stirring of the reaction mixture may enhance 35 the rate of reaction.

Of

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 température, preferably at reflux température. Alternatively, a reactive ester dérivative of (IX) can 5 also be used in this type of reaction to prépare an intermediate of formula (VIII).

The compounds of the présent invention according to formula (I-c), wherein R^5b is defined as H-(CH₂)|.3-CH(OH)- and wherein the other substituents are defined as before, can be prepared according to Scheme 2:

Scheme 2

(l-ab)

1) LiAIH₄ or

NaBH₄

2) H_ZO

R^5ab is C^alkylcarbonyl

d-c)

R^5b is H-iCH^-CHiOH)A compound of formula (I-ab) may be prepared according to the reaction protocols described in Scheme 1. In formula (I-ab), R^5ab is defined as Ci.îalkylcarbonyl and ail other substituents are as defined before.

The carbonyl group of R^iah in compounds of formula (I-ab) can be reduced to obtain compounds according to formula (I-c). Typically this reaction can be performed in the presence of a reducing agent such as, for example, lithium aluminium hydride (LiAlH₄) or sodium borohydride (NaBH₄). This reaction may be carried out in the presence of a dried aprotic organic solvent, usually DCM, Et₂O or THF, followed by aqueous workup

Compounds of formula (I-f)

R^5f is C₁.₄alkyl substituted with one hydroxyl group wherein R^5f représente Cmalkyl substituted with one hydroxyl moiety, may be prepared by using analogous reaction protocols as described in Scheme 1. In that case, an

intermediate of formula (ΧΙΙ-a) may be used instead of an intermediate of formula (ΧΠ).

An intermediate of formula (ΧΙΙ-a) may be prepared according to well known protocols as shown in Scheme 2b In a first step, the hydroxyl group of an intermediate of formula (XVIII) may be blocked by protecting groups (PG). They can be deprotected after a reaction step. Conventional protecting groups can be used in accordance with standard practice. Typically, the 2-tetrahydropyranyl group may be used as a protecting group for alcohols. In that case, an intermediate of formula (XVIII) may be reacted with dihydropyran in the presence of an acid such as, for example, PPTS (4-methyl10 benzenesulfonic acid). In a second step, an intermediate of formula (XIX) is converted into an intermediate of formula (ΧΙΙ-a). This is typically done with n-butyllithium in aprotic anhydrous solvents e.g. THF in a first step, followed by addition of DMF in a second step. The reaction may be performed under an inert atmosphère such as, for example, N₂.

Scheme 2b halo halo CHO

The compounds ofthe présent invention wherein R^5c is defined as Ci-ialkylsulphonyl and wherein the other substituents are defined as before, can be prepared according to Scheme 3:

Scheme 3

R¹ R² R¹ R²

(XV) oxidation 1

A compound of formula (I-d) can bc prepared by oxidation of the sulphur group in an intermediate of formula (XVI). Typically, the 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 (XVI) can be prepared from the intermediates represented by the formula (XV), following art-known amine to imine oxidation reactions. Thèse oxidation réactions may bc conductcd by reacting an intermediate of formula (XV) 10 with a mild oxidant such as, for examplc, lead tctra-acctate or manganèse dioxide, in a réaction inert solvent such as a halogcnatcd hydrocarbon e.g. dichloromethane (DCM)

-25or trichloromethane The reaction rate can be enhanced by stirring and optionally heating the reaction mixture.

An intermediate of formula (XV) can be prepared from an intermediate of formula (TV) by converting it in a sait (III) by reaction with an acid H*X of formula (XI), and reactîng said sait of formula (III) with an aldéhyde of formula (XIV) in an appropriate solvent such as an alcohol, e g. methanol (MeOH), éthanol (EtOH), isopropanol, at an elevated température, preferably at reflux température.

Alternatively, the intermediate of formula (IV) may be reacted first with the aldéhyde of formula (XIV) and the thus formed imine may be cyclized in the presence of an acid H⁺X' of formula (XI) to an intermediate of formula (XV).

Compounds of formula (I-e)

may be prepared by using analoguous reactions as described in Scheme 3 for intermediate (XV), but starting from an intermediate of formula (XVII)

O

(XVII)

Alternatively compounds of formula (I-e) may be prepared from intermediates of formula (XV). In this type of reaction, the NII group of the intermediate of formula (XV) is first protected with a amine protecting group such as typically tertbutyloxycarbonyl, benzyl or tosyl, and subsequently the sulphur is oxidized by using reaction conditions such as described for ‘oxidation 2’ in Scheme 3. Finally the protected NU group is deprotected,

Ail starting matériels are commercially available or can be easily prepared by those skilled in the art.

In ail these préparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to méthodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. In particular, stereoisomers can be isolated chromatographically using

-26a chiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5 dimethylphenyl carbamate) or Chiralpak® AS, both purchased from Daicel Chemical Industries, 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 sélective crystallization of their diastereomeric salts with opttcally active acids. Altematively, enantiomers may be separated by chromatographie techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the 10 appropriate starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably if a spécifie stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of préparation. These methods will advantageously employ chirally pure starting materials. Stereoisomeric forms of the compounds of Formula (I) are obviously intended to be included within 15 the scope of the invention.

The chirally pure forms of the compounds of Formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their sait forms are particularly useful in the préparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the 20 préparation of compounds of Formula (I) with the corresponding configuration.

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

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés 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 solvatés thereof, may be active 30 against moulds.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida kniceï, Candida parapsilosis, Candida kefyr, Candida tropicalis;

Aspergillus spp., e.g. Aspergiihts fiimigaïus, Aspergillus niger, Aspergillusflavus:

-27Cryptococcus neoformans; Sporothrix schenckii; Epidermophytonfloccosim; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton ruhrttm, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrttcositm, Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanaise; Fusarium spp., e.g. Fttsarittm solani, Fusarium oxysponim, Fusarium proliférât uni, Fusarium verticillioides; Rhizomucor spp., e.g Rhizomucor miehei, Rhizomucorpitsillus; Mucor circineUoides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia fiirfiir; Acremonium spp., Paecilomyces; Scopidariopsis; Arthrographis spp.;

Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium proliflcans; Trichoderma spp.; Pénicillium spp., Pénicillium marneffei; Rlastoschizomyces.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as Candidaparapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergilltts niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophytonfloccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans, Trichophyton verrttcosum, Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanaise; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporttm, Fusarinm proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mttcor circineUoides; Rhizoptts spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces;

Scopttlariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans; Trichoderma spp.; Pénicillium spp., Pénicillium marneffei; Rlastoschizomyces.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as Candidaparapsilosis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Epidermophyton floccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, Trichophyton tonsurans,

Trichophyton verrucosum, Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanaise; Fusarium spp., e.g. Fusarium solani, Fusarium oxysportim,

Y

Fusariumproliferatum, Fusarium verticillioides-, Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucorpusillus, Mucor circiné!loides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, 5 Scedosporiumprolificans', Trichoderma spp.; Pénicillium spp. ; Pénicillium marneffei;

Blastoschizomyces; in particular Aspergillus spp., e.g. Aspergillus fitmigatits, Aspergillus Niger, Aspergillusflavus; Cryptococcus neoformans; Epidermophyton floccosum; Microsporum spp., e.g. Microsporum canis, Microsporum gypseum;

Trichophyton spp., e.g. Trichophyton mernagrophytes, Trichophyton rubrum,

Trichophyton quinckeanum, Trichophyton tonsttrans, Trichophyton verrucosmn,

Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanaise;

Fusarium spp,, e.g. Fusarium solani, Fusarium oxysporttm, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus-, Mucor circinélloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.;

Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium proliftcans; Trichoderma spp.; Pénicillium spp.; Pénicillium marneffei;

Blastoschizomyces.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as Candidaparapsilosis; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;

in particular Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans;

Microsporum spp.; Fusarium spp.; Scedosporium spp.;

more in particular Aspergillus spp.; Cryptococcus neoformans; Microsporum spp.;

Fusarium spp.; Scedosporium spp.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as Candidaparapsilosis; Aspergillus spp.;

Cryptococcus neoformans; Trichophyton spp.; Sporothrix schenckii; Microsporum spp.; Fusarium 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 solvatés thereof, may be active against fungi such as Candidaparapsilosis; Aspergillus spp., e.g. Aspergillus

-29fumigatiis, AspergiUus niger, AspergiUus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeatmm;

in particular Candidaparapsilosis; AspergiUus spp., e.g. Aspergilltis fumigatus,

AspergiUus niger, AspergiUusflavus; Cryptococcus neoformans; Epidermophyton floccosum; Microspornm canis; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum;

more in particular AspergiUus spp., e.g. AspergiUus fumigatus, AspergiUus niger, AspergiUus flavus; Cryptococcus neoformans; Epidermophyton floccosum;

I0 Microspornm canis; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton qttinckeanum.

The compounds of Formula (I) and stereoisomerïc forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candidaparapsilosis, AspergiUusfumigatus, Cryptococcus neoformans,

Sporothrix schenckii, Microspornm canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium proliflcans; in particular AspergiUus fumigatus, Microspornm canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium proliflcans.

The compounds of Formula (I) and stereoisomerïc forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against fungi such as Candidaparapsilosis; AspergiUus spp.; Cryptococcus neoformans-, Microspornm spp.; Trichophyton spp.; Scedosporium spp..

Sporothrix schenckii, Microspornm canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium proliflcans;

in particular Candidaparapsilosis. AspergiUusfumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum.

Scedosporium apiospermum and Scedosporium proliflcans;

more in particular AspergiUus fumigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium proliflcans.

The compounds of Formula (I) and stereoisomerïc forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active

against Candida parapsilosis, Aspergillus fumigants, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton ruhrum, Scedosporium apiospermum, Scedosporium prolificans, Rhizopus oryzae, Rhizomucor miehei, Mucor circiné!laides.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candidaparapsilosis B66126, Aspergillusfumigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis 868128, Trichophyton mentagrophytes B70554, Trichophyton ruhrum B68183, Scedosporium apiospermum 1HEM3817, Scedosporiumprolificans 1HEM21157.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candidaparapsilosis B66126, Aspergilhisfumigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128,

Trichophyton mentagrophytes B70554, Trichophyton ruhrum B68183, Scedosporium apiospermum 1HEM3817, Scedosporium prolificans IHEM21157, Rhizopus oryzae IHEM5223, Rhizomucor miehei IHEM13391 and Mucor circinelloides IHEM21 !05.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a variety of fungi 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 solvatés thereof, may be active against the 3 dermatophyte généra: /Trichophyton, Microsporum andEpidermophytoir, in particular against Trichophyton and Microsporum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against dermatophytes and Aspergillus spp.; in particular dermatophytes and Aspergillus fumigatus; more in particular Microsporum canis, Trichophyton mentagrophytes, Trichophyton ruhrum and Aspergilhis fumigatus; even more in particular Microsporum canis, Trichophyton mentagrophytes and Trichophyton ruhrum.

The compounds of Formula (I) and stereoisomeric fornts thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Trichophyton mentagrophytes, Trichophyton ruhrum and Aspergillus spp., in

T

-31particular Trichophyton mentagrophytes, Trichophyton ruhrum and AspergiUus fumigants.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Trichophytonmentagrophytes; Trichophyton ruhrum-, AspergiUus spp., e.g. AspergiUus fumigatus-, Fusarium spp.; Mucor Spp.; Zygomycetes spp.; Scedosporium spp.; Microsporum canis; Sporothrix schetickii; Cryptococcus neoformans and Candida parapsitosis.

