OA16460A

OA16460A - Novel antifungal 5,6-dihydro-4H-pyrrolo[1,2a][1,4]-benzodiazepines and 6H-pyrrolo[1,2a][1,4]benzodiazepines substituted with bicyclic benzene derivatives.

Info

Publication number: OA16460A
Application number: OA1201300256
Authority: OA
Inventors: Lieven Meerpoel; Louis Jules Roger Marie Maes; Kelly De Wit
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2010-12-21
Filing date: 2011-12-19
Publication date: 2015-10-15

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 substituted with bicyclic benzene derivatives of Formula (I) wherein R1, R2, R3, R4, R5, R6 and R7 have the meaning defined in the claims. The compounds according to the present invention are active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

The présent invention is concemed with novel antifungal 5,6-dihydro-4ZT-pyrrolo[l,2-a][l,4]benzodiazepines and 6Z/-pyrrolo[l,2-a][l,4]benzodiazepines, both substituted with bicyclic benzene dérivatives, active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active 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) 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 tîssues and inflammation is caused by host response to metabolic by-products. They are usually 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 tîssues, 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 hospitals 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 increased incidence of infections due to other molds like Scedosporium apiospermum, Fusarium spp., and Zygomycetes, Rhizopus andMucor 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.

' I

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 (Noxafil™) show much improvement of treatment towards Hfe threatening invasive SFI such as candidiasis, aspergillosis, and infections due to Fusarium species at clinical relevant dosages, Moreover posaconazole shows efïicacy against infections caused by the emerging Zygomycetes spp. Echinocandins, such as anidulafungin, caspofungin, and micafungin, which are non-competitive inhibitors of 1,3-p-glucan synthesis in fungal cell walls, display high efficacy against Candida spp. and Aspergillus spp., but no activity against Cryptococcus, Fusarium, or Zygomycetes spp.. Of ail 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 constïtutes about a half of ail 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 ffequently involved in the tropics and subtropics.-Zrâftopftytort rubrum is the most common dermathophyte involved in onychomycosis. Other dermatophytes that may be involved are Trichophyton interdigitale, Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, Trichophyton soudanense and Trichophyton verrucosum. Other causative pathogens include Candida and non-dermatophytic moulds, in particular members of the mould génération Scytalidium (also Neoscytalidium), Scopulariopsis, and Aspergillus.

5,6-Dihydro-4/i^r-pyrrolo[l,2-aJ[l,4]benzodiazepines hâve been described in J. Chem. Soc.(C), 2732-2734 (l 971); J. Heterocyclic Chem., 13, 711-716 (1976); and J. Heterocyclic Chem., 16, 241-244 (1979). The compounds disclosed in these references ail hâve a different substitution on the phenyl moiety in the 4-position and moreover no biological activities were reported in any of these references.

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

Compounds 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine (CAS Registry Number [845288-06-4]) and 4-(l,3-benzodîoxol-5-yl)-5,616460

dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HCl (CAS Registry Number [121554657-8]) are commercially available, but no use is known for these compounds.

WO02/34752 describes 4-substituted 5,6-dihydro-4//-pyrrolo[l,2-a][l,4]benzodiazepines as a new class of antifungal compounds. However, WO02/34752 does 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 of the présent invention are structurally different and may hâve improved potency, improved metabolic stabîlity properties, improved soiubility, improved plasma binding, reduced hERG channel inhibition, reduced cytochrome P450 liabilities, or improved bioavailability compared with compounds disclosed in the prior art. Preferably said compounds hâve a broad antifungal spectrum, and maintain adequately high thereapeutic efficacy and adequately low toxicity or other side effects.

It is accordingly an object of the présent invention to provide novel compounds with antifungal activity to overcome or ameliorate at least one of the disadvantages of the 20 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, Cnalkyl or Ci^alkyloxy; R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

t or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or Cnalkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CH2)m-Y^l-(CH2)_n._m- (a), -Y^2a-(CH₂)_t-Y^2b- (d),or

-(CH₂)_n._m-Y¹-(CH2)m- (b), -(CH2)rY^2a-CH2-Y^2b-(CH₂)_q-(e);

-<CH₂)r-(c), wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci_salkyl, hydroxyl, Ci^alkyloxy and oxo;

Y¹ represents O, NR⁸® or S;

Y^2a and Y^2b each independently represent O, NR^8b or S;

R⁸⁸ represents hydrogen or Ci^alkyl;

□l

R represents hydrogen or Cmalkyl;

m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5;

t represents 1, 2 or 3;

r represents 0 or 1;

q represents 0 or 1;

provided that at least one of r and q is 1;

and the pharmaceutically acceptable addition salts, and the solvatés thereof; provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4HpyrTolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[ 1,2-a][ 1,4]benzodiazepine .HCl.

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

The présent compounds are useful agents for corn bâti ng 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 albicans, Candida glabrata, Candida kruceï, Candidaparapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., e.g, Aspergillusfiimigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp., e.g.

Microsporum canis, Microsporum gypseum; Trichophylon spp., e.g. Trichophyton mentagrophyles, Trichophyton rubrum, Trichophylon quinckeanum, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Trichophyton interdigitale, Trichophyton soudanense; Fusarium spp., e.g. Fusarium solani,

Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucorpusillus, Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia jurfiir; 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 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 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 foliowing passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Detailed description

When describing the compounds of the invention, the terms used are to be construed in accordance with the foliowing définitions, unless a context dictâtes otherwise.

Whenever the term “substituted” is used in the présent invention, it is meant, unless otherwise is indicated or is clear from the contexf to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a sélection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable

I compound, i.e. a compound that is sufïiciently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. Whenever the bivalent radical -R⁶-R⁷- is substituted with one or more substituents, those substituents may replace any hydrogen atom bound to a carbon atom.

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

The term Ci^alkyi as a group or part of a group refers to a hydrocarbyl radical of Formula CnHïtt+i wherein n is a number ranging from l to 4. CMalkyl groups comprise from l 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 example, CMalkyl includes ail linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, w-propÿl, ipropyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, «’obutyl and ierAbutyl), and the like.

The term “CMalkyloxy” as a group or part of a group refers to a radical having the Formula -OR^a wherein R^fl is Ci^alkyl. Non-limiting examples of suitable C«alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyl oxy, butyloxy, isobutyloxy, Aec-butyloxy and /er/-butyloxy.

The chemîcal 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 DevelopmenL 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):

(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 (I)” is used, it 5 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 10 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)” tnherently includes ail stereoisomers of the compound of formula (I) either as a pure stereoisomer or as a mixture of two or 15 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 that are not enantiomers, Le. they are not related as mirror images. More in particular, stereogenic centers may hâve the R- or S-configuration; substituents on bivalent cyclic (partialiy) 20 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 embraced within the scope ofthis invention. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, 25 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 polarized light.

When a spécifie stereoisomeric form is indicated, this means that said form is substantially free, Le. 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 35 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 is 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 of the 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 5 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. ΑΠ 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-toxic 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, tartaric, 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 organic and inorganic bases. Appropriate base sait forms comprise, for example, the 30 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, isopropyl ami ne, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, di isopropyl ami ne, di-H35 butylamine, pyrrolidine, piperidine, morpholine, trimethyiamine, triethylamine,

tripropyl amine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathîne, Nmethyl-D-glucamine, 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 term 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 10 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 stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the 15 reaction occurs stereospecifically. Preferably if a spécifie stereoisomer is desired, said compound would be synthesized by stereospecific 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 20 the framework of this application, a chemical element, in particular when mentioned in relation to a compound according to Formula (I), comprises ail isotopes and isotopic mixtures of this element. For example, when hydrogen is mentioned, it is understood to refer to ^!H, ²H, ³H and mixtures thereof.

A compound according to the invention therefore inherently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, 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 pharmaceutically 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-binding techniques, the ³H-atom or the ^lzîI-atom is the atom of choice to be replaced. For imagîng, the most commonly used positron emitting (PET) radioactive isotopes are ¹ *C, ^l8F, ¹⁵O and ^l3N, 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 «

ΙΟ them at institutions which have an accelerator on site for their production, thus limiting their use. The most widely used of these are ^IBF, “Te, ²⁰¹Tl and ^,23I. 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 (I):

and stereoisomeric forms thereof, wherein

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

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or Ci4alkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CH2)m-Y¹-(CH2)_n._m- (a), -Y^2a-(CH₂)_t-Y^2b- (d),or

-(CHiio-m-Y'-ÎCHï)™- (b), -(CH₂)_rY^2a-CH2-Y^2b-(CH2)_q-(e);

-(CH₂)_s-(c), wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cualkyl, hydroxyl, Cwalkyloxy and oxo;

Y¹ represents O, NR⁸* or S;

Y^2a and Y^2b each independently represent O, NR^Sb or S;

R^Sa represents hydrogen or Cualkyl;

R^8b represents hydrogen or Cnalkyl;

m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5;

t represents 1, 2 or 3;

r represents 0 or 1;

q represents 0 or 1;

provided that at least one of r and q is 1;

and the pharmaceutically acceptable addition salts, and the solvatés thereof; provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[ 1,2-a][l ,4]benzodiazepine or 4-( 1,3-benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[ 1,2-a][ 1,4]benzodiazepine .HCl.

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

R¹ is halo, Ci_ialkyl or CMalkyloxy, in particular wherein R¹ is halo;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or CMalkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CH2)m-Y¹-(CH2)_n._m- (a), -Y^2a-(CH₂),-Y^2b- (d),or —(CH₂)n-m^—Y^1-(CH2)m^— (b), -(CH2)_rY^2a-CH2-Y^2b-(CH2)_q-(e);

-(CH₂)_s-(c), wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cualkyl, hydroxyl, CMalkyloxy and oxo;

Y¹ represents O, NR⁸* or S;

Y^2a and Y^2b each independently represent O, NR^8b or S;

R^8a represents hydrogen or Cj^alkyI;

R^ab represents hydrogen or Cualkyl;

m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3,4 or 5;

t represents I, 2 or 3;

r represents 0 or 1;

q represents 0 or 1 ;

provided that at least one of r and q is 1;

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 halo, C î-talky 1 or Cj^alkyloxy; in particular 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 hydrogen or Ci-jalkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CHîJnr-Y’-iCHî)^- (a), -Y^2a-(CH₂)_t-Y^2b- (d),or

-(CHï^-Y'-ÎCHî)™- (b), -(CH₂)rY^2a-CH2-Y^2b-(CH2)_q-(e);

-(CH₂)_s-(c), wherein the bivalent radical -R⁶-R⁷- having formula (a), (b), (c) or (e) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, CMalkyl, hydroxyl, Ci^alkyloxy and oxo, and wherein the bivalent radical -R⁶-R⁷- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Cmalkyl, hydroxyl, Ci_ialkyloxy and oxo;

Y¹ represents O, NR⁸® or S;

Y^2a and Y^2b each independently represent O, NR^8b or S;

R^8a represents hydrogen or Ci^alkyl;

R represents hydrogen or CMalkyl;

m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5;

t represents 1, 2 or 3;

r represents 0 or 1;

q represents 0 or 1;

provided that at least one of r and q is I;

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

R¹ is hydrogen, halo, Cinalkyl or Cnalkyloxy,

R² îs hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or Cuaikyloxy;

R⁶ and R⁷ taken together form a bivalent radical —R⁶-R⁷-, having formula: -(CHîVY'-fCHîJn.m- (a), -(CH₂)_S- (c), or

-(CH₂)_n._m-V4CH₂)_m- (b), -Y^2a-(CH₂)_t-Y^2b- (d);

wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cmalkyl and oxo; Y¹ représente O or NR^8a,

Y^2a and Y^2b each independently represent O or NR^8b;

R^8a représente hydrogen or Cmalkyl; in particular R^8a repreeente hydrogen;

R^8b représente hydrogen or Cmalkyl; in particular R^8b represents hydrogen; m represents 0,1 or 2;

n represents 2 or 3;

s represents 3 or 4;

t represents 1;

and the pharmaceutically acceptable addition salts, and the solvatés thereof; provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[l,2-a][l,4]benzodiazepine or 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[ 1,2-a][ 1,4]benzodiazepine .HCl.

R¹ is hydrogen, halo, Cmalkyl or Cmalkyloxy;

R is hydrogen or halo;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or Cmalkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CH^-Y'-ÎCH^m- (a), -(CH₂)₅- (c), or

-(CH₂)n._m-Y^,-(CH2)m- (b), -Y^2a-(CH2)_t-Y^2b- (d);

wherein the bivalent radical -R^û-R⁷- having formula (a), (b) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cmalkyl and oxo;

wherein the bivalent radical -R⁶-R⁷- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Cmalkyl and oxo; Y¹ represents O or NR^Sa;

Y^2a and Y^2b each independently represent O or NR^8b;

R^8a représente hydrogen or Cualkyl; in particular R^8a représente hydrogen;

R^8b représente hydrogen or Ci^alkyl; in particular R^8b represents hydrogen;

m représente 0, 1 or 2;

n represents 2 or 3;

s represents 3 or 4;

t represents 1;

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

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

R² is hydrogen or halo,

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R^s is hydrogen or Ci^alkyloxy,

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula:

-(CH2)_m-Y^,-(CH2)n.m- (a), -Y^2a-(CH2)_t-Y^2b- (d),or

-(CH₂)_n._m-Y¹-(CH₂)_ni- (b), -(CH₂)_rY^2a-CH2-Y^2b-(CH2)_q-(e);

-(CH₂)_s-(c), wherein the bivalent radical -R⁶-R⁷- having formula (a), (b), (c) or (e) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cualkyl, hydroxyl, Ci^alkyloxy and oxo;

and wherein the bivalent radical -R⁶-R⁷- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Cnalkyl, hydroxyl, Ci^alkyloxy and oxo;

Y¹ represents O, NR⁸® or S;

Y^2a and Y^2b each independently represent O, NR^8b or S;

R^8a represents hydrogen or Cualkyl;

R^8b represents hydrogen or Cmalkyl, m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5;

t represents 1, 2 or 3;

r represents 0 or 1;

q represents 0 or 1 ;

provided that at least one of r and q îs 1, and the pharmaceutically acceptable addition salts, and the solvatés thereof

R¹ is hydrogen, halo or CMalkyloxy; in particular hydrogen, chloro, fluoro or methoxy; R is hydrogen or halo; in particular hydrogen, chloro or fluoro;

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or CMalkyloxy; in particular hydrogen, methoxy or ethoxy;

(a), -(CH₂)_S- (c), or

-Y^2a-(CH₂),-Y^2b- (d);

wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cmalkyl and oxo; in particular fluoro, methyl and oxo;

Y¹ represents O or NH;

Y^2a represents O;

Y^2b represent O or NH;

m represents 0, 1 or 2;

n represents 2 or 3;

s represents 3 or 4;

t represents 1 ;

and the pharmaceutically acceptable addition salts, and the solvatés thereof; provided that the compound is not 4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[ 1,2-a] [ 1,4]benzodiazepi ne or 4-( 1,3 -benzodioxol-5-yl)-5,6-dihydro-4Hpyrrolo[l,2-a][l,4]benzodiazepine .HCl.

R¹ is hydrogen, halo or CMalkyloxy; in particular hydrogen, chloro, fluoro or methoxy;

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

R³ and R⁴ are hydrogen;

or R³ and R⁴ taken together form a bond;

R⁵ is hydrogen or CMalkyloxy; in particular hydrogen, methoxy or ethoxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CHjim-Y'-CCHîK-œ- (a), -(CH₂)_S- (c), or

-Y^2a-(CH₂)_t-Y^2b- (d);

wherein the bivalent radical -R⁶-R⁷- having formula (a) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ci^alkyl and oxo; in particular fluoro, methyl and oxo;

wherein the bivalent radical -R⁶-R⁷- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Ci^alkyl and oxo; in particular halo; more in particular fluoro;

Y¹ represents O or NH;

Y^2a represents 0;

Y^2b represent 0 or NH;

m represents 0, 1 or 2;

n represents 2 or 3;

s represents 3 or 4;

t represents 1;

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

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

R¹ is halo; in particular chloro or fluoro;

R² is hydrogen;

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

R⁴ are taken together to form a bond;

R⁵ is hydrogen;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula;

^—(CH2)m^—θ (CH₂)n-m^—,

-(CH₂)_s-, or

-O-CH2-O-;

wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo;

m represents 0 or 1;

n represents 3;

s represents 3 or 4;

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

R¹ is halo; in particular chloro or fluoro;

R² is hydrogen;

R³ and R⁴ are hydrogen; or R³ and R⁴ taken together form a bond; in particular R³ and t

R⁴ are taken together to form a bond;

R^s is hydrogen;

-(CH₂)_s- , or

-O-CH₂-O- ;

wherein the bivalent radical -(CH₂)_m-O-(CH₂)_n.m- or -(CH₂)_S- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo;

wherein the bivalent radical -O-CH₂-O- is substituted with one or more substituents selected from the group consisting of halo and oxo; in particular halo; more in particular fluoro;

m represents 0 or 1 ;

n represents 3;

s represents 3 or 4;

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 of the other embodiments wherein the bivalent radical -R⁶-R⁷- when having formula (d) is always substituted with one or more substituents selected from the group consisting of halo, CMalkyl and oxo; in particular halo; more in particular fluoro.