The compounds of Formula (1) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against dermatophytes.

The compounds of Formula (1) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active again st AspergiUus fimiigalus.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active againstMicrosporum canis, in particularMicrosporum canis B68128.

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

The compounds of Formula (1) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as one or more of the fungi mentioned hereinbefore.

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

The compounds of the présent 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 animais, including humans, suffering from, or a method of preventing warm-blooded animais, including humans, to suffer from any one of the 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

-32medicament useful in treating fungal infections is provided. 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 ali processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of an infection, 5 but does not necessarily indicate a total élimination of ali symptoms.

The invention 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 solvatés thereof, for use as a médicament.

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 solvatés thereof, for the treatment or prévention 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 (1), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition 15 salts and the solvatés 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 (1), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for use in the treatment or prévention 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 solvatés thereof, for use in the treatment of fungal infections; in particular 25 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 solvatés thereof, for use in the treatment or prévention, in particular treatment, of fungal infections; in particular fungal infections caused by one or more of 30 the fungi selected from a group consisting of 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 solvatés thereof, for use in the treatment or prévention of a fungal

-33infectïon, in particular a fungal infection caused by one or more of the fungi mentioned hereinbefore.

The invention also relates to a compound according to the general Formula (I), the stereoisonteric fornts thereof and the pharmaceutically acceptable acid or base addition 5 salts and the solvatés thereof, for use in the treatment or prévention of a fungal infection, wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp., Aspergi/his spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophytonfloccosum; Microsporum spp.;

Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Malassezia furfur; Acremonhtm spp.; Paecilomyces; Scoptilariopsis;

Arthrographis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp.; Pénicillium spp.; Pénicillium marneffei; and Blastoschizomyces;

în particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candidaparapsilosis; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.;

Trichophyton spp.; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Acremonium spp.; Paecilomyces; Scoptilariopsis; Arthrographis spp.;

Scytalidium; Scedosporium spp.; Trichoderma spp.; Pénicillium spp.; Pénicillium marneffei; and Blastoschizomyces;

even more in particular wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fiimigatus.

The novel compounds described in the présent invention may be useful in the treatment or prévention of diseases or conditions selected from the group consisting of infections 25 caused by dermatophytes, systemic fungal infections and onychomycosis.

The novel compounds described in the présent invention may be useful in the treatment or prévention 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 Formula 30 (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the solvatés thereof, for the manufacture of a médicament.

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 solvatés thereof, for the manufacture of a médicament for the

-34treatment or prévention, in particular treatment, of fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore

The compounds of the présent invention can be administered to mammals, preferably humatis, for the treatment or prévention, 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 of the compound of Formula (I), there is provîded a method of treating warm-blooded animais, including hunians, suffering from or a method of preventing warm-blooded animais, including humans, to suffer from fungal infections, in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.

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), a stereoisomeric form thereof or a pharmaceutically acceptable addition sait or solvaté thereof, to warm-blooded animais, including humans.

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 animais, including hunians.

Those of skill in the treatment of such diseases could détermine 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 particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from 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 présent invention, also referred to here as the active ingrédient, 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 âge and condition of the récipient, and the particular disorder or disease being treated.

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

-35While it is possible for the active ingrédient to be administered alone, it is préférable to présent it as a pharmaceutical composition.

The présent invention also provides compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of Formula (l) 5 and a pharmaceutically acceptable carrier or diluent

The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingrédients of the composition and not deleterious to the récipients thereof.

The compounds of the présent invention,that are suitable to treat or prevent fungal infections, may be administered alone or in combination with one or more additional 10 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 example, a compound of Formula (I) and a therapeutic agent 15 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 sait thereof, a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited ail compositions usually employed for systemically administering drugs.

To préparé the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingrédient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of préparation desired 30 for administration. These pharmaceutical compositions are désirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parentéral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media inay be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid préparations such as suspensions, syrups, élixirs, émulsions and solutions, or solid

Y

-36carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.

For parentéral compositions, the carrier will usually comprise stérile water, at least in large part, though other ingrédients, for example, to aid solubility, may be included. 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, 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 action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures ofthese and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspendîng agents and the like may be employed. Also included are solid form préparations that are intended to be converted, shortly before use, to liquid form préparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a pénétration enhancing agent and/or a suitable wetting agent, optionally 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 compositions 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 (I) due to their increased water solubility over the corresponding base or acid form, are more suitable in the préparation of aqueous compositions.

Transungual compositions are in the form of a solution and the carrier optionally comprises a pénétration enhancing agent which favours the pénétration of the antifungal 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. éthanol.

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 α-, β- or γcyclodextrins or their dérivatives, in particular hydroxyalkyl substituted cyclodextrins,

e.g. 2-hydroxypropyl-p-cyclodextrin or sulfobutyl-p-cyclodextrin. Also co-solvents

-37such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.

The ratio of active ingrédient over cyclodextrin may vary widely For example ratios of I/IOO to lOO/l may be applied. Interesting ratios of active ingrédient over cyclodextrin range from about I/IO to ÎO/I. More interesting ratios of active ingrédient over cyclodextrin range from about l /5 to 5/l.

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 l to 50 % by weight of the compound of Formula 10 (I), and, from l 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, ail percentages being based on the total weight of the composition.

For parentéral compositions, also other ingrédients, to aid solubility for example, e.g. cyclodextrins, may be included. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or 15 ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C j .gaikyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyCj.galkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyCj.galkyl, particularly carboxymethyl or carboxy-ethyl; C|.6alkylcarbonyl, particularly acetyl.

Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-p-CD, 2-hydroxyethyl-p-CD, 2-hydroxyethyl-y-CD, 2-hydroxypropyl-v-CD and (2-carboxymethoxy)propyl-p-CD, and in particular 2-hydroxypropyl-p-CD (2-HP-p-CD).

The tenu mixed ether dénotés cyclodextrin dérivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, 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 substitution 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 techniques such as nuclear magnetic résonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin dérivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges froin 0.125 to 3.

-38Other 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 polymers.

The terni ”a solid dispersion” defînes a System in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, in casu the compound of Formula (I) and the water-soluble polymer, wherein one component is dispersed more or less evenly throughout the other component or components ( in case additional pharmaceutically acceptable 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 uniform or homogenous 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 physicaï Systems because the components therein are usually readily bioavailable to the organisme to which they are administered. This advantage 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 solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. For example, the term “a solid dispersion” also relates to a System having domains or small régions 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 Formula (I), or a solid solution comprising compound of Formula (I) and water-soluble polymer. Said domains are régions within the solid dispersion distinctîvely marked by some physicaï feature, small in size, and evenly and randomly distributed throughout the solid dispersion.

It may further be convenient to formulate the présent antifungal compounds in the form of nanoparticles which hâve a surface modifier adsorbed on the surface thereof in an amount suflficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhéré to the surface of the antifungal agent but do not chemically bond to the antifungal agent.

-39Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the présent compounds involves a pharmaceutical composition whereby the présent antifungals are incorporated in hydrophiIîc polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical 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 hâve appropriate dimensions and fïrnmess Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and dérivatives thereof.

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

Unit dosage form as used in the spécification and claims herein refers to physically discrète units suitable as unitary dosages, each unit containing a predetermined quantity of active ingrédient 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, suppositories, 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 présent invention.

Experimental part

Hereinafter, the term “DCM” means dichloromethane; “LCMS” means Liquid Chromatography/Mass spectrometry; “TLC” means thin layer chromatography;

“DIPE” means diisopropyl ether; “PE” means petroleum ether, “TFA” means trifluoroacetic acid; “HPLC” means high-performance liquid chromatography, “r.t.” means room température; “m.p.” means melting point; “min” means minute(s); “h”

-40means hour(s); “EtOAc” means ethyl acetate; “EtOH” means éthanol; “r.m.” means reaction mixture(s); “q.s.” quantum sufficit; “THF” means tetrahydrofuran; “HOAc” means acetic acid; “HOBT” means l-hydroxy-1H-benzotriazole; “Me₂S” means dimethyl sulfîde; “PPTS” means 4-methyl-benzenesulfonic acid, compound with pyridine (1:1); “DHP means dihydropyran; and “EDCI” means A^-iethylcarbonimidoyO-AA-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 protecting atmosphère such as, for example, N₂ or argon, must be used.

A. Préparation of the intermediates

Example Al

2-Amino-4,6-dichlorobenzamide (30 g, 0,15 mol) was dissolved in POC1₃ (108 g, 0.7 mol). The solution was stirred at 100 °C for 2 h, and was then poured into ice. The obtained mixture was filtered and dried. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 20/1). The desired fractions were collected and the solvent was evaporated, to yield 10.5 g of intermediate 1 (37.5 % yield).

b) Préparation of intermediate 2

A mixture of intermediate 1 (8.13 g, 0.043 mol) and tctrahydro-2,5-dimcthoxyfuran (6.55 g, 0.049 mol) in HOAc (80 ml) was stirred and rcfluxcd until the reaction was completcd (followed by TLC). The mixture was cooled and evaporated. The residue was purified by column chromatography (eluent: DIPE/EtOAc 20/1). The desired fractions were collectcd and the solvent was evaporated, yielding 8.2 g of intermediate 2 (80.5 % yield).

c) Préparation of intermediate 3

H,N

Cj/ HCI

Cl

Borane-dimethyl sulphide (l;l) (3.1 ml of a 10 M solution ofBH₃ in Me₂S, 0.03 moi) was added dropwise to a mixture of intermediate 2 (6.52 g, 0.0275 mol) and THF (50 ml) under N₂ atmosphère. The r.m. was heated at reflux température for 10 h.

Subsequently, the mixture was cooled to r.t., and HCl (6 N) was added dropwise. The mixture was heated at reflux température again for 30 min, and was then cooled to 0 °C. NaOH (6 N) was added and the lîberated amine was extracted with EtOAc. The separated organic layer was dried (Na₂SO₄), filtered and the solvent was evaporated. HCl in dioxane (q.s.) was added and evaporated again. The product was washed with DCM. Yield: 6.5 g of intermediate 3 (85.5 %; HCl).

Example A2

a) Préparation of intermediate 4 .CN

Cl

A mixture of 3-chloro-2-fluoro-benzonitrile (25 g, 160.7 mmol), pyrrole (12.94 g, 192.8 mmol) and Cs₂CO₃ (62.81 g, 192.8 mmol) in DMF (150 ml) was stirred overnight at 100 °C. The mixture was cooled and poured into ice-water. The solid was filtered off and dissolved in DCM. The solution was dried (Na₂SO₄), filtered and evaporated to yield 29 g of intermediate 4 (90.1 % yield).

b) Préparation of intermediate 5

.HCl

Intermediate 4 (29 g, 143 mmol) was dissolved in THF (200 ml). A 10 M BH₃.Me₂S solution ( 15.45 ml, 154.5 mmol) was added slowly to the solution under N₂atmosphère. The r.m. was stirred and refluxed overnight. Then, the mixture was cooled and acidified with 6 N HCl until pli l. Subsequently, the mixture was stirred and refluxed for 30 min. The mixture was cooled again and poured into ice-water. This mixture was adjusted to pH 8-9 with NaOH, and was then extracted with EtOAc. The separated organic layer was dried (Na₂SO₄), filtered and concentrated. The residue was

-42dîssolved in HCl/dioxane. The solvent was evaporated under reduced pressure. The residue was washed with DCM (50 ml). The solid was filtered off and dried in vacuo. Yield: 22 g of intermediate 5 (64.7% yield; HCI).

Example A3

a) Préparation of intermediate 6

Telrahydro-2,5-dimethoxyfuran (49.9 g, 0.378 mol) was added to a solution of 2amino-4-chlorobenzonitrile (50.0 g, 0.328 mol) in HOAc (300 ml). The r.m. was stirred and refluxed for 2 h, and was then cooled. Subsequently the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated. Yield: 13 g of intermediate 6 (98.4 % yield).

b) Préparation of intermediate 7

Intermediate 6 (33 g, 0,163 mol) was dissolved in THF (250 ml). A 10 M solution of BH3 in Me₂S (17.6 ml, 0.176 mol) was added slowly to the solution under N₂atmosphère. The r.m. was stirred and refluxed overnight. Subsequently, the mixture was cooled and acidified with a 6 N HCl solution to pH 1. The mixture was stirred and refluxed again for 30 min. The mixture was cooled and poured into ice-water. This mixture was adjusted to pH 8-9 with NaOH, and was then extracted with EtOAc. The separated organic layer was dried (Na₂SO4), filtered and the solvent was evaporated. The residue was dissolved in HCl/dioxanc. The solvent of this solution was evaporated and the residue was washed with DCM (50 ml). The solid was filtered off and dried in vacuo. Yield: 23.5 g of intermediate 7 (59.4 % yield; HCl).

Example A4

a) Préparation of intermediate 8

-43A mixture of 3,5-difluorobenzenamine (129 g, l .00 mol) and concentrated HCl (350 ml) in H₂O (1 1) was added to a mixture of 2,2,2-trichloro-acetaldehyde (179 g, 1.22 mol) and Na₂SO₄ (1500 g) in H₂O (2 1). Subequently, NH2OH.HCI (207 g, 3.00 mol) in HiO (500 ml) was added and the r.m. was heated to reflux for 1 h. Then, the r.m. was cooled to 0 °C. The solid was collected and dissolved in EtOAc This solution was dried (Na₂SO₄), filtered and the solvent was evaporated to yield a grey solid. Yield: 160 g of intermediate 8 (80 % yield).

b) Préparation of intermediate 9

Intermediate 8 (160 g, 0.8 mol) was added portionwise to conc. H₂SO₄ ( 1 I) at 50 °C. The solution was heated to 100 °C for 2 h, and was then poured into ice-water (3 1). The precipitate (approximately 0.8 mol) was collected and was dissolved in 1 N NaOH (2 1). H₂O₂ (300 ml) was added to this solution at 0 °C, and after allowing the r.m. to reach r.t. it was stirred overnight. Subsequently, the mixture was filtered and 2N HCl was added to the filtrate until pH 1. The precipitate was filtered off and dissolved in EtOAc (2 1). The solution was dried (Na₂SO₄), filtered and the solvent was evaporated to yield 120 g of intermediate 9 (83 % yield) as a yellow solid.

c) Préparation of intermediate 10

A mixture of intermediate 9 (60.0 g, 0.346 mol), tetrahydro-2,5-dimethoxyfuran (45.7 g, 0.346 mol) and pyridine hydrochloride (1:1) (40 g, 0.346 mol) in dioxane (500 ml) was heated to reflux overnight. The solvent was removed, and the residue was dissolved in EtOAc (100 ml). This solution was washed with brine and H₂O. The separated organic layer was dried (MgSO₄), filtered and the solvent was evaporated to yield 70 g of intermediate 10 which was used as such directly in the next reaction step.

d) Préparation of intermediate 11

NHj.H₂O (IOO ml) was added to a solution of intermediate IO (70 g (crude), approximately 0.311 mol), HOBT (47 g, 0.346 mol) and EDCI (70 g, 0.346 mol) in DMF (300 ml). The r.m. was stirred overnight. The solvent was removed, and the residue was dissolved in EtOAc. This solution was washed with brine and H₂O. The separated organic layer was dried (MgSOi), filtered and the solvent was evaporated. Yield: 55 g of intermediate 11 which was used as such directly in the next reaction step.

e) Préparation of intermediate 12

.HCl

A 10 M solution of BHj in Me₂S (40.5 ml, 0.405 mol) was added to a mixture of intermediate 11 (45 g, 0.2025 mol) in THF (500 ml). The r.m. was retluxed overnight under N₂ atmosphère. Subsequently, 6 N HCl (10 ml) was added while the mixture was 10 cooled on an ice-water bath. The mixture was retluxed again for 30 min, and then solid

NaOH was added until pH >9 while the mixture was cooled on an ice-water bath. The mixture was extracted with DCM (2 times 300 ml), The separated organic layer was dried (MgSOi), filtered and the solvent was evaporated. The brown residue was converted to the HCl sait (.HCl) with HCl/2-propanol). Yield: 35 g of intermediate 12 (71% yield).

Example A5

a) Préparation of intermediate 13

HCl

-45A mixture of intermediate 3 (2.8 g, 10.0 mmol) and 4-(methylthio)benzaldehyde (1.8 g, 12.0 mmol) in EtOH (l 5 ml) was refluxed for 4 h. The mixture was cooled and crystallized overnight. The precipitate was filtered off, washed with isopropyl ether and dried in vacuo. Yield: 2.85 g of crude intermediate 13 ( HCI) which was used as such in the next reaction step. If desired, the product can be further purified by HPLC.

b) Préparation of intermediate 14

Crude intermediate 13 (2.8 g; approximately 6.9 mmol) was neutralized with NLL.HîO (10 ml) and the mixture was extracted with DCM, The separated organic layer was dried (NaîSO-i), filtered, and the solvent was evaporated in vacuo. The residue was stirred in DCM (40 ml) and MnOî (7.2 g, 83.1 mmol) was added to this solution. The r.m. was stirred for 48 h at r.t., and was then filtered over diatomaceous earth (eluent: PE/EtOAc from 5/1 to 2/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 1.60 g of intermediate 14 (62.2 % yield).

Example A6

a) Préparation of intermediate 15

DHP (7 ml) and PPTS (0.58 g) were added to a solution of 4-bromo-benzeneethanol (9.4 g; 0.0467 mol) in DCM (q.s.) at 25 °C. The solution was stirred at 25 °C for 10 hours. The mixture was washed with water (3 x 50 ml), dried (MgSO₄), filtered and the solvent was evaporated. Yield: 12.63 g of intermediate 15 (95 % yield).

b) Préparation of intermediate 16

Reaction under anhydrous conditions.

A 2 M solution of n-butyllithium in n-hexane (15 ml) was added dropwise to a solution of intermediate 15 (8 62 g) in THF (150 ml) at -78 °C. This mixture was stirred for 1 hour at -78 °C. Then DMF (7 ml) was added dropwise, and the reaction mixture was stirred for another 2 hours at -78 °C. The reaction mixture was combined with a NH.iCl

-46solution and extracted with EtOAc. The combined organic layers were washed 3 times with a saturated NaCI solution, dried (Na₂SO₄), filtered and the solvent was evaporated. The purification was carried out by column chromatography over silica gel (eluent: petroleum ether/EtOAc 8/1 ). The desired fractions were collected and the solvent was evaporated. Yield: 6.57 g of intermediate 16 (94 % yield).

Example A7

a) Préparation qf intermediate 17

2,5-Dimethoxytetrahydrofuran (180 mmol) was added to a mixture of 2-amino-4chlorobenzonitrile (164 mmol) in HOAc (250 ml). The reaction mixture was stirred at reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, A saturated aqueous solution of NaHCCh was added to the concentrate. The mixture was extracted with EtOAc. The combined organic layers were washed with a saturated aqueous solution ofNaHCOi and water, dried over anhydrous Na₂SO₄, filtered and evaporated. Dark coloured crystals were obtained. The obtained crude was dissolved in DCM and filtered over a silica plug. Yield: Intermediate 17 (99 % yield; yellow crystalline solid).

b) Préparation of intermediate 18

Aluminum(III) lithium hydride (250 mmol) in THF anhydrous (20 ml) was added over 2 minutes to an ice cooled solution of intermediate 17 (114 mmol) in anhydrous THF anhydrous (200 ml). After addition the reaction mixture was stirred for 1 hour. The reaction mixture was added to an ice cooled 15 % aqueous solution of potassium sodium 2,3-dihydroxysuccinate tetrahydrate (Rochelle's salt)under vigourously stirring foliowed by EtOAc (300ml). The mixture was stirred for 30 min. 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 over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to yield a yellow translucent oil.

The obtained oil was dissolved in diethyl ether (800 ml) and HCl in dioxane 4 M (28,5 ml) was added to this solution. The resulting suspension was filtered and washed with

-47diethyl ether. The filter residue was dried at 50°C to yield intermediate 18 (65 % yield; yellow solid).

B. Préparation of the compounds

Example B l

a) Préparation of compound 12

A mixture of intermediate 3 (0.552 g, 0.002 mol) and 4-acetyl-benzaldehyde (0.385 g, 0.0026 mol) in EtOH (4 ml) was stirred and refluxed for 3 h. Then, the mixture was cooled and crystallized from the mixture by standing overnight. The product was filtered off and washed (EtOH) and dried. Vield: 0.684 g of compound 12 (84.2 % yield).

b) Préparation of compound 22

Compound I2 (0.390 g, 0.00096 mol) was stirred in NH3.H2O (4 ml). This mixture was extracted with DCM (20 ml). The separated organic layer was dried (Na2SO₄) and filtered. The solution was stirred with MnO_z (2.5 g, 0.028 mol) for 4 days after filtration, and then the solvent was removed. The product was dried in vacuo. Yield: 0.010 g of compound 2 (2.8 % yield).

Example B2

a) Préparation of compound 32

A mixture of intermediate 5 (1.5 g, 6.17 mmol) and 4-acetyl-benzaldehyde (1.0 g, 6.78 mmol) in EtOH (10 ml) was refluxed for 4 h. Subsequently, the mixture was left standing overnight at r.t. The solvent was evaporated in vacuo. The residue was purified by préparative HPLC (SEPAX™: 21.2 x 250 mm; eluent: I0%-40% CH₃CN (0.1 % TFA)/H2Ü (0.1 % TFA); flow rate 25 ml/min; 20 min). The desired fractions

-48were collected and neutralized with a saturated NaHCO₃ solution. The mixture was extracted with DCM. The separated organic layer was dried (Na₂SO₄), filtered and the solvent was evaporated to yield 0.68 g of compound 31 as an oil (33 % yield).

b) Préparation of compound 15

A mixture of compound 32 (0.68 g, 2,02 mmol) and MnO₂ (2.63 g, 30.28 mmol) in DCM (20 ml) was stirred for 48 h at r.t. Subsequently, the mixture was filtered over diatomaceous earth, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (clucnt; PE/EtOAc 10/1 ). The desired fractions were collected and the solvent was evaporated to yield 0.6 g of compound 15 (89 % yield).