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 R³ and R⁴are 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 R³ and R⁴are taken together to 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 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 (I) or any subgroup thereof as mentioned in any of the other embodiments wherein R¹ is halo, Ci.jalkyl or CM^lkyloxy.

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 R² is halo.

An embodiment ofthe présent invention relates to those compounds of formula (I) or any subgroup thereof as mentioned in any ofthe other embodiments wherein R¹ is halo, and R³ and R⁴ are taken together to form a bond.

An embodiment of the présent invention relates to those compounds of formula (I) or 10 any subgroup thereof as mentioned in any of the other embodiments wherein R* is halo and is in the 7-position, and R³ and R⁴ are taken together to 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 R² is 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 and R² is hydrogen.

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 R¹ is halo 20 and is in the 9-position; in particular wherein R¹ is chioro or fluoro and is in the 9posîtion; more in particular wherein R¹ is chioro and is in the 9-position.

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 and is in the 7-position; in particular wherein R¹ is chioro or fluoro and is in the 725 position; more in particular wherein R¹ is chioro and is in the 7-position.

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 and is in the 7-posîtîon, and R² is hydrogen;

in particular wherein R¹ is chioro or fluoro and is in the 7-position, and R² is hydrogen; 30 more in particular wherein R* is chioro and is in the 7-position, and R² is 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 and is in the 7-position, and R² is hydrogen or halo and is in the 9position;

in particular wherein R¹ is chloro or fluoro and is in the 7-position, and R² is hydrogen, chloro or fluoro and is in the 9-position;

more in particular wherein R¹ is chloro and is in the 7-position, and R² is hydrogen or chloro and is in the 9-position.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentîoned in any of the other embodiments wherein R¹ is halo and is in the 7-position, R² is hydrogen, and R³ and R⁴ are taken together to form a bond.

An embodiment of the présent invention relates to those compounds of formula (I) or 10 any subgroup thereof as mentîoned in any of the other embodiments wherein R¹ is chloro and is in the 7-position, R² is hydrogen, and R³ and R⁴ are taken together to form a bond.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentîoned in any of the other embodiments wherein R⁶ and R⁷15 taken together form a bivalent radical -R⁶-R⁷-, having formula (a), (b), (c) or (d), in particular having formula (a), (c) or (d), wherein said bivalent radical -R⁶-R⁷- may, where possible, be substituted according to any of the other embodiments.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentîoned in any of the other embodiments wherein R⁶ and R⁷20 taken together form a bivalent radical -R⁶-R⁷-_] having formula (a), (b), (c) or (e), in particular having formula (a), (b) or (c), wherein said bivalent radical -R⁶-R⁷- may, where possible, be substituted according to any of the other embodiments.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentîoned in any ofthe other embodiments wherein R⁶ and R⁷25 taken together form a bivalent radical -R^û-R⁷-, having formula (a) or (b), wherein said bivalent radical -R⁶-R⁷- may, where possible, be substituted according to any of the other embodiments.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentîoned in any ofthe other embodiments wherein R⁶ and R⁷30 taken together form a bivalent radical -R⁶-r⁷_ having formula (c), wherein said bivalent radical -R⁶-R⁷- may, where possible, be substituted according to any of the other embodiments.

An embodiment of the présent invention relates to those compounds of formula (I) or any subgroup thereof as mentîoned in any ofthe other embodiments wherein R⁶ and R⁷

taken together form a bivalent radical -R⁶-R⁷-, having formula (d) or (e), in particular having formula (d), wherein said bivalent radical -R⁶-R⁷- may, where possible, be substituted according to any of the other embodiments.

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 and R⁷taken together form a bivalent radical -R⁶-R⁷-, having formula (d); wherein said bivalent radical -R⁶-R⁷- may, where possible, be substituted according to any of the other embodiments;

wherein t représente 1; and wherein Y^2a and Y^2b each independently represents O or 10 NR^8b, in particular wherein Y^2a and Y^2b represent O.

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 R⁶ and R⁷taken together form a bivalent radical -R⁶-R⁷-, having formula -(CHîVY'-tCHîJn.m-, -(CH^n-tn-Y'-fCHî),»- -(CH₂)_S-, -0-CH₂-015 -O-CF₂-O-, or -O-C(=O)-N(CH₃)-;

wherein the bivalent radical -(CHojm-Y'-iCTjn.m-, -(CH₂)_n._m-Y‘-(CH^-, or ~(CH₂)_s~, may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cmalkyl, hydroxyl, Ci^alkyloxy and oxo;

Y¹ represents O, NR⁸⁹ or S;

R^8a represents hydrogen or C ualkyl;

m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5.

An embodiment of the présent invention relates to those compounds of formula (I) or 25 any subgroup thereof as mentioned in any of the other embodiments wherein R⁶ and R⁷taken together form a bivalent radical -R⁶-R⁷-, having formula -(CH2)m-Y¹-(CH2)_n._m-, -(CH₂)_t^-Y'-(CH₂)_m- -(CH₂)_S-, -O-CF₂-O-, or -O-C(=O)-N(CH₃)-;

wherein the bivalent radical -(CHîJm-Y’-fCH^n.m-, -(CHîJn-m-Y^ÎCHîjm-, or

-(CH₂)_s-, may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Cnalkyl, hydroxyl, Ci-^alkyloxy and oxo;

Y¹ represents O, NR⁸⁴ or S;

R^8a represents hydrogen or Cualkyl;

m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5.

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 and R⁷taken together form a bivalent radical -R⁶-R⁷-, having formula:

-(CH₂)_m-O-(CH₂)_n._m-(CH₂)_s- , or

-0-CH₂-0- ;

wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo.

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 R⁶ and R⁷taken together form a bivalent radical -R⁶-R⁷-, having formula:

-(CH₂)_m-O-(CH₂)_n._m-(CH₂)_s- , or

-O-CH₂-O- ;

wherein the bivalent radical -(CH₂)_m-O-(CH₂)₀._m- or -(CH₂)_S- may, where possible, 10 be substituted with one or more substituents selected from the group consisting of halo and oxo; and wherein the bivalent radical -O-CH₂-O- is substituted with one or more substituents selected from the group consisting of halo and oxo.

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 m represents 0, 1 or 2; n represents 2 or 3; s represents 3 or 4; t represents 1; r represents 0 or 1; q represents 0 or 1; provided that exactly one of q and r represents 0 and the other one represents 1.

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 and R⁷20 taken together form a bivalent radical -R⁶-R⁷-, having formula:

-(CH₂)_m-Y¹“(CH2)n.m- (a), -Y^2a-(CH2)t-Y^2b- (d);

(b), ~(CH₂)_S~ (c), wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, CMalkyl, hydroxyl, CMalkyloxy and oxo;

wherein m represents 0,1 or 2; n represents 2 or 3; s represents 3 or 4; t represents 1.

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 and R⁷taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CHOm-Y’-tCHaW (a), -Y^2a-(CH₂),-Y^2b- (d);

-(CHa^-Y'-ÎCHa)^ (b),

-(CH₂)_s- (c), wherein the bivalent radical -R⁶-R⁷- having formula (a), (b) or (c) may, where possible, be substituted with one or more substituents selected from the group consisting of halo, C^alkyl, hydroxyl, Ct-ialkyloxy and oxo;

wherein the bivalent radical ~R⁶-R⁷- having formula (d) is substituted with one or more substituents selected from the group consisting of halo, Cwalkyi, hydroxyl, Cj^alkyloxy and oxo;

wherein m represents 0,1 or 2; n represents 2 or 3; s represents 3 or 4, t represents 1.

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 and R⁷taken together form a bivalent radical -R⁶-R⁷-, wherein -R⁶-R⁷- is selected from the group consisting of-O-CH₂-O-, -(CH₂)3“, -(CH₂)4-, -(CH₂)₂-O15 -CH₂-CH(CH₃)-O-, -C(=O)-(CH₂)₂-, -C(=O)-(CH₂)₃-, -O-(CH₂)₂-, -O-(CH₂)₃-,

-CH₂-O-(CH₂)₂-, -(CH₂)₂-C(=O)-, -OCF₂-(CH₂)₂-, -(CH₂)₂-C(=O)-CF₂-(CH₂)₂-, -C(=O)-O-CH₂-, -CH₂-O-C(=O)-, -o-cf₂-o-O-C(-O)-N(CH₃)-, -N(CH₃)-(CH₂)₂- and -N(CH₃)-C(=O)-C(CH₃)₂-;

in particular wherein -R⁶-R⁷- is selected from the group consisting of ~(CH₂)3-,

-(CH₂)₄-, -(CH₂)₂-O-, -CH₂-CH(CH₃)-O-, -C(=O)-(CH₂)₂-, -C(-O)-(CH₂)3-O-(CH₂)₂-, -O-(CH₂)₃-, -CH₂-O-(CH₂)₂-, _(CH₂)₂-C(=O)-, -O-CF₂-(CH2)2-, -(CH₂)2-C(=O)-, -CF₂-(CH₂)2-, -C(=O)-O-CH₂-, -CH₂-O-C(=O)_, -o-cf₂-o-O-C(=O)-N(CH₃)-, -N(CH₃)-(CH₂)2-, and -N(CH₃)-C(=O)-C(CH₃)₂-.

An embodiment of the présent invention relates to those compounds of formula (I) or 25 any subgroup thereof as mentioned in any of the other embodiments wherein R⁶ and R⁷taken together form a bivalent radical -R⁶-R⁷-, wherein -R⁶-R⁷- is selected from the group consisting of-O-CH₂-O- and -O-CF₂-O-; in particular wherein -R⁶-R⁷- is -O-CF2-O-.

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 and R⁷ taken together form a bivalent radical -R⁶-R⁷- having the formula -O-CH2-O-, wherein -0-CH₂-0- may be substituted with one or two substituents selected from the group consisting of halo, Cnalkyl, hydroxyl, Cwalkyloxy and oxo; in particular halo and Cnalkyl,

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 R and R taken together form a bivalent radical -R⁶-R⁷- having the formula -O-CHj-O-, wherein -0-CH₂-0- is substituted with one or two substituents selected from the group consisting of halo, Cualkyl, hydroxyl, Ci^alkyloxy and oxo; in particular halo and Ci_4alkyl; more in particular halo; even more in particular fluoro.

IO An embodiment of the présent invention relates to those compounds of formula (I) or * *67 any subgroup thereof as mentioned in any of the other embodiments wherein R and R when representing a bivalent radical of formula (d), is always substituted with a substituent as defined in any of the other embodiments.

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 R^8a and R^8b represent 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 Y^2a and Y^2b represent O.

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

4-(l,3-benzodioxol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HBr,

4-(l,3-benzodioxol-5-yl)-7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

4-(l,3-benzodioxol-5-yl)-7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HBr,

4-(l,3-benzodioxol-5-yl)-8-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HBr,

4-(l,3-benzodioxol-5-yl)-8-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

4-(l,3-benzodioxol-5-yl)-9-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HBr,

4-(l,3-benzodioxol-5-yl)-9-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

4-( 1,3-benzodioxol-5-yl)-l 0-chloro-5,6-dihydro-4H-pyrrolo[ 1,2-a][ 1,4]benzocZ diazepine .HBr,

4-(1,3-benzodioxol-5-yl)-10-chloro-5_J6-dihydro-4H-pyrrolo[ l,2-a][l,4]benzodiazepine,

4-( 1,3-benzodioxol-5-yl)-5,6-dihydro-7-methoxy-4H-pyrrolo[ 1,2-a][ 1,4]benzodiazepine .HBr,

4-(l,3-benzodioxol-5-yI)-5,6-dihydro-7-methoxy-4H-pyrToIo[l,2-a][l,4]benzodiazepine,

4-(1,3 -benzodioxol-5-y 1) -6H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepi ne, 4-(l,3-benzodioxol-5-yl)-7-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 4-(l,3-benzodioxol-5-yl)-8-chloro-6H-pyirolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepine .HCl,

7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HBr,

7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(6-ethoxy-2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [l,4]benzodiazepine .HBr,

7-chioro-4-(6-ethoxy-2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][ 1,4]benzodiazepine,

7-chl oro-5,6-dihy dro-4-(5,6,7,8 -tetrahydro-3 -methoxy-2-naphthaleny 1 )-4H-pyrrolo[1,2-a] [1,4]benzodiazépine .HBr,

7-chloro-5,6-dihydro-4-(5,6,7₁8-tetrahydro-3-methoxy-2-naphthalenyl)-4H-pyrrolo[ 1,2-a] [ 1,4] b enzodi azepi ne,

7.10- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HCl,

7_>10-dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

8.10- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepine .HCl,

8.10- dichloro-4-(2,3 -dihydro-1 H-inden-5-yl)-5,6-dihy dro-4H-py rrolo[ 1,2-a] [1,4]benzodiazepine,

7.8- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]- benzodiazepine .HCl,

7.8- dichloro-4-(2,3-dihydro-IH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4Jbenzodiazepine,

7.9- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]X

benzodiazépine .HCl,

7,9-dichloiO-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydiO-4H-pyrrolo[l,2-a][l,4]benzodiazépine,

7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chl oro-4-(5,6,7,8-tetrahydro-2-naphth al eny I )-6H-pyrrolo[ l, 2-a] [ 1,4]benzodiazepine,

7.8- dichloro-4-(2,3-dihydiO-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7.9- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7.10- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

8.10- dichloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HCl, 7-chloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(2,3-dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HCl,

7-chloro-4-(2,3-dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-5,6-dihydro-4H-pyrrolo[l,2-a]- [l,4]benzodiazepine .HCl,

7-chl oro -4-(3,4-dihy d ro-1 H-2-benzopyran-6-y 1 )-5,6-dihydro-4H-py rrolo[ 1,2-a][ 1,4]benzodiazepîne, 4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4H-pyrrolo[l,2-a]- [l,4]benzodiazepine .HCl,

4-(3,4-dihy dro-1 H-2-benzopy ran-6-y I )-7-fluoro-5,6-di hy dro-4H-py rrol o[ 1,2-a][ 1,4]benzodiazepine,

7.8- dichloro-4-(2,3-dihydro-5-benzofüranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine .HCl,

7.8- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

7.9- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepine .HCl,

7.9- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepine,

7.10- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepine .HCl,

7.10- dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]16460

benzodiazépine,

7, ΙΟ-dichloro-4-(2,3-dihydro-6-benzofuranyl)-5,6-dihydro-4H-pyaolo[l,2-a][l,4]benzodiazepine .HCl,

7.10- dichloro-4-(2,3-dihydro-6-benzofuranyl)-5,6-dihydro-4H-pynolo[l,2-a][l,4]benzodi azepi ne,

8, lO-dichloro-4-(2,3-dihydro-5-benzofuranyl)-5,6-dihydro-4H-pyrrolo[ l,2-a][l,4]benzodiazepîne .HCl,

8.10- dichloro-4-(2,3-dihydro-5 -benzofurany l ) -5,6-di hy dro-4H-py rrol o[ 1,2-a] [ 1,4]benzodiazepine, 7-chloro-4-(2,3-dihydro-5-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,3-dihydro-6-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[ l,2-a][ 1,4]benzodiazepine,

4-(3,4-dihy dro-1 H-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepine,

4-(3,4-dihydro-2H-l-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

9-chl oro-4-(3,4-dihy d ro-1 H-2-benzopy ran-6-y I) -6H-pyrrolo [ 1,2-a] [ 1,4]benzodiazepîne,

9- chloro-4-(3,4-dihydro-2H-l -benzopyran-6-yl)-6H-pyrrolo[ 1,2-a][ 1,4]benzodiazepine,

10- chloro-4-(3,4-dihydiO-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepîne,

7.8- dichloro-4-(2,3-dihydro-5-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7.9- dichloro-4-(2,3-dihydro-5-benzoftiranyl)-6H-pynOlo[l,2-a][l,4]benzodiazepine, 4-(3,4-dihydro-2H-l-benzopyran-6-yl)-7,9-difluoro-6H-pynOlo[l,2-a][l,4]benzodiazepine,

7.10- d i chioro-4-(2,3-di hydro-6-benzofùrany 1 )-6H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepine,

8.10- dichloro-4-(2,3-dihydro-5-benzofuranyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(2,3-dihydro-5-methoxy-2-methyl-6-benzofuranyl)-5,6-dihydro-4Hpyrrolo[ 1,2-a][l,4]benzodiazepine HBr,