Example B3

a) Préparation of compound 8

4-Acetyl-benzaldehyde (l 46 g, 9.78 mmol) was added to a solution of intermediate 7 (2.00 g, 8.23 mmol) in EtOH (15 ml). The r.m. was stirred and refluxed for 4 h, and was then cooled. After standing overnight, the precipîtate was filtered off and dried in vacuo to yield the crude product. The crude product was purified by HPLC (SEPAX™: 21.2 x 250 mm; eluent: 35%-55% CH₃CN (0.1 % TFA)/H₂O (0.1 % TFA); flow rate 15 ml/min; 25 min). The product fractions were collected and the organic solvent was evaporated. The residue was adjusted to pH 7 with a saturated NaHCO₃ solution. DCM (q.s.) was added and the organic layer was separated. The separated organic layer was dried (Na₂SO₄), filtered and the solvent was evaporated. Yield: 2.1 g of compound 8 (68.4 % yield).

b) Préparation of compound 18

A solution of compound 8 (2.0 g, 5.9 mmol) and MnO₂ (6.1 g, 71.2 mmol) in DCM (50 ml) was stirred at r.t. for 2 days, The mixture was filtered, and the filtrate was concentrated to yield 0.650 g of compound 18 (36.3 % yield).

Example B4

a) Préparation of compound 33

A mixture of intermediate I2 (1.5 g, 6,13 mmol) and 4-acetylbenzaldehyde (l g, 6.74 mmol) in EtOH (I0 ml) was refluxed for 4 h, and was then left standing overnight at r.t. The precipitate was filtered off, washed with EtOH (q.s.) and dried in vacuo to yield the crude product as an off-white solid. The crude product was purified by HPLC (Synergi™: 50 x 250 mm; eluent: l0%-40% CH₃CN (0.1 % TFA)/H₂O (0.1 % I FA); flow rate 80 ml/min; 25 min). The desired fraction were collected and the solvent was evaporated to yield the trifluoroacetic acid sait. The product was neutralized with a saturated NaHCO₃ solution and was extracted with DCM. The separated organic layer was dried, evaporated, and the residue was converted into the HCl sait ( l : l ) with HCI/dioxane. Yield: 0.7 g of compound 33 (30.5 % yield; .HCl).

b) Préparation of compound 24

Compound 33 (0.6 g, l .6 mmol) was neutralized with NH₃,H₂O ( 10 ml) and was extracted with DCM. The separated organic layer was dried (Na₂SO.i), filtered and the solvent was evaporated in vacuo. The residue was dissolved in DCM (20 ml), and

MnO₂ (l .67 g, 19.2 mmol) was added to the solution. The mixture was stirred at r.t. for 48 h. Subsequently, the mixture was filtered over diatomaceous earth. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (eluent: PE/EtOAc 15/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.37 g of compound 24 (69 % yield; white solid).

X

-50Example B5

a) Préparation of compound 5

HCl

A mixture of 2-chloro-6-(lH-pyrrol-l-yl)benzenemethanamine hydrochlorîde (l :l) (l .00 g, 0,004 mol, prepared by a protocol analogue to the protocol described for intermediate 3 in A l.c) and 4-acetylbenzaldehyde (0.59 g, 0.004 mol) in EtOH (10 ml) was stirred and refluxed for 2 h. The mixture was crystallized ovemight. The precipate was filtered off, washed 3 times with EtOH (5 ml) and dried in vacuo at 80 °C. Yield: 0.94 g of compound 5 (63 % yield).

b) Préparation of compound 17

A mixture of H₂O (25 ml) and NH₄OH (5 ml) was added to a suspension of DCM (50 ml) and compound 5 (0.380 g, 0.97 mmol) at 25 °C. The mixture was stirred for 15 min at 25 °C. Subsequently, the layers were separated. The separated organic layer was dried (MgSO-i), filtered and the solvent was evaporated. The residue was stirred in DCM (50 ml) and MnO₂ (0.90 g, 0.01 mol) was added to the solution. The mixture was stirred for 120 h at 25 °C. The mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was crystallized from EtOH. The product was filtered off and dried. Yield: 0.25 g of compound 17 (75 % yield).

Example B6

a) Préparation of compound 14

.HCl

A mixture of 3,5-dichloro-2-(lH-pyrrol-l-yl)benzenemethanamine hydrochlorîde (1:1) (1.86 g, 0.0067 mol, prepared by a protocol analogue to the protocol described for intermediate 3 in Al.c) and 4-acetylbenzaldehyde (0.992 g, 0.0067 mol) in EtOH (20 ml) was stirred and refluxed for 2 h. The mixture was crystallized ovemight. The

product was filtered off, washed 2 times with EtOH (10 ml) and dried //? vacuo at 80 °C. Yield: 2.49 g of compound 14 (91 % yield; HCl).

b) Préparation of compound 26

A mixture of compound 14 (0.812 g, 0.002 mol) in DCM (20 ml) was washed with

H₂O (30 ml), NH4OH (10 ml), and H₂O (20 ml). The organic layer was dried (MgSOj) and filtered. MnO₂ (1.8g, 0.02 mol) was added to the filtrate. The mixture was stirred for 96 h at 25 °C, and was then filtered over diatomaceous earth. The filtrate was evaporated to yield 0.24 g of compound 26 (33 % yield).

Example B7

Préparation of compound 30

A solution of oxone (3.3 g, 5.4 mmol) in H₂O (10 ml) was added slowly to a mixture of 10 intermediate 14 (1.0 g, 2.7 mmol) in THF (15 ml) at r.t. The r.m. was stirred for 2 h.

Subsequently, the mixture was partitioned between DCM and NaHCOi. The organic layer was dried (MgSO-ι), filtered and the solvent was evaporated to yield a light yellow residue. This residue was purified by column chromatography over silica gel (eluent: PE/EtOAc from 8/1 to 3/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 550 mg of compound 30 (50 % yield).

Example B8

Préparation of compound 1

Cl

A mixture of compound 5 (0.372 g, 0.001 mol), DCM (20 ml), NH._fOH (5 ml) and H₂O (20 ml) were stirred for 15 min at 25 °C. The layers were separated. The separated organic layer was washed with H₂O (20 ml), dried (MgSO.|), and filtered. The filtrate

was cooled on ice, and NaBH₄ (0.019 g, 0.0005 mol) was added slowly to the cooled r.m. which was stirred at 0 °C for 2 h. Subsequently, HjO (30 ml) was added and the product was extracted with EtOAc. The separated organic layer was dried (MgSOj), filtered, and the solvent was evaporated. The residue was purified by préparative TLC 5 (eluent: DCM/MeOH 30/1). Yield: 0.18 g of compound 1 (53 % yield).

Example B9

Préparation of compound 34

A mixture of intermediate 3 (0.552 g; 0.002 mol) and intermediate 16 (0.609 g; 0.0026 mol) in EtOH (10 ml) was stirred and refluxed for 3 hours. Then, the mixture was cooled off and crystallized ovemight. The crystals were filtered off and dried to yield 10 0.410 g of compound 34 (50 % yield).

Example BIP

Préparation of compound 39

Intermediate 18 was converted to the free amine form through basic extraction to DCM followed by drying over anhydrous Na₂SO4· This free amine of intermediate 18 (5.55 mmol) was added to a mixture of intermediate 16 (4.27 mmol) in anhydrous DCM (100 15 ml), AcOH (1747 mmol) and an excess of anhydrîc Na₂SO4. The reaction mixture was stirred for 5 days. Then, the reaction mixture was added to an aqueous solution of NalICOi (foaming) until basic. After extraction with DCM, the combined organic layers were dried over anhydrous Na₂SC>4, filtered and evaporated under reduced pressure to yield a crude. The obtained crude was purified with flash chromatography 20 (ISOLERA 1 - Bi otage*) ( 10% EtOAc in hexane to 100% EtOAc). The desired fractions were collected and the solvent was evaporated. Yield: Compound 39 (2.5 % yield).

By using analogous reaction protocols as described in the foregoing examples, the 25 following compounds hâve been prepared. ‘Co. No.’ means compound number. ‘Pr.’ refers to the Example number according to which protocol the compound was

synthesized. In case no sait form is indicated, the compound was obtained as a free base

A compound wherein R³ and R⁴ are hydrogen, and for which no spécifie stereochemistry is indicated for a stereocenter in Table la or Ib, was obtained as a 5 racemic mixture of R and S enantiomers.

Table la:

Co. No.	Pr.	R¹	R²	R³	R⁴	R⁵	R⁶	Sait Form
I	B8	7-Cl	H	H	H	OH η₃ο	H
2	BS	7-Cl	8-Cl	H	H	y... h₃c	H	HCl
3	B8	8-Cl	ÎO-CI	H	H	OH >- HjC	H	.HCl
5	B5.a	7-Cl	H	H	II	y- h₃c	H	HCl
6	B5.a	7-Cl	H	H	H	y- h₃c	H	HBr
8	B3.a	9-Cl	H	H	H	y.. h₃c	H
9	B3.a or B4.a	7-Cl	8-Cl	H	H	y- h₃c	H	HCl
H	B3.a	7-Cl	9-Cl	H	H	y- h₃c	H
12	Bl.a	7-Cl	9-Cl	H	H	J-	H	HCl
14	B6.a	8-Cl	ÎO-CI	H	H	J-	H	.HCl

Co. No.	Pr.	R¹	R²	R³	R³	R⁵	Rfi	Sait Form
32	B2.a	10-C1	H	H	H	h₃c	H
33	B4.a	7-F	9-F	H	H	y- H₃C	H	HCl
34	B9	7-C1	9-C1	H	H	HO-(CH₂)₂-	H	HCl
35	B9	7-C1	H	H	H	HO-(CH₂)₂-	H	.HCl
36	B9	8-C1	10-C1	H	H	HO-(CH₂)₂-	H	HCl
37	B9	7-CI	8-C1	H	H	HO-(CH₂)₂-	H	HCl
38	B9	7-C1	10-C1	H	H	ho-(ch₂)₂-	H	HCl
39	BIO	9-C1	H	H	H	HO-(CH₂)_z-	II
40	Bl.a	7-F	H	H	H		H	HCl
41	Bl.a	7-CI	10-C1	H	H	J-	H	HCl
15	B2.b	10-C1	H	bond	y- h₃c	H
17	B5.b	7-CI	H	bond	J-	H
18	B3.b	9-C1	H	bond	y-	H
20	B3.b or Bl.b	7-F	H	bond	y- h₃c	H
21	B3.b or Bl.b	7-CI	8-C1	bond	y- h₃c	H	HCl
22	Bl.b	7-CI	9-CI	bond	y- h₃c	H
24	B4.b	7-F	9-F	bond	y- h₃c	H
25	Bl.b	7-CI	10-C1	bond	y- h₃c	H

Co. No.	Pi.	R¹	R²	R^J	R⁴	R^s	R⁶	Sait Form
26	B6.b	8-CI	10-C1	bond	h₃c	H
28	B7	7-C1	H	bond	0 II HjC—S--- II o	H
29	B7	7-F	H	bond	o II H₃C—s--- II 0	H
30	B7	7-CI	9-CI	bond	0 II H’C-r 0	H

Table lb:

(i-y)

Co. No.	Pr.	R¹	R¹	R¹	R⁴	R^f’	R⁵	Sait Form
4	B3.a	7-CI	H	H	H	H	y- h₃c
7	B4.a	7-CI	H	H	H	F	y- h₃c	HCl
10	B4.a	7-CI	9-CI	H	H	H	J-	HCl
13	B3.a	7-CJ	9-CI	H	H	F	y- h₃c
16	B4.b	7-CI	H	bond	H	J-
19	B4.b	7-CI	H	bond	F	y- h₃c
23	B4.b	7-CI	9-CI	bond	F	y- h₃c

Co. No.	Pi.	R¹	R²	R³	R⁴	R⁶	R^s	Sait Form
27	B7	7-CI	H	bond	H	O II h₃c—s—- II o
31	B7	7-CI	9-CI	bond	H	0 11 h₃c-j— o

Analytical results

LCMS - General procedure

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 specified in the respective methods below. Flow from the column was split to a Agilent MSD Sériés G1946C and G1956A. MS detector was configured with APIES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary needle voltage was 2500 V for positive and

3000 V for négative ionization mode. Fragmentation voltage was 50 V. Drying gas température was maintained at 350 °C at a flow of 10 l/min.

LCMS Method l

In addition to the general procedure: Reversed phase HPLC was carried out on a YMCPack ODS-AQ, 50x2.0 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 gradient was applied to 40 % A and 60 % B in 4 minutes and hold for 2.5 minutes. Typical injection volumes of 2 μΐ were used. Oven température was 50 °C. (MS polarity: positive)

LCMS Method 2

In addition to the general procedure: Reversed phase HPLC was carricd out on a YMCPack ODS-AQ, 50x2.0 mm 5 pm column with a flow rate of 0.8 ml/min. 2 mobile phases (mobile 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 μΐ were used. Oven température was 50 °C. (MS polarity: positive)

Melting Points

For a number of compounds, melting points (m.p.) were determined with a WRS-2A melting point apparatus purchased from Shanghai Précision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2-5.0 °C/min

Y

Co. No.	R<	\|M+H\|*	LCMS Method	m.p. (°C)
I	3.02	339	2	118.5-121.2
2	4.33	373	l	215,3-216,7
3	3.58	373	2	n.d.
4	3.30	337	2	dcc
5	3.07	337	2	dcc
6	n.d.	n.d.		n.d.
7	4.32	355	I	174.3-176.0
8	3.44	337	2	185.4-186.9
9	3.36	371	2	253.3-256.1
10	3.63	371	2	274.2-274.3
II	3.70	371	2	204.8-206.6
12	3.42	371	2	dcc
13	3.52	389	2	n.d.
14	3.63	371	2	259.3-264.5
15	3.21	335	2	171.4-171.8
16	3.24	335	2	n.d.
17	3.05	335	2	252.3-252.6
18	3.18	335	2	H4.4-H5.7
19	3.07	353	2	146.2-147.7
20	3.9I	3I9	l	215.2-216.0
2I	3.16	369	2	209.2-212.3
22	3.62	369	2	250.2-254.2
23	3.41	387	2	192.3-193.4
24	3.98	337	l	226.9-230.0
25	3.49	369	2	n.d.
26	3.58	369	2	183.6-186.7
27	4.05	371	l	189.8-191.0
28	4.00	37I	l	218.5-219.9
29	3.83	355	l	92.0-95.0

The reported values are melt ranges. The maximum température was 300 °C.

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

Table 2: Rétention time (RJ in min., [M+H]⁺ peak (protonated moiecule), and m.p (melting point in °C) (“n.d ” means not determined; “dec” means decomposed).

Co. No.	R.	\|M+H\|⁺	LCMS Method	m.p. (°C)
30	3.20	405	2	n.d.
31	3.29	405	2	221.2-221.5
32	n.d.	n.d.
33	n.d.	n.d.	-	dcc
34	3.48	373	2	-
35	4.27	339	l	237.3-239.9
36	3.61	373	2	248.7-250.3
37	3,37	373	2	244.9-245.5
3«	3.36	373	2	236.3-237.9

-58’HNMR

For a number of compounds, 'H NMR spectra were recorded on a Broker DPX-300, or on a Broker DPX-400 spectrometer with standard puise sequences, operating at 300 MHz and 400 MHz respectively, using CHLOROFORM-rt (deuterated chloroform,

CDCh) or DMSO-t/_f, (deuterated DMSO, dimethyl-dô sulfoxide) as solvents. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internai standard.

Compound l : ^lH NMR (300 MHz, DMSO-cfc) δ ppm l .30 (d, 7=6.4 Hz, 3H), 3.52 (d, 7=13.5 Hz, 1 H), 4.22 (d, 7=13.5 Hz, 1 H), 4.65 - 4.76 (m, 2H), 5.10 (d, 7=4.2 Hz, IH), 10 5.34-5.39 (m, IH), 6.11 (t, 7=3.2 Hz, 1 H), 7.12 (dd, 7=3.0, 1.5 Hz, IH), 7 26 (d, J=8.0

Hz, 2H), 7.36 (d, 7=7.9 Hz, 2H), 7.41 - 7.48 (m, 3H).

Compound 5: 'H NMR (400 MHz, DMSO-tA) δ ppm 2.63 (s, 3H), 3.88 (br. d, 7=14.1 Hz, IH), 4 59 (d, 7=13.8 Hz, IH), 5.39 (s, IH), 5.83 (s, IH), 6.30 (s, IH), 7.44 (s, IH), 7.60 - 7.74 (m, 3H), 7.92 (d,7=8.0 Hz, 2H), 8.06 (d,7=8.0 Hz, 2H), 10.58 (br. s, IH), 15 10.45 (br. s, 1 H).

Compound 15: ^lH NMR (300 MHz, DMSO-î/₆) δ ppm 2.60 (s, 3H), 4.12 (d, 7=10.9 Hz, IH), 4.92 (d, 7=11.0 Hz, IH), 6.46 (dd, 7=3.8, 2.8 Hz, IH), 6.49 (dd, 7=3.8, 1.7 Hz, IH), 7.39 (t, 7=7.8 Hz, IH), 7.62 (d, 7=7.8 Hz, 2H), 7.70 (dd, 7=2.8, 1.6 Hz, IH), 7.83 (d, 7=8.3 Hz, 2H), 7.99 (d, 7=8.5 Hz, 2H).

Compound 16: 'H NMR (300 MHz, CHLOROFORM-^ Ô ppm 2.56 (s, 3H), 4.14 (br. s, IH), 5.47 (br. s, IH), 6.35-6.49 (m, 2H), 7.15-7.36 (m, 4H), 7.41 (t, 7=7.7 Hz, IH), 7.87 (d, 7=7.7 Hz, IH), 7.97 (d, 7=7.8 Hz, IH), 8.22 (s, IH).

Compound 17: ^]H NMR (300 MHz, CHLOROFORM-7) δ ppm 2.63 (s, 3 H) 4.23 (br. s., 1 H) 5.53 (br. s„ 1 H) 6.33 - 6.60 (m, 2 H) 7.28 - 7.44 (m, 4 H) 7.72 - 7.90 (m, 2 H) 25 7.89 - 8.10 (m, 2 H).

Compound 18: 'H NMR (400 MHz, CHLOROFORM-7) ô ppm 2.64 (s, 3H), 4.71 (br. s, 2H), 6.49 - 6.54 (m, IH), 6,54 - 6.61 (m, IH), 7.32 (d,7=8.1 Hz, IH), 7.41 (s, IH), 7.45 (s, IH), 7.48 (d, 7=8.1 Hz, IH), 7,81 (d, 7=8.0 Hz, 2H), 7.98 (d, 7=8.0 Hz, 2H).

Compound 19: 'H NMR (400 MHz, CHLOROFORM-cZ) Ô ppm 2.65 (d, 7=4.7 Hz, 3H), 30 4.16(br. s, 1 H), 5.51 (br. s, JH), 6.46 (s, 2H), 7.16 (dd, 7=10.6, 8.6 Hz, IH), 7.28 - 7.43 (m, 4H), 7.93 - 8.03 (m, IH), 8.17 (dd, 7=7.2, 2.4 Hz, IH).

Compound 20: 'il NMR (400 MHz, CHLOROFORM-7) δ ppm 2.63 (s, 3 H) 4.69 (br. s., 2 H) 6.39-6.54(m, 2 H) 7.09 (t, 7=8.5 Hz, 1 H) 7.19 (d, 7=8.0 Hz, 1 H) 7.30 - 7.43 (m, 2 H) 7.81 (m, 7=8.3 Hz, 2 H) 7.96 (ni, 7=8.3 Hz, 2 H).

-59Compound 21 : ‘H NMR (400 MHz, CHLOROFORM-dàï/ 0 degrees!) δ ppm 2.65 (s, 3 H), 4.23 (br. d, J=11.4 Hz, 1 H), 5.60 (br. d,>l 1.4 Hz, 1 H), 6.47 - 6.51 (m, 2 H), 7.25 (d, .7=8.6 Hz, 1 H), 7.36 (t, .7=2.2 Hz, 1 H), 7 51 (d, .7=8,6 Hz, 1 H), 7 81 (d, .7=8 3 Hz, 2 H), 7.96 (d, .7=8.4 Hz, 2 H).

Compound 22: 'H NMR (400 MHz, CHLOROFORM-rt) δ ppm 2 63 (s, 3H), 4.17 (br. s, 1H), 5.50 (br. s, 1H), 6.43 - 6.56 (m, 2H), 7 30 (s, IH), 7 35 (s, 1H), 7.42 (s, 1H), 7.80 (d, .7=8,0 Hz, 2H), 7.96 (d, .7=8 0 Hz, 2H).

Compound 23: 'H NMR (300 MHz, CHLOROFORM-ίΖ) δ ppm 2.65 (d, .7=4.7 Hz, 3 H) 4.13 (br. s., 1 H) 5.45 (br. s., 1 H) 6.47 (ni,.7=2.3 Hz, 2 H) 7.17 (dd, .7=10 5, 8.7Hz, 1 H) 7.30 (d, .7=1.9 Hz, I H) 7 35 (t,.7=2.2 Hz, 1 H) 7 41 (d, .7=1 9 Hz, 1 H) 7.83 - 8.02 (m, 1 H) 8.16 (dd, .7=7.1,2.4 Hz, 1 H)

Compound 24: 'H NMR (400 MHz, CHLOROFORM-iT) Ô ppm 2.64 (s, 3 H) 4.72 (br. s., 2 H) 6.49 (ni,.7=2.3 Hz, 2 H) 6.85 (td, .7=8.9, 2.3 Hz, 1 H) 6.96 (d, .7=9.0 Hz, l H) 7.35 (t, .7=2.0 Hz, 1 H) 7.80 (m, .7=8.3 Hz, 2 H) 7.96 (m, .7=8.3 Hz, 2 H).

Compound 25: *H NMR (400 MHz, CHLOROFORM-iT) δ ppm 2 64 (s, 3 H) 4.11 (d, .7=11.5 Hz, 1 H) 5.52 (d, .7=9,3 Hz, 1 H) 6.35 - 6.64 (m, 2 H) 7.35 - 7.48 (m, 2 H) 7.54 7.68 (m, 1 H) 7.85 - 8.09 (m, 4 H).

Compound 26: 'H NMR (400 MHz, DMSO-î/₆) Ô ppm 2.60 (s, 3H), 4.10 (d, .7=11.0 Hz, 1 H), 4.94 (d, .7=11.0 Hz, 1H), 6.45 - 6.53 (ni, 2H),7.71 (br. s., 1H), 7.77 - 7.88 (m, 4H), 7.99 (d, ,7=8.1 Hz, 2H).

Compound 27: 'H NMR (300 MHz, CHLOROFORM-rt) δ ppm 3.06 (s, 3 H) 4.21 (br. s., 1 H) 5.55 (br. s., 1 H) 6.49 (br. s., 2 H) 7.28 - 7.47 (m, 4 H) 7.61 (t, .7=7.7 Hz, 1 H) 7.97 - 8.13 (m, 2 H) 8.29 (br. s., 1 H).