7-chloro-4-(2,3-dihydro-5-methoxy-2-methyl-6-benzofuranyl)-5,6-dihydro-4Hpyrrolo[ 1,2-a] [ 1,4]b enzodi azepi ne,

7-chloro-4-(5-ethoxy-2,3-dihydro-2-methyl-6-benzofuranyl)-5,6-dihydro-4Hpyrrolof 1,2-a] [ 1,4]benzodiazépine . HBr,

7-chl oro-4-(5 -ethoxy-2,3 -di hy dro-2-methy l-6-benzofurany l)-5,6 -di hy dro -4Hpyrrolo[l,2-a][l,4]benzodiazepine,

5-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydrolH-inden-l-one .HCl,

5- (7-chloro-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydrolH-inden-l-one,

6- (7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydrolH-inden-l-one,

6-(7-chloro-5,6-dihydro-4H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydrol H-inden-1-one .HCl,

4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4Hpyrrolo[l,2-a][l,4]benzodiazepine .HCl,

4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7-fluoro-5,6-dihydro-4Hpyrrolo[ 1,2-a] [ 1,4]benzodi azepi ne,

4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7,9-difluoro-5,6-dihydro-4Hpyrrolo[ 1,2-a] [ 1,4]benzodiazepine .HCl,

4- (2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7,9-difluoro-5,6-dihydro-4Hpyrrolof 1,2-a] [ 1,4]benzodiazepine,

6-(7-chloro-6H-pyrrolo[ 1,2-a][l ,4]benzodiazepin-4-yl)-2,3-dihydro-1 H-inden-1 one,

5- (7-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydro-lH-inden-lone,

5- ( 10-chloro-ôH-pyrrolof 1,2-a][ 1,4]benzodiazepin-4-yl)-2,3-dihydro-1 H-inden-1 one,

6- (7-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-3,4-dihydro-l(2H)naphthalenone,

6-(7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-3,4-dihydro-l(2H)naphthalenone,

6-(9-chloro-6H-pynolo[l,2-a][l,4]benzodiazepin-4-yl)-3,4-dihydro-l(2H)naphthalenone,

6-(10-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-3,4-dihydro-l(2H)naphthalenone,

6-(7-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-l(3H)-isobenzofuranone,

6-(7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yi)-l(3H)-isobenzofuranone,

6-(7,9-dichloro-6H-pyirolo[l,2-a][l,4]benzodiazepin-4-yl)-l(3H)-

i sobenzofuran one,

5-(7-chloro-6H-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-l(3H)-isobenzofuranone,

7-chloro-4-(l,l-difluoro-2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

9- chl oro-4-( 1,1-di fl uoro-2,3 - dihy dro-1 H-i nden-5-y i)-6H-pyiTolo [ 1,2-a] [ 1,4 ]b enzodiazepine,

10- chloro^-Q.l-difluoro-ZJ-dihydro-lH-inden-S-yO-ôH-pyriOlotLZ-aKl/lJbenzodiazepine,

7-chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a]- [l,4]benzodiazepine,

4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[l,2-a][ 1,4]benzodiazepine,

9- chl oro-4-(2,2-d i fl uoro-3,4-dihy dro-2H-1 -b enzopy ran-6-y l)-6H-pyrrolo[ 1,2-a]- [ 1,4]benzodiazepine,

10- chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a]- [ 1,4]benzodiazepine,

4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-7,9-difluoro-6H-pyrrolo[l,2-a]- [l,4]benzodiazepine,

7-chloro-4-(2,2-difl uoro-1,3 -b enzodioxol-5-y l)-6H-pyrrolo[ 1,2-a] [ 1,4]b enzodiazepine,

9- chl oro-4-(2,2-d i fl uoro-1,3-benzodioxol-5-yl )-6H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepine,

10- chloro-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

4-(2,2-difluoro-l,3-benzodioxol-5-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

4- (2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7,9-dichloro-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-6H-pyiTolo[l,2-a][l,4]benzodiazepine,

5- (7-chloro-6H-pynOlo[l,2-a][l,4]benzodiazepin-4-yl)-3-methyl-2(3H)benzoxazolone,

4-(2,3-dihydro-l-methyl-lH-indol-5-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(2,3-dihydro-l-methyl-lH-indol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodîazepine,

10-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzo16460

dîazepine,

9-chloro-4-(2,2-difluoro-3,4-dihydro-2/f-l-benzopyran-6-yl)-5,6-dihydro-4/fpyrrolo [ 1,2-a] [ 1,4]b enzodi azepi ne,

5-(10-chloro-5,6-dihydro-4//-pyrrolo[l,2-iï][l,4]benzodiazepin-4-yl)-2,3-dihydro12/-inden-l-one,

5-(10-chloro-5,6-dihydro-477-pyrrolo[l,2-a][l,4]benzodiazepin-4-yl)-2,3-dihydrolH-inden-l-one .HCl,

9- chloro-4-(3,4-dihydro-17/-2-benzopyran-6-yl)-5,6-dihydro-4//-pyrrolo[l,2-iï]- [l,4]benzodiazepine,

10- chloro-4-(2,2-difluoro-3,4-dihydro-2//-l-benzopyran-6-yl)-5,6-dihydro-4/7pyrrolo[ 1,2-a][l ,4]benzodiazepine,

7-chloro-4-(l,l-difluoro-2,3-dihydro--l//-inden-5-yl)-9-f1uoro-6//-pyrrolo[l,2-tz]- [ 1,4]benzodiazepine, 5-(7-chloro-6H-pyrroio[l,2-a][l,4]benzodiazepin-4-yl)-l,3-dihydro-l,3,3-trimethyl2H-indol-2-one, including stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts and the solvatés thereof.

7-ch I oro-4-(2,3-di hy d ro-1 H-inden-5 -y l)-6H-py rrol o[ 1,2-a] [ 1,4] benzodiazépine,

7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,2-difIuoro-l,3-benzodioxol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzo10 dîazepine,

4-(2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difIuoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

4-(2,2-difluoro-1,3-benzodi oxol-5-yl)-7-fluoro- 6H-pyrrolo[ 1,2-a] [ 1,4]b enzo dîazepine,

6-(7“fluoro-6H-pyrrolo[l ,2-a][l ,4]benzodiazepin-4-yl)-3,4-dihydro-1 (2H)naphthalenone,

7-chl oro-4-(2,2-di fluoro-3,4- dihy dro-2H-1 -benzopy ran-6-y l)-6H-pyrrolo[ 1,2-a]- [l,4]benzodiazepine,

4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzo20 dîazepine,

7-chIoro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pyiTolo[l,2-a][l,4]benzodiazepine,

9-chloro-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, and 10-chloro-4-(3,4-dihydro-2H-l-benzopyran-6-yi)-6H-pyrrolo[l,2-a]5 [l,4]benzodiazepine.

7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pynolo[l,2-a][l,4]benzodiazepine .HCl,

7-chloro-4-(2,3-dihydro- lH-inden-5-yl)-5,6-dihydro-4H-py rrolo[ 1,2-a] [ 1,4]benzodiazepine .HBr,

7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(2,2-difluoro-l ,3-benzodioxol-5-yl)-6H-pynOlo[ 1,2-a][l,4]benzodiazepine, 4-(2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

6-(7-fluoro-6H-pyrrolo[ 1,2-a] [1,4]benzodiazepin-4-yl)-3,4-dihydro-1 (2H)naphthalenone,

7-chl oro-4-(2,2-di fluoro-3,4-d i hy dro-2H-1 -benzopy ran-6-y 1) -6H-pyrrolo [ 1,2-a] [ 1,4]benzodiazepine,

4-(3,4-dihydro-lH-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chioro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pynOlo[l,2-a][l,4]benzodiazepine, 9-chloro-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, and 10-chloro-4-(3,4-dihydro-2H-1 -benzopyran-6-yl)-6H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepine, including stereoisomeric forms 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 prepared using standard synthetic processes commonly used by those skilled in the art of organic chemistry.

The compounds of the présent invention, can be prepared according to Scheme 1 :

Scheme ί

réduction

The compounds of Formula (I) wherein R³ and R⁴ together form an extra bond, said compounds being represented by formula (I-b), can be prepared from the compounds represented by the formula (I-a), following art-known amine to imine oxidation reactions. These oxidation reactions may be conducted by reacting a compound of formula (I-a) with an oxidant such as, for example, lead tetra-acetate or 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 (II). In the presence of an acid such as, for example, POCI3, the amide in the intermediate of formula (II) can fonction as a Celectrophile, 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 (ΠΙ) by reaction with an acid H⁺X' of formula (XI), and reacting said sait of formula (ΠΙ) 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 skilled in the art.

An intermediate of formula (H) may be prepared by a coupling reaction between an intermediate of formula (ΠΙ) and (ΧΙΠ). Said reaction may be performed in the presence of coupling agents such as typically 1-hydroxy-lH-benzotriazole (HOBT) and A^/’-(ethylcarbonimidoyl)-jVjV-dimethyl-],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 (ΧΠΙ) or a reactive ester dérivative of (ΧΠΙ) can also be used in this type of reaction to préparé an intermediate of formula (II).

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

Intermediates of formula (ΠΙ) and (IV) are prepared by reducing a l-(2-cyanopheny!)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. LiAlHVTHF [S. Raines, S.Y. Chai and F.P. Palopoli; J. Heterocyclic Chem., 13, 711-716 (1976)]

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

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

3a. i. KBH4/CF3COOH, THF; ii. H₂O; iii. HCI [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/NHj)

Even other well-known methods for reducing the nitrile function may also be used.

An intermediate of formula (V) in tum 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 tetrahydrofùran (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, Cs₂COî 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 reaction 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 (Vffi) can be reacted with a nitrogen source such as, NH3.H₂O in the presence of HOBT and EDCI. This type of réaction typically can be performed in a suitable solvent like DMF. Stirring of the reaction mixture may enhance the rate of reaction.

An intermediate of formula (VIII) can be easily prepared by treating an intermediate of formula (IX) with tetrahydro-2,5-dimethoxyfuran in an inert solvent such as dioxane in the presence of an acid such as pyridine hydrochloride (l ;l) at an elevated température, preferably at reflux température. Alternatively, a reactive ester dérivative of (IX) can also be used in this type of reaction to préparé an intermediate of formula (VIII).

Ail other intermediates and starting materials are commercially available or can be easily prepared by those skilled in the art. The synthesis of some intermediates and some of the starting materials is exemplified in the experimental part.

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

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 a 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 optically active acids. Alternatively, 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 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 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 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 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 kruceï, Candida parapsilosis, Candida kefyr, Candida tropicalis;

Aspergillus spp., e.g. Aspergillusfiumigattis, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; 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 soudanense; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticilhoides, Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Malassezia fiirfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.;

Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium prolificans-, 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., e.g. Aspergillusfitmigalus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; 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 soudanense; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces;

Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium proliflcans, Trichoderma spp.; Pénicillium spp., Pénicillium marneffei; Blastoschizomyces.

The compounds of Formula (I) and stereoisomerïc forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against a wide variety of fungi, such as Candidaparapsilosis; AspergiUus spp., e.g. AspergiUusfumigatus, AspergiUus niger, AspergiUus flavus; Cryptococcus neoformans; Epidermophytonfloccosum; 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 inter digitale, Trichophyton soudanense; Fusarium spp., e.g, Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucorpusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis;

Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporiumproliflcans; Trichoderma spp.; Pénicillium spp,, Pénicillium marneffei; Blastoschizomyces; in particular AspergiUus spp., e.g. AspergiUus fumigatus, AspergiUus niger, AspergiUus 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 soudanense; Fusarium spp., e.g. Fusarium solani, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides; Rhizomucor spp., e.g. Rhizomucor miehei, Rhizomucor pusillus; Mucor circinelloides; Rhizopus spp., e.g. Rhizopus oryzae, Rhizopus microspores; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp., e.g. Scedosporium apiospermum, Scedosporium proliflcans; 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; AspergiUus spp.; Cryptococcus neoformans; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;

in particular Candidaparapsilosis: AspergiUus spp.; Cryptococcus neoformans;

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

more in particular AspergiUus 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; AspergiUus spp.;

Cryptococcus neoformans; Trichophyton spp.; Sporothrix schenckii; Microsporum spp.; Fusarium spp.; Scedosporium spp.;

in particular AspergiUus 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, AspergiUus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against fungi such as Candidaparapsilosis; AspergiUus spp., e.g. AspergiUus fiimigatus, AspergiUus niger, AspergiUus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum; in particular Candidaparapsilosis; AspergiUus spp., e.g. AspergiUusfiimigatus,

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

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

Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum.

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

Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophytes, Trichophyton *

rubrum, Scedosporium apiospermum and Scedosporiumprolificans; in particular Aspergillusfiimigatus, Microsporum canis, Trichophyton mentagrophyies, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium prolificans.

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.; Cryptococcus neoformans; Microsporum spp.; Trichophyton spp.; Scedosporium spp..

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candida parapsilosis, Aspergillusfiimigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophyies, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium prolificans;

in particular Candida parapsilosis, Aspergillus fiimigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton mentagrophyies, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium prolificans;

more in particular Aspergillusfiimigatus, Cryptococcus neoformans, Microsporum canis, Trichophyton menlagrophytes, Trichophyton rubrum, Scedosporium apiospermum and Scedosporium prolificans.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candidaparapsilosis, Aspergillusfiimigatus, Cryptococcus neoformans, Sporothrix schenckii, Microsporum canis, Trichophyton mentagrophyies, Trichophyton rubrum, Scedosporium apiospermum, Scedosporium prolificans, Rhizopus oryzae, Rhizomucor miehei.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candidaparapsilosis B66126, Aspergillusfiimigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophyies B70554, Trichophyton rubrum B68183, Scedosporium apiospermum IHEM3817, 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, Aspergillusfiimigatus B42928, Cryptococcus neoformans B66663, Sporothrix schenckii B62482, Microsporum canis B68128, Trichophyton mentagrophyies B70554, Trichophyton rubrum B68183, Scedosporium

apiospermum IHEM3817, Scedosporium prolificans 1HEM21157, Rhizopus oryzae 1HEM5223 and Rhizomucor miehei IHEM13391.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candida parapsilosis, Aspergillus fiimigatus, Cryptococcus neoformans, Microsporum canis, Trichophylon mentagrophytes, Trichophyion rubrum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Microsporum canis, Trichophylon rubrum, Aspergillusfitmigatus, Cryptococcus neoformans and Trichophyton mentagrophytes;

in particular Microsporum canis B68128, Trichophyton rubrum B68183, Aspergillus fumigaius B42928, Cryptococcus neoformans B66663 and Trichophyton mentagrophytes B70554,

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Candida parapsilosis B66126, Aspergillus fiimigatus B42928, Cryptococcus neoformans B66663, Microsporum canis B68128, Trichophyton mentagrophytes B70554, Trichophyton rubrum B68183, Rhizopus oryzae IHEM5223, Rhizomucor miehei IHEMJ3391.

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, Aspergillus fiimigatus B42928, Cryptococcus neoformans B66663, Microsporum canis B68128, Trichophyton mentagrophytes B70554, Trichophyton rubrum B68183.

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 and Epidermophyton·, in particular against Trichophyton and Microsporum.

against dermatophytes and Aspergillus spp.; in particular dermatophytes and Aspergillusfiimigatus; more in particular Microsporum canis, Trichophyton mentagrophyles, Trichophyton rubrum and Aspergillusfiimigatus; even more in particular Microsporum canis, Trichophyton mentagrophyles and Trichophyton rubrum.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Trichophyton mentagrophyles, Trichophyton rubrum and Aspergillus spp.; in particular Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fiimigatus.

The compounds of Formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvatés thereof, may be active against Trichophyton mentagrophytes; Trichophyton rubrum, Aspergillus spp., e.g. Aspergillusfiimigatus-, Fusarium spp:,Mucor Spp.; Zygomycetes spp.; Scedosporium spp.; Microsporum canis; Sporothrix schenckii; Cryptococcus neoformans and Candida parapsilosis.

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

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

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

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

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 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 topîcally.

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 10 use as a medicine. Also the use of a compound of Formula (I) in the manufacture of a médicament 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 ail processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of an infection, 15 but does not necessarily indicate a total élimination of ail 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 (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition 25 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 (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 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

*

k.

salts and the solvatés thereof, for use in the treatment of fungal infections; in particular fungal infections caused by one or more of the fungi mentioned hereinbefore.

The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the 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 the fungi selected from a group consisting of fungi mentioned hereinbefore.

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

The invention also relates to compounds according to the general Formula (I), the stereoisomeric forms thereof and the pharmaceutically acceptable acid or base addition salts and the 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.; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Malasseziafitrfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp.; Pénicillium spp.; Pénicillium marneffei; and Blastoschizomyces;

in 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; Scopulariopsis; 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 ofMicrosporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillusfiimigatus.

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 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 (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 treatment 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, preferabiy humans, 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 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 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, preferabiy 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, preferabiy oral administration, of an effective amount of a compound of Formula (I), to warm-blooded animais, including humans.

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, preferabiy from about 0.01 mg/kg to about 15 mg/kg, more preferabiy from about 0.01 mg/kg to about 10 mg/kg, even more preferabiy from about 0,01 mg/kg to about 1 mg/kg, most preferabiy 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

I here as the active ingrédient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for exemple 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.

While 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 (I) 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 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 ofthe 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 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 înto 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 empioyed 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 5 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 may 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 carriers 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, com oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form préparations that are intended tobe 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 5 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 10 such 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 1/100 to 100/1 may be applied. Interesting ratios of active ingrédient over cyclodextrin range from about 1/10 to 10/1. More interesting ratios of active ingrédient over cyclodextrin range from about 1/5 to 5/1.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight ofthe compound of Formula (I), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, 20 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 ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the 25 anhydroglucose units of the cyclodextrin are substituted with C i.(jalkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyCi.galkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyCi.^alkyl, particularly carboxymethyl or carboxy-ethyl; Ci^alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-p-CD, 2-hydroxyethyl^-CD, 2-hydroxyethyl-y-CD, 2-hydroxypropyl-Y-CD and (2-carboxymethoxy)propyl-p-CD, and in particular 2-hydroxypropyl^-CD (2-HP-p-CD).

The term mixed ether dénotés cyclodextrin dérivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, 35 hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.5.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.5.) refers to the average number of substituted hydroxyls per anhydroglucose unit, The M.S. and D.5’. value can be determined by various analytical techniques such as nuclear magnetic résonance (NMR), mass spectrometry (MS) and inffared 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.5. ranges from 0.125 to 3. Other suitable compositions for oral or rectal administration comprise particles consisting of a solid dispersion comprising a compound of Formula (I) and one or more appropriate pharmaceutically acceptable water-soluble polymers.

The term ”a solid dispersion” defines 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 20 solid dispersion will be called “a solid solution”. Solid solutions are preferred physical Systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This 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 25 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 30 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 35 Formula (I), or a solid solution comprising compound of Formula (I) and water-soluble polymer. Said domains are régions within the solid dispersion distinctively marked by some physical 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 suffïcient 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.

Suitable surface modifiers can preferably be selected from known organic and Înorganic 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 hydrophilic 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 firmness. 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 unifonmity 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, “Pd(OAc)₂ means palladium(II) acetate; “Et3N” means trietylamine; “DMF” means Λζ/V-dimethylformamide; “TLC” means thin layer chromatography; “PE” means petroleum ether; “TFA” means trifluoroacetic acid; “psi” means pound-force per square inch; “HPLC means high-performance liquid chromatography; “r.tmeans room température; “m.p.” means melting point; “min” means minute(s); “h” means hour(s); “EtOAc” means ethyl acetate; “EtOH” means éthanol; “MeOH” means methanol; “r.m.” means reaction mixture(s); “q.s.” quantum sufficit, “THF” means tetrahydrofùran; “HOAc” means acetic acid; “DPPP” means l,r-(l,3-propanediyl)bis[l,l-diphenylphosphine]; “HOBT” means l-hydroxy-lHbenzotriazole; “Me₂S” means dimethyl sulfide; and “EDCr means A-(ethy l carbonim i doy 1)-Λζ N-di methyl -1,3 -propanediam i ne monohy d rochloride.

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

a) Préparation of intermediate 1

Cl CN

A mixture of 2-amino-6-chlorobenzonitrile (17.72 g, 0.116 mol) and tetrahydro-2,5dimethoxyfuran (0.116 mol) in HOAc (100 ml) was stirred and refluxed for 30 min. Subsequently, the mixture was cooled and evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). The product fractions were collected and the solvent was evaporated. The residue was crystallized from EtOH. Yield: 18.83 g of intermediate 1 (80 % yield).

b) Préparation of intermediate 2

Borane-dimethyl sulphide (1:1) (2.5 ml of a 10N solution of BH3 in Me₂S, 0.0247 mol) was added at r.t. under N₂ atmosphère to a solution of intermediate 1 (5.0 g, 0.0247

mol) in THF (20 ml). The mixture was heated to reflux for 10 h. After cooling to r.t., HCl (6 N aqueous solution; 15 ml) was added dropwise. Subsequently the mixture was heated under reflux for 30 min. The solution was cooled to 0 °C and then NaOH (6 N;

q.s.) was added. The mixture was extracted with DCM (50 ml x 3) and the separated organic layer was dried (Na2SO₄), filtered, and the solvent was evaporated to yield an oil. HCl/dioxane (6 N; 5 ml) and dioxane (20 ml) were added and the precipitate was collected by filtration and dried. Yield: 5.14 g of intermediate 2 (86 % yield; .HCl).

Example A2

a) Préparation of intermediate 3

NaH (60 % in minerai oil; 5.66 g, 141.48 mmol) was added portionwise to a mixture of 5-bromo-l,3-dihydro-2H-Indol-2-one (10.0 g, 47.16 mmol) in THF (100 ml) at 0 °C. The mixture was stirred for 30 min, and then CHjI (21.42 g, 150.91 mmol) was added. The r.m. was stirred at 0 °C for 30 min. Subsequently, H2O (2 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in H2O (q.s.) and extracted with EtOAc. The separated organic layer was washed with brine, dried (Na2SO₄), filtered and evaporated in vacuo. The residue was purified by column chromatography (eluent: PE/EtOAc 20/1). The desired fractions were collected and the solvent was evaporated. Yield: 9.5 g of intermediate 3 (79 % yield).

b) Préparation of intermediate 4

Pd(OAc)î (0.31 g, 1.38 mmol) was added to a mixture of intermediate 3 (5.0 g, 19.7 mmol), DPPP (0.568 g, 1.38 mmol) and Et₃N (27 ml) in MeOH (200 ml) and DMF (200 ml). The solution was stirred and pressurized to 40 psi with CO at 70 °C for 4 h. Subsequently, the mixture was cooled to r.t. and diluted with H2O. The mixture was extracted with EtOAc. The separated organic layer was washed with H₂O and brine, was dried (Na2SO₄), filtered, and concentrated in vacuo. The crude was purified by column chromatography (eluent: PE/EtOAc 10/1). The desired fractions were collected and the solvent was evaporated. Yield: 2.4 g of intermediate 4 (52 % yield).

»

c) Préparation of intermediate 5

A mixture of intermediate 4 (2.4 g, 10.3 mmol) in NaOH (2N; 20 ml) and EtOH (30 ml) was stirred at r.t. for 4 h. Subsequently, HCl was added to pH 1-2. The mixture was extracted with EtOAc. The separated organic layer was dried (NaaSO-i), filtered, and the solvent was evaporated in vacuo to yield 2.1 g of intermediate 5 as a white solid (100% yield).

d) Préparation of intermediate 6

Intermediate 5 (1.35 g, 6.17 mmol) was dissolved in DCM (30 ml). Et₃N (4.5 ml, 30.86 mmol), HOBT (0.83 g, 6.17 mmol), EDCI (1.18 g, 6.17 mmol) and intermediate 2 (1.5 g, 6.17 mmol) were added to the solution. The r.m. was stirred overnight at r.t. The mixture was concentrated, and H₂O was added to the residue. This aqueous mixture was extracted with DCM. The separated organic layer was dried (Na₂SO4), filtered and the solvent was evaporated. The crude product was purified by HPLC (YMC column 25 x 150 mm; mobile phase: 35%-45% CHjCN (0.1 % TFA)/H₂O (0.1 % TFA); flow rate 20 ml/min; 20 min). The product fractions were collected and the solvent was evaporated. Yield: 0.77 g of intermediate 6 (34 % yield).

Example A3

Préparation of intermediate 7

The mixture of intermediate 2 (1.0 g, 4.2 mmol), 5,6,7,8-tetrahydro-2naphthalenecarboxylîcacid (0.88 g, 5.0 mmol), Et₃N (5.0 ml, 36.2 mmol), HOBT (0.62 g, 4.6 mmol) and EDCI (0.96 g, 5.0 mmol) in DCM (50 ml) was stirred overnight at r.t. Subsequently, the mixture was washed with H2O (3 x 100 ml), dried (MgSOi), filtered

k and the solvent was evaporated. The residue was washed with MeOH. The solid was collected and dried in vacuo. Yield: 0.9 g of intermediate 7 (59 % yield).

Example A4

a) Préparation of intermediate 8

Br

A mixture of 1,2-ethanedithiol (1.88 g, 20 mmol) in DCM (20 ml) was added to trimethylaluminum (20 ml) at -78 °C. After addition, the mixture was warmed to r.t. for 30 min. Subsequently, the mixture was cooled again to -20 °C, and a mixture of 6bromo-3,4-dihydro-277-l-benzopyran-2-one (4.54 g, 20 mmol) in DCM (80 ml) was added dropwise. The r.m. was stirred overnight at r.t., poured into ice-water, acidified (concentrated HCl), and extracted with DCM. The separated organic layer was dried (MgSO<i), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 100/1). The desired fractions were collected and the solvent was evaporated to yield 3.5 g of intermediate 8 (58 % yield; white solid).

b) Préparation of intermediate 9

Br

Triethylamine trihydrofluoride (8.05 g, 50 mmol, (CîHjjjN · 3HF) was added to a mixture of intermediate 8 (3.0 g, 10 mmol) in DCM (50 ml) at -78 °C. Then 1,3dibromo-5,5-dimethyl-2,4-imidazolidinedione (14.3 g, 50 mmol) in DCM (30 ml) was added in 30 min. The mixture was stirred for 2 h at r.t. Subsequently, the solution was quenched with NaOH (IN, q.s.) and extracted with DCM (200 ml). The separated organic layer was dried (MgSOx), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: PE) The desired fractions were collected and the solvent was evaporated. Yield; 2 g of intermediate 9 (80 % yield; oil).

c) Préparation of intermediate 10

O;

OH

Et 3 N (13 ml, 92.4 mmol) was added to a mixture of intermediate 9 (2.0 g, 8.03 mmol),

DPPP (0.267 g, 0.646 mol) and Pd(OAc)2 (0.145 g, 0.646 mol) in H₂O (40 ml) and

CH₃CN (100 ml). The r.m. was stirred and pressurized to 4 MPa with CO at 100 °C for 24 h. Then, the mixture was cooled to r.t. and diluted with H₂O. The precipitate was filtered off, and the filtrate was adjusted with HCl. The precipitate was filtered off, washed with H₂O, and dried in vacuo to yield 0.3 g of intenmediate 10(17% yield).

d) Préparation of intermediate 11

Et₃N (2 ml, 12.18 mmol), HOBT (0.1 g, 0.77 mmol), EDCI (0.15 g, 0.77 mmol) and intermediate 2 (0.17 g, 0.7 mmol) were added to a solution of intermediate 10 (0.17 g, 0,77 mmol) in DCM (15 ml). The r.m. was stirred at r.t. overnight. H₂O was added and the aqueous mixture was extracted with DCM. The separated organic layer was dried (Na₂SO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: ΡΕ/EtOAc from 15/1 to 10/1). The product fractions were collected and the solvent was evaporated in vacuo to yield 0.180 g of intermediate 11 (64 % yield).

Example A5

A mixture of 2,6-difluorobenzonitrile (27.8 g, 200 mmol), pyrrole (13.4 g, 400 mmol) and CS2CO3 (97 g, 600 mmol) in DMF (500 ml) was stirred and heated overnight to 80 °C. The mixture was cooled to r.t,, the solid was filtered off, and the solvent was removed. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 5/1). The desired fractions were collected and the solvent was evaporated to yield 19 g of intermediate 12 (51 % yield; white solid).

b) Préparation of intermediate 13

.HCl * .

Borane-dimethyl sulphide (1:1) (12 ml of a 10 M solution of BH3 in Me₂S, 0.120 mol) was added at r.t. under N₂ atmosphère to a solution of intermediate 12 (19 g, 0.102 mol) in THF (250 ml). The mixture was heated to reflux overnight under N₂. Then, HCl (6 N; 10 ml) was added to the mixture while the mixture was cooled on an ice-water bath, The mixture was refluxed 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 x 300 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The brown residue was converted tothe HCl sait (1:1) with HCl/2-propanol, Yield: 17 g of intermediate 13 (75 % yield; .HCl).

c) Préparation of intermediate 14

A mixture of intermediate 13 (0.95 g, 4.2 mmol), 2,2-difluoro-l,3-benzodioxole-5carboxylic acid (1.0 g, 5.0 mmol), EtjN (5.0 ml, 36 mmol), HOBT (0.62 g) and EDCI (0.95 g) in DCM (50 ml) was stirred overnight at r.t. The mixture was washed with H₂O (3 x 100 ml), dried (MgSOi), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc from 20/1 to 10/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0,8 g of intermediate 14 (51 % yield).

Example A6

a) Préparation of intermediate 15

A mixture of 2-amino-3-chlorobenzoic acid (25 g, 145.7 mmol), tetrahydro-2,5dimethoxyfuran (145.7 mmol), and 4-chloropyridine hydrochloride (1:1) in dioxane (300 ml) was heated to reflux overnight. The reaction mixture was washed with H₂O (3 x 300 ml) and extracted with DCM (3 x 200 ml). The separated organic layer was dried and evaporated in vacuo. Yield: 32 g of crude intermediate 15 (99 % yield), used as such in the next reaction step.

i

b) Préparation of intennediaÏe 16

A mixture of intermediate 15 (32 g crude, approximately 145 mmol), HOBT (22.3 g, 165 mmol), EDCI (31.6 g, 165 mmol) and ΝΗ₃.Η₂Ο (35 ml) in DMF (300 ml) was stirred overnight at r.t. The mixture was quenched with H₂O (300 ml), and the product was filtered off. Yield: 23 g of intermediate 16 (72 % yield).

c) Préparation of intermediate 17

Reaction under N₂ atmosphère: Intermediate 16 (2.0 g, 9.1 mmol) was dissolved in THF (50 ml). L1AIH4 (1.7 g, 45.5 mmol) was added while the solution was cooled on an ice-water bath. Subsequently, the mixture was heated to reflux for 3 h, and then the solution was cooled to r.t. H₂O (5 ml) was added while the r.m. was cooled on an icewater bath. EtOAc (50 ml) was added and the mixture was filtered. The filtrate was extracted with EtOAc (3 x 25 ml). The separated organic layer was dried (Na₂SO4), filtered, and evaporated in vacuo. Yield: 1.2 g of intermediate 17 (64 % yield).

d) Préparation of intermediate 18

A mixture of intermediate 17 (1.1 g, 5.3 mmol), 3,4-dihydro-2H-l-Benzopyran-6carboxylic acid (1.1 g, 6.4 mmol) EtîN (7.5 ml, 47.7 mmol), HOBT (0.77 g, 5.7 mmol) and EDCI (1.1 g, 5.8 mmol) in DCM (40 ml) was heated to reflux for 5 h, and was then cooled to r.t. The solution was poured into ice-water. A 2 M NaOH solution was added to pH 8. This mixture was extracted with DCM (3 x 50 ml). The organic layers were combined, washed with H₂O (3 x 20 ml), washed with brine (3 x 20 ml), dried (Na₂SO4), filtered, and the solvent was evaporated in vacuo. The residue was purified by HPLC (Luna column 50 x 300 mm; mobile phase: 0%-30% CH3CN (0.1 % TFA)/H₂O (0.1 % TFA); flow rate 80 ml/min; 25 min). The product fractions were

collected and neutrahzed with a saturated NaHCCh solution. The mixture was extracted with DCM. The separated organic layer was dried (NajSOj), filtered and the solvent was evaporated. Yield: 0.8 g of intermediate 18 (41 % yield).

Example A7

a) Préparation of intermediate 19

Reaction under N₂ atmosphère. Tetrahydro-2,5-dimethoxyfuran (11.1 g, 83.6 mmol) was added to a mixture of 2-amino-4-chlorobenzonitrile (10 g, 65.5 mmol) in acetic acid (45 ml). The mixture was heated to reflux and stirred for 1 h. Subsequently, the solvent was evaporated in vacuum. The residue was purified by column chromatography over silica gel (eluent: PE/EtOAc 4/1). The desired fractions were collected and the solvent was evaporated in vacuum. Yield: 13.0 g of intermediate 19 (98% yield).

b) Préparation of intermediate 20

Intermediate 19(13 g, 64.2 mmol) was dissolved in THF (80 ml). Borane-dimethyl sulphide (1:1) (6.9 ml of a 10 M solution of BH3 in Me₂S, 69.3 mmol) was added slowly inot the solution under N₂. The r.m. was stirred and refluxed overnight. Subsequently, the mixture was cooled off. MeOH (15 ml) was added to the mixture (cooled on an ice-water bath). The mixture was stirred for 30 min. HCI/MeOH (15 ml of a 4 N solution) was added slowly. The solvent of the mixture was evaporated in vacuo and an additional amount of HCI/MeOH (20 ml of a 4 N solution) was added to the residue. The solvent of the mixture was evaporated in vacuo. The crude intermediate 20 (15 g) was used as such in the next reaction step.