Compound 28: 'H NMR (300 MHz, DMSOY,) δ ppm 3.25 (s, 3 H) 4.16 (br. s., 1 H) 5.32 (br. s„ 1 H) 6.54 (m, J=2.3 Hz, 2 H) 7.38 - 7.60 (m, 3 H) 7.79 (t, .7=2,2 Hz, 1 H) 7.83 - 7.93 (m, 2 H) 7.93 - 8.00 (m, 2 H).

Compound 29. 'H NMR (300 MHz, CHLOROFORM-tT) ô ppm 3.06 (s, 3H), 4.81 (br. s, 2H), 6.48 - 6.57 (m, 2H), 7.12 (t, .7=8.5 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.38 (td, J=8.3, 5.8 Hz, 1H), 7.45 (t, J=2.3 Hz, 1H), 7.90 - 8.02 (m, 4H).

Compound 30: 'H NMR (300 MHz, CHLOROFORM-c/) Ô ppm 3.06 (s, 3 H) 4.19 (br. s., 1 H) 5.50 (br. s., 1 H) 6.38 - 6.60 (m, 2 H) 7.30 (d, J=1.9 Hz, 1 H) 7.35 - 7.40 (m, 1 H) 7.43 (d, J=1.9 Hz, 1 H) 7.84 - 8.04 (m, 4 H).

-60Compound 31 : *H NMR (300 MHz, CHLOROFORM-î/) Ô ppm 3.05 (s, 3 H) 4.17 (br. s., I H) 5.49 (br. s., I H) 6.36-6.58 (m, 2 H) 7.31 (d, J=l.9Hz, l H) 7.35 - 7.40 (m, l H) 7.42 (d, .7=1.9 Hz, 1 H) 7 60 (t, ./=7.7 Hz, I H) 8.03 (ni, >7.7 Hz, 2 H) 8.27 (s, 1 H).

Compound 34: 'H NMR (400 MHz, DMSO-î/₆) δ ppm 2.75 (t, >6.8 Hz, 2 H) 3.61 (t, >6.8 Hz, 2 H) 3.81 (d, >14.3 Hz, 1 H) 4.53 (d,>14.1 Hz, 1 H) 4.65 (br. s„ 1 H) 5.29 (br. s., 1 H) 5.87 (br. s., 1 H) 6.28 (br. s.» 1 H) 7.33 (d, ./=7 8 Hz, 2 H) 7.46 (br. s., 1 H) 7.56 (d, >7.8 Hz, 2 H) 7.78 (s, 1 H) 7.83 (s, 1 H) 9.66 (br. s., 1 H) 10.38 (br. s., 1 H). Compound 35: 'H NMR (400 MHz, DMSCMi) δ ppm 2.76 (t, ./=6.8 Hz, 2 H) 3.62 (t, ,7=6.9 Hz, 2 H) 3.84 (d, > 12.5 Hz, 1 H) 4.53 (d,>14.l Hz, 1 H) 4.67 (br. s., 1 H) 5.17 (br. s., 1 H) 5.84 (br. s., I H) 6.28 (t, .7=3.1 Hz, I H) 7.32 (d, ./=8.0 Hz, 2 H) 7.39 (br. s„ 1 H) 7.56 - 7.74 (m, 5 H) 10.13 (br. s., 1 H) 10.42 (br. s„ 1 H).

Compound 36: 'H NMR (300 MHz, DMSO-î/₆) δ ppm 2.76 (t, >6.8 Hz, 2 H) 3.51 3.69 (m, 3 H) 4.36 (d, >13.9 Hz, 1 H)4.67(br s., 1 H)5.26(br. s„ 1 H) 5.91 (d, ./=3.8 Hz, 1 H) 6.28 (t, .7=3.4 Hz, 1 H) 7 33 (m, .7=7.9 Hz, 2 H) 7.38 (dd, .7=3,0, 1.5 Hz, 1 H) 7.63 (m, >7.9 Hz, 2 H) 7.78 (d, >2.3 Hz, 1 H) 8 06 (d, .7=2,3 Hz, 1 H) 9.77 (br. s., 1 H) 10.31 (br. s., 1 H)

Compound 37: ’H NMR (300 MHz, DMSO-î/₆) δ ppm 2.76 (t, .7=6.8 Hz, 2 H) 3.62 (t, ,7=7.0 Hz, 2 H) 3.88 (d, >13.9 Hz, 1 H) 4.58 (d, >13.9 Hz, 1 H)5.25(br. s., 1 H) 5.86 (d, >3.4 Hz, 1 H) 6.29 (t, >3.4 Hz, 1 H) 7.33 (d, >8.3 Hz, 2 H) 7.41 (dd,>2.8, 1.7 Hz, 1 H) 7.59 - 7.68 (m, 3 H) 7.96 (d, .7=9.0 Hz, 1 H) 10.15 (br. s„ 1 H) 10.44 (br. s., 1 H).

The 'H NMR spectrum of compound 39 was recorded on a 400 MHz Bruker Avance III nanobay spectrometer: (DMSO-d6) Ô ppm 2.71 (t, .7=8 Hz, 2H), 3.48 (s, 1H), 3.57 (dt, .7=8 Hz, 4 Hz, 2H), 3.86 (d, >12 Hz, 1H), 4.65 (t, > 4Hz, 1H), 4 71 (s, 1H), 5.36 (m, 1H), 6.10(t, >4Hz, 1H), 7.16 (d, > 8Hz, 2H), 7.17(m, 1 H),7.33 (d, > 8Hz, 2H), 7.39 (dd, >8 Hz, 2 Hz, 1H), 7.42 (d, >8 Hz, 1H), 7.57 (d, >2 Hz, 1H).

D. Pharmacological exampies

Example D. 1 : Measurement of antifungal activity in vitro

The standard susceptibility screen was performed in 96-well plates (U-bottom, Greiner Bio-One). Serial dilutions (2-fold or 4-fold) of 20 mM compound stock solutions were made in 100 % DMSO, followed by an intermediate dilution step in water. These serial dilutions (10 μΙ) were then spotted onto test-plates that could be stored in the dark at 4 °C for a maximum period of2 weeks. An adéquate broad dose-range was included with 64 μΜ as the highest in-test concentration. The culture medium RPMI-1640 was

supplemented with L-glutamine, 2% glucose and buffered with 3-(7V-morpholino)propanesulfonic acid (MOPS) at pH 7.0 ±0.1

The different fungal species/i sol aies (Table 3a) were cryopreserved and I i 1000 diluted in medium just prior touse. A standard inoculum of200 pl containing I0³ colony5 forming unit (cfu) was then added to each well. A positive control (100 % growth = fungal culture without antifungal) and a négative control (0 % growth = RPMÏ-MOPS medium) were included on each plate. Optimal incubation time and température were dépendent on the fungal species and varied from 24 h for yeasts (37 °C) to one week or more for dermatophytes (27 °C). Inhibition of fungal growth was measured after adding 10 10 μΐ 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 fluorimetric reading (λ«χ550 nm and 590 nm) after an additional incubation period (‘resa’ time mentioned in Table 3a). Results are shown in Table 3b as pICso values.

Table 3a: Incubation conditions for the different fungal species. ‘Resa time’ represents the additional incubation time after the addition of resazurin to the test System.

Species	Température (°C)	Time	Resa time
Microsporum catds	27	9 days	24 hours
Trichophyton mentagrophytes	27	7 days	24 hours
Trichophyton rubrum	27	7 days	24 hours
Scedosporium apiosperm uni	37	48 hours	17 hours
Scedosporium prolificans	37	48 hours	17 hours
Sporothrix schenkii	27	4 days	24 hours
Aspergillus fumigatus	27	48 hours	17 hours
Candidct parapsilosis	37	24 hours	4 hours
Cryptococcus neoformans	37	24 hours	4 hours
Rhizopus oryzae	37	24 hours	6 hours
Rhizomucor miehei	37	48 hours	17 hours
Mucor circinelloides	27	48 hours	17 hours

Table 3b: Activities of the test compounds in vitro (‘n.d.’ means not determined; ‘lnf.’ nieans infection, values are plCso values)

lnf. ‘A’: Sporothrix schenkii B62482

Inf. ‘B’: Microsporum canis B68128 lnf. ‘C’: Trichophyton ruhriim B68183

Inf, ‘D’: Candidaparapsilosis B66126

Inf, ‘G’: Trichophyton mentagrophvies B70554

Inf Ή’: Scedosporiumapiospermum IHEM3817

Inf. T: Scedosporium prolificans IHEM2H57

Inf. ‘J’: Rhizopus oryzae IHEM5223

Inf. Έ’: Aspergillits fitmigaïus B42928 Inf. ‘K’: Rhizomitcor niiehei IHF.Ml3391

Inf, * F’: Cryptococcus neoformans B66663 Inf. ‘ L’ : Mucor circinelloides 1HEM21105

Co. No.	Inf. A	Inf. B	Inf. C	Inf. D	Inf. E	Inf. F	Inf. G	Inf. H	Inf*. 1	Inf. J	Inf. K
5	4.4	6.1	6.3	5.1	5.7	4.6	6.2	n.d.	n.d.	n.d.	n.d.
6	4.7	6.2	6.4	<4.2	4.5	< 4.2	n.d.	n.d.	n.d.	n.d.	n.d.
17	<4.5	6.7	7.4	<4.5	<4.5	<4.5	6.6	<4.2	<4.2	<4.2	<4.2
9	5.0	5.6	5.7	<4.2	<4.2	4.5	4.5	n d.	n.d.	n.d.	n.d.
14	4.6	5.6	6.2	<4.2	<4.2	4.3	4.6	n.d.	n.d.	n.d.	n.d.
26	5.9	6.2	7.1	<4.2	5.8	5.0	5.4	n.d.	n.d.	n.d.	n.d.
1	<4.2	5.5	5.5	<4.2	<4.2	4.2	4.9	n.d.	n.d.	n.d.	n.d.
21	<4.2	<4.2	<4.2	<4.2	<4.2	<4.2	<4.2	n.d.	n.d.	n.d.	n.d.
2	<4.2	4.7	<4.2	< 4.2	<4.2	<4.2	<4.2	n.d.	n.d.	n.d.	n.d.
3	<4.2	5.0	6	<4.2	<4.2	4.7	4.4	n.d.	n.d,	n.d.	n.d.
4	<4.2	5.0	5.3	<4.2	<4.2	<4.2	4.6	n.d.	n.d.	n.d.	n.d.
11	4.3	6.0	5.7	<4.2	<4.2	5.2	5.3	n.d.	n.d.	n.d.	n.d.
12	<4.2	4.9	5.7	<4.2	<4.2	<4.2	5.1	n d.	n.d.	n.d.	n.d.
10	<4.2	5.3	5.7	<4.2	<4.2	<4.2	5.2	n.d.	n.d.	n.d.	n.d.
22	5.4	7.0	7.3	4.6	6.6	5.0	6.5	4.3	5.9	<4.2	<4.2
16	4.6	6.5	7.3	<4.2	6.2	<4.2	6.4	<4.2	<4.2	<4.2	<4.2
25	<4.2	5.5	5.3	<4.2	<4.2	<4.2	5.0	n.d.	n.d.	n.d.	n.d.
27	<4.2	5.2	5.1	<4.2	<4.2	4.2	5.1	n.d.	n.d.	n.d.	n.d.
31	<4.2	<4.2	<4.2	<4.2	<4.2	<4.2	<4.2	n.d.	n.d.	n.d.	n.d.
29	<4.2	5.0	5.6	<4.2	4.3	4.5	5.2	n.d.	n.d.	n.d.	n.d.
28	<4.2	5.9	5.7	<4.2	<4.2	<4.2	5.6	<4.2	5.1	<4.2	<4.2
13	<4.2	5.1	5.7	<4.2	<4.2	<4.2	<4.2	n d.	n.d.	n.d.	n.d.
30	4.3	5.4	5.7	<4.2	4.2	4.8	5.2	n.d.	n.d.	n.d.	n.d.
8	4.5	<4.2	5.7	<4.2	4.9	4.3	5.3	n.d.	n.d.	n.d.	n.d.
7	< 4.2	5.1	6.0	<4.2	<4.2	<4.2	5.2	n.d.	n.d.	n.d.	n.d.
23	<4.2	<4.2	<4.2	<4.2	<4.2	<4.2	<4.2	n.d.	n.d.	n.d.	n.d.
15	5.8	6.2	6.9	<4.2	6.3	5.7	6.4	5.0	5.7	<4.2	5.1
19	<4.2	5.8	6.7	< 4.2	5.7	<4.2	6.1	<4.2	5.9	<4.2	<4.2
18	5.1	5.7	6.5	4.2	6.3	5.8	6.0	4.4	4.9	<4.2	<4.2
24	4.7	5.7	6.9	5.4	6.1	5.0	6.2	5.1	5.6	<4.2	<4.2
20	<4.2	5.9	7.0	<4.2	6.3	<4.2	6.4	<4.2	6.2	<4.2	<4.2