Example A8

a) Préparation of intermediate 21

1,2-Ethanedithiol (4.7 g, 50 mmol) in DCM (100 ml) was added to trimethylaluminium (50 ml of a 2 M solution in toluene; 100 mmol) at -78 °C. After addition, the mixture was warmed to r.t. for 30 min. The mixture was cooled to -20 °C, and then 6-Bromo3,4-dihydro-2H-l-Benzopyran-2-one (11.35 g, 50 mmol) in DCM (200 ml) was added dropwise to the mixture. The mixture was stirred ovemight. The mixture was poured out into ice-water, acidified by concentrated HCl, and extracted with DCM. The separated organic layer was dried (Na2SO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: PE/EtOAc from 80/1 to 50/1). The product fractions were collected and the solvent was evaporated in vacuo to yield 2 g of intermediate 21 (15 % yield).

b) Préparation of intermediate 22

Br

Triethylamine tri(hydrogen fluoride) (5.36 g, 33.24 mmol) was added to the mixture of intermediate 21 (2 g, 6.59 mmol) in DCM (100 ml) at -78 °C. Then l,3-dibromo-5,5dimethyl-2,4-imidazolidinedione (9.54 g, 33.24 mmol) in DCM (100 ml) was added slowly, and the resulting mixture was stirred for 2 h at r.t. Subsequently, the mixture was quenched with NaOH (1 N) and extracted with DCM. The separated organic layer was dried (Na2SO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography (gradient eluent: PE/EtOAc from 50/1 to 30/1). The product fractions were collected and the solvent was evaporated in vacuo to yield 1.1g of intermediate 22 (69 % yield; oil).

c) Préparation of intermediate 23

Reaction under anhydrous conditions.

A 2.5 M solution of n-butyllithium in n-hexane (4.02 ml, 10 mmol)) was added dropwise to a solution of intermediate 22 (1.25 g, 5.02 mmol) in THF (30 ml) under Nî.

The mixture was stirred for 2 h at -78 °C. DMF (0.78 ml, 10 mmol) was added and the mixture was stirred for 2 h at -78 °C. Subsequently the mixture was quenched with

NH4CI, and was then extracted with DCM. The separated organic layer was dried (NaîSCh), filtered and the solvent was evaporated in vacuo. Yield; 1.0 g of intermediate 23 (100% yield).

B. Préparation of the compounds

Example B1

Préparation of compound 1

Intermediate 6 (0.77 g, 1.88 mmol) was dissolved in POCI3 (5 ml). The mixture was stirred and refluxed overnight. Subsequently, the mixture was cooled and poured into H2O (q.s.). The aqueous mixture was neutralized with NaOH to pH 7, and was then extracted with DCM. The separated organic layer was dried (MgSO<i), filtered, and the 10 solvent was evaporated. The residue was washed with isopropyl ether. The solid was filtered off and dried in vacuo. Yield; 0.587 g of compound 82 (80 % yield).

Example B2

Préparation of compound 21

Intermediate 7 (0.9 g, 2.5 mmol) was dissolved in POCI3 (12.0 ml). The mixture was stirred overnight at 100 °C, and was then poured into ice water. The aqueous mixture 15 was extracted with DCM. The separated organic layer was dried (NaîSOi), filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: ΡΕ/EtOAc from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.450 g of compound 21 (52 % yield).

Example B3

a) Préparation of compound 12

A mixture of intermediate 2 (1.00 g, 0.004 mol) and 2,3-dihydro-l/f-Indene-5carboxaldehyde ( 0.004 mol) in EtOH (20 ml) was stirred and refluxed for 3 h. The mixture was crystallized overnight. The product was filtered off, washed 3 x with

EtOH, and dried. Yield: 1.02 g of compound 12 (69 % yield; .HCl).

b) Préparation of compound 20

A mixture of H₂O (20 ml) and NH3.H2O (5 ml) was added to a solution of compound 12 (0.185 g, 0.0005 mol) in DCM (10 ml). The layers were separated and dried, filtered and MnO₂ (1.2 g) was added. The r.m. was reacted for 96 h at 25 °C. The precipitate was filtered off over diatomaceous earth and the filtrate was evaporated. The residue 10 was purified by préparative TLC (eluent: PE/EtOAc 5/1). The desired fractions were collected and the solvent was evaporated. Yield: 0.04 g of compound 20 (25 % yield).

Example B4

Préparation of compound 69

Intermediate 11 (0.18 g, 0.45 mmol) was dissolved in POCI3 (4 ml). The mixture was stirred and refluxed overnight. Subsequently, the mixture was cooled and poured into 15 H₂O. The aqueous mixture was neutralized with NaOH to pH 7, and was then extracted with DCM. The separated organic layer was dried (Na₂SO4), filtered and the solvent

» was evaporated. The residue was purified by préparative HPLC (Synergy column 30 x 150 mm; mobile phase: 33%-63% CH₃CN (O.l % TFA)/H₂O (0.1 % TFA); flow rate 25 ml/min; 19 min). The product fractions were collected and the solvent was evaporated. The residue was neutralized with a saturated NaHCO₃ solution. The organic layer was dried (Na₂SO₄), filtered and the solvent was evaporated. Yield: 0.050 g of compound 69 (29 % yield).

Example B5

Préparation of compound 77

Intermediate 14 (0.80 g, 2.1 mmol) was dissolved in POC1₃ (3 ml). The mixture was stirred overnight at 100 °C, and was then poured into ice-water. NaOH was added to pH 8-9. The mixture was extracted with DCM. The separated organic layer was dried (Na₂SO₄), filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: ΡΕ/EtOAc from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.5 g of compound 77 (67 % yield).

Example B6

Préparation of compound 43

Intermediate 18 (0.8 g, 2.18 mmol) was dissolved in POC1₃ (5 ml). The solution was heated to reflux for 5 h, and was then cooled to r.t. The solution was poured into ice. A 2 M NaOH solution was added to pH 8. Subsequently, the mixture was extracted with DCM (3 x 50 ml). The combined organic layers were washed with H₂O (3 x 20 ml), brine (3 x 20 ml), dried (Na₂SO₄), filtered, and the solvent was evaporated in vacuo. The residue was purified by HPLC (Luna column 50 x 300 mm; mobile phase: 35%50% CH₃CN (0.1 % TFA)/H₂O (0.1 % TFA); flow rate 80 ml/min; 25 min). The product fractions were 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. Yield: 0.560 g of compound 43 (74 % yield).

Example B7

a) Préparation of compound 84

Intermediate 23 (0.3 g, 1.5 mmol) was added to a solution of intermediate 20 (0.36 g, 1.5 mmol) in EtOH (1 ml). The r.m. was heated to reflux température and stirred overnight. The solution was filtered through diatomaceous earth and the filtrate was collected. The solvent of the filtrate was evaporated in vacuum. The residue was purified by HPLC (Synergy column 25 x 150 mm; mobile phase: 35%-5O% CH₃CN (0.1 % TFA)/H₂O (0.1 % TFA); flow rate 25 ml/min; 14.4 min). The product fractions were collected and neutralized with a saturated NaHCO₃ solution. The mixture was extracted with DCM. The separated organic layers were dried (Na₂SO«), filtered and the solvent was evaporated. Yield: 0.120 g of compound 84 (21 % yield).

b) Préparation of compound 71

Compound 84 (0.120 g, 0.31 mmol) was dissolved in DCM (10 ml). MnO₂ (0.27 g, 3.1 mmol) was added to the solution. The r.m. was stirred overnight, and was then filtrated through diatomaceous earth. The filtrate was collected and the solvent was evaporated in vacuum. The residue was purified by column chromatography over silica gel (eluent: 15 PEÆtOAC from 10/1 to 5/1). The desired fractions were collected and the solvent was evaporated in vacuo. Yield: 0.040 g of compound 71 (34 % yield).

By using analogous reaction protocols as described in the foregoing examples, the 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.

HBr sait forms were obtained by using procedures known to those skilled in the art. A typical procedure is described in WO02/34752.

Compounds for which no spécifie stereochemistry is indicated for a stereocenter in 25 Tables la, lb, le or ld were obtained as racemic mixtures of R and S enantiomers.

I

Table la:

Co. No.	Pr.	R¹	R²	R³	R⁴	Sait Form
2	B3.a	H	H	H	H	HBr
3	B3.a	7-Cl	H	H	H
4	B3.a	7-CI	H	H	H	HBr
5	B3.a	8-Cl	H	H	H	HBr
6	B3.a	9-Cl	H	H	H	.HBr
7	B3.a	10-CI	H	H	H	.HBr
8	B3.a	7-OCHj	H	H	H	HBr
9	B3.b	H	H	bond
10	B3.b	7-Cl	H	bond
11	B3.b	8-Cl	H	bond

Table lb:

Co. No.	Pr.	R¹	R¹	R³	R⁴	R⁵	s	Sait Form
12	B3.a	7-Cl	H	H	H	H	3	HCl
13	B3.a	7-Cl	H	H	H	H	3	HBr
14	B3.a	7-Cl	H	H	H	OCH₂CH₃	3	HBr
15	B3.a	7-Cl	H	H	H	och₃	4	HBr
16	B3.a	7-Cl	10-C1	H	H	H	3	HCl
17	B3.a	8-Cl	10-C1	H	H	H	3	HCI
18	B3.a	7-Cl	8-Cl	H	H	H	3	HCl
19	B3.a	7-Cl	9-Cl	H	H	H	3	HCl
20	B3.b	7-Cl	H	bond	H	3
21	B2	7-Cl	H	bond	H	4
22	B3.b	7-Ci	8-Cl	bond	H	3
23	B3.b	7-Cl	9-Cl	bond	H	3
24	B3.b	7-Cl	10-CI	bond	H	3
25	B3.b	8-Cl	10-C1	bond	H	3

Table le:

Co. No.	Pr.	R¹	R³	R³	R⁴	R^s	m	n	Sait Form
26	B3.a	7-CI	H	H	H	H	0	2	HCI
27	B3.a	7-C1	H	H	H	H	2	2	HCl
28	B3,a	7-CI	H	H	H	H	1	3	HCl
29	B3.a	7-F	H	H	H	H	1	3	HCl
30	B3.a	7-C1	8-C1	H	H	H	0	2	HCl
31	B3.a	7-CI	9-C1	H	H	H	0	2	HCl
32	B3.a	7-C1	10-C1	H	H	H	0	2	.HCl
33	B3.a	7-C1	10-C1	H	H	H	2	2	.HCl
34	B3.a	8-C1	10-C1	H	H	H	0	2	.HCl
85	B7,a	9-C1	H	H	H	H	1	3
35	B3,b	7-CI	H	bond	H	0	2
36	B3.b	7-C1	H	bond	H	2	2
37	B3.b	7-CI	H	bond	H	1	3
38	B6	7-C1	H	bond	H	0	3
39	B6	7-F	H	bond	H	1	3
40	B3.b or B6	7-F	H	bond	H	0	3
41	B3.b or B7.b	9-CI	H	bond	H	1	3
42	B6	9-C1	H	bond	H	0	3
82	B6	10-C1	H	bond	H	1	3
43	B6	10-C1	H	bond	H	0	3
44	B3.b	7-C1	8-C1	bond	H	0	2
45	B3.b	7-C1	9-C1	bond	H	0	2
46	B6	7-F	9-F	bond	H	0	3
47	B3.b	7-CI	10-C1	bond	H	2	2
48	B3,b	8-CI	10-C1	bond	H	0	2

Table ld:

(D

Co. No.	Pr.	R¹	R²	R³	R⁴	R^s	-r⁶-r⁷-	Sait Form
49	B3.a	7-Ci	H	H	H	OCHj	-CH₂-CH(CH₃)-O-	HBr
50	B3.a	7-CI	H	H	H	OCH₂CHj	-CH_rCH(CH₃)-O-	.HBr
51	B3.a	7-CI	H	H	H	H	-C(=O)-(CH₂)₂-	.HCl
52	B3.a	7-CI	H	H	H	H	-(CH₂)₂-C(=O)-	HCl
53	B3.a	7-F	H	H	H	H	-O-CF₂-(CH₂)2-	.HCl
54	B3.a	7-F	9-F	H	H	H	-O-CF₂-(CH₂)₂-	HCl
84	B7.a	9-C1	H	H	H	H	-O-CF₂-(CH₂)₂-
86	B7.a	10-C1	H	H	H	H	-O-CF₂-(CH₂)₂-
87	B3.a	10-C1	H	H	H	H	-C(=O)-(CH₂)₂-	HCl
55	B3.b	7-CI	H	bond	H	-(CH₂)₂-C(=O)-
56	B3.b	7-CI	H	bond	H	-C(=O)-(CH₂)₂-
57	B3.b	10-C1	H	bond	H	-C(=O)-(CH₂)₂-
58	B2	7-0	H	bond	H	-c(=ohch₂)₃-
59	B2	7-F	H	bond	H	-C(=O)-(CH₂)₃-
60	B2	9-C1	H	bond	H	-C(=O)-(CH₂)r
61	B2	10-C1	H	bond	H	-C(=OXCH₂).,-
62	B1	7-CI	H	bond	H	-CH₂-O-C(=O)-
63	B1	7-F	H	bond	H	-CH₂-O-C(=O)-
64	B1	7-CI	9-C1	bond	H	-CH₂-O-C(=O)-
65	B1	7-CI	H	bond	H	-C(=O)-O-CH₂-
66	B2	7-CI	H	bond	H	-CF₂-(CH₂)₂-
67	B2	9-C1	H	bond	H	-CF₂-(CH₂)₂-
68	B2	10-CI	H	bond	H	-CF₂-(CH₂)₂-
88	B2	9-F	7-C)	bond	H	-CF₂-(CH₂)₂-
69	B4	7-Ci	H	bond	H	-O-CF₂-(CH₂)₂-
70	B3,b	7-F	H	bond	H	-O-CF₂-(CH₂)₂-
71	B3.b or B7.b	9-CI	H	bond	H	-O-CF₂-(CH₂)₂-
72	B3,b or B7.b	10-C1	H	bond	H	-O-CF₂-(CH₂)₂-
73	B3.b	7-F	9-F	bond	H	-O-CF₂-(CH₂)₂-
74	B5	7-CI	H	bond	H	-o-cf₂-o-
75	B5	9-C1	H	bond	H	-o-cf₂-o-
76	B5	10-C1	H	bond	H	-o-cf₂-o-
77	B5	7-F	H	bond	H	-o-cf₂-o-
78	B1	7-F	9-F	bond	H	-o-cf₂-o-
79	81	7-CI	9-C1	bond	H	-o-cf₂-o-

Co. No.	Pr.	R¹	R²	R³	R*	R^s	-R⁶-R⁷-	Sait Form
80	B1	7-C1	H	bond	H	-O-C(=O)-N(CH₃)-
81	B1	7-F	H	bond	H	-N(CH₃)-(CH₂)₂-
83	B1	7-C1	H	bond	H	-N(CH₃)-(CH₂)₂-
1	B1	7-C1	H	bond	H	-N(CH₃)-C(=O)-C(CHj)₂-

C. 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 1/min.

LCMS Method 1

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 μΙ were used. Oven température was 50 °C. (MS polarity: positive)

LCMS Method 2

In addition to the general procedure: Reversed phase HPLC was carried 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 pl were used. Oven température was 50 °C. (MS polarity: positive)

LCMS Method 3

In addition to the general procedure: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50x2.1 mm 5pm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C: 10 mmol/1 NH4HCO3; mobile phase D: CH3CN) were used.

First, 100 % C was hold for 1 minute. Then a gradient was applied to 40 % C and 60 %

D in 4 minutes and hold for 2.5 min. Typical injection volumes of 2 μΙ 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 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 (Rt) in min., [M+H]⁺ peak (protonated molécule), and m.p.

(melting point in °C). (“n.d.” means not determined; “dec” means decomposed).