Co. No.	Inf. A	Inf. B	Inf. C	Inf. D	Inf. E	Inf. F	Inf. G	Inf. H	Inf. 1	Inf. J	Inf. K
34	<4.2	5.7	4.9	<4.2	<4.2	4.5	4.7	n.d.	n.d.	n.d.	n.d.
35	<4.2	4.4	5.1	<4.2	<4.2	4.3	4.9	n.d.	n.d.	n.d.	n.d.
36	<4.2	4.3	4.5	<4.2	<4.2	4.6	4.7	n.d.	n.d.	n.d.	n.d.
37	4.8	<4.2	4.5	<4.2	4.4	5.0	4.4	n.d.	n.d.	n.d.	n.d.
38	<4.2	5.7	5.1	<4.2	<4.2	4.7	4.7	n.d.	n.d.	n.d.	n.d.

The pICso values for Inf. ‘L’ were determined for compounds 15, 16, 18, 19, 20, 22, 24, and 28, and were <4.2.

Example D.2: Liver metabolic stability assay

Liver préparations (microsomal fractions) were obtained from BD Gentest (San José, Ca, US). Metabolic stabilily was assessed using the following assay conditions. Ail incubations were conducted by shaking réaction mixtures (250 μΐ) containing I mg of microsomal protein preparation/inl, NADPH-generaling System (“NADPH” means βnicotinamide adenine dinucleotide phosphate, reduced) (0.1 mM N ADP, 5.0 mM

MgCh, 1.65 mM glucose-6-phosphate and 0.125 U glucose-6-phosphate dehydrogenase), and 0.5 M Na-K-phosphate buffer (pH 7.4). The mixture was preincubated at 37 °C for 5 min and the enzymatic reaction was started by addition of 5 μΜ test compound. After 0 (control) and 15 minutes (min), the reactions were terminated by addition of DMSO (500 μΐ). The precipitated material was removed by centrifugation at 1200 g for 10 min. The supematant was analysed by LC-MS/MS on a ThermoFinnigan LCQ Deçà XP ion-trap mass spectrometer equipped with an atmospheric pressure chemical ionisation source. Calculation of %-compound rentaining was as described by Kantharaj et al. 2003 ((Kantharaj E., Tuytelaars A, Proost PEA, Ongel Z, van Assouw HP & Gilissen RAHJ (2003). Simultaneous measurement of drug metabolic stability and identification of métabolites using iontrap mass spectrometry. Rapid Commun. Mass Sprectrom, vol 17, 2661-2668), and the %-compound metabolised was calculated by the following équation : %-compound metababolised = 100%- %-compound rentaining.

The results are shown in Table 4.

Table 4: % -compound metabolised using human liver microsomes (KLM), mouse liver microsomes (mLM) and guinea pig microsomes (gpLM) _______________

Co. No.	%-conipound metabolised Met hLM	%-compound metabolised Met mLM	%-compound metabolised Met gpLM
5	59	72	88
17	50	70	84
26	19	45	44
21	17	24	64
22	27	37	73
16	87	97	100
25	80	n.d.	n.d.
13	69	n.d.	95
23	22	n.d.	39
15	17	n.d.	44
19	36	n.d.	80
18	17	n.d.	36
24	20	n.d.	53
20	26	n.d.	88
28	2	41	21
1	43	51	86

Example D.3: Plasma protein binding assay

Plasma was freshly prepared by centrifugation of guinea pig blood for 10 min at 1900 g 5 in K3-EDTA (Ethylenediaminetetraacetic acid) coated tubes. The plasma protein binding of compounds was assessed at 5 μΜ concentrations as described by Van Liemp et al. 2010 (Van Liemp S, Morrison D, Sysmans L, Nelis P & Mortishire-Smith R (2010). Development and Validation of a Higher-Throughput Equilibrium Dialysis Assay for Plasma Protein Binding. Journal of the Association for Laboratory

Automation, 2010, in press) using a rapid equilibrium device (RED). Briefly, guinea pig plasma was mixed with 5 μΜ test compound and then applied to the RED. Equilibrium was achieved after 4 h incubation at 37 °C. Compound concentrations in the buffer and plasma compartment of the device were measured by LC-MS/MS.

For compound 15, the fraction bound was 98.48 %.

-65Example D.4: Cytochrome P450 inhibition assavs

Protocol A: Cytochrome P450 resulfs (% inhibition) itsingcDNA expressed proteins. Ail fluorogenic based assays were performed in Black Costar 96-well plates according to Crespi et al 1997 with minor modifications (Crespi CL, Miller VP & Penman BW (1997). Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem. Vol 248, 1898-1900). Assay conditions are outlined in Table 5a. For cytochrome P450 3A4, three different fluorogenic substrates were used. Each reaction mixture consisted of the appropriate concentration of enzyme, NADPHgenerating System (“NADPH” means β-nicotinamide adenine dinucleotide phosphate, reduced), substrate in sodium/potassium buffer (pH 7 4). For each cytochrome P450 batch Michealis-Menten kinetics were determined using 11 concentrations.

To détermine IC50 values or %-inhibition at 10 μΜ with the fluorogenic substrates, inhibitor stock solutions of 5mM were made in dimethylsulfoxide (DMSO). Thereafter, further dilutions were made in acetonitrile. The final organic solvent concentration was, causing less than 10% inhibition, 2% (v/v). The compounds were serially diluted to give final concentrations ranging from 1 nM to 10 μΜ. The reation mixtures, whereby 1 pL of buffer was replaced by compound solution, were pre-warmed for 5 min at 37 °C and the reaction was initiated by the addition of β-nicotinamide adenine dinucleotide phosphate (NADP+). Reactions were terminated by addition of stopping reagent and the fluorescence was measured using a Fluoroscan (Labsystems, Brussel, Belgium).

Table 5a: Cytochrome P450 in tibition assay conditions

Condition	CYP1A2	CYP2C9	CYP2D6	CYP3A4
Enzyme Amouiit(pmol P450/ml)	5	60	42	84/20/5
Incubation Time (min)	15	30	45	30/30/10
Substrate	CEC	MFC	AMMC	BFC/BQ/DBF
Substrate concentration (KM)	5	10	3	150/150/150
Excitation (nm)	410	405	405	405/405/485
Emission (»^m)	460	535	460	535/535/535

In Table 5a, the following abbreviations were used: 3-cyano-7-ethocycoumarin (CEC), 7-methoxy-4-trifluoromethylcoumarin (MFC), 3-[2-(N,N-diethyl-Nmethylamino)ethyl]’7-methoxy“4-methylcoumarin (AMMC), 7-benzyloxytrifiuoromethyl coumarin (BFC), 7-benyloxyquinoline(BQ)and dibenzyl fluorescein (DBF)

Table 5b shows the Cytochrome P450 results (% inhibition) using cDNA expressed protein s at 10 μΜ

Co. No.	hCYP3A4_ BFC_ Pet Inh	hCYP3A4_ BQ_ Pet Inh	I1CYP3A4 DBF Pet Inh	hCYP2C9_ MFC Pet Inh	hCYP2D6_ AMMC_ Pet Inh	hCYPlA2_ CEC_ Pet Inh
26	33	32	55	69	74	34
21	0	26	26	54	39	27
22	39	63	89	85	53	20
16	29	46	64	84	55	55
25	21	29	21	45	11	21
13	81	78	91	61	51	64
23	51	56	40	51	3	17
15	1	40	16	60	63	38
19	26	49	49	60	33	44
24	3	39	3	54	3	18
20	1	25	5	43	20	18

Table 5c Cytochrome P450 results (% inhibition) using cDNA expressed protein at 10 μΜ - présent application vs. prior art

hCYP3A4_ BFC_ Pet Inh	hCYP3A4_ BQ_ Pet Inh	hCYP3A4_ DBF_ Pet Inh	hCYP2C9_ MFC_ Pet Inh	hCYP2D6_ AMMC_ Pet Inh	hCYPlA2_ CEC_ Pet Inh
	O		ΡυΊι
				.HCl
			H T
			Cl
	Compound 5 of the présent ap	pli cation
57	57	70	54	53	12

hCYP3A4_	hCYP3A4_	I1CYP3A4	hCYP2C9_	liCYP2D6_	hCYPlA2_
BFC_	BQ_	DBF_	MFC_	AMMC_	CEC_
Pet Inli	Pet Inh	Pet Inh	Pet Inh	Pet Inh	Pet Inh

Cl __ Hydrochloric acid sait of compound 2 of WO02/34752 __ | 57 T 6⁹ I ⁶⁸ I ,48

___ ____Compound 18 of the présent application______ ! 50 I 40 J 69 I 20 ^: 21

Compound 23 ofWO02/34752 _______ ] 66 | 70 | 50 | 33 40

Cl ________Compound 17 of the présent application___ | 33 2I ; 82 I 1833

hCYP3A4_	I1CYP3A4	hCYP3A4_	hCYP2C9_	I1CYP2D6_	hCYPlA2_
BFC_	BQ_	DBF_	MFC_	AMMC_	CEC_
Pet Inh	Pet Inh	Pet Inh	Pet Inh	Pet Inh	Pet Inh

Compound 22 of WO02/34752 I 64 41 !

Compound 28 of the présent application l | 48 | 5

Protocol B: Human liver microsomal cytochrome P450 inhibition assays.

The CYP450 inhibition potential was also determined for compound 18 using human liver microsomes against cytochrome l A2 and 2D6.

Test compounds (TCs) were incubated across a concentration range (0 to 30 micromolar) with human liver microsomes and separate probe substrates ((resorufin for CYPl A2 and dextromethorphan for CYP2D6) to estimate the ICjo-value for inhibition of the probe substrate by the TC. TCs were dissolved in solvent condition Λ (0.15% DMSO + 0.46% acetonitrile) or condition B (0.30% DMSO + 0.68% acetonitrile). Assays were performed in 0.1 M phosphate buffer (pH 7.4), containing l .0 mg/ml human liver microsomes (BD Gentest) and the probe substrate (either resorufin or dextromethorphan) and a range of test compound concentrations (0 to 30 micromolar) in a total volume of 250 microliters. After a 10 min pre-incubation at 37 °C, the reaction was started with addition of NADPH at a final concentration of 1.0 mM. After an incubation of 10 min at 37 °C the reaction is quenched with 2 volumes of chilled DMSO, The samples are centrifuged for I0 min at 4 °C at 4000 rpm and the supernatant is analyzed. Analysis for CYPl A2 with resorufin was performed by fluorescence while the CY2D6 inhibition potential was assessed using LC-MS détection.

No IC50 curves could be constructed to détermine the IC50-values for Compound 18 since the %-inhibition for the two cytochrome P450s (l A2 and 2D6) was weak : For CYPl A2 using solvent condition A, the inhibition was 20-25 % at 30 μΜ; and by

using solvent condition B, the inhibition was 25-35 % at 30 μΜ. For CYP2D6 using solvent condition B, the inhibition was 40-45 % at 30 μΜ.

Protocol C: Human liver microsoma! cytochrome P450 cocktail inhibition assay

Test compounds (TCs) were incubated across a concentration range (0 to 30 micromolar) with human liver microsomes and probe substrates for each of the six cytochrome P450s to estimate the IC₅o-value for inhibition of the probe substrate by the TC.

Probe substrates and final assay concentrations with the appropriate internai standard are outlined in Table 6a.

Assays were performed in 0.1 M phosphate buffer (pH 7.4), containing 0.2 mg/ml human liver microsomes (BD Gentest) and a probe substrate mix consisting of: phenacetin, tolbutamide, S-mephenytoin, dextromethorphan, amodiaquine and midazolam (Table 6a) and a range of test compound concentrations (0 to 30 micromolar) in a total volume of 100 microliters. After a 10 min pre-incubation at 37 °C, the reaction was started with addition of NADPH at a final concentration of 1.0 mM. The final organic solvent in the incubation is 0.15% DMSO and 0.8% acetonitrile. After an incubation of 10 min at 37 °C the reaction is quenched with 1.6 volumes of chilied quenchîng solution consisting of DMSO and the internai standards (Table 6a).

The samples are centrifuged for 10 min at 4 °C at 4000 rpm and 60 microliters supematant is diluted with 180 microliters water. Each sample is injected onto a UPLC/MS System for the simultaneous measurement of the probe substrate métabolites and their associated deuterated internai standards. Percentage inhibition is calculated according to :

%-inhibition = (1 - Ri/R) * 100, whereby Ri and R are the métabolite to internai standard peak area ratios in the presence and absence of inhibitor respectively. Percentage inhibition data are plotted against the Log transformed test compound concentration and after curve fitting the ICso-value is determined

Table 6a: Probe substrate and internai standards for the Human liver microsomal P450 inhibition cocktail assay.

Cytochrome P450	Probe Substrate	Probe Substrate concentration (microM)	Internai Standard
1A2	Phenacetin	80	Acetaminophen-D4
2C8	Amodiaquine	2	N-desethy 1 am od i aqui n e- D4

Cytochrome P450	Probe Substrate	Probe Substrate concentration (microM)	Internai Standard
2C9	Tolbutamide	100	4-hy droxytol butami deD9
2C19	S-Mephenytoin	30	4-hydroxymephenytoin- D3
2D6	Dextromethorphan	3	D extromethorph an-D3
3A4/5	Midazolam	2	l ’-hydroxymidazolam- D4

Tablc 6b shows the pICso values - présent application vs prior art

1A2 Phen	2C8 Amod	2C9Tolbut	2C19 S-Meph	2D6 Dextro	3A4 mido
				Xji
			o	nX	V
					Cl
		Compound 17 of the présent application
<5.0	<5.0		<5.0	<5.0		<5.0	<5.0
				Π
				N—'	V
					Cl
			Compound 22 of WO02/34752
<5.0	<5.0		<5 0	5.8		<5.0	<5.0
			\ /o=s—(^z O \=		Q
					Cl
		Compound 28 oi	The présent application
<5.0 I	<5.0		<5.0	<5.0		5.12	Not detennïned

1A2 Phen	2C8 Amod	2C9Tolbut	2CI9 S-Meph	2D6 Dextro	3A4 mido
	C	\ /=\	Pys
				HCl
			H T
			Cl
	Compound 5 of the présent application
<5.0	5J	5.5	5.5	5.5	5.1

.HCl

<5.0

Hydrochloric acid sait of compound 2 of WO02/34752 <5.0 | 5,0 j 6.0 5.5

5.2

<5.0

CompoundJ>of the présent application

5.1 I 5.6 | 5.9 5.7 ! 5.3

<5.0

Compound I of the présent application <5.0

5.29

<5.0

Compound 2 of WO02/34752

I [ <5.0 ! 5.1 6.I 5.7 <5.0

Example D.5: Calculated log of the octanol/water partition coefficient (ClogP)

The calculated log of the octanol/water partition coefficient was obtained by using BioLoom software (BioByte).

-73Table 7: ClogP

Compound (présent application)	ClogP
18	4.13
17	3.92
28	3.10
5	3.71
8	3.91
6	3.71
4	3.71
1	3.54
Compound (prior art)	ClogP
25 (WO02/34752)	5.30
23 (WO02/34752)	5.47
22 (WO02/34752)	5.47
32 (WO02/34752)	5.30
16 (WO02/34752)	5.30
2 (WO02/34752)	5.30
HCl sait of compound 2 of WO02/34752	5.30

E. Composition example “Active ingrédient as used throughout these examples, relates to a compound of

Formula (I), including any stereochemically isomeric form thereof, a pharmaceutically 5 acceptable sait thereof or a solvaté thereof; in particular to any one of the exemplified compounds.

Example El : Injectable solution.

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams sodium hydroxide are dissolved in about 0.5 I of boiling water for injection. After cooling to about 50°C there are added while stirring 0.05 grams propylene glycol and 4 grams of the active ingrédient. The solution is cooled to room température and supplemented with water for injection q.s. ad l l, gîving a solution comprisîng 4 mg/mi of active ingrédient. The solution is sterilized by filtration and fi lied in stérile containers.

Example E2 : Transungual composition.

0.144 g KH2PO4, 9 g NaCI, 0.528 g ΝηϊΗΡΟτ.ΣΗϊΟ is added to 800 ml H₂0 and the mixture is stirred. The pH is adjusted to 7.4 with NaOH and 500 mg NaNj is added. Ethanol (42 v/v %) is added and the pH is adjusted to 2.3 with HCl.

-7415 mg active ingrédient is added to 2.25 ml PBS (Phosphate Buffer Saline)/Ethanol (42 %; pH 2.3) and the mixture is stirred 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 ail active ingrédient is dissolved, yielding the desired transungual composition.

Example E3 : Oral drops

500 Grams of the A J. is dissolved in 0.5 I of a sodium hydroxide solution and 1.5 I of the polyethylene glycol at 60-80 °C. After cooling to 30~40°C there is added

1 of polyethylene glycol and the mixture is stirred well. Then there is added a solution of 1750 grams of sodium saccharin in 2.5 I of purified water and while stirring there are added 2.5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of 50 I, providing an oral drop solution comprising 10 mg/ml of AJ . The resulting solution is filled into suitable containers.

Example E4 : Capsules

Grams of the A J., 6 grams sodium lauryl sulfate, 56 grams starch, 56 grams lactose,

0.8 grams colloïdal silicon dioxide, and 1.2 grams magnésium stéarate are vigorously stirred together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, comprising each 20 mg of the active ingrédient.

Example E5 : Film-coated tablets

Prepa ration of tab let core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 grams starch is mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 grams microcrystalline cellulose and 15 grams hydrogenated vegetable oil. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ingrédient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturated éthanol 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 magnésium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus.

-75Example E6 : 2 % Cream

Stearyl alcohol (75 mg), cetyl alcohol (20 mg), sorbitan monostearate (20 mg) and isopropyl myristate (l 0 mg) are introduced in a doublewall jacketed vessel and heated until the mixture has completely molten. This mixture is added to a seperately prepared 5 mixture of purified water, propylene glycol (200 mg) and polysorbate 60 ( 15 mg) having a température of 70 to 75 °C while using a homogenizer for liquids. The resulting mixnire is allowed to cool to below 25°C while continuously mixing. A solution of A.1.(20 mg), polysorbate 80 (1 mg) and purified water q.s. ad lg and a solution of sodium sulfite anhydrous (2 mg) in purified water are next added to the émulsion while continuously mixing. The cream is homogenized and filIed into suitable tubes

Example E7 : 2 % Cream

A mixture of A.I. (2 g), phosphatidyl choline (20 g), cholestérol (5 g) and ethyl alcohol (10 g) is stirred and heated at 55-60 °C until complété 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 complété.

Claims

1. A compound of formula (I) or a stereoisomeric form thereof, wherein

R¹ is hydrogen, halo, Cι-ialky 1 or Ci-ialkyloxy;

R² is hydrogen or halo;

R³ and R⁴ arc hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is C|_;aikylcarbonyl, Ci^alkylsulphonyl, Cnalkylsulphinyl, or Ci^alkyl substituted with one hydroxyl moiety;

R⁶ is hydrogen or halo;

or a pharmaceutically acceptable addition sait or a solvaté thereof.

2. The compound according to claim 1 wherein

R* is hydrogen, halo, Ci_;alkyl or Ci-ialkyloxy;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is Cwalkylcarbonyl; Ci_ialkylsulphonyl; or Ci-»alky 1 substituted with one hydroxyl moiety;

R⁶ is hydrogen or halo;

or a pharmaceutically acceptable addition sait or a solvaté thereof.

3. The compound according to claim 1 wherein

R¹ is chloro or fluoro;

R² is hydrogen, chloro of fluoro;

R⁵ is methylcarbonyl, methylsulphonyl or 1-hydroxyethyl;

R^e is hydrogen or fluoro.

4. The compound according to claim 1 wherein

R⁵ is C Malkylcarbonyl.

5. The compound according to claim l wherein

R¹ is halo.

6. The compound according to claim 1 wherein the compound is a compound of formula (I-x) or (I-y) (l-x) (i-y)

7. The compound according to any one of daims 1 to 6 wherein R³ and R⁴ are taken together to form a bond.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of a compound as defined in any one of daims 1 to 7.

9. A compound as defined in any one of daims 1 to 7 for use as a médicament.

10. A compound as defined in any one of daims 1 to 7 for use in the treatment or prévention of a fungal infection

11. The compound for use according to claim 10 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp.; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Malassezia futfur;

Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp., Pénicillium spp.; Pénicillium marneffei; Blastoschizomyces.

12. The compound for use according to claim 10 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida parapsilosis; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii;

Epidermophytonfloccosum; Microsporum spp ; Trichophyton spp.; Fusarium spp,; Rhizomucor spp.; Mucor circinéUoides; Rhizopus spp.; Acremonium spp.; Paecilomyces; Scopulariopsis; Arlhrographis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp.; Pénicillium spp., Pénicillium marneffei;

5 Blastoschizomyces.

13. The compound for use according to claim 10 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and AspergiUus

10 fumigatus.