Co. No.	Rt	[μ+ηΓ	LCMS Method	m.p. (°C)	Co. No.	Rt	[M+H]⁺	LCMS Method	m.p. (°C)
2	n.d.	n.d.	-	n.d.	32	3.69	371	2	n.d.
3	n.d.	n.d,	-	n.d.	33	3.62	371	2	262.9-264.4
4	n.d.	n.d.		n.d.	34	3.75	371	2	261.7-263.6
5	n.d.	n.d.		n.d.	35	3.17	335	2	206.4-208.9
6	n.d.	n.d.		n.d.	36	3,42	335	2	180.5-181.2
7	n.d.	n.d.		n.d.	37	2.78	349	2	190.5-193.4
8	n.d.	n.d.		n.d.	38	3.23	349	2	>280
9	n.d.	n.d.		n.d.	39	3.96	333	1	168.6-169.0
10	n.d.	n.d.		n.d.	40	3.75	333	2	>280
11	n.d.	n.d.		n.d.	41	3.63	349	2	n.d.
12	3.81	335	2	242.7-243.5	42	3.86	349	2	>280
13	n.d.	n.d.		n.d.	43	3.79	349	2	103.7-103.7
14	n.d.	n.d.		n.d.	44	3.39	369	2	n.d.
15	n.d.	n.d.		n.d.	45	3.80	369	2	190.0-191.8
16	4.10	369	2	172.5-176.6	46	3,70	351	2	n.d.
17	4.04	369	2	n.d.	47	7.06	369	3	203.5-205.2
18	3.99	369	2	238.8-240.2	48	3,65	369	2	102.7-105.6
19	4.16	369	2	205.7-207.3	49	n.d.	n.d.	-	n.d.
20	3.74	333	2	181.3-182.7	50	n.d.	n.d.	-	n.d.
21	3.92	347	2	180.0-181.5	51	2.95	349	2	>280
22	3.87	367	2	199.3-201.6	52	3.04	349	2	n.d.
23	4.12	367	2	n.d.	53	3.21	371	2	n.d.
24	3.89	367	2	194.0-194,2	54	3.29	389	2	n.d.
25	2.62	367	2	178.5-180.2	55	5.86	347	3	214.0-217.0
26	3.22	337	2	237.9-239.7	56	5.89	347	3	226.7-227.6
27	3.47	337	2	165.1-167.2	57	3.41	347	2	n.d.
28	2.79	351	2	n.d.	58	3,04	361	2	209.8-210.7
29	3.90	335	1	n.d.	59	2,93	345	2	n.d.
30	3.44	371	2	224.9-226.0	60	3.70	361	2	>280°C
31	3.83	371	2	257.7-260.6	61	3.65	361	2	n.d. \|

Co. No.	K	[M+H]⁺	LCMS Method	m.p. (°C)
62	3.76	349	1	107.9 (dec)
63	3.60	333	1	224.6-246.0
64	3.33	383	2	210.5-212.0
65	3.84	349	1	251.2-253.0
66	3.90	369	2	193.4-193.8
67	3.95	369	2	>280°C
68	3.95	369	2	n.d.
69	4.38	385	1	199.7-201.2
70	3.16	369	2	158.9-159.3
71	3.99	385	2	n.d.
72	3.88	385	2	n.d.
73	3.88	387	2	n.d.

Co. No.	Rt	\|M+H]⁺	LCMS Method	m.p. (°C)
74	3.66	373	2	184.9-186.0
75	4.39	373	1	151.3-152.7
76	4.34	373	1	139.3-141.1
77	3.39	357	2	n.d.
78	3.46	375	2	n.d.
79	3,61	407	2	85.3-87.3
80	4.15	364	1	218.6-221.0
81	3.36	332	2	164.0-165.4
82	6.00	349	3	n.d.
83	4.63	348	2	n.d.
88	3.84	387	2	170.2-171.8
1	3.49	390	2	233.7-235.1

‘HNMR

For a number of compounds, ‘H NMR spectra were recorded on a Bruker DPX-300, a Bruker DPX-400, or on a Bruker Avance 600 spectrometer spectrometer with standard puise sequences, operating at 300 MHz, 400 MHz and 600 MHz respectively, using

CHLOROFORM-tZ (deuterated chloroform, CDClj) or DMSO-cA (deuterated DMSO, dimethyl-d6 sulfoxide) as solvents. Chemical shifts (Ô) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internai standard.

Compound 17: *H NMR (300 MHz, DMSOa/₆) δ ppm 2.04 (quin, >7.4 Hz, 2 H), 2.79 - 2.97 (m, 4 H), 3.59 (d, >13.2 Hz, 1 H), 4.34 (d, >13.4 Hz, 1 H), 5.22 (s, 1 H), 5.92 (d, >3.7 Hz, 1 H), 6.27 (t, >3.3 Hz, 1 H), 7.32 (d, >7.7 Hz, 1 H), 7.37 (dd, >3.0, 1.5

Hz, 1 H), 7.51 (d, >7.8 Hz, 1 H), 7.63 (s, 1 H), 7.78 (d, >2.4 Hz, 1 H), 8.05 (d, >2.3 Hz, 1 H), 10.01 (br. s, 1 H), 10.62 (br. s, 1 H).

Compound 20: ^]H NMR (400 MHz, CHLOROFORMEZ) δ ppm 1.99-2.13 (m, 2 H)

2.79 - 2.97 (m, 4 H) 4.15 (br. s., 1 H) 5.47 (br. s., 1 H) 6.43 (br. s„ 1 H) 6.51 (br. s., 1

H) 7.18 (d, >7.8 Hz, 1 H) 7.26 - 7.33 (m, 3 H) 7.36 (d, >7.0 Hz, 1 H) 7,43 (d, >7.8 Hz, 1 H) 7.60 (s, 1 H).

Compound 22: 'H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.01 - 2.14 (m, 2 H)

2.80 - 2.98 (m, 4 H) 4.19 (br. s., 1 H) 5.52 (br. s., 1 H) 6.45 (br. s., 1 H) 6.53 (br. s„ 1

H) 7.21 (m, >9.2, 9.2 Hz, 2 H) 7.29 (br. s., 1 H) 7.43 (d, >7.5 Hz, 1 H) 7.47 (d, >8.8 20 Hz, 1 H) 7.60 (s, 1 H).

Compound 23: *H NMR (300 MHz, CHLOROFORMAT) δ ppm 2.08 (quin, >7.4 Hz, 2 H) 2.80 - 3.02 (m, 4 H) 4.11 (br. s, 1 H) 5.44 (br. s, 1 H) 6.46 (br. s., 1 H) 6.54 (br. s.,

H) 7.19 (d, >7.9 Hz, 1 H) 7.27 (d, >1.9 Hz, 1 H) 7,31 (br. s„ 1 H) 7.36-7.40 (m, 1 H) 7.42 (d, >7.9 Hz, 1 H) 7.59 (s, 1 H).

' 4

Compound 24: H NMR (300 MHz, DMSCM,) Ô ppm 2.02 (quin, >7.4 Hz, 2 H) 2.78 - 2.99 (m, 4 H) 3.94 (d,>11.3 Hz, l H) 5.20 (d, >11.3 Hz, 1 H) 6.43 - 6.48 (m, 1 H)

6.48 - 6.52 (m, 1 H) 7.25 (d, >7.7 Hz, 1 H) 7.47 (d, >7.9 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 7.64 (d, >8.8 Hz, 1 H) 7.66 - 7.69 (m, 1 H).

Compound 25: *H NMR (400 MHz, CHLOROFORM-^) δ ppm 2.08 (quin, >7.4 Hz, 2 H) 2.91 (m, >8.0, 8.0, 8.0 Hz, 4 H) 4.23 (d, >11.3 Hz, 1 H) 4.73 (d, >11.0 Hz, 1 H) 6.39 (t, >3.0 Hz, 1 H) 6.50 (d, >2.3 Hz, 1 H) 7.20 (d, >7.8 Hz, 1 H) 7.36 - 7.42 (m, 1 H) 7,43 - 7.46 (m, I H) 7.48 (br. s., 1 H) 7.51 (d, >8.0 Hz, 1 H) 7.64 (s, 1 H).

Compound 27: ^]H NMR (300 MHz, DMSO-i/_fi) δ ppm 3.22 (t, >8.7 Hz, 2 H), 3.83 (d, >13.8 Hz, 1 H), 4.53 (d, >13.9 Hz, 1 H), 4.57 (t, >8.7 Hz, 2 H), 5.15 (br. s., 1 H), 5.88 (d, >3.8 Hz, 1 H), 6.29 (t, >3.3 Hz, 1 H), 7.19 (d, >7.6 Hz, 1 H), 7.23 (s, 1 H), 7.31 (d, >7.6 Hz, 1 H), 7.37 - 7.43 (m, 1 H), 7.58 - 7.74 (m, 3 H), 10.21 (br. s, 1 H), 10.56 (br. s, 1 H).

Compound 28: *H NMR (400 MHz, DMSO-^) δ ppm 2.71 - 2.86 (m, 2 H), 3.83 (br. s, 1 H), 3.88 (t, >5.7 Hz, 2 H), 4.53 (d, >13.8 Hz, 1 H), 4.70 (s, 2 H), 5.16 (br. s, 1 H), 5.90 (d, >3.0 Hz, 1 H), 6.28 (t, >3.3 Hz, 1 H), 7.13 (d, >7.8 Hz, 1 H), 7.40 (s, 1 H),

7.48 - 7.55 (m, 2 H), 7.57 - 7.64 (m, 2 H), 7.67 (t, >7.9 Hz, 1 H), 10.05 (br. s, 1 H),

10.40 (br. s, 1 H).

Compound 31 : *H NMR (300 MHz, DMSO-t/₆) δ ppm 3.14 - 3.30 (m, 2 H), 3.74 - 3.86 (m, 1 H), 4.49 (d, >13.9 Hz, 1 H), 4.59 (t, >8.7 Hz, 2 H), 5.17 - 5.25 (m, 1 H), 5.93 (d, >3.6 Hz, 1 H), 6.30 (t, >3.2 Hz, 1 H), 6,85 (d, >8.2 Hz, 1 H), 7.42 - 7.51 (m, 2 H), 7,65 (s, l H), 7.78 (d, >2.3 Hz, 1 H), 7.84 (d,>2.3 Hz, 1 H), 10.08 (br. s, 1 H),

10.41 (br. s, 1 H).

Compound 36: *H NMR (400 MHz, CHLOROFORM-i/) δ ppm 3.21 (t, >8.7 Hz, 2 H), 4.14 (br. s, 1 H), 4.57 (t, >8.6 Hz, 2 H), 5.47 (br. s, 1 H), 6.37 - 6.47 (m, 1 H), 6.47 6.59 (m, 1 H), 7.12 (s, 1 H), 7.15 (d, >7.7 Hz, 1 H), 7.21 (d, >8.0 Hz, 1 H), 7.23 7.34 (m, 3 H), 7.36 (d, >7.0 Hz, 1 H).

Compound 37: *H NMR (400 MHz, CHLOROFORM-t/) δ ppm 2.88 (br. s, 2 H), 3.97 (t, >5.7 Hz, 2 H), 4.16 (br. s, 1 H), 4.80 (s, 2 H), 5.49 (br. s, 1 H), 6.42 - 6.48 (m, 1 H),

6.48 - 6.55 (m, 1 H), 6.97 (d, >8.0 Hz, 1 H), 7.23 - 7.32 (m, 2 H), 7.34 (s, 1 H), 7.38 (dd, >7.2,1.8 Hz, 1 H), 7.46 (d, >8.0 Hz, 1 H), 7.53 (s, 1 H).

Compound 39: 'H NMR (300 MHz, CHLOROFORM-^ δ ppm 2.87 (t, J=5.7 Hz, 2 H),

3.96 (t, >5.7 Hz, 2 H), 4.61 (br. s, 2 H), 4.79 (s, 2 H), 6.44 (dd, >3.8, 2.8 Hz, 1 H),

6.51 (dd, >3.8, 1.5 Hz, 1 H), 6.96 (d, >8.0 Hz, 1 H), 7.06 (t, >8.5 Hz, 1 H), 7.16 (d, >8.0 Hz, 1 H), 7.27 - 7.38 (m, 2 H), 7.45 (dd, >8.1, 1.3 Hz, 1 H), 7.51 (s, 1 H).

Compound 42: ^]H NMR (400 MHz, CHLOROFORM-rf) ô ppm 2.01 (quin, >6.4 Hz, 2 H) 2.80 (t, >6.5 Hz, 2 H) 4.21 (t, >5.0 Hz, 2 H) 4.34 (br. s., 1 H) 4.80 (br. s„ 1 H)

6,45 (ζ >3.3 Hz, 1 H) 6,54 (dd, >305.0, 1.3 Hz, 1 H) 6,75 (d, >8.5 Hz, 1 H) 7.23 7.27 (m, 1 H) 7.30 - 7.34 (m, 1 H) 7.35 - 7.43 (m, 3 H) 7.47 (s, 1 H).

Compound 43: *H NMR (400 MHz, CHLOROFORM-ίΖ) δ ppm 1.95 - 2.06 (m, 2 H) 2.70 - 2.91 (m, 2 H) 4.17 - 4.22 (m, 2 H) 4.24 (d, >11.3 Hz, 1 H) 4.76 (d, >11.3 Hz, 1 H) 6.40 (dd, >3.8, 3.0 Hz, 1 H) 6.51 (dd, >3.8, 1.8 Hz, 1 H) 6.76 (d, >8.5 Hz, 1 H)

7.22 (t, >7.9 Hz, 1 H) 7.41 (dd, >7.5, 1.3 Hz, 1 H) 7.44 (dd, >8.0, 1.3 Hz, 1 H) 7.50 (dd, >8.5, 2.3 Hz, 1 H) 7.53 (ddd, >3.3, 2.1, 1.8 Hz, 2 H).

Compound 44: *H NMR (400 MHz, CHLOROFORM-îZ) δ ppm 3.20 - 3.38 (m, 2 H) 4.38 (br. s., 1 H) 4.66 - 4.80 (m, 2 H) 5.68 (br. s., 1 H) 6.69 - 6.80 (m, 1 H) 6.88 (d, >8.3 Hz, 1 H) 7.10 (d, >3.3 Hz, 1 H) 7,28 (d, >7.0 Hz, 1 H) 7.53 (d, >8 3 Hz, 1 H) 15 7.64 (d, >8.5 Hz, 1 H) 7.75 (br. s., 1 H) 7.84 (br. s., 1 H).

Compound 45: 'H NMR (400 MHz, CHLOROFORM-îZ) δ ppm 3.22 (t, >9.5 Hz, 2 H) 4.12 (br. s., 1 H) 4.62 (t, >8.8 Hz, 2 H) 5.41 (br. s., 1 H) 6.47 (t, >2.8 Hz, 1 H) 6.56 (br. s., 1 H) 6.74 (d, >8.5 Hz, 1 H) 7.28 (d, >2.0 Hz, 1 H) 7.29 - 7.35 (m, 1 H) 7.40 (d, >1.8 Hz, 1 H) 7.44 (d, >8.0 Hz, 1 H) 7.66 (br. s„ 1 H).

Compound 46: ^lH NMR (400 MHz, CHLOROFORM-îZ) δ ppm 2.00 (qd, >6.2, 4.5 Hz, 2 H), 2.79 (ζ >6.5 Hz, 2 H), 4.03 (br. s, 1 H), 4.20 (dd, >5.8, 4.5 Hz, 2 H), 5.19 (br. s, 1 H), 6.45 (dd, >3.8, 2.9 Hz, 1 H), 6.53 (dd, >3.8, 1.6 Hz, 1 H), 6.74 (d, >8.5 Hz, 1 H), 6.81 (td, >9.0, 2.5 Hz, 1 H), 6,92 (dt, >9.1, 2.0 Hz, 1 H), 7.28 (dd, >2.9, 1.7 Hz, 1 H), 7.36 (dd, >8.5, 2.3 Hz, 1 H), 7,47 (d, >2.3 Hz, 1 H).

Compound 47: *H NMR (300 MHz, CHLOROFORM-îZ) δ ppm 3.21 (t, >8.6 Hz, 2 H), 4.03 (d, >11.3 Hz, 1 H), 4.57 (ζ >8.7 Hz, 2 H), 5.39 (d, >11.3 Hz, 1 H), 6.34 - 6.45 (m, 1 H), 6.51 (dd, >3.8, 1.5 Hz, 1 H), 7.17 (d, >7.6 Hz, 1 H), 7.19-7.23 (m, 1 H), 7.23 - 7.39 (m, 3 H), 7.48 (dd, >2.7, 1.4 Hz, 1 H).

Compound 53: 'H NMR (400 MHz, DMSO-4,) δ ppm 2.42 - 2.48 (m, 2 H), 2.86 - 3,06 (m, 2 H), 3.72 (d, >13.7 Hz, 1 H), 4.43 (d, >13.8 Hz, 1 H), 5.22 (s, 1 H), 5.90 (d, >2.9 Hz, 1 H), 6.29 (ζ >3.3 Hz, 1 H), 7.12 (d, >8.5 Hz, 1 H), 7.35 - 7,44 (m, 2 H),

7.49 (d, >8.0 Hz, 1 H), 7.65 - 7.75 (m, 3 H), 10.30 (br. s., 1 H), 10.62 (br. s., 1 H).

Compound 55: 'H NMR (400 MHz, CHLOROFORM-îZ) δ ppm 2.71 - 2.76 (m, 2 H),

3.15 - 3.26 (m, 2 H), 5.39 (br. s, 2 H), 6.49 - 6,54 (m, 1 H), 6.56 - 6.62 (m, 1 H), 7.27

7.31 (m, I H), 7,34 (t, >8.0 Hz, 1 H), 7.42 (d, >7.5 Hz, 1 H), 7.46 (s, 1 H), 7.59 (d, >8.0 Hz, 1 H), 7.99 (s, 1 H), 8.19 (d, >8.0 Hz, 1 H).

Compound 56: ^lH NMR (300 MHz, CHLOROFORM-ίΖ) δ ppm 2.61 - 2.83 (m, 2 H) 3.02 - 3.27 (m, 2 H) 4.24 (br. s„ 1 H) 5.51 (br. s., 1 H) 6.37 - 6.60 (m, 2 H) 7.27 - 7.44 (m, 4 H) 7.63 - 7.78 (m, 2 H) 7.87 (s, 1 H).

Compound 57: 'H NMR (300 MHz, CHLOROFORM-cZ) δ ppm 2.61 - 2.81 (m, 2 H) 3.03 -3.28 (m, 2 H) 4.31 (d, >10.9 Hz, 1 H) 4.89 (d, >11.3 Hz, 1 H) 6.40 - 6.46 (m, 1 H) 6.46 - 6.51 (m, 1 H) 7.20 - 7.26 (m, 1 H) 7.49 (d, >7.9 Hz, 1 H) 7.44 (d, >7.2 Hz, 1 H) 7.60 (br. s., 1 H) 7.69 - 7.84 (m, 2 H) 7.91 (s, 1 H).

Compound 58: ’H NMR (400 MHz, CHLOROFORM-t/) δ ppm 2.15 (quin, >6.3 Hz, 2 H), 2.68 (ζ >6.5 Hz, 2 H), 2.99 (t, >5.8 Hz, 2 H), 4.20 (br. s, 1 H), 5.54 (br. s, 1 H), 6.44 - 6.50 (m, 2 H), 7.28 - 7.29 (m, 1 H), 7.32 (t, >7.8 Hz, 1 H), 7.37 (dd, >2.7, 1.7 Hz, 1 H), 7.40 (dd, >7.5, 1.8 Hz, l H), 7.57 (dd,>8.1, 1.8 Hz, 1 H), 7.68 (s, 1 H), 8.01 (d, >8.1 Hz, 1 H).

Compound 59: *H NMR (600 MHz, CHLOROFORM-îZ) δ ppm 2.14 (m, 2 H), 2.67 (dd, >7.3, 5.8 Hz, 2 H), 2.98 (t, >6.0 Hz, 2 H), 4.72 (br. s., 2 H), 6.45 (dd, >3.8, 2.8 Hz, 1 H), 6.48 (dd, >3.8, 1.7 Hz, 1 H), 7.07 (t, >8.5 Hz, 1 H), 7.17 (d, >8.1 Hz, 1 H), 7.33 (td, >8.2, 5.8 Hz, 1 H), 7.37 (dd,>2.8, 1.6 Hz, 1 H), 7.56 (dd,>8.2, 1.7 Hz, 1 H), 7.66 (d, >1.7 Hz, 1 H), 8.00 (d, >8.2 Hz, l H).

Compound 60: *H NMR (400 MHz, CHLOROFORM-îZ) δ ppm 2.14 (quin, >6.5 Hz, 2 H) 2.63 - 2.73 (m, 2 H) 2.99 (t, >5.9 Hz, 2 H) 4.63 (br. s, 2 H) 6.43 - 6.52 (m, 2 H) 7.29 (dd, >8.0, 2.3 Hz, 1 H) 7.36 (dd, >2.8, 1.8 Hz, 1 H) 7.40 (d, >2.0 Hz, 1 H) 7.42 (d, >8.3 Hz, 1 H) 7.57 (dd, >8.0, 1.8 Hz, 1 H) 7.64 (d, >1.0 Hz, 1 H) 8,01 (d, >8.0 Hz, 1 H)

Compound 61: *H NMR (400 MHz, CHLOROFORM-îZ) δ ppm 2.13 (quin, >6.3 Hz, 2 H), 2.63 - 2.70 (m, 2 H), 2.91 - 3.05 (m, 2 H), 4.28 (d, >11.1 Hz, 1 H), 4.86 (d, >11.1 Hz, 1 H), 6.41 (dd, >3.9, 3.0 Hz, 1 H), 6.47 (dd, >3.8, 1.5 Hz, 1 H), 7.23 (t, >7.8 Hz, 1 H), 7.42 (dd, >7.6, 1.5 Hz, 1 H), 7.47 (dd,>8.1, 1.4 Hz, 1 H), 7.57 (dd,>2.9, 1.5 Hz, 1 H), 7.67 (dd, >8.3, 1.8 Hz, 1 H), 7.70 (d, >1.8 Hz, 1 H), 8.01 (d, >8.1 Hz, 1

H).

Compound 63: *H NMR (400 MHz, CHLOROFORM-îZ) δ ppm 4.62 (br. s, 2 H), 5.35 (s, 2 H), 6.44 - 6.50 (m, 2 H), 7.08 (t, >8.5 Hz, 1 H), 7.19 (d, >8.1 Hz, 1 H), 7.35 (td, >8.2, 5.8 Hz, 1 H), 7.38 (t, >2.3 Hz, 1 H), 7.51 (d, >8.1 Hz, 1 H), 8.15 - 8.21 (m, 2 H).

I

Compound 64: Ή NMR (400 MHz, DMSOeZô) δ ppm 4.12 (br. s., 1 H) 5.27 (br. s., 1 H) 5.48 (s, 2 H) 6.47 - 6.61 (m, 2 H) 7.65 - 7.78 (m, 3 H) 7.86 (s, 1 H) 7.96 (s, 1 H) 8.09 (d, >9.0 Hz, 1 H).

Compound 65: *H NMR (300 MHz, CHLORO FORM-/Z) δ ppm 4.26 (br. s, 1 H), 5.32 (s, 2 H), 5.50 (br. s, 1 H), 6,37 - 6.62 (m, 2 H), 7.27 - 7.47 (m, 4 H), 7.79 - 7.98 (m, 3 H).

Compound 66: ‘H NMR (400 MHz, CHLOROFORMEZ) δ ppm 2.60 (tt, >13.9, 6.9 Hz, 2 H), 3.04 (br. s, 2 H), 4.18 (br. s, 1 H), 5.52 (br. s, 1 H), 6.39 - 6.54 (m, 2 H), 7.23

- 7.28 (m, 1 H), 7.31 (t, >8.0 Hz, 1 H), 7.36 (s, 1 H), 7.39 (d, >7.6 Hz, 1 H), 7.51 (d, >8.0 Hz, 1 H), 7.63 (d, >8.1 Hz, 1 H), 7.68 (s, 1 H).

Compound 67: ‘H NMR (400 MHz, CHLOROFORM-^ δ ppm 2.50 - 2.73 (m, 2 H)

2.97 - 3.17 (m, 2 H) 4.64 (br. s., 2 H) 6.43 - 6.51 (m, 2 H) 7.29 (dd, >8.0, 2.0 Hz, 1 H) 7.36 (dd, >2.8, 1.8 Hz, 1 H) 7.40 (d, >2.0 Hz, 1 H) 7.42 (d, >8.0 Hz, 1 H) 7.53 (d, >7.8 Hz, 1 H) 7,63 (d, >8.5 Hz, 1 H) 7,65 (br. s, 1 H).

Compound 68: *H NMR (400 MHz, CHLOROFORM-^ Ô ppm 2.54 - 2.68 (m, 2 H) 2.99 - 3.13 (m, 2 H) 4.30 (d, >11.0 Hz, 1 H) 4.89 (d, >11.5 Hz, 1 H) 6.45 (t, >2.9 Hz, 1 H) 6.53 (br. s., 1 H) 7.27 - 7.29 (m, 1 H) 7.49 (d, >8.3 Hz, 1 H) 7.45 (d, >7.5 Hz, 1 H) 7.55 (d, >7.5 Hz, 1 H) 7.62 (br. s„ 1 H) 7.76 (m, >7.8 Hz, 2 H).

Compound 69: *H NMR (300 MHz, CHLOROFORMeZ) δ ppm 2.34 (tdd, >7.8, 7.8, 7.7, 7.4 Hz, 2 H) 2.99 (ζ >5.6 Hz, 2 H) 4.17 (br. s., 1 H) 5.47 (br. s., 1 H) 6.42 - 6.47 (m, 1 H) 6.48 - 6.53 (m, 1 H) 6.93 (d, >8.3 Hz, 1 H) 7.20 - 7.42 (m, 4 H) 7.52 (d, >9.0 Hz, 1 H) 7.61 (s, 1 H).

Compound 70: *Η NMR (400 MHz, CHLOROFORMeZ) δ ppm 2.28 - 2.39 (m, 2 H),

2.98 (t, >7.0 Hz, 2 H), 4.15 (br. s, 1 H), 5.20 (br. s, 1 H), 6.44 (dd, >3.9, 2.9 Hz, 1 H),

6.50 (dd, >3.8, 1.6 Hz, 1 H), 6.92 (d, >8.5 Hz, 1 H), 7.06 (t, >8.5 Hz, 1 H), 7.16 (d, >8.0 Hz, 1 H), 7.35 (dd, >2.8, 1.8 Hz, 1 H), 7.32 (td, >8.2, 5.8 Hz, i H), 7.50 (dd, >8.5, 2.2 Hz, 1 H), 7.60 (d, >2.3 Hz, 1 H).

Compound 71 : NMR (400 MHz, CHLOROFORMEZ) δ ppm 2.34 (quin, >7.7 Hz, 2 H), 2.98 (ζ >6.9 Hz, 2 H), 4,38 (br. s, 1 H), 4.75 (br. s, 1 H), 6.44 - 6.48 (m, 1 H), 6,48

- 6.52 (m, 1 H), 6.93 (d, >8.6 Hz, 1 H), 7.27 - 7.29 (m, 1 H), 7.33 (s, 1 H), 7.37 - 7.42 (m, 2 H), 7.48 - 7.52 (m, 1 H), 7.57 (s, 1 H).

Compound 72: ^]H NMR (300 MHz, CHLOROFORMEZ) δ ppm 2.34 (quin, >7.8 Hz, 2 H), 2.89 - 3.08 (m, 2 H), 4.25 (d, >11.2 Hz, 1 H), 4.80 (d, >11.2 Hz, 1 H), 6.41 (t,

>3.2 Hz, 1 H), 6.49 (d, >3.8 Hz, 1 H), 6.94 (d, >8.3 Hz, 1 H), 7.23 (t, >7.8 Hz, 1 H), 7.42 (d, >7.4 Hz, 1 H), 7.46 (d, >8.1 Hz, 1 H), 7.56 (s, 1 H), 7.58 - 7,69 (m, 2 H). Compound 79: 'H NMR (400 MHz, CHLOROFORMA) Ô ppm 4.11 (br. s, 1 H), 5.43 (br. s, 1 H), 6.45 - 6.49 (m, 1 H), 6.49 - 6.54 (m, 1 H), 7.03 (d, >8.3 Hz, 1 H), 7.28 (d, >1.9 Hz, 1 H), 7.33 (s, 1 H), 7.40 (d, >2.0 Hz, 1 H), 7.45 (dd, >8.3, 1.3 Hz, 1 H),

7.49 (d, >1.2 Hz, 1 H).

Compound 80; ’H NMR (300 MHz, CHLOROFORM-J) δ ppm 3.47 (s, 3 H), 4.21 (br. s, 1 H), 5.58 (br. s, 1 H), 6.50 - 6.58 (m, 1 H), 6.65 (br. s, 1 H), 7.17 (d, >8.3 Hz, 1 H), 7.27 - 7.31 (m, 1 H), 7.35 (t,>7.9 Hz, 1 H), 7.40 - 7.50 (m, 3 H), 7.73 (br. s, 1 H).

Compound 81: *H NMR (300 MHz, CHLOROFORMA) δ ppm 2.78 (s, 3 H), 2,95 (t, >8.2 Hz, 2 H), 3.37 (t, >8.3 Hz, 2 H), 4.06 (br. s, 1 H), 5.23 (br. s, 1 H), 6.35 (d, >8.2 Hz, 1 H), 6.42 (dd, >3.8, 2.8 Hz, 1 H), 6.56 (dd, >3.8, 1.7 Hz, 1 H), 7.03 (t, >8.5 Hz, 1 H), 7.15 (d,>7.9Hz, 1 H), 7.27 - 7.34 (m, 2H), 7.41 (dd,>8.1, 1.8 Hz, 1 H), 7.52 (d, >1.9 Hz, 1 H).

Compound 82: *H NMR (400 MHz, CHLOROFORMA) δ ppm 2.77 - 3.00 (m, 2 H) 3.97 (t, >5.6 Hz, 2 H) 4.27 (d, >11.0 Hz, 1 H) 4.80 (s, 2 H) 4.83 (d, >11.5 Hz, 1 H) 6.38 - 6.46 (m, 1 H) 6.52 (br. s„ 1 H) 6.99 (d, >8.0 Hz, 1 H) 7.21 - 7.26 (m, 1 H) 7.47 (d, >8.0 Hz, 1 H) 7.43 (d, >7.3 Hz, 1 H) 7.54 - 7.63 (m, 3 H).

D, Pharmacological ex amples

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 μΐ) were then spotted onto test-plates that could be stored in the dark at 25 4 °C for a maximum period of 2 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/isolates (Table 3a) were cryopreserved and 1/1000 diluted 30 in medium just prior to use. A standard inoculum of200 μΐ containing 10³ colonyforming unit (cfu) was then added to each well. A positive control (100 % growth = fungal culture without antifungal) and a négative control (0 % growth = RPMI-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 35 more for dermatophytes (27 °C). Inhibition of fungal growth was measured after adding μΐ of 0.005% (w/v) resazurin (Sigma Aldrich) to each well, based on the principle that living cells convert the non-fluorescent biue 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 5 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 canis	27	9 days	24 hours
Trichophyton mentagrophytes	27	7 days	24 hours
Trichophyton rubrum	27	7 days	24 hours
Scedosporium apiospermum	37	48 hours	17 hours
Scedosporium prolificans	37	48 hours	17 hours
Sporothrix schenkii	27	4 days	24 hours
AspergiUus fumigatus	27	48 hours	17 hours
Candida 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

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

Inf. ‘A Sporothrix schenkii B62482

Inf, ΊΓ. Microsporum canis B68128

Inf. ‘C’: Trichophyton rubrum B68183

Inf. ‘D*: Candida parapsilosis B66126

Inf. Έ’: AspergiUus fiimigatus B42928

Inf. ‘F’: Cryptococcus neoformans

B66663

Inf. ‘G’: Trichophyton mentagrophytes B70554

Inf. Ή’: Scedosporium apiospermttm IHEM3817

Inf. T; Scedosporium prolificans 1HEM21157

Inf. ‘J’: Rhizopus oryzae IHEM5223

Inf. ‘K’: Rhizomucor miehei IHEM13391

Co. No.	Inf. A	Inf. B	Inf. C	Inf. D	Inf. E	Inf. F	Inf. G	Inf. H	Inf. I	Inf. J	Inf. K
3	<4.19	4.91	4.47	<4.19	<4.19.	4.30	4.71	n.d.	n.d.	n.d.	n.d.
4	<4.19	5.09	5.70	<4.19	<4,19	4.38	n.d.	n.d.	n.d.	n.d.	n.d.
2	<4.19	4.42	4.96	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.	n.d.
17	<4,19	<4.19	5.70	<4.19	5.46	<4.19	4.71	n.d.	n.d.	n.d.	n.d.
25	5.70	6.08	6.10	<4.19	6.81	6.00	6.42	<4.19	n.d.	<4.19	4.40
12	4.19	6.42	6.86	6.24	6.82	5.52	7.23	<4.19	<4.19	<4.19	<4.19
13	5.15	6.36	6.47	5.52	5.70	5.30	6.95	4.52	5.72	<4.19	<4.19
18	<4.19	4.62	5.70	<4.19	4.67	<4.19	5.26	n.d.	n.d.	n.d.	n.d.
22	<4.49	5.52	6.00	<4.49	4.85	5.60	n.d.	n.d.	n.d.	n.d.	n.d.
20	5.70	6.89	7.15	6.47	6.57	6.42	n.d.	5.05	6.07	<4.95	4.86
34	<4.19	5.70	5.70	<4.19	<4.19	5.52	4.96	n.d.	n.d.	n.d.	n.d.
48	5.40	6.30	6.78	<4.19	5.00	5.70	6.29	4.94	5.79	<4.19	<4.19

Co. No.	Inf. A	Inf. B	Inf. C	Inf. D	Inf. E	Inf. F	Inf. G	Inf. H	Inf. I	Inf. J	Inf. K
26	<4.19	6.00	6.25	4.25	4.85	<4.19	5.70	n.d.	n.d.	n.d.	n.d.
30	<4.19	6.00	5.22	<4.19	<4,19	5.22	5.00	n.d.	n.d.	n.d.	n.d.
7	<4.19	5.30	5.40	<4.19	<4.19	4.64	4.47	n.d.	n.d.	n.d.	n.d.
6	4.21	5.00	5.15	<4.19	<4.19	5.10	4.50	n.d.	n.d.	n.d.	n.d.
8	<4.19	4.66	5.22	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
5	<4,19	5.11	5.05	<4.19	<4.19	¹ 4.42	n.d.	n.d.	n.d.	n.d.	n.d.
49	<4.19	5.05	5.10	<4.19	<4.19	4.34	n.d.	n.d.	n.d.	n.d.	n.d.
50	<4.19	4.92	5.52	<4.19	<4.19	4.74	<4.19	n.d.	n.d.	n.d.	n.d.
14	<4.19	5.10	5.52	<4.19	<4.19	4.82	n.d.	n.d.	n.d.	n.d.	n.d.
15	<4.19	<4.19	5.40	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
31	<4.19	5.52	6.00	<4.19	<4.19	<4,19	5.80	n.d.	n.d.	n.d.	n.d.
16	<4.19	5.00	5.40	<4.19	<4.19	<4,19	4.52	n.d.	n.d.	n.d.	n.d.
19	<4.19	5.40	6.00	<4.19	4.96	5.70	5.63	n.d.	n.d.	n.d.	n.d.
45	5.52	6.59	6.48	5.10	6.00	6.00	6.48	4.49	5.21	<4.19	<4,19
24	<4.49	5.05	5.40	<4.49	<4.49	<4.49	5.22	n.d.	n.d.	n.d.	n.d.
23	4.47	6.00	6.17	5.70	6.04	6.34	6.10	4.62	6.22	<4.19	<4.19
44	5.30	5.30	5.30	4.92	<4.19	5.15	5.10	n.d.	n.d.	n.d.	n.d.
35	4,85	6.00	6.36	5.70	5.70	5.30	6.10	4.41	5.89	<4.19	4.27
32	<4.19	5.52	5.22	<4.19	<4.19	4.64	4.92	n.d.	n.d.	n.d.	n.d.
10	<4.19	5.00	5.70	<4.19	<4.19	4.48	5.30	n.d.	n.d.	n.d.	n.d.
11	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
9	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
27	<4.19	5.15	6.32	<4.19	<4.19	<4.19	4.96	n.d.	n.d.	n.d.	n.d.
33	<4.19	5.52	5,15	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
36	4.89	6.17	6.88	4.68	5.70	4.30	6.62	5.55	5.92	<4.19	<4.19
47	<4.19	5.40	5.92	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
62	<4.19	<4.19	<4.19	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
1	<4.19	5.03	5.10	<4.19	5.65	5.37	4.58	n.d.	n.d.	n.d.	n.d.
21	5.86	6.31	6.77	5.85	7.33	6.47	6.22	6.92	7.40	5.70	6.03
65	5.11	5.69	5.74	5.29	6.43	4.99	5.72	6.12	6.23	<4.19	<4.19
64	<4.19	<4.19	<4.19	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
74	<4.19	6,87	7.39	<4.19	7.08	<4.19	6.58	5.5	7.05	<4.19	<4,19
78	5.28	6.26	6.85	5.64	6.44	<4.19	6.24	4.19	5.98	<4.19	<4.19
77	5.45	6.87	7.71	5.47	7.25	5.27	6.94	4.65	5.76	4,92	<4.19
80	5.04	5.80	5.94	4.65	6.25	<4.19	5.27	4.25	4.65	<4.19	<4.19
52	<4.19	<4,80	4.55	<4.19	<4.19	<4.19	4.31	n.d.	n.d.	n.d.	n.d.
55	<4.19	5.41	5.71	<4,19	<4.19	<4.19	4.60	n.d.	n.d.	n.d.	n.d.
51	4.46	5.59	5.84	4.91	5.24	4.74	5.32	4.67	5.32	<4.19	4.29
79	4.90	6.28	6.29	5.62	5.71	5.60	5.79	5.72	5.98	<4.19	<4.19
63	<4.19	4.26	5.13	<4.19	<4.19	<4.19	<4,19	6,03	5.8	<4,19	<4.19
56	5.65	6.77	6.74	5.54	6.44	5.88	6.25	6,35	6.96	<4,19	5.32
58	5.67	6.78	6.69	<4.19	6.87	6.38	6.49	5.23	5.03	4.31	5.16
59	5,37	6.43	6.89	5.56	6.40	5.95	6.47	6.13	5.83	<4.89	5.83
81	4.49	5.28	5.65	4.60	4.39	5.29	4,90	n.d.	n.d.	n.d.	n.d.

Co. No.	Inf. A	Inf. B	Inf. C	Inf. D	Inf. E	Inf. F	Inf. G	Inf. H	Inf. I	Inf. J	Inf. K
69	5.98	6.89	6.91	6.15	6.89	7.02	6.42	6.64	6.15	5.92	6.33
28	<4.19	6.24	6.66	5.53	5.99	4.71	6.29	4.97	4.63	<4.19	4.39
29	<4.19	<4.19	4.44	<4.19	<4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
39	4.95	6.36	6.89	5.83	6.77	5.21	6.54	5.40	5.76	<4.19	4.38
37	5.26	6.62	6.89	5.79	6.77	5,88	6.47	4.48	5.85	<4.19	<4.19
75	4.85	5.74	6.85	5.09	6.24	5,84	6.42	<4.19	<4.19	<4.19	<4.19
76	5.69	6.70	6.82	5.18	5.94	5.82	6.38	5.13	5.04	4.57	4.98
68	<4.19	<4.19	<4.19	<4.19	4.19	<4.19	<4.19	n.d.	n.d.	n.d.	n.d.
61	4.50	<4.19	4.31	5.36	4,49	5,09	<4.19	n.d.	n.d.	n.d.	n.d.
60	4.52	<4.19	<4.19	5.44	<4.19	5.15	<4.19	n.d.	n.d.	n.d.	n.d.
41	<4.19	4.48	<4.19	5.60	<4.19	4.52	4.49	n.d.	n.d.	n.d.	n.d.
67	5.10	5.09	<4.19	5.90	5,10	5.36	5.09	n.d.	n.d.	n.d.	n.d.
66	4.46	4.49	<4.19	5.55	5.09	6.11	<4.19	n.d.	n.d.	n.d.	n.d.
40	<4.19	4.49	<4.19	5.56	<4.19	5.87	<4.19	n.d.	n.d.	n.d.	n.d.
46	4.49	4.48	4.44	5.79	4.49	5.49	<4.19	n.d.	n.d.	n.d.	n.d.
38	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
54	<4.19	5.09	5.10	<4.19	<4.19	5.11	4.49	n.d.	n.d.	n.d.	n.d.
53	<4.19	4.49	4.50	<4.19	4.97	4,87	4.49	n.d.	n.d.	n.d.	n.d.
42	5.10	4.49	<4.19	5.63	<4.19	6,82	<4.19	n.d.	n.d.	n.d.	n.d.
73	4.50	5.03	4.49	5.67	<4.19	5.33	4.49	n.d.	n.d.	n.d.	n.d.
70	<4.19	4.19	<4.19	6.12	<4.19	6.02	<4.19	n.d.	n.d.	n.d.	n.d.
43	6.04	6.80	6.89	5.36	6.85	6.68	6.66	n.d.	n.d.	n.d.	n.d.
71	5.71	6.21	6.57	5.09	6.66	7.00	6.51	n.d.	n.d.	n.d.	n.d.
72	5,58	6.39	6.39	4.96	6.21	6.42	5,79	n.d.	n.d.	n.d.	n.d.
57	5.65	5.70	5.80	<4.19	5.62	5,23	5.40	n.d.	n.d.	n.d.	n.d.
82	5.06	5.69	5.95	4.77	5,56	5.26	5.56	n.d.	n.d.	n.d.	n.d.
83	5.14	5.66	5.71	5.28	5,89	5,57	5.06	4.76	5.85	<4.19	<4.19
88	4,27	6.27	6.35	<4.19	6.38	6.39	6.06	6.77	5.59	<4.19	<4.19

E. Composition example

Active ingrédient” as used throughout these examples, relates to a compound of Formula (I), including any stereochemîcally 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 1 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 1 1, giving a solution comprising 4 mg/ml of active ingrédient. The solution is sterilized by filtration and filled in stérile containers.

Example E2 : Transungual composition.

0.144 g KH₂PO₄, 9 g NaCl, 0.528 g Na₂HPO₄.2H₂O is added to 800 ml H₂0 and the mixture is stirred. The pH is adjusted to 7.4 with NaOH and 500 mg NaN₃ is added. Ethanol (42 v/v %) is added and the pH is adjusted to 2.3 with HCl.

15 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.I. is dissolved in 0.5 1 of a sodium hydroxide solution and 1.5 1 of the polyethylene glycol at 60-80 °C. After cooling to 30~40°C there are added 35 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 1 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 A.I.. The resulting solution is filled into suitable containers.

Example E4 : Capsules

Grams of the A.I., 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 ES : Film-coated tablets

Preparation.of tablet core

A mixture of 100 grams ofthe 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 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.

Example E6 :2 % Cream

Stearyl alcohol (75 mg), cetyl alcohol (20 mg), sorbitan monostearate (20 mg) and isopropyl myristate (10 mg) are introduced in a doublewall jacketed vessel and heated until the mixture has completely molten. This mixture is added to a seperately prepared mixture 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 mixture is allowed to cool to below 25°C while continuously mixing. A solution of A.I.(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 fi lied 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 homogenîzing. 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, Cmalkyl or CMalkyloxy;

R² is hydrogen or halo;

R³ and R⁴ are hydrogen;

10 or R³ and R⁴ taken together form a bond;

R^s is hydrogen or Cualkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CHîJm-Y’-ÎCHî)^- (a), -Y^2a-(CH₂)_t-Y^2b- (d),or

-(CHîU-Y’-ÎCHjV (b), -(CH₂)_rY^2a-CH2-Y^2b-(CH2)_q-(e);

-(CH₂)_s-(c), wherein the bivalent radical —R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, CMalkyl, hydroxyl,

15 Ci-4alkyloxy and oxo;

Y* represents O, NR⁸ or S;

Y^2a and Y^2b each independently represent O, NR^8b or S,

R^8a represents hydrogen or Cmalkyl;

R^8b represents hydrogen or Cualkyl;

20 m represents 0, 1 or 2;

n represents 2, 3 or 4;

s represents 3, 4 or 5;

t represents 1, 2 or 3;

r represents 0 or 1 ;

25 q represents 0 or 1;

provided that at least one of r and q is 1;

or a pharmaceutically acceptable addition sait or a solvaté thereof;

provided that the compound is not 4-(l,3-benzodioxol-5-yi)-5,6-dihydro-4H- pyrrolo[l,2-a][l,4]benzodiazepine or 4-(1,3-benzodioxol-5-yl)-5,6-dihydro-4Hpynrolo[ 1,2-a][l,4]benzodiazepine .HCl.

2. The compound according to claim 1 wherein

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula: -(CHi^-Y^CHa)™- (a), -(CH₂)_S- (c), or

-(CHîkm-Y'-iCH^- (b), -Y²MCH₂)₍-Y^2b- (d);

wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, Ciuialkyl and oxo;

Y¹ represents O or NR^8a;

Y^2a and Y^2b each independently represent O or NR^8b;

R^Sa represents hydrogen or Cmalkyl, □ L

R represents hydrogen or Ci^alkyl;

m represents 0, 1 or 2;

n represents 2 or 3;

s represents 3 or 4;

t represents 1.

3. The compound according to claim 1 wherein

R¹ is hydrogen, halo or CMalkyloxy;

R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, having formula; -(CH2)m-Y^l-(CH2)_n.m- (a), -(CH₂)_S- (c), or

-Y^2a-(CH₂)t-Y^2b- (d);

wherein the bivalent radical -R⁶-R⁷- may, where possible, be substituted with one or more substituents selected from the group consisting of halo, CMalkyl and oxo;

Y¹ represents O or NH;

Y represents O;

Y^2b represent O or NH;

m represents 0, 1 or 2;

n represents 2 or 3;

s represents 3 or 4;

t represents 1.

4. The compound according to claim 1 wherein

R¹ is halo;

R² is hydrogen;

R⁵ is hydrogen;

xi 7 Λ 7

R and R taken together form a bivalent radical -R. -R -, having formula:

-(CH₂)_m-O-(CH₂)_n._m-(CH₂)_s- , or

-O-CHj-O- ;

wherein the bivalent radical -(CH₂)_m-O-(CH₂)n-m- or -(CH₂)₅- may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo;

wherein the bivalent radical -O-CH₂-O- is substituted with one or more substituents selected from the group consisting of halo and oxo;

m represents 0 or 1;

n represents 3;

s represents 3 or 4.

5. The compound according to claim 1 wherein R* is halo.

6. The compound according to claim 1 wherein R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷-, wherein -R⁶-R⁷- is selected from the group consisting of -(CH₂)₃-, -(CH₂)₄-, -(CH₂)2-O-, -CH₂-CH(CH₃)-O-, -C(=O)-(CH₂)₂-C(=O)-(CH₂)₃-, -O-(CH₂)₂-, -O-(CH₂)₃-, -CH₂-O-(CH₂)₂-, -(CH₂)₂-C(=O)-O-CF₂-(CH₂)₂-, -(CH₂)₂-C(=O)-, -CF₂-(CH₂)₂-, -C(=O)-O-CH₂-CH₂-O-C(=O)-, -O-CF₂-O-, -O-C(=O)-N(CH₃)-, -N(CH₃)-(CH₂)₂-, and -N(CH₃)-C(=O)-C(CH₃)₂-

7. The compound according to claim 1 wherein R⁶ and R⁷ taken together form a bivalent radical -R⁶-R⁷- having the formula -O-CH₂-O-, wherein -O-CH₂-O- is substituted with one or two substituents selected from the group consisting of halo, Cwalkyl, hydroxyl, Ci-talkyloxy and oxo.

8. The compound according to any one of daims 1 to 7 wherein

R³ and R⁴ are taken together to form a bond.

9. The compound according to claim 1 wherein the compound is 7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydrO“4H-pyrrolo[l,2-a][l,4]benzodiazepine,

7-chloro-4-(2,3-dihy dro-1 H-inden-5-yl)-5,6-dihydro-4H-pyrrolo[ 1,2-a][l ,4]benzodiazepine .HCl, 7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-5,6-dihydro-4H-pynOlo[l,2-a][l,4]benzodiazepine .HBr, 7-chloro-4-(2,3-dihydro-lH-inden-5-yl)-6H-pyrTolo[l,2-a][l,4]benzodiazepine, 7-chl oro-4-(5,6,7,8-tetrahydro-2-nap hth aleny 1) -6H-py rrolo[ 1,2-a] [ 1,4]b enzodiazepine, 7-chloro-4-(2,2-difluoro-l,3-benzodioxol-5-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 4-(2,2-difluoro-l,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine,

4-(2,2-di fl uoro-1,3 -benzodi oxol-5-y 1 )-7- fluoro-6H-py rrolo[ 1,2-a] [ 1,4] b enzodiazepine,

6- (7-fluoro-6H-pyrrolo[l,2-a][l,4jbenzodiazepin-4-yl)-3,4-dihydro-l(2H)naphthalenone,

7- chloro-4-(2,2-difluoro-3,4-dihydro-2H-l-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepîne, 4-(3,4-dihydro-lH-2-benzopyran-6-yI)-7-fluoro-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 7-chloro-4-(3,4-dihydro-lH-2-benzopyran-6-yl)-6H-pyrrolo[l,2-a][l,4]benzodiazepine, 9-chloro-4-(2,2-difluoro-l ,3-benzodioxol-5-yl)-6H-pyrrolo[ 1,2-a] [ 1,4]benzodiazepine, or 10-chloro-4-(3,4-di hy dro-2H-1 -benzopy ran-6-y l)-6H-pyrrolo[ 1,2-a] [ 1,4]b enzodiazepine, a stereoisomeric form thereof, or a pharmaceutically acceptable addition sait or a solvaté thereof.

10. 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 9.

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

12. A compound as defined in any one of daims 1 to 9 for use in the treatment or prévention of a fungal infection.

13. The compound for use according to claim 12 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 circinélloides; Rhizopus spp.,' Malasseziafiirfiir; Acremonium spp.;

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

14. The compound for use according to claim 12 wherein the fungal infection is caused 5 by one or more of the fungi selected from the group consisting of Candida parapsilosis,

Aspergillus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.

15. The compound for use according to claim 12 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis,

10 Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillusfiimigates.