NL1030503C2 - Octahydropyrrolo [3,4-c] pyrrole derivatives. - Google Patents

Description

* · I ► · <*

! OCTAHYDROPYRROLO [3,4 - c] - PYRROOL DERIVATIVES

5

This invention relates to octahydropyrrolo [3,4-c] pyrrole derivatives and to processes for the preparation of compositions containing them and to the uses of these derivatives.

The octahydropyrrolo [3,4-c] pyrrole derivatives of the present invention are histamine H4 receptor ligands and therefore have a number of therapeutic uses, in particular in the treatment of asthma and allergic rhinitis.

The histamine H4 receptor is a 390 amino acid, 7-trans membrane G protein-coupled receptor with approximately 40% homology to the histamine H3 receptor. In contrast to the H3 receptor, which is primarily located in the brain, the H4 receptor is expressed at higher levels in eo-sinophils and mast cells, including inflammatory cells. H4 receptor ligands may therefore be suitable for the treatment of various inflammatory conditions. Examples of diseases where treatment with E ^ ligands is particularly appropriate are bowel inflammatory disease, Crohn's disease, ulcerative colitis, dermatitis, psoriasis, conjunctivitis, rheumatoid arthritis, respiratory diseases such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis syndrome, bronchitis chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced respiratory responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic obstruction.

Some histamine H4 receptor ligands have recently been developed. An overview of current advances in H4 ligand research and patenting is given 10 * 0 * 03 "- 2 -, I 1 f * in Expert Opin. Ther. Patents (2003) 13 (6). Examples of histamine H4 receptor ligands can be found in WO 02/07548, WO 04/022537 and in Terzioglu et al., J. Bioorg Med Chem Lett 14 (2004), 5251-5256.

Although H4 ligands are known, there is still a need to further provide new H4 ligands that are good drug candidates. In particular, preferred compounds should bind powerfully to the histamine H4 receptor and show little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and have favorable pharmacokinetic properties. They must also be non-toxic and have few side effects.

The present invention thus relates to octahydropyrrolo [3,4-c] pyrrole derivatives of formula (I): - or pharmaceutically acceptable salts and solvates thereof, wherein: R1 is H or (C1 -C1 alkyl optionally substituted with a hydroxy • X is N or C-R 9, wherein R 9 is H or methyl, • Y is O or NH, • R * is H or methyl, and • R 2, R 3, R 4 and R 5 are independently selected from H, halogen, cyano , (C1 -C1 alkyl, (C1 -C4) alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2) n C (O) O-R7, (CH2) n-O- (CH2) m -R8 and (CH2) a-R8, wherein n and m are both independently - 3 - (1, 1, O or 1, R 7 is H or (C 1 -C 7 alkyl and R 8 is phenyl.

These compounds have been shown to be histamine H4 receptor ligands.

In the above formula, "halogen" means a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

(C1 -C4) alkyl groups means a straight or branched group with 1, 2, 3 or 4 carbon atoms. This also applies if they carry substituents such as hydroxy substituent or occur as substituents of other groups, for example in (C 1 -C 4 alkoxy groups. Examples of suitable (C 1 -C 4) alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl and tert-butyl.

Examples of suitable (C 1 -C 4) alkoxy groups are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy. Examples of suitable (C 1 -C 4) alkyl groups substituted with a hydroxy group are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, etc.

The compounds of the general formula (I) of the present invention can be prepared by conventional procedures such as by the following illustrative methods, wherein R 1, R 2, R 3, R 4, R 5, R 6, X 6 and Y are as defined above unless indicated otherwise.

The compound of formula (I) wherein Y is O can be prepared by coupling an acid of formula (II) R 2 "VVv /

OH

R5 R

35 with an amine of formula (III):

- 4 -H

N—.

(III) R 1 wherein R 1, R 2, R 3, R 4, R 5, R 6 and X are as defined above.

The coupling of the acid (II) to the amine (III) is generally carried out in an excess of the said amine, with a conventional coupling agent (for example 1- (3-dimethylaminopropyl) -3-ethylcarbodi-imide hydrochloride, O-benzotriazo-1-yl-Ν, Ν, Ν ', N'-tetra-methyluronium-hexafluorophosphate or N, N'-dicyclohexylcarodimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1- hydroxy-7-azabenzotriazole) and optionally in the presence of a tertiary amine base (e.g. N-methylmorpholine, triethylamine or N, N-diisopropylethylamine). The reaction can be carried out in a suitable solvent such as pyridine, Ν, Ν-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate and at a temperature between 10 ° C and 40 ° C (room temperature). The coupling is preferably carried out using an excess of the amine (1.2-1.5 equivalents), with O-benzotriazo-1-yl-N, N, N, t'-tetramethyl-uronium-hexafluorophosphate as coupling agent. The reaction is also preferably carried out using Ν, Ν-dimethylformamide as a solvent.

The amine of formula (III) can be prepared as described in the literature (J. Heterocyclic Chem 1983, 20, 321).

The acids of formula (II) wherein X is C-R9, wherein R9 is as defined above, are commercially available or may be prepared according to well-known methods. i | Methods described in the literature.

The acids of formula (II) wherein X is N can be prepared by oxidation of an alcohol of formula (IV): 5 ΤΤΚ (IV)

OH

T "e

10: H

wherein R 2, R 3, R 4, R 5 and R 6 are as defined above.

The oxidation is generally carried out using a conventional oxidizing agent (e.g., potassium permanganate) optionally in the presence of a base (e.g., NaOH) in a suitable solvent (e.g., water) at a temperature comprised between 40 ° C and 100 ° C . Preferably, the oxidation is carried out using potassium permanganate in the presence of sodium hydroxide using water as a solvent with a reaction temperature of 100 ° C for 1 hour 30 minutes.

The alcohol of formula (IV) can be prepared by condensing an aniline of formula (V) with glycolic acid:

Rz (v) 30t R ° where R2, R3, R4, R5 and R6 are as defined above.

The condensation is generally carried out in the presence of an acid catalyst (e.g. HCl) in a suitable solvent (e.g. water) at a temperature between 40 ° C and 100 ° C. Preferably, the condensation is carried out using 6 N aqueous hydrochloric acid as a solvent at a temperature of 100 ° C with a reaction time of 16 hours.

The aniline of formula (V) is commercially available or can be prepared by conventional methods well known to those skilled in the art (e.g. nitration, reducing, alkylating, chlorinating) of commercially available material as detailed in the experimental section .

Alternatively, the compound of formula (I) wherein X is N and Y is O can be prepared by coupling a trichloromethylbenzimidazole of formula (VI): R2 15, c11 V-fci <VI> r5 r8 with an amine of formula ( III):

H

N—, r>

Nv! wherein R1, R2, R3, R4, Rs and Re are as described above.

The coupling is generally carried out with an excess of the amine (III), optionally in the presence of a base (e.g. triethylamine, N, N-diethyl isopropylamine, potassium carbonate) in a suitable aqueous solvent or mixture of solvents (e.g. acetonitrile, tetrahydrofuran, water) at a temperature between 10 ° C and 40 ° C (room temperature). The change - 7 -

II

binding of formula (VI) can be prepared by condensing an aniline of formula (V): R2 "VVNH" tv »ΆτΗ ·

RS R

10 with a trichloroacetimidate ester of formula (VII):

NH

R5, S5 <C1 (VII) C1 Cl where R is methyl or ethyl and wherein R2, R3, R4, R5 and R6 are as defined above.

The coupling is generally carried out with an excess of the acetimidate in a suitable solvent (for example AcOH) at a temperature between 10 ° C and 40 ° C (room temperature).

The aniline of formula (V) is prepared as described above and the trichloroacetimidate of formula 25 (VII) is commercially available.

The compound of formula (I) wherein Y is NH and X is N can be prepared by condensing a trichloromethylbenzimidazole of formula (VI): 3 ° r 2 ci (VI) T T y-f α

Cl R 5 R 35 with a source of ammonia and an amine of formula (III): - 8 - 1 k, i

H

N-1 V / (III) 5 H, R 1 wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as described above.

The condensation is generally carried out with equimolar amounts of the amine (III) and the source of ammonia (for example ammonia in dioxane, ammonium acetate), optionally in the presence of a base (for example triethylamine, Ν, Ν-diisopropylethylamine, potassium carine -15 bonate) in a suitable solvent (for example acetonitrile, tetrahydrofuran) at a temperature between 10 ° C and 40 ° C (room temperature). Preferably, the amine of formula (III) is reacted with the trichloromethyl-benzimidazole (VI) for a period of 0.5 to 2 hours prior to the addition of the ammonia equivalent.

Alternatively, the compound of formula (I) wherein X is N and Y is NH can be prepared by reacting an amine of formula (III) with a nitrile of formula (VIII): R2

Yr V 4 (for R 5 is H 30 wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined above.

The reaction is generally carried out with an excess of the amine (III) in a suitable solvent (isopropanol, methanol * tetrahydrofuran) and a temperature ranging between 60 ° C and 85 ° C (solvent reflux perature). The reaction is preferably carried out. with 1.2 equivalents of the amine in isopropanol under reflux for a period of 3 hours.

The nitrile of formula (VIII) can be prepared by reacting the trichloromethylbenzimidazole of formula (VI) with ammonia followed by treatment with aqueous acid. The reaction is generally carried out with an excess of ammonia in a suitable solvent (e.g. ethanol, tetrahydrofuran) at a temperature between -7 ° C and 0 ° C for a period of 0.5-2 hours. The resulting intermediate compound is then treated with aqueous hydrochloric acid at a temperature between 0 ° C and 5 ° C. Preferably the reaction is carried out using tetrahydrofuran as a solvent.

The compound of formula (I) wherein X is CR9 and Y is NH 15 can be prepared by condensing a thioamide of formula (IX): R2 R9

"TrW

πτν α

—N

R1 with ammonia or an ammonia equivalent and wherein R1, R2, R3, R4, R5 and R6 are as defined above.

The condensation is generally carried out in the presence of an activating agent (for example methyl iodide, mercuric acetate) with an excess of ammonia in a suitable solvent (acetonitrile, tetrahydrofuran) at a temperature between -78 ° C and 50 °.

The thioamide of formula (IX) can be prepared from an amide of formula (I) wherein X is CR 9 and Y is 0.

The conversion is generally carried out using an excess of Lawesson reagent (2,4-bis (4- -10-

4 I

1 'methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide) in suitable solvent (toluene, tetrahydrofuran) at a temperature between 50 ° C and 110 ° C. ;

All of the above reactions and the preparations of starting materials used in the above methods are conventional and suitable reagents and reaction conditions for the implementation or preparation thereof as well as procedures for isolating the desired products will be well known to those skilled in the art with reference. 10 to precedents in the literature and the examples and preparations described below.

For some of the steps of the above-described process for the preparation of the compounds of formula (I), it may be necessary to protect the potential reactive functions that one does not want to react and then to cleave said protecting groups. In such a case, any compatible protecting group can be used. In particular, methods of protection and removal of protection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P.J. Kocienski (Protecting Groups, Georg Thieme Verlag, 1994).

According to the present invention, the preferred compounds are those of formula (I) wherein: - R 1 is H or methyl, preferably methyl; and / or - R 6 is H; and / or - X is N or CH; and / or - R2, R3, R4 and R5 are independently selected from H, halogen, methyl, hydroxy, phenyl and COOH, preferably from H, fluorine, chlorine, bromine, methyl, hydroxy, phenyl and COOH and with more preferably from H, fluoro, chloro, bromo, hydroxy and methyl.

In a further aspect, the compounds of formula (I) wherein R 1 is H or methyl and R 2, R 3, R 4 and R 5 are independently selected from H, halogen, methyl, hydroxy, phenyl and COOH are preferred.

- 11 - y! * *

In a further aspect, the compounds of formula (I) wherein R1 is methyl, R1 is H, XN or CH and R2, R3, R4 and R5 are independently selected from H, fluorine, chlorine, bromine, hydroxy and methyl more In a further aspect, the compounds of formula (I) wherein Y is NH, R 1 is methyl, R 5 is H, X is N or CH and R 2, R 3, R 4 and R 5 are independently selected from H, fluoro, chloro, bromo, hydroxy and methyl are most preferred.

In another aspect, the compounds of formula (I) as described above in which at least two of R 2, R 3, R 4 and R 5 are H are preferred.

In another preferred aspect, the compounds of formula (I) as described above have the cis-15 configuration, i.e., the (3aR, 6aS) configuration as follows:

"—N

R1 where R1, R2, R3, R4, R5, Rs, X and Y are as defined above.

More preferred compounds are those selected from Examples 1 to 6Θ and 6-bromo-4-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole - 2 (1H) -yl] carbonyl) -ΙΗ-benzimidazole and 6-fluoro-4-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} - 1 H -benzimidazole.

Most preferred compounds are those selected from the compounds of Examples 1, 3, 7, 15, 16, 17, 21, 22, 25, 26, 27, 41, 48, 58, 59, 60, 61, 62, 63, 64, 35.65, 66, 67 and 68.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts

• I

. · Thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glucate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate -, 2-napsyate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumin, olamine, potassium, sodium, tromethamine-20 and zinc salts.

Hemi salts of acids and bases can also be formed, e.g., hemisulfate and hemicalcium salts.

For an overview of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use 25 by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of three methods: (i) reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening an appropriate cyclic precursor, for example a lactone or lactam, using the desired acid or the desired base; or (iii) by converting a salt of the compound of formula (1) to another by reaction with an appropriate acid or an appropriate base or by means of an appropriate ion exchange column.

All three reactions are typically carried out in solution I. The resulting salt can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.

The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes that contain two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For an overview of such complexes, see J Pharm 30 Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

Hereinafter, all references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The compounds of the invention comprise compounds of formula (I) as defined above, comprising all polymorphs and crystal habitats thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined below and with isotope-labeled compounds of formula (I).

As indicated, so-called "prodrugs" of the compounds of formula (I) also fall within the scope of the invention. For example, certain derivatives of compounds j of formula (I) which themselves have little or no pharmacological activity, when administered in or on the body, can be converted into compounds of formula (I) with the desired activity, for example by hydrolytic cleavage . Such derivatives are referred to as 'prodrugs'. Further information regarding the use of prodrugs can be found in Prodrugs as New Delivery Systems, Vol. 14, ACS Symposium Series (T.

15 Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association). ,

Prodrugs of the invention can be produced, for example, by replacing appropriate functionalities present in the compounds of formula (I) by certain groups known to those skilled in the art as "pro-groups" as described, for example, in Design of Prodrugs by H. Bundgaard ( Elsevier, 1985).

Some examples of prodrugs according to the invention include: (i) when the compound of formula (I) contains a carboxylic acid functionality (-C00 H), an ester thereof, for example a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (C1 -C6 alkyl) (ii) when the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example a compound in which the hydrogen of the alcohol functionality of the compound of formula (I) has been replaced by (C 1 -C 12 alkanoyloxyraethyl; and

(iii) when the compound of formula (I) has a primary or secondary amino functionality (-NH 2 or -NHR)

i - 15 - «. 9 wherein R does not contain H), an amide thereof, for example a compound in which, depending on the case, one or both hydrogens of the amino functionality of the compound of formula (I) has been replaced by 5 (C 1 -C 10 alkanoyl) .

Further examples of replacement groups according to the preceding examples and examples of other prodrug types can be found in the aforementioned references.

Furthermore, certain compounds of formula (I) may themselves serve as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula (I), i.e. compounds formed in vivo after administration of the drug. Some examples of metabolites according to the invention include: (i) when the compound of formula (I) contains a methyl group, a hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH); (Ii) when the compound of formula (I) contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH)? (iii) when the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NRaRb -> -NHRa or -NHRb); (Iv) when the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR3 - »-NH2); (v) when the compound of formula (I) contains a phenyl group, a phenol derivative thereof (-Ph - »-PhOH), and (vi) when the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONR ° Rd - -COOH).

Compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When structural isomers are inter-convertible via a low energy threshold, tautomeric isomerism ('tautomerism') can occur. This can take the form of

* I

!

: "I

- 16 - Adopt tonne automerism in compounds of formula (I) which contain, for example, an imino, keto or oxime group, or so-called valence automerism in compounds containing an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof are included within the scope of the present invention. Also included are acid addition or base salts in which the counter ion is optically active, for example d-lactate or 1-lysine, or racemically, for example dl-tartrate or dl-arginine.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis of a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC ).

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or, in the case where the compound of formula (I) contains an acid or basic portion, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers can be converted to the corresponding pure enantiorate (s) by means well known to those known in the art. experts.

Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by chromatography, typically HPLC, on an asymmetric mobile phase resin consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50 % by volume of isopropanol, typically 2% to 20% by volume and 0 to 5% by volume of an alkylamine, typically * 17 - 0.1% diethylamine. Evaporation of the eluate provides the enriched mixture.

Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds by E.L. Eliel and S.H. Wilen (Wiley, New York, 1994).

The present invention encompasses all pharmaceutically acceptable isotope-labeled compounds of formula (I) in which one or more atoms is replaced by atoms with the same atomic number but with an atomic mass or mass different from the atomic mass or mass number that predominates in nature.

Examples of isotopes suitable for incorporation into the compounds of the invention include hydrogen isotopes such as 2 H and 3 H, carbon such as 13 C, 13 C and 14 C, chlorine such as 36 Cl, fluorine such as IF, iodine such as 123I and 12SI nitrogen, such as 13 N and 15 N, oxygen such as 150, 170 and 180, phosphorus such as 32 P and sulfur, such as 35 S.

Certain isotope-labeled compounds of formula (I), for example those containing a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and their easy detectability.

Substitution with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic benefits resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosing requirements, and may therefore be preferred under certain circumstances.

Substitution with positron-emitting isotopes, such as "c, ieF, 150 and 13N, may be useful in Positron Emission Topography (PET) studies for investigating substrate receptor occupancy.

Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations using an appropriate isotope-labeled reagent instead of the previously used unlabelled reagent.

Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotope-substituted, for example D20, d6-acetone, d6-DMSO.

The compounds of the invention intended for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, in the form of solid pills, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or by evaporative drying. Microwave or radio frequency drying can be used for this purpose.

They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in the form of any combination thereof). In general, they will be administered in the form of a preparation in association with one or more pharmaceutically acceptable excipients. The term "excipients" is used herein to describe a component that is not a compound of the invention. The choice of the excipient will largely depend on factors such as the specific method of administration, the effect of the excipients on the solubility and the stability and the nature of the dosage form.

Pharmaceutical compositions suitable for the release of compounds of the present invention and methods! the preparation thereof will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

- 19 -% f

The compounds of the invention can be administered orally. Oral administration can mean swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be used whereby the compound enters the blood stream directly from the mouth.

Preparations suitable for oral administration include solid preparations such as tablets, capsules containing particulate material, liquids, or powders, diamonds (including liquid-filled), chewing gums, multi- and nano-particulate materials, gels, solid solution, liposome, films, eggs, sprays and liquid preparations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such compositions can be used as a filling in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstituting a solid, for example from a sachet.

The compounds of the invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms such as those described in Expert Opinion in

Therapeutical Patents, 11 (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on the dose, the drug may form 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxy methyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, low alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium. In general, the disintegrant will form 1 wt% to 25 wt%, preferably 5 wt% to 20 wt% of the dosage form.

Binders are generally used to provide cohesive qualities to a tablet preparation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may optionally also include surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. If present, surfactants can form 0.2% by weight to 5% by weight of the tablet and lubricants can form 0.2% by weight to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally form 0.25% to 10% by weight, preferably 0.5% to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavorants, preservatives, and flavor masks.

Examples of tablets include up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% by weight to about 10% by weight of lubricant.

Tablet mixtures can be pressed directly or with a roll to form tablets. Tablet mixtures; - 21 -! Alternatively, portions of mixtures may be granulated wet, dry, or melted, melt-frozen, or extruded for tableting. The final composition may comprise one or more layers and may or may not be coated; it may even be enveloped.

The formulation of tablets is discussed in Phar-maceutical Dosage Forms: Tablets, Vol. 1, by H. Lieber-man and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically foldable water-soluble or water-swellable thin film dosage forms that can be rapidly soluble or mucoadhesive and typically a compound of formula (I), a film-forming polymer, a binder, a solvent , a wetting agent, a plasticizer, a stabilizing or emulsifying agent, a viscosity modifying agent and a solvent. Some components of the preparation can perform more than one function.

The compound of formula (I) can be water-soluble or insoluble. A water-soluble compound typically comprises 1 wt% to 80 wt%, more typically 20 wt% to 50 wt%, of the dissolved materials. Less soluble compounds can form a larger portion of the composition, typically up to 88% by weight of the dissolved materials. Alternatively, the compound of formula (I) may be in the form of multi-particle granules.

The filra-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range 0.01 to 99% by weight, more typically in the range 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, coolants, auxiliary solvents (including oils), softeners, volume-providing agents, anti-foaming agents, surfactants, and taste-masking agents. resources.

- 22 - «« • *

Films according to the invention are typically prepared by evaporative drying of thin aqueous films applied to a peelable support or paper.

This can be done in a drying oven or tunnel, typically a combined coating and drying device, or by freeze drying or vacuum suction.

Solid compositions for oral administration can be formulated such that they release immediately and / or have modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release preparations.

Suitable modified release preparations for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable delivery technologies such as high energy dispersions and osmotic and coated particles can be found in Pharmaceutical Technology On-line, 25 (2), 1-14, by Verma et al. (2001). The use of chewing gum for achieving controlled release is described in WO 00/35298.

The compounds of the invention can also be administered directly into the blood stream, into muscle tissue or into an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intra-urethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include injectors with a needle (including a micro needle), injectors without a needle, and infusion techniques.

Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably up to a pH of 3 to 9), but for some applications they may be more suitably formulated in the form of a sterile non - aqueous solution or in dried form ♦ 4 "23 - to be used in combination with a suitable carrier such as sterile, pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be easily achieved using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by applying appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Preparations for parenteral administration can be formulated such that they release immediately and / or have modified release. Modified release preparations include delayed, sustained, pulsed, controlled, targeted and programmed release preparations. For example, compounds of the invention can be formulated in the form of a solid, a semi-solid or a thixotropic liquid for administration in the form of an implanted depot providing modified release of the active compound.

Examples of such compositions include drug-coated stents and poly (dl-lactic acid-co-glycolic acid) (PGLA) microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, waffles, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used.

Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancing agents can be included - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan ji i ---------- -----.---- - * - 24 - (October 1999).

Other means for topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and injection with a micro needle or without needle (e.g., Powderjectw, Bioject ™, etc.).

Preparations for topical administration can be formulated such that they release immediately and / or have modified release. Preparations for modified delayed release include delayed, sustained, pulsed, controlled, targeted and programmed release preparations.

The compounds of the invention can also be administered intranally or by inhalation, typically in the form of a dry powder (either alone, in the form of a mixture, for example in a dry mixture with lactose, or in the form of a mixed component particle, for example mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or in the form of an aerosol spray from a pressurized container, pump, spray can, spray (preferably an atomizer using electrohydrodynamics to provide a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1.1, 1,2-tetrafluoroethane or 1,1,1,2,3,3,3 heptafluoropropane. For intranasal use, the powder may comprise a biological adhesive, for example chitosan or cyclodextrin.

The pressurized container, pump, spray can, sprayer or nebulizer contains a solution or suspension of the compound (s) of the invention, for example comprising ethanol, aqueous ethanol or a suitable alternative means for dispersing, solubilizing or extending the release of the active substance, one or more propellants as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligamic acid.

Prior to use in a dry powder or suspension preparation, the drug product is micronized to a size suitable for administration by inhalation (typically less than 5 μπι). This can be accomplished by any appropriate method of refinement, such as. 5 spiral jet mills, fluid bed jet mills, supercritical fluid processing to form nano particles, high pressure homogenization or spray drying.

Capsules (for example made from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated such that they comprise a powdered mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as 1-leucine, mannitol or magnesium stearate.

The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution preparation for use in a sprayer using electrohydrodynamics to provide a fine mist can contain 1 μg to 20 mg of the compound of the invention per release and the release volume can vary from 1 μΐ to 100 μΐ. A typical preparation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable aromas, such as menthol and levomenthol, or sweetening agents, such as saccharin or saccharin sodium, may be added to those compositions of the invention intended for inhaled / intranasal administration.

Preparations for inhaled / intranasal administration may be formulated such that they release immediately and / or have modified release, using, for example, PGLA. Preparations for modified release include preparations for delayed, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhaler preparations and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units according to the invention are typically adapted to administer a metered dose or "puff" containing 1 µg to 4000 µg of the compound of formula (I). The total daily dose will typically be in the range of 1 g to 20 mg, which can be administered in a single dose or, more usually, in the form of divided doses over the day.

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, a pessary or an enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Preparations for rectal / vaginal administration can be formulated such that they release immediately and / or have modified release. Modified release preparations include delayed, sustained, pulsed, controlled, targeted and programmed release preparations.

The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic sterile saline with adjusted pH. Other compositions suitable for ocular and aural administration include ointments, biodegradable implants (e.g. absorbable gel sponges, collagen) and non-biodegradable implants (e.g. silicone), waffles, lenses and particulate or vesicular systems, such as niosomes or liposomes.

A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example, can be incorporated together with a preservative, such as benzalkonium chloride. Such compositions can also be administered by iontophoresis.

Preparations for ocular / aural administration can be formulated such that they release immediately and / or have modified release. Modified release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release preparations.

The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve solubility, dissolution rate, taste masking, bioavailability and / or stability for use in each of the aforementioned delivery modes.

Drug-cyclodextrin complexes, for example, have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizing agent. Usually used for these purposes are: α, S and γ-cyclodextrins, examples of which can be found in International Patent Applications WO 91/11172, WO 94/02518 and WO 98/55148.

To the extent that it may be desirable to administer a combination of active compounds, for example to treat a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which a compound according to invention may suitably be combined in the form of a kit suitable for co-administration of the compositions. Therefore, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which one compound of formula (I) according to the invention and means for separately containing said preparations, such as a container, a divided bottle or a divided film package. An example of such a kit is the known blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example oral and parenteral, for administering the individual preparations in different dosing intervals, or for titrating the individual preparations relative to each other . To support compliance, the kit typically comprises a manual and may be provided with a so-called memory support.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.001 mg to 2000 mg, of course depending on the mode of administration. For example: oral administration may require a total daily dose of 0.1 mg to 2000 mg, while an intravenous dose may require only 0.01 mg to 100 mg. The total daily dose can be administered in single or divided doses and, at the physician's discretion, may fall outside the typical range given herein.

These doses are based on an average person with a weight of approximately 60 kg to 70 kg. The physician will readily be able to determine doses for patients weighing outside this range, such as infants and the elderly.

For the avoidance of doubt: when "treatment" is involved, this includes curative, palliative and prophylactic treatment.

According to another embodiment of the present invention, the compounds of formula (I) or pharmaceutically acceptable salts, derived forms or preparations thereof, can also be used in the form of a combination with one or more additional therapeutic agents that will be co-administered to a patient to achieve a particular desired therapeutic end result. The second and further therapeutic agents may also be a compound of formula (I) or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more histamine H4 receptor ligand known in the art. More typically, second and further therapeutic agents will be selected from a different class of therapeutic agents.

As used herein, the terms "co-administration", "co-administered" and "in combination with", with respect to the compounds of formula (I) and one or more other therapeutic agents, mean the following refer to the following and include: • co-administration of such a combination of compound (s) of formula (I) and therapeutic agent (s) to a patient in need of treatment when these components are taken together are formulated in a single dosage form that delivers said components to said patient at substantially the same time, substantially simultaneous administration of this combination of compound (s) of formula (I) and therapeutic agent (s) to a patient in need of treatment, when these components are formulated separately from each other in separate dosage forms taken by said patient at substantially the same time, after which the gene said components are delivered to said patient at substantially the same time, • sequential administration of this combination of compound (s) of formula (I) and therapeutic agent (s) to a patient in need of treatment, when these components formulated separately from each other in separate dosage forms taken by said patient at consecutive times with a significant time difference between administrations, whereafter said components are delivered to said patient at substantially different times; and • sequential administration of this combination of compound (s) of formula (s) and therapeutic agent (s) to a patient in need of treatment when these components are formulated together in a single dosage form comprising the delivers said components in a controlled manner, whereafter they are administered to said patient simultaneously, successively and / or overlappingly at the same time and / or at different times, wherein all parts can be administered by the same route or by different routes.

Suitable examples of other therapeutic agents that can be used in combination with the compound (s) of formula (I) or pharmaceutically acceptable salts, derived forms or preparations thereof include, but are in no way limited to: • Histamine-Hi- receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine • Histamine H3 receptor or antagonists • Histamine H2 receptor antagonists • Leukotriene antagonists, including antagonists of LTB4, LTC4, LTD4 and LTE4, in particular Montelukast · Phosphodiesterase inhibitors, namely PDE4 inhibitors and PDE5 inhibitors • neurotransmitter reuptake inhibitors, in particular fluoxetine, setraline, paroxetine, ziprasidone • 5-Lipoxygenase (5-L0) inhibitors or 5-lipoxy-30 genase activating protein (FLAP) antagonists, ax and a2 adrenoceptor agonist vasoconstrictor sympathomimetic agents for use as a decongestant • Muscarin M3 receptor a ntagonists or anticholinergic agents, • g2 adrenoceptor agonists, • Theophylline, • Sodium cromoglycate, - 31 - * • COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors, • Oral or inhaled glucocorticosteroid drugs, • Monoclonal antibodies active against endogenous inflammatory entities, • Anti-tumor necrosis factor (anti-TNF-α) agents, • Adhesion molecule inhibitors comprising VLA-4 antagonists, • Kinine B1 and B2 receptor antagonists, • Immune suppressants, • Inhibitors of matrix metalloproteases (MMPs), • Tachykinin NK 1, NK 2 and NK 3 receptor antagonists, • Blastase inhibitors, • Adenosine A 2a receptor agonists, • Inhibitors of urokinase, • Compounds that act on dopamine receptors, for example D2 agonists, • Modulators of the NFKb pathway, for example IKK inhibitors, • Agents that can be classified as raucolytics or anti-cough agents, • Antibiotics, • Modulators of cytokine signaling pathways such as p38 MAP kinase inhibitors, syk tyrosine kinase inhibitors or JAK kinase inhibitors. Prostaglandin D2 receptor antagonists (DPI and CRTH2) • Inhibition of Prostaglandin D synthase (PGDS) • Phospho-inositide-3-kinase and 30-HDAC inhibitors.

According to the present invention, combination of the compounds of formula (I) with: • Histamine Hj receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine, • Histamine H3 receptor antagonists, • Histamine Hj receptor antagonists, Leukotriene antagonists, including LTB4, LTC4, LTD4 and LTE4 antagonists, in particular Montelukast, and Posfiesterase - PDE4 inhibitors are preferred.

The compounds of formula (I) have the ability to interact with the H4 receptor and therefore have a wide range of therapeutic applications, as further described below, due to the essential role that the H4 receptor plays in the physiology of all suckle-10 animals. According to this invention, H4 ligands are intended to include H4 receptor antagonists, agonists, and inverse agonists. For the preferred indications that can be treated according to the invention, antagonists are considered to be most suitable.

Therefore, a further aspect of the present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts, derived forms or compositions thereof, for use as medicaments, more particularly in the treatment of diseases, conditions and conditions involving the H4 receptor. More specifically, the present invention also relates to the compounds of formula (I) or pharmaceutically acceptable salts, derived forms or preparations thereof, for use in the treatment of diseases, conditions and conditions selected from the group consisting of: inflammatory diseases ; Respiratory diseases (for example, respiratory distress syndrome in adults, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced respiratory rhinitis, allergic allergic rhinitis responses, allergic rhinitis, non-allergic rhinitis, such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease

"I

Disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced respiratory responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion; • sexual dysfunction in women and men; • skin diseases such as dermatitis and psoriasis; • cardiac dysfunctions such as myocardial ischemia and arrhythmia / gastrointestinal tract diseases such as daramitis, Crohn's disease and ulcerative colitis; • cancer; Rheumatoid arthritis; • hypotension; • pain and overactive bladder conditions.

The compounds of formula (I) according to the present invention are particularly suitable for the treatment of asthma, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion .

A still further aspect of the present invention also relates to the use of the compounds of formula (I), or pharmaceutically acceptable salts, derived forms or preparations thereof, for the preparation of a medicament that is an H4 ligand. In particular, the present invention relates to the use of the compounds of formula (I), or pharmaceutically acceptable salts, derived forms or compositions thereof. of, for the preparation of a medicament for the treatment of H4-mediated diseases and / or conditions, in particular the diseases and / or conditions mentioned above.

The present invention thus provides a particularly interesting method for treating a mammal, comprising a human, with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, derived form or preparation thereof. More precisely: the present invention provides a particularly interesting method for the treatment of H4-mediated diseases and / or conditions in a mammal, including a human, in particular the aforementioned diseases and / or conditions, including the aforementioned mammalically administering an effective amount of a compound of formula (I), the pharmaceutically acceptable salts and / or derived forms thereof.

The following examples illustrate the preparation of compounds of formula (I) according to the present invention.

^ Nuclear magnetic resonance (NMR) spectra are consistent with the proposed structures in all cases. Characteristic chemical shifts (5) are given in parts per million (ppm) downwards relative to tetramethyl. silane using conventional abbreviations to indicate major peaks: for example s (singlet), d (doublet), t (triplet), q (quartet), m20 (multiplet) and br (broad). The mass spectra (m / z) were recorded using either electrospray ionization (ESI) or chemical ionization at atmospheric pressure! (APCI). Purification by SCX indicates the use of strong cation exchange resin.

25 SECTION EXAMPLES

Preparation 1: (5-Methoxy-1H-benzimidazol-2-yl) -methanol

A solution of 4-methoxybenzene-1,2-diamine (1.13 g, 8.18 mraol) and hydroxyacetic acid (1.85 g, 24.5 mmol) in 6N hydrochloric acid (25 ml) was heated under reflux for 16 hours . The reaction mixture was cooled to room temperature and neutralized by the addition of solid sodium hydroxide. The resulting precipitate was filtered off and dried under vacuum to provide the title compound in the form of a pale yellow solid (638 mg).

Preparation 2: (5-Fluoro-1H-benzimidazol-2-yl) methanol

Prepared from 4-fluorobenzene-1,2-diamine using 35 of the method of Preparation 1 to provide the title compound in the form of a brown crystalline solid.

Preparation 3: (5-Methyl-1H-benzimidazol-2-yl) methanol 5 Prepared from 4-methyl-1,2-diamine using the method of Preparation 1 to provide the title compound in the form of a pale yellow solid.

Preparation 4: (5-Chloro-1H-benzimidazol-2-yl) methanol Prepared from 4-chloro-1,2-diamine using the method of Preparation 1 to provide the title compound in the form of a pale yellow solid.

Preparation 5: 5-Methoxy-1H-benzimidazole-2-carboxylic acid A suspension of (5-methoxy-1H-benzimidazol-2-yl) -methanol (Preparation 1) (638 mg, 3.58 mmol) in 1 N aqueous 15 sodium hydroxide (0.95 ml) and water (40 ml) was heated to reflux and a solution of potassium permanganate (848 mg, 5.36 mmol) in water was added dropwise over a 30 minute period. heated under reflux for 1 hour and then cooled to room temperature. The reaction mixture was acidified to pH 4 by the addition of acetic acid and the resulting solid was filtered and dried in vacuo to give the title compound as a pale yellow solid (332 mg).

Preparation 6: 5-Fluoro-1H-benzimidazole-2-carboxylic acid

Prepared from the alcohol of Preparation 2 using the method of Preparation 5 to provide the title compound in the form of a pale brown solid.

Preparation 7: 5-Methyl-1H-benzimidazole-2-carboxylic acid

Prepared from the alcohol of Preparation 3 using the method of Preparation 5 to provide the title compound in the form of a pale yellow solid.

Preparation 8: 5-Chloro-1H-benzimidazole-2-carboxylic acid

Prepared from the alcohol of Preparation 4 using the method of Preparation 5 to provide the title compound in the form of a pale yellow solid.

Preparation 9: 6,7-Dimethyl-2- (trichloromethyl) -1H-benzimidazole 5 A solution of 3,4-dimethylbenzene-1,2-diamine (1.0 g, 7.34 mmol) in acetic acid (10 ml) was treated with methyl 2,2,2-trichloroacetimidate (1.0 ml, 8.07 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was poured onto ice (ca. 100 g) and then extracted with dichloromethane (100 ml). The organic phase was separated, dried (sodium sulfate) and the solvent removed in vacuo. The residue was triturated with diethyl ether and the title compound was isolated by filtration (360 mg) in the form of a brown solid. The material was used roughly in the next step without further characterization.

Preparation 10: 6,7-Difluoro-2- (trichloromethyl) -1H-benzimidazole

A solution of 3,4-difluorobenzene-1,2-diamine (274 mg, 1.90 mmol) in acetic acid (4 ml) was treated with methyl 2, 2, 2-trichloroacetimidate (0.25 ml, 2, 09 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was poured onto ice (ca 50 g) and the resulting precipitate was filtered and dried under vacuum to provide the title compound in the form of a brown solid (496 mg). The material was used roughly in the next step without further characterization.

Preparation 11: 7-Methyl-2- (trichloromethyl) -1H-benzi-midazole

Prepared from 3-methylbenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step without further characterization.

Preparation 12: 5,6-Difluoro-2- (trichloromethyl) -1H-ben-zimidazole - 37 -

Prepared from 5,6-difluorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step 5 without further characterization.

Preparation 13: 5,7-Difluoro-2- (trichloromethyl) -1H-benzimidazole

Prepared from 3,5-difluorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step without further characterization.

Preparation 14: 5-Chloro-7-methyl-2- (trichloromethyl) -1H-benzimidazole Prepared from 5-chloro-3-methylbenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a yellow solid. The material was used roughly in the next step without further characterization.

Preparation 15: 7-Chloro-5-methyl-2- (trichloromethyl) -1H-benzimidazole

Prepared from 3-chloro-5-methylbenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step without further characterization.

Preparation 16: 5-Iodo-2- (trichloromethyl) -1H-benzimidazole

Prepared from 4-iodobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step.

Preparation 17: Methyl 2- (trichloromethyl) -1H-benzimidazole-5-carboxylate Prepared from methyl 3,4-diaminobenzoate using the method of Preparation 10 to provide the title compound in the form of a brown solid.

- 38 -

The material was used roughly in the next step.

Preparation 18: 5-Chloro-6-fluoro-2- (trichloromethyl) -ΙΗ-benz imidazole

Prepared from 4-chloro-5-fluorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step without further characterization.

Preparation 19: 5,6-Dimethyl-2- (trichloromethyl) -1H-10 benzimidazole

Prepared from 4,5-dimethylbenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step 15 without further characterization.

Preparation 20: 5,6-dichloro-2- (trichloromethyl) -1H-benzimidazole

Prepared from 4,5-dichlorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid. The material was used roughly in the next step without further characterization.

Preparation 21: 2- (Trichloromethyl) -5- (trifluoromethyl) -1H-benzimidazole Prepared from 4- (trifluoromethyl) benzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a pale yellow solid. The material was used roughly in the next step.

Preparation 22: 4-Chloro-6-fluoro-2- (trichloromethyl) -1H-benzimidazole

Prepared from 3-chloro-5-fluorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of an orange solid. The material was used roughly in the next step without further characterization.

«* - 39 -

Preparation 23: 4,6-dichloro-2- (trichloromethyl) -1H-benzimidazole

Prepared from 3,5-dichlorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a yellow solid. The material was used roughly in the next step without further characterization.

Preparation 24: 5-Phenyl-2- (trichloromethyl) -1H-benzimidazole 10 Prepared from biphenyl-3,4-diamine using the method of Preparation 10 to provide the title compound in the form of a brown oil. The material was used roughly in the next step without further characterization.

Preparation 25: 5-Fluoro-4-methyl-2- (trichloromethyl) -1H-benzimidazole

Prepared from 4-fluoro-3-methylbenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown oil. The material was used roughly in the next step without further characterization.

Preparation 26: N- (2-Fluoro-4-methylphenyl) acetamide

A solution of 2-fluoro-4-methylaniline (2.0 g, 15.9 mmol) in dichloromethane (25 ml) was cooled to 0 ° C and treated with a solution of acetic anhydride (1.50 ml, 15.9 mmol) in dichloromethane (50 ml). The resulting mixture was allowed to warm gradually to room temperature over a period of one hour. Saturated aqueous sodium bicarbonate solution (50 ml) was added and the organic phase was separated, washed with further saturated aqueous sodium bicarbonate solution (50 ml), dried (sodium sulfate) and the solvent was reduced in vacuo to provide the title compound in the form of a colorless solid (2.26 g).

Preparation 27: 2-Fluoro-4-methyl-6-nitroaniline

A solution of the acetamide of Preparation 26 - 40 - (1.0 g, 5.9 mmol) in nitric acid (70%, 10 ml) was cooled to 0 ° C and treated with fuming nitric acid (90%, 10 ml) with the reaction temperature was kept below 0 ° C. The reaction was stirred at 0 ° C for one hour and then poured onto ice and allowed to warm gradually to room temperature. The resulting precipitate was collected by filtration and dried under vacuum to provide a colorless solid (1 g, mixture of isomers). The solid was dissolved in methanol (20 ml) and solid KOH was added to adjust the pH to 10. The solution was stirred at room temperature for 16 hours and then the solvent was removed in vacuo. Water (50 ml) and dichloromethane (50 ml) were added and the organic phase was separated. The aqueous phase was extracted with further dichloromethane (50 ml) and the combined organic layers were dried (sodium sulfate) and evaporated in vacuo. Purification by flash column chromatography on silica gel eluting with pentane / ethyl acetate (80:20 volume ratio, changing to 20:80) gave the title compound as a yellow solid (124 mg). Preparation 28: 3-Fluoro-5-methylbenzene-1,2-diamine A solution of the nitroaniline of Preparation 27 (124 mg, 0.72 mmol) in ethanol (5 ml) was treated with 10% Pd / C and 4 hydrogenated at 50 psi for 1 hour at room temperature. The reaction mixture was filtered and the solvent was removed in vacuo to provide a colorless solid (79 mg).

Preparation 29: 4-Chloro-3-methylbenzene-1,2-diamine 30 A solution of 3-chloro-2-methyl-6-nitroaniline (500 mg, 2.67 mmol) in a mixture of acetic acid (5 ml) and water (1 ml) was heated to 90 ° C and treated with iron powder (900 mg, 16.0 mmol). The reaction mixture was heated at 90 ° C for an additional 2 hours and then cooled to room temperature and poured onto ice. The pH was adjusted to 8 and ethyl acetate (50 ml) was added. The resulting mixture was filtered and the organic phase was separated, dried (sodium sulfate) and the solvent reduced in vacuo. Purification by flash column chromatography on silica gel eluting with pentane / ethyl acetate (volume ratio 70:30, changing from 5 to 30:70) gave the title compound in the form of a brown oil (213 mg).

Preparation 30: Methyl 5,6-difluoro-1H-benzimidazole-2-carboxylate

A solution of 5,6-difluorobenzene-1,2-diamine (1.76 g, 12.2 mmol) in acetic acid (70 ml) was treated with methyl 2,2,2-trichloroacetimidate (1.5 ml, 12.2 mmol) and the resulting solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was dissolved in methanol (100 ml) and refluxed for 4 hours. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The organic phase was separated, dried (sodium sulfate) and reduced in vacuo.

Purification by flash column chromatography on silica gel eluting with pentane / ethyl acetate (90:10 volume ratio, changing to 50:50) gave the title compound as a yellow solid (963 mg).

Preparation 31: 5,6-Difluoro-1H-benzimidazole-2-25 carboxylic acid

A solution of the ester of Preparation 30 (963 mg, 4.53 mmol) in tetrahydrofuran (10 ml) was treated with lithium hydroxide (9.0 ml of a 1M aqueous solution, 9.0 mmol) and stirred for 16 hours at room temperature. Hydrochloric acid 30 (9.0 ml of a 1M aqueous solution, 9.0 mmol) was added and the resulting precipitate was filtered, washed with water (10 ml) and dried in vacuo to give the title compound as a pale yellow solid substance (700 mg).

Preparation 32: 5,6-Difluoro-2- (trichloromethyl) -1H-benzimidazole

Prepared from 4-fluorobenzene-1,2-diamine using the method of Preparation 10 to provide the title compound in the form of a brown solid that was used roughly in the next step without further characterization.

Preparation 33: 5,6-difluoro-1H-benzimidazole-2-carbonitrile

A solution of the trichloromethylbenzimidazole of Preparation 12 (5 g, 18.4 tmmol) in tetrahydrofuran (25 ml) was added dropwise to a cooled solution of 880 ammonia (10 ml) in water (30 ml) while maintaining a internal temperature below -5 ° C. The reaction mixture was stirred at 0 ° C for 2 hours and then poured out on ice and acidified to pH 5 by slow addition of concentrated hydrochloric acid. The resulting solid was filtered and washed with water (50 ml). The residue was partitioned between diethyl ether (50 ml) and aqueous sodium carbonate (2.5 g in 50 ml of water). The aqueous phase was separated, poured out on ice and acidified to pH 5 by the slow addition of concentrated hydrochloric acid. The resulting solid was filtered off and dried in vacuo to give the title compound as a pale brown solid (2.63 g). X H NMR (400 MHz, CD3 OD): 7.62-7.58 (2H, m) ppm.

MS (APCI): m / z 180 [M + H] +, 178 [M-H] +

Example 1: 2- {[(3aR, 6aS) 5-Methylhexahydropyrrolo (3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole OH, "

V ~ -N

ch3 A solution of 1 H-benzimidazole-2-carboxylic acid (456 mg, 2.81 mmol) in N, N-dimethylacetamide (5 ml) was treated with (3aR, 6aS) -2-methyloctahydropyrrolo (3,4-c] pyr-i-43-rooi (322 mg, 2.55 mmol), triethylamine (0.71 mL, 5.11 mmol) and O-benzotriazo-i-yl-Ν, Ν, Ν ', N'-tetramethyluronium- hexafluorophosphate (1.16 g, 3.06 mmol) and the resulting solution was stirred for 16 hours at room temperature.The reaction mixture was purified directly with SCX resin, eluting non-basic compounds with methanol and the basic compounds with 1 N ammonia in methanol.

The basic washings were evaporated in vacuo and purified by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 99: 1: 0.1 changing to 90: 10: 1) to give the title compound in the form of a pale yellow solid (499 mg).

1 H NMR (400 MHz, CD3 OD): δ 7.71-7.69 (2 H, m), 7.39-7.34 (2 H, m), 4.42-4.30 (2 H, m), 3.95-3.77 (2H, m), 3.15-2.98 (2H, m), 2.84-2.77 (2H, m), 2.56-2.52 (2H, m) ), 2.37 (3 H, s) ppm.

MS (electrospray): m / z 271 [M + H] +, 269 [M-H] "

Example 2: 5-Methoxy-2 - {[(3aR, 6 aS) -5-methylhexahyl-20-pyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole H ' C10 TXV <0 w CH3

Prepared from 5-methoxy-1H-benzimidazole-2-carboxylic acid (preparation 5) using the method of Example 1 to provide the title compound in the form of a pale brown solid.

NMR (400 MHz, CD 3 OD): δ 7.55 (1 H, d), 7.09 (1 H, s), 6.95 (1 H, d), 4.36-4.24 (2 H, m), 3 , 89-3.71 (5H, m), 3.10-2.89 (2H, m), 2.79-2.72 (2H, m), 2.49-2.46 (2H, m) ), 2.32 (3 H, s) ppm.

MS (APCI) m / z 301 [Μ + ΗΓ, 299 [Μ-ΗΓ - 44 -]

Example 3: 5-Fluoro-2 - {[(3aR, 6aS) -5-methylhe3cahydropyrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole ool, ch 3

Prepared from 5-fluoro-1H-benzimidazole-2-carboxylic acid (Preparation 6) using the method of Example 1 to provide the title compound in the form of a pale brown solid.

15 '-H NMR (400 MHz, CD 3 OD): δ 7.65 (1H, dd), 7.33 (1H, dd), 7.13-7.07 (1H, m), 4.37-4, 26 (2H, m), 3.90-3.74 (2H, m), 3.10-2.92 (2H, m), 2.79-2.71 (2H, ifi), 2.51- 2.48 (2 H, m), 2.32 (3 H, s) ppm.

MS (APCI) m / z 289 [M + H] +, 287 [M-H] + Example 4: 5-Methyl-2 - {[(3aR, 6aS) -5-methylhexahydroopyrrolo [3,4-c ] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimida-sol "* ° YYVf 'ς ς,

N

CH3 Prepared from 5-methyl-1H-benzimidazole-2-carboxylic acid (Preparation 7) using the method of Example 1 to provide the title compound in the form of a pale yellow solid.

XK NMR (400 MHz, CD3 OD): δ 7.54 (1H, d), 7.42 (1H, s), 7.15 (1H, d), 4.35-4.23 (2H, m) , 3.89-3.72 (2H, m), 3.11-2.91 (2H, m), 2.79-2.71 (2H, m), 2.50-2.47 (2H, m), 2.32 (3 H, s) ppm.

- 45 - 9 ψ MS (APCX) m / z 285 [M + H] +, 283 [M-H] +

Example 5: 5-Chloro-2- {[(3aR, 6aS) -5-methylhexahydroprrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole

Xcnm ° N-v "

N

CH3

Prepared from 5-chloro-1H-benzimidazole-2-carboxylic acid (Preparation 8) using the method of Example 1 to provide the title compound in the form of a pale yellow solid.

X H NMR (400 MHz, CD 3 OD): δ 7.64 (1 H, d), 7.60 (1 H, s), 7.29 (1 H, d), 4.37-4.25 (2 H, m), 3.88-3.71 (2H, m), 3.11-2.91 (2H, m), 2.78-2.70 (2H, m), 2.51-2.48 (2H, m) ), 2.32 (S, 3H) ppm.

MS (APCI) m / z 305/307 [M + H] +, 303/305 [M-H] "

Example 6: 5-chloro-2- [(3aR, 6aS) -hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -ylcarbonyl] -1H-benzimidazole rxvf

^ —H H

A solution of 5-chloro-1H-benzimidazole-2-carboxylic acid (Preparation 8) (100 mg, 0.50 mmol) in N, N-dimethyl-acetamide (5 ml) was treated with tert-butyl- ( 3aR, 6aS) -hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate (108 mg, 0.51 mmol) and O-benzotriazo-1-yl-Ν, Ν, Ν ', N'-tetramethyluro 35 -ium hexafluorophosphate (256 mg, 0.67 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml) and the organic phase was separated, dried (sodium sulfate) and the solvent was reduced in vacuo. The residue was treated with a 1 M solution of HCl in methanol (15 ml) and stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 99: 1: 0.1 changing to 90: 10: 1) to give the title compound in the form of a colorless solid (50 mg).

X H NMR (400 MHZ, CD 3 OD): δ 7.69-7.65 (2 H, m), 7.34 (1 H, d), 4.45-4.40 (1 H, m), 4.24-4 , 20 (1H, m), 3.99-3.94 (1H, m), 3.71-3.66 (1H, m), 3.19-3.11 (2H, m), 3.09 -2.92 (2H, m), 2.83-2.79 (2H, m) ppm.

MS (APCI) m / z 291/293 [M + H] \ 289/291 [M-H] +

Example 7: 5-Chloro-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole

20 YYU

* —N

ch3 25

Prepared from 5-chloro-1H-indole-2-carboxylic acid by the method of Example 1 to provide the title compound as a colorless solid.

* Ή NMR (400 MHz, CD3 OD): δ 7.67 (1 H, s), 7.46 (1 H, d), 7.24 (1 H, dd), 6.97 (1 H, s), 4, 20-3.73 (4H, m), 3.17-2.96 (2H, m), 2.82-2.75 (2H, m), 2.61-2.54 (2H, m), 2.38 (3 H, s) ppm.

MS (APCI) m / z 304/306 [M + H] +, 302/304 [M-H] "

Example 8: 5-Chloro-2 - {[(3aR, 6aS) -hexahydropyrro-3510 [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole ♦ - 47 - C, TTV / "^

5 '—N

5 H

A solution of 5-chloro-1 H -indole-2-carboxylic acid (100 mg, 0.51 mmol) in N, N-dimethylacetamide (5 ml) was treated with tert-butyl (3aR, 6aS) -hexahydropyrrolo [3, 4-10 c] pyrrole-2 (1 H) -carboxylate (108 mg, 0.51 mmol) and 0-benzotriazo-1-yl-N, N, N · W-tetramethyluronium hexafluorophosphate (256 mg (0.67 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml) and the organic phase was separated and dried (sodium sulfate) and the solvent was reduced in vacuo. The residue was treated with a 1 M solution of HCl in methanol (15 ml) and stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 99: 1: 0.1 changing to 90: 10: 1) to provide the title compound in in the form of a pale yellow solid (42 mg).

25 * H NMR (400 MHZ, DMSOd?): Δ 11.77 (1H, bs), 7.69 (1H, bs), 7.45 (1H, d), 7.20 (1Η, d), 6 , 93 (1H, S), 4.13-3.45 (4Η, m), 2.99-2.63 (6Η, m), 2.52 (3H, s) ppm (poorly resolved spectrum).

MS (APCI) rn / z 290/292 [M + H] +, 288/290 [M-H] + Example 9: 5-Methoxy-3-methyl-2 - {[(3aR, 6aS) -5-Me-

thylhexahydro-pyrrolo [3,4-c] pyrrole ^ 2 (1Η) -yl] carbonyl} -1H-indole CH

^ ° γγ ^ ° ch3 - 48 -

Prepared from 5-methoxy-3-methyl-1 H -indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a pale yellow solid.

X H NMR (400 MHz, CDCl 3): δ 9.42 (1 H, bs), 7.28 (1 H, 5 d), 6.99 (1 H, s), 6.92 (1 H, d), 3.88 -3.58 (7H, m), 2.91-2.78 (2H, m), 2.56-2.46 (4H, m), 2.37 (3H, S), 2.32 (3H , s) pptn.

MS (APCI) m / z 314 [M + H] +, 312 [M-H] +

Example 10: 5- (Benzyloxy) -2 - {[(3aR, 6aS) -5-methyl-hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole. .

4-NI

ch3

Prepared from 5- (benzyloxy) -3-methyl-1 H -indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

X H NMR (400 MHz, CDCl 3): δ 9.39 (1H, bs), 7.47 (2H, d), 7.39 (2H, dd), 7.30 (2H, d), 7.13 ( 1 H, s), 7.05 (1 H, 25 d), 6.76 (1 H, s), 5.10 (2 H, s), 4.15-4.03 (2 H, m), 3.83 - 3.72 (2H, m), 3.11-2.91 (2H, m), 2.75-2.69 (2H, m), 2.59-2.54 (2H, m), 2, 38 (s, 3H) ppm.

MS (APCI) m / z 376 [M + H] +

Example 11: 6-Methyl-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole

"—N

CH3 - 49 -

Prepared from 5-methyl-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title binding in the form of a pale yellow solid.

1 H NMR (400 MHz, CDCl 3): δ 9.69 (1 H, bs), 7.54 (1 H, 5 d), 7.23 (1 H, s), 6.98 (1 H, d), 6.81 (1H, s), 4.19-4.02 (2H, m), 3.86-3.72 (2H, m), 3.11-2.85 (2H, m), 2.68-2 , 64 (2H, m), 2.57-2.55 (2H, m), 2.47 (3H, s), 2.35 (3H, s) ppm.

MS (APCI) m / z 284 [M + H] +, 282 [MH] + Example 12: 4-Methoxy-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole xh3 ccv <CH. Prepared from 4-methoxy-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CDCl 3): δ 9.38 (1 H, bs), 7.21 (1 H, t), 7.05 (1 H, d), 6.96 (1 H, s), 6.51 ( 1 H, s), 4.14-4.04 (2 H, m), 3.97 (3 H, s), 3.89-3.78 (2 H, m), 3.12-3.00 (2 H , m), 2.90-2.75 (2H, m), 2.60-2.57 (2H, m), 2.42 (3H, s) ppm.

MS (APCI) m / z 300 [M + H] \ 298 [M-H] +

Example 13: 6-Chloro-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole ch3> 50 -

Prepared from 6-chloro-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a pale yellow solid.

NMR (400 MHz, CDCl 3): δ 10.24 (1 H, bs), 7.55 (1 H, 5 d), 7.46 (1 H, S), 7.06 (1 H, d), 6.81 ( 1 H, s), 4.16-4.08 (m, 2 H), 3.83-3.76 (m, 2 H), 3.14-2.91 (m, 2 H), 2.68-2, 59 (4H, m), 2.36 (s, 3H) ppm.

MS (APCI) m / z 304/306 [M + H] +, 302/304 [M-H] "

Example 14: 5-Methoxy-2 - {[(3aR, 6aS) -5-methylhexa-10-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole h / yVU! ch3

Prepared from 5-methoxy-ΙΗ-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid. ! X H NMR (400 MHz, CDCl 3): δ 9.68 (1H, bs), 7.34 (1H, jd), 7.06 (1H, s), 6.96 (1H, dd), 6.77 ( 1 H, s), 4.15-4.02 (2 H, m), 3.85 (3 H, s), 3.83-3.75 (2 H, m), 3.11-2.91 (2 H, 25 m), 2.71-2.65 (2 H, m), 2.59-2.53 (2 H, m), 2.35 (3 H, s) ppm.

MS (APCI) m / z 300 [M + H] *, 298 [M-H] +

Example 15: 2- {[(3aR, 6aS) -5-Methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole-5-ol 30

35 lS

l ~~ n

ch3

1 I

! * j - 51 -

Prepared from 5-hydroxy-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CD 3 OD): δ 7.33 (1 H, d), 7.02 (1 H, d), 5.86 (1 H, dd), 6.83 (1 H, s), 4.20 -3.72 (4H, m), 3.17-2.95 (2H, m), 2.83-2.79 (2H, m), 2.57-2.54 (2H, m), 2 , 39 (s, 3H) ppm.

MS (APCI) m / z 286 [M + H] \ 284 [M-H] *

Example 16: 5-Fluoro-2 - {[(3aR, 6aS) -5-methylhexa-10-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole 'Cc * Hbs CH3

Prepared from 5-fluoro-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

X H NMR (400 MHz, CDCl 3): δ 7.37 (1 H, dd), 7.28 (1 H, dd), 7.08-7.02 (1 H, m), 6.81 (1 H, s), 4.14-4.02 (2H, m), 3.84-3.74 (2H, m), 3.09-2.95 (2H, m), 2.74-2.70 (2H, m) ), 2.59-2.56 (2 H, m), 2.37 (3 H, s) ppm.

MS (APCI) m / z 288 [M + H] +, 286 [M-H] +

Example 17: 5-Methyl-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-pypyrrole-2 (1H) -yl] carbonyl} -ih-indole X? 35 CH3 - 52 -

Prepared from 5-methyl-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CDCl 3): δ 7.43 (1 H, s), 7.33 (1 H, d), 5 7.12 (1 H, d), 6.77 (1 H, s), 4.15 -4.03 (2H, m), 3.84-3.74 (2H, m), 3.09-2.94 (2H, m), 2.80-2.71 (2H, m), 2 , 60-2.55 (2 H, m), 2.44 (3 H, s), 2.38 (3 H, s) ppm.

MS (APCI) m / z 284 [M + H] 282 [Μ-ΗΓ

Example 18: 3,5-Dimethyl-2 - {(3aR, 6aS) -5-methylhexa-10-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole PH3

HaCYYM ° Y)

"—N

CH3

Prepared from 3,5-dimethyl-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a pale yellow solid.

X H NMR (400 MHz, CD3 OD): δ 7.32 (1 H, s), 7.23 (1 H, d), 7.03 (1 H, d), 3.79-3.74 (2 H, m), 3.65-3.50 (2H, m), 2.95-2.90 (2H, m), 2.79-2.67 (2H, m), 2.41-2.33 (11H, m) ppm.

MS (APCI) m / z 298 [M + H] *, 296 [M-H]

Example 19: 5-Chloro-3-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole CH3

"SS

ch3

Prepared from 5-chloro-3-methyl-1H-indole-2-carboxylic acid according to the method of Example 1 to provide 35% ί - 53 - Title compound in the form of a colorless solid.

* H NMR (400 MHz, CD3 OD): δ 7.53 (1H, s), 7.32 (1H, d), 7.15 (1H, d), 3.82-3.46 (4H, m) , 2.98-2.89 (m, 2H), 2.76-2.66 (2H, m), 2.43-2.34 (2H, m), 2.33 (3H, s), 2 , 32 (3H, 5 s) ppm.

MS (APCI) m / z 318/320 [M + H] +, 316/318 [M-H] +

Example 20: 1-Methyl-2- {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 <1 H) -yl] carbonyl} -1 H-indole νλ

* "- N

CH3

Prepared from 1-methyl-1 H -indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CD 3 OD): δ 7.60 (1 H, d), 7.42 (1 H, d), 7.28 (1 H, t), 7.10 (1 H, t), 6.76 (1H, S), 3.89-3.83 (5H, m), 3.73-59 (2H, m), 2.96-2.89 (2H, m), 2.79-2.56 (2 H, m), 2.55-2.33 (2 H, m), 2.32 (3 H, m) ppm.

MS (APCI) m / z 284 [M + H] + Example 21: 5-Bromo-2- {β (3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole

Vrvf 30 / Ν ~ · \

N

CH3 35 Prepared from 5-bromo-1H-indole-2-carboxylic acid by the method of Example 1 to provide the title compound in the form of a colorless solid.

r - 54 - * Η NMR (400 MHz, CD3 OD): δ 7.79 (1 H, S), 7.37 (1 H, d), 7.31 (1 H, dd), 6.92 (1 H, s) , 4.18-3.72 (4H, m), 3.15-2.96 (2H, m), 2.86-2.78 (2H, m), 2.62-2.54 (2H, m), 2.39 (3 H, s) ppm.

5 MS (APCI) m / z 348/350 [M + H] +, 346/348 [M-H]

Example 22: 7-Fluoro-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-indole J?

io \\ TM

N N-y r ^

Nn!

ch3 I

15

Prepared from 7-fluoro-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CD 3 OD): δ 7.47 (1H, d), 7.08-6.97 (3H, m), 4.18-3.68 (4H, m), 3.16- 2.92 (2H, m), 2.79-2.75 (2H, m), 2.57-2.53 (2H, m), 2.38 (3H, s) ppm.

MS (APCI) m / z 288 [M + H) +, 286 [M-H] +

Example 23: 5,6-Dimethoxy-2 - {[(3aR, 6aS) -5-methyl-hexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-in-25 dool ηV, 30 CH3

Prepared from 5,6-dimethoxy-1H-indole-2-carboxylic acid according to the method of Example 1 to provide the title compound in the form of a colorless solid.

* Η NMR (400 MHz, CD 3 OD): δ 7.16 (1 H, s), 7.04 (1 H, s), 6.91 (1 H, s), 4.20-3.93 (2 H, m) , 3.92 (3 H, s), 3.89 (3 H, 55- s), 3.86-3 / 77 (2 H, m), 3.15-2.98 (2 H, m), 2, 83-2.79 (2H, m), 2.57-2.53 (2H, m), 2.38 (s, 3H) ppm.

MS (APCI) m / z 330 [M + H] +, 328 [MH] + Example 24: 6,7-Dimethyl-2- {[(3slR, 6aS) -5-methyl-5 hexahydropyrrolo [3,4- c] pyrrole-2 (1 H) -yl] carbonyl} -1 H -benzimidazole 10 ch 3 VA.

ch3

A solution of the trichloromethylbenzimidazole of Preparation 9 (100 mg, 0.37 mmol) in a mixture of acetonitrile (3 ml) and water (1 ml) was treated with a solution of (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (95 mg, 0.76 mmol) in a mixture of acetonitrile (0.75 ml) and water (0.25 ml). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5 ml) and saturated aqueous sodium bicarbonate (5 ml). The organic phase was separated and dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 100: 0: 0 changing to 93: 7: 0.7) gave the title compound as a pale brown solid (48 mg).

30 * Η NMR (400 MHz, CD 3 OD): δ 7.43-7.35 (1 H, m), 7.17 (1 H, d), 4.43-4.27 (2 H, m), 3.94 -3.76 (2H, m), 3.15-2.98 (2H, m), 2.86-2.78 (2H, m), 2.56 (3H, s), 2.54-2 , 49 (2 H, m), 2.43 (3 H, s), 2.37 (3 H, s) ppm.

MS (electrospray): m / z 299 [M + H] +, 297 [MH] + Example 25: 6,7-Difluoro-2 - {[(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4 -c] pyrrole-2 (1 H) -yl] carbonyl} -1 H -benzimidazole - 56 - [η] ^ ch3

Prepared from the trichloromethylbenzimidazole of Preparation 10 according to the method of Example 24 with a reaction time of 2 hours to provide the title compound in the form of a pale brown solid.

1 H NMR (400 MHz, CD 3 OD): δ 7.43-7.39 (1 H, m), 7.32-7.25 (1 H, m), 4.45-4.33 (2 H, m), 3.95-3.76 (2 H, m), 3.15-15 2.98 (2 H, m), 2.83-2.76 (2 H, m), 2.58-2.53 (2 H, m), 2.37 (3 H, s) ppm.

MS (electrospray): m / z 307 [M + H] *, 305 [M-H] "

Example 26: 7-Methyl-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimi-20 dazole (Ύνμ ° CH1 x> ch3

Prepared from the trichloromethylbenzimidazole of 30 Preparation 11 according to the method of Example 24 with a reaction time of 2 hours to provide the title compound in the form of a pale brown solid.

X H NMR (400 MHz, CD3 OD): δ 7.45 (1 H, d), 7.20 (1 H, t), 7.09 (1H, d), 4.37-4.24 (2H, m), 3.90-3.71 (2H, m), 3.09-35 2.91 (2H, m), 2 , 79-2.71 (2 H, m), 2.59 (3 H, s), 2.49-2.44 (2 H, m), 2.32 (3 H, s) ppm.

MS (APCI): m / z 285 [M + H] +, 283 [M-H] "* -57-.

Example 27: 5,6-Difluoro-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole 5 WhO

"—N

ch3 10

A solution of the acid of Preparation 31 (700 mg, 3.53 mmol) and (3aR, 6aS) -2-methyl octahydropyrrolo [3,4-c] pyrrole (490 mg, · 3.88 mmol) in N, N -dimethylformamide (35 ml) was treated with O-benzotriazo-1-yl-Ν, Ν, Ν ', N'-tetra-methyluronium hexafluorophosphate (1.60 g, 4.24 mmol) and the resulting solution became 16 stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate in vacuo.

20 NMR (400 MHz, DMSOd 6): δ 13.29 (1H, bs), 7.74-7.58 (2H, m), 4.34-4.29 (1H, m), 4.15- 4.11 (1H, m), 3.83-3.78 (1H, m), 3.55-3.50 (1H, m), 2.95-2.87 (1H, m), 2, 83-2.75 (1H, m), 2.49-2.38 (4H, m), 2.18 (3H, s) ppm.

MS (APCI): m / z 307 [M + H] +, 305 [Μ-ΗΓ Example 28: 5,7-Difluoro-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4 -c] pyrrole-2 (1 H) -yl] carbonyl} -1 H -benzimidazole phyYm ° 30 (3 ch 3 j 35 Prepared from the trichloromethylbenzimidazole of

Preparation 13 according to the method of Example 24 with a reaction time of 2 hours to provide the title t

• I

58 compound in the form of a pale brown solid.

1 H NMR (400 MHz, CD3 OD): δ 7.15-7.12 (1H, m), 6.93-6.88 (1H, m), 4.40-4.29 (2H, m), 3.90-3.71 (2H, m), 3.12-2.94 (2H, m), 2.79-2.72 (2H, m), 2.53-2.49 (2H, m) ), 2.33 (3 H, s) ppm.

MS (APCI): m / z 307 [M + H] +

Example 29: 5-Chloro-7-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole

Qr5

Tfl Γ \

CH3 \ A

"~~ N

15 ch8

Prepared from the trichloromethylbenzimidazole of Preparation 14 by the method of Example 24 with a reaction time of 2 hours to provide the title compound in the form of a pale brown solid.

X H NMR (400 MHz, CD 3 OD): δ 7.44 (1 H, s), 7.10 (1 H, s), 4.39-4.27 (2 H, m), 3.90-3.71 (2 H , m), 3.10-2.94 (2H, m), 2.80-2.73 (2H, m), 2.58 (3H, m), 2.51-2.47 (m, 2H ), 2.33 (3 H, s) ppm.

MS (APCI): m / z 319/321 [M + H] \ 317/319 [M-H] +

Example 30: 7-Chloro-5-methyl-2- {ί (3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole

H3CV ^^ N O

30 YH

ΥΉ / N ~ \ ch3

Prepared from the trichloromethylbenzimidazole of Preparation 15 by the method of Example 24 with a reaction time of 16 hours to provide the title compound in the form of a pale orange solid.

X H NMR (400 MHz, CD 3 OD): δ 7.31 (1 H, s), 7.19 (S, 1 H), 4.42-4.26 (2 H, m), 3.92-3.71 (2 H , m), 3.15-3.03 (2H, m), 5.82-2.72 (2H, m), 2.55-2.44 (2H, m), 2.35 (3H, S) ppm.

MS (APCI): m / z 319/321 [M + H] +, 317/319 [MH] + Example 31: 5-Iodo-2 - {[(3aR, 6aS) -5-methylhexahydro-pyrrolo [3, 4-c] pyrrole-2 (1 H) -yl] carbonyl} -1 H -benzimidazole 10?

Y TH

"—N

CH3

Prepared from the trichloromethylbenzimidazole of Preparation 16 according to the method of Example 24 with a reaction time of 3 hours to provide the title compound in the form of a pale brown solid.

X H NMR (400 MHz, CD3 OD): δ 8.07 (1 H, s), 7.65 (1 H, d), 7.51 (1 H, d), 4.42-4.31 (2 H, m), 3.95-3.76 (2H, m), 3.17-2.98 (2H, m), 2.84-2.77 (2H, m), 2.58-2.54 (2H, m) ), 2.38 (3 H, s) ppm.

MS (APCI): m / z 397 [M + H] +, 395 [M-HJ]

Example 32: Methyl 2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzi-midazole-5-carboxylate N - "CH3

Prepared from the trichloromethylbenzimidazole of

Preparation 17 according to the method of Example 24 with a - 60 - fc (reaction time of 3 hours to provide the title compound in the form of a pale brown solid.

1 H NMR (400 MHz, CD3 OD): δ 8.41 (1 H, s), 8.03 (1 H, d), 7.73 (1 H, d), 4.44-4.34 (2 H, m), 3.97 (3H, s), 3.96-3.77 (2H, m), 3.18-3.00 (2H, m), 2.87-2.80 (2H, m), 2 , 62-2.59 (2H, ra), 2.37 (3H, s) ppm.

MS (APCI): m / z 329 [M + H] \ 327 [M-H]

Example 33: 5-Chloro-6-fluoro-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole

W

15 '' N

CH3

Prepared from the trichloromethylbenzimidazole of j

Preparation 18 according to the method of Example 24 with a reaction time of 1.5 hours to provide the title Binding in the form of a colorless solid.

X H NMR (400 MHz, CD 3 OD): δ 7.76 (1 H, d), 7.48 (1 H, d), 4.38-4.28 (2 H, m), 3.90-3.71. (2H, m), 3.10-2.93 (2H, m), 2.78-2.71 (2H, m), 2.53-2.49 (2H, m), 2.33 (3H , s) ppm.

MS (APCI): m / z 323 [M + H] +, 321 [MH] + Example 34: 5,6-Dimethyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4- c] pyrrole-2 (1 H) -yl] carbonyl} -1 H -benzimidazole CH,

Prepared from the trichloromethylbenzimidazole of Preparation 19 according to the method of Example 24 with a reaction time of 1.5 hours to provide the title compound in the form of a pale yellow solid.

X H NMR (400 MHz, CD 3 OD): 6 7.41 (2 H, s), 4.34-4.21 (2 H, m), 3.88-3.70 (2 H, m), 3.08-2 , 92 (2H, m), 2.79-2.72 (2H, m), 2.49-2.45 (2H, ra), 2.37 (6H, s), 2.32 <3H, s) ppm.

MS (APCI): m / z 297 [M + H] +, 299 [M-H] +

Example 35: 5,6-Dichloro-2 - {[(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole c yynm °

15 '—N

ch3 i

Prepared from the trichloromethylbenziraidazole of Preparation 20 according to the method of Example 24 with a reaction time of 16 hours to provide the title compound in the form of a pale brown solid.

1 H NMR (400 MHZ, CD3OD): δ 7.81 (2H, s), 4.39-4.28 (2H, m), 3.92-3.72 (2H, m), 3.15-2 , 94 (2 H, m), 2.79-2.70 (2 H, m), 2.56-2.48 (2 H, m), 2.35 (3 H, s) ppm.

MS (APCI): m / z 339/341 [M + H] *, 337/339 IM-H]

Example 36: 2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -5- (trifluoromethyl) -1H-benzimidazole CF3 ^ N, 0 3 ° Y, Xv-f NN -, "CH 3

A solution of 2- (trichloromethyl) -5- (trifluoromethyl) -1H-benzimidazole (Preparation 21) (100 mg, 0.33 35 62 - 62 - mmol) in a mixture of acetonitrile and water (3.2 ml , volume ratio 3: 1) was treated with (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (83 mg, 0.66 mmol) and potassium carbonate (0.24 ral of a 4M solution, 0 , 96 mmol).

The resulting mixture was stirred at room temperature for 16 hours. Dichloromethane (30 ml) and water (30 ml) were added and the organic phase was separated and dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (95: 5: 0.5 volume ratio) gave the title compound as a colorless solid (20 mg).

1 H NMR (400 MHz, CD 3 OD): δ 8.00 (1H, s), 7.80 (1H, d), 7.59 (1H, d), 4.42-4.30 (2H, m) , 3.93-3.74 (2 H, m), 3.14-15 2.95 (2 H, m), 2.79-2.72 (2 H, m), 2.55-2.51 (2 H , m), 2.34 (3 H, s) ppm.

MS (APCI): m / z 339 [M + H] \ 337 [M-H] "

Example 37: 2- {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-20 carboxylic acid q j N-v CH3

Methyl 2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-carboxylate 30 (1.6 g, 5 0.1 mmol in a mixture of water (8 ml) and 1,4-dioxane (60 ml) was treated with sodium hydroxide (0.6 g, 15.0 mmol) and the resulting suspension was refluxed for 16 hours. The reaction mixture was cooled to 10 ° C and neutralized with concentrated hydrochloric acid.

The solvent was removed in vacuo and the residue was solubilized in methanol and filtered, and the solvent was removed in vacuo to provide 1. - 63 -! . !

i I

j of the title compound in the form of a colorless solid (1.41 g).

X H NMR (400 MHz, CD 3 OD): δ 8.33 (1 H, bs), 7.98 (1 H, d), 7.64-7.60 (1 H, m), 3.50-3.41 (2 H , m), 3.20-3.12 (4H, 5 m), 2.90-2.88 (2 H, m), 2.68-2.60 (2 H, m), 2.48 (3 H, s) ppm.

MS (APCI): rn / z 315 [M + H] +, 313 [M-H] "

Example 38: 4-Chloro-6-fluoro-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-10 benzimidazole h3

Prepared from the trichloromethylbenzimidazole of Preparation 22 according to the method of Example 24 with a reaction time of 16 hours to provide the title compound in the form of a pale yellow foam.

1 H NMR (400 MHz, CD 3 OD): 6 7.32-7.29 (1 H, dd), 7.24-7.22 (1 H, dd), 4.45-4.33 (2 H, m), 3 , 94-3.75 (2H, m), 3.16-2.99 (2H, m), 2.84-2.77 (2H, m), 2.57-2.54 (2H, m) , 2.37 (3 H, s) ppm.

MS (APCI): m / z 323/325 [M + H] +, 321/323 [M-H] +

Example 39: 4,6-Dichloro-2 - {[(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-ben-zimidazole 30 Cl IVm0 35 CH3

Prepared from the trichloromethylbenzimidazole of i * - 64 -

Preparation 23 according to the method of Example 24 with a reaction time of 16 hours to provide the title compound in the form of a pale yellow foam.

1 H NMR (400 MHz, CD 3 OD): δ 7.60 (1H, s), 7.38 (1H, s), 5.44-4.32 (2H, m), 3.95-3.75 ( 2 H, m), 3.17-2.99 (2 H, m), 2.84-2.77 (2 H, m), 2.58-2.54 (2 H, m), 2.37 (3 H, s) ppm.

MS (APCI): m / z 339/341 [M + H] +, 337/339 [MH] "Example 40: 2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole -2 (1H) -yl] carbonyl} -5-phenyl-1H-benzimidazole after 6

4-N

; CH3

Prepared from the trichloromethylbenzimidazole of Preparation 24 by the method of Example 24 with a reaction time of 16 hours to provide the title compound in the form of a colorless solid.

X H NMR (400 MHz, CD3 OD): δ 7.88 (1 H, s), 7.75 (1 H, d), 7.69-7.67 (2 H, m), 7.63-7.61 (1 H , m), 7.49-7.45 (2H, m), 7.38-7.34 <1H, m), 4.43-4.31 (2H, m), 3.94-3.76 (2H, m), 3.13-2.97 (2H, m), 2.82-2.75 (2H, m), 2.55-2.51 (2H, m), 2.36 ( 3 H, s) ppm.

MS (APCI): m / z 347 [M + H] \ 345 [M-H] "

Example 41: 5-Fluoro-4-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-30 benzimidazole CH3 "6η," 6

N

ch3 • * - 65 -

Prepared from the trichloromethylbenzimidazole of Preparation 25 according to the method of Example 24 with a reaction time of 16 hours to provide the title compound in the form of a yellow foam.

5 1 H NMR (400 MHz, CD 3 OD): δ 7.49-7.46 (1 H, m), 7.13-7.08 (1 H, m), 4.43-4.31 (2 H, m), 3.95-3.76 (2H, m), 3.15-2.98 (2H, m), 2.85-2.77 (2H, m), 2.53 (3H, s), 2, 37 (3 H, s) ppm.

MS (APCI): m / z 303 [M + H] +, 301 [MH] ”Example 42: 5-Chloro-2 - {[(3aR, 6aS) -5-ethylhexa-hydropyrrolo [3,4-c ] pyrrole-2 (1 H) -yl] carbonyl} -1 H-indole

N

^ CHg 20 A solution of the compound of Example 8 (170 mg, 0.58 mmol) in dichloromethane (5 ml) was treated with acetaldehyde (66 µl, 1.18 mmol), acetic acid (33 µL, 0.58 mmol) ) and sodium triacetoxyborohydride (147 mg, 70 mmol) and the resulting mixture was stirred at room temperature for 16 hours. Further, dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml) were added and the organic phase was separated. The aqueous phase was extracted with further dichloromethane (20 ml) and the combined organic layers were dried (sodium sulfate) and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 99: 1: 0.1 changing to 90: 10: 1) to give the title compound in the form of a pale yellow solid (60 mg).

1 H NMR (400 MHz, CD 3 OD; δ 7.67 (1 H, S), 7.46 (1 H, d), _______! * ♦.

66 - 7.23 (1H, dd), 6.97 (1H, d), 4.19-3.74 (4H, bm), 3.19-2.97 (2H, m), 2.92 -2.85 (2H, m), 2.58-2.51 (4H, m), 1.16 (3H, t) ppra.

MS (APCI): m / z 318/320 [M + H] +, 316/318 [MH] + Example 43: 5-Chloro-2 - {[(3aR, 6aS) -5-isopropylhexahydropyrrolo [3 4-c] pyrrole-2 (1 H) -yl] carbonyl} -1 H-indole

"Oh" H

* —N

) -CH,

i HaC

Prepared according to the method of Example 42 using the compound of Example 8 and acetone to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, DMSOd 6): δ 11.75 (1 H, S), 7.69 (1 H, j 20 S), 7.46 (1 H, dd), 7.21 (1 H, dd), 6, 93 (1H, dd), 4.16-4.01 (1H, m), 3.94-3.84 (1H, m), 3.73-3.64 (1H, m), 3.59- 3.50 (1H, m), 2.98-2.77 (2H, m), 2.63-2.53 (4H, m), 2.34 (1H, m), 1.02 (6H) , d) ppm.

MS (APCI): m / z 332/334 [M + H] + 330/332 [MH] + Example 44: 5-Chloro-2 - {[(3aR, 6aS) -5-ethylhexa-hydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzi-midazole ΎΧμ °

N-i '-N

Prepared according to the method of Example 42 using the compound of Example 6 and acetaldehyde to provide the title compound in the form of a 4 to 67 colorless solid.

X H NMR (400 MHz, CD 3 OD): δ 7.70-7.68 (1 H, m), 7.66 (1 H, s), 7.30 (1 H, d), 4.42-4.33 {2 H (ra), 3.93-3.79 (2H, ra), 3.13-2.90 (4H, m), 2.61-2.53 (4H, m), 1.17 (3H, t ) 5 ppm.

MS (APCI): m / z 319/321 [M + H] +, 317/319 [M-H] "

Example 45: 5-Chloro-2 - {[(3aR, 6aS) -5-isopropyl-hexahydropyrrolo [3,4-c] pyrrole -2 (1H) -yl] carbonyl - 1H-benzimidazole

"OK

"$>

1 N

15 \ Λ> -ch3 h3c

Prepared according to the method of Example 42 using the compound of Example 6 and acetone to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CD3 OD): δ 7.70-7.67 (2H, m), 7.36-7.34 (1H, ra), 4.43-4.31 (2H, ra), 3.92-3.80 (2 H, m), 3.13-2.98 (4 H, m), 2.56-2.46 (3 H, m), 1.17 (6 H, d) ppm.

MS (APCI): tl / z 333/335 [M + H] +, 331/333 [M-H] +

Example 46: 2- [(3aR, 6aS) -5 - [(5-Chloro-1H-benzimidazol-2-yl) carbonyl) hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] ethanol

CisvV'N .O

30 N - λ

"—N

^ \) H

Prepared according to the method of Example 42 using the compound of Example 6 and 1,4-dioxane-2,5-diol-2,5-diol to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHZ, CD 3 OD): δ 7.70-7.65 (2 H, m), 7.36-7.33 (1 H, m), 4.38-4.36 (2 H, m), 3 , 94-3.78 (2 H, m), 3.70 (2 H, t), 3.13-2.92 (4 H, m), 2.73-2.65 (4 H, m) ppm.

MS (APCI): m / z 335/337 [M + H] +, 333/335 [M-H] +

Example 47: 7-Fluoro-5-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole F

CCVf Y> 1-Ni 15 ch3

A solution of aniline from Preparation 28 (79 mg, 0.56 mmol) in acetic acid (3 mL) was treated with methyl 2,2,2-trichloroacetimidate (77 µl, 0.62 mmol) and the resulting solution was stirred at room temperature for 16 hours. Water (10 ml) was added and the reaction was stirred for an additional hour. The precipitate was filtered off and dried under vacuum. The resulting solid was suspended in a mixture of acetonitrile and water (volume ratio 3: 1, 4 ml) and treated with a solution of (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (148 mg, 1.17 mmol) in a mixture of acetonitrile (0.75 ml) and water (0.25 ml). After 3 hours the solvent was removed in vacuo and the residue was dissolved in dichloromethane (15 ml), washed with saturated sodium bicarbonate (2 x 15 ml), dried (sodium sulfate) and evaporated in vacuo. Purification by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 99: 1: 0.1 changing to 93: 7: 0.7) gave the title compound in the form of a colorless solid (133 mg).

X H NMR (400 MHz, CD 3 OD); Δ 7.19 (1H, s), 6.87-6.84 - 69 - (1H, d), 4.39-4.27 (2H, m), 3.90-3.84 (1H, m) ), 3.75-3.71 (1 H, m), 3.09-2.95 (2 H, m), 2.79-2, 72 (2 H, m), 2.51-2.40 (2 H , m), 2.46 (3 H, s), 2.33 (3 H, s) ppm.

MS (APCI): m / z 303 [M + H] +, 301 [MH] + Example 48: 5-Chloro-4-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3 , 4-c] pyrrole-2 (1 H) -yl] carbonyl} -1 H-benzimidazole 9 H 3.

CH3 Prepared from the diamine of Preparation 29 using the method of Example 47 to provide the title compound in the form of a colorless solid.

X H NMR (400 MHz, CD 3 OD): δ 7.43 (1H, d), 7.30 (1H, d), 4.40-4.29 (2H, m), 3.90-3.85 ( 1 H, m), 3.76-3.72 (1 H, m), 3.08-2.95 (2 H, m), 2.80-2.73 (2 H, m), 2.62 (3 H, s), 2.51-2.47 (2 H, m), 2.33 (3 H, s) ppm.

MS (APCI): m / z 319 [M + H] +, 317 [M-H] +

Example 49: 4-Fluoro-2 - {[(3aR, 6aS) -5-methylhexahyl] -pyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole P

1-ch3

Prepared from 3-fluorobenzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a colorless solid.

> --- - 70 - * Η NMR (400 MHz, CD3 OD): δ 7.41 (1Η, d), 7.31-7.26 (1H, m), 7.03-6.98 (1H, m ), 4.40-4.28 (2 H, m), 3.91-3.85 (1 H, m), 3.77-3.73 (1 H, m), 3.11-2.95 (2 H , m), 2.80-2.73 (m, 2H), 2.52-2.49 (tn, 2H), 2.33 (3H, s) ppm.

5 MS (APCI): m / z 289 [M + H] +, 287 [M-H] "

Example 50: 4,6-Dimethyl-2 - {[(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole YH3

10 nrM

^ CH3 15

Prepared from 3,5-dimethylbenzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a pale yellow solid. | 20 H NMR (400 MHz, CD3 OD): δ 7.22 (1 H, s), 6.94 (1 H, s), 4.37-4.24 (2 H, m), 3.89-3.84 ( 1 H, m), 3.76-3.71 (1 H, m), 3.09-2.92 (2 H, m), 2.81-2.73 (2 H, m), 2.55 (3 H, s), 2.49-2.44 (2H, m), 2.42 (3H, s), 2.33 (3H, s) ppm.

MS (APCI): m / z 299 [M + H] +, 297 [M-H] "Example 51: 4,5,6,7-Tetrafluoro-2 - {[(3aR, 6aS) -5-

methylhexahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl] carbonyl} -ΙΗ-benzimidazole P

Prepared from 3,4,5,6-tetrafluorobenzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a - 71 - colorless solid.

NMR (400 MHz, DMSOd 6): δ 4.22-4.17 (1H, m), 4.05-4.01 (1H, m), 3.79-3.74 (1H, m), 3, 58-3.54 (1H, m), 2.93-2.83 (2H, m), 2.64-2.53 (4H, m), 2.28 (3H, s) ppm.

MS (APCI): m / z 343 [M + H] \ 341 [M-H] +

Example 52: 6-Fluoro-2 - {[(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -4- (trifluoromethyl) -1H benzimidazole I 10 Fa

^ —N

I 1 C \ 15 ch3

Prepared from 5-fluoro-3- (trifluoromethyl) benzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a colorless solid.

1 H NMR (400 MHz, CD 3 OD): δ 7.57 (1 H, d), 7.42 (1 H, d), 4.39-4.33 (2 H, m), 3.91-3.72 (2 H , tn), 3.10-2.97 (2 H, ra), 2.80-2.73 (2 H, m), 2.54-2.50 (2 H, m), 2.34 (3 H, s ppm.

MS (APCI): m / z 357 [M + H] + 355 [MH] * Example 53: 6-Fluoro-4-iodo-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3, 4-c3 pyrrole-2 (1 H) yl] carbonyl} -1 H -benzimidazole ch3 Prepared from 5-fluoro-3-iodobenzene-1,2-diamine below. using the method of Example 47 to provide the title compound in the form of a yellow solid m - 72 substance.

* H NMR (400 MHz, CD 3 OD): δ 7.53 (1H, d), 7.31-7.28 (1H, m), 4.44-4.35 (2H, m), 3.90- 3.85 (1H, m), 3.76-3.71 (1H, m), 3.12-2.96 (2H, tn), 2.80-2.74 (2H, m), 2, 54-2.50 δ (2H, m), 2.34 (3H, s) ppm.

MS (APCI): m / z 415 [M + H] +, 413 [M-H] +

Example 54: 6-Chloro-4-fluoro-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl} carbonyl} -1H-benzimidazole 10 1 is -K, CH,

Prepared from 5-chloro-3-fluorobenzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a yellow solid.

X H NMR (400 MHz, CD 3 OD): δ 7.76 (1 H, d), 7.50-7.48 (1 H, m), 4.38-4.28 (2 H, m), 3.90-3 , 83 (1H, m), 3.75-3.71 (1H, m), 3.12-2.96 (2H, m), 2.78-2.71 (2H, m), 2.52 -2.49 (2 H, m), 2.33 <3 H, s) ppm.

MS (APCI): m / z 323 [M + H) +, 321 [M-H] +

Example 55: 6-Chloro-5-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole »K · 1— CH3 i 35!

Prepared from 4-chloro-5-methylbenzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a colorless solid.

X H NMR (400 MHz, CD 3 OD): δ 7.67 (1 H, s), 7.55 (1 H, s), 4.37-4.25 (2 H, m), 3.90-3.84 (1 H , m), 3.75-3.71 (1H, m), 3.09-2.95 (2H, m), 2.79-2.72 (2H, m), 2.51-2, 49 (2 H, m), 2.47 (3 H, s), 2.33 (3 H, s) ppm.

MS (APCI): m / z 319 [M + H] \ 317 [M-H] +

Example 56: 2 - {[(3aR, 6aS) -5-Methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-car-10 bonitrile

TXM

CH3

Prepared from 3,4-diaminobenzonitrile using the method of Example 47 to provide the title compound in the form of a pale brown solid. 1 H NMR (400 MHz, CD3 OD): δ 8.09 (1H, s), 7.78-7.76 (1H, d), 7.62-7.59 (1H, d), 4.40-4 29 (2H, m), 3.92-3.86 (1H, m), 3.77-3.73 (1H, m), 3.13-2.94 (2H, m), 2.79 -2.72 (2H, m), 2.55-2.51 (2H, m), 2.34 (3H, s) ppm.

MS (APCI): m / z 296 [M + H] +, 294 [M-H] "

Example 57: 6-Fluoro-2 - {[(3aR, 6aS) -5-methylhexahydroprrolo [3,4-c] pyrrole-2 (1H) -yl] carbonyl} -5- (trifluoromethyl) -1H benzimidazole

FsCXXNy ^ CH3 35 3

Prepared from 4-fluoro-5- (trifluoromethyl) benzene-1,2-di-74-atnine using the method of Example 47 to provide the title compound in the form of a colorless solid.

* Η NMR (400 MHz, CD 3 OD): δ 8.01-8.00 (1H, d), 7.54-5 7.51 (1H, d), 4.41-4.30 (2H, m) , 3.92-3.86 (1 H, m), 3.77-3.72 (1 H, m), 3.10-2.96 (2 H, m), 2.79-2.72 (2 H, m), 2.55-2.51 (2H, m), 2.34 (3H, s) ppm.

MS (APCI): m / z 357 [M + H] +, 355 [M-H] +

Example 58: 4,5,6-Trifluoro-2 - {[(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) carbonyl} -1H-ben- i zimidazole 'Am n-

SS

ch3

Prepared from 3,4,5-trifluorobenzene-1,2-diamine using the method of Example 47 to provide the title compound in the form of a colorless solid.

* Η NMR (400 MHz, CD 3 OD): δ 7.33-7.30 (1H, m), 4.40-3.30 (2H, m), 3.90-3.71 (2H, m), 3.11-2.95 (2 H, m), 2.79-25 2.73 (2 H, m), 2.55-2.50 (2 H, m), 2.34 (3 H, s) ppm.

MS (APCI): m / z 325 [M + H] *, 323 [M-H] +

Example 59: 1- (5,6-Difluoro-1H-benzimidazole-2-y) -1 - [(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] methanimine

Xo-c

"SS

1-N

35 'CH3

A suspension of the trichloromethylbenzimidazole 4 - 75 - of Preparation 12 (1.17 g, 4.3 mmol) and 4A molecular sieve (1g) in acetonitrile (15 ml) was treated with a solution of (3aR, 6aS) - 2-Methyl octahydropyrrolo [3,4-c] pyrrole (598 mg, 4.74 ml) in acetonitrile (2 ml). The resulting mixture was stirred at room temperature for 30 minutes prior to the addition of ammonium acetate (397 mg, 5.16 mmol). The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium hydrogen carbonate (20 ml) was added and the mixture was extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried (sodium sulfate) and reduced in vacuo. Purification by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (changing the volume ratio 98: 2: 0.2 to 90: 10: 1) gave the title compound as a pale brown solid ( 155 mg).

1 H NMR (400 MHz, CD3 OD): δ 7.37 (2H, t), 4.26-4.10 (2H, bm), 3.96-3.78 (2H, m), 3.13-3 .06 (2H, m), 2.68-2.59 (4H, m), 2.34 (3H, s) ppm.

20 MS (APCI): m / z 306 [M + H] +, 304 [M-H] "

Alternative method for Example 59: 1- (5,6-Difluoro-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4-c] pyrrole-2 (1H ) -yl] methane imine

A solution of the nitrile of Preparation 33 (8.66 g, 48.3 mmol) and (3aR, 6aS) -2-methyl-octahydropyrrolo [3,4-cpypyrrole (7.32 g, 58.0 mmol) in isopropanol ( 100 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to cool gradually to room temperature and the resulting precipitate was filtered off, washed with further isopropanol (20 ml) and dried in vacuo to give the title compound as a colorless crystalline solid (13). 57 g).

Example 60: 1- (5-Fluoro-1H-benzimidazol-2-yl) -1-35 [(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] methanimine 4 .

- 76 -

FYYV / H

* - ch3

Prepared from the trichloromethylbenzimidazole of Preparation 32 using the method of Example 10 to provide the title compound in the form of a pale yellow solid.

X H NMR (400 MHz, CD 3 OD): δ 7.58-7.54 (1H, dd), 7.25-7.22 (1H, dd), 6.93-6.88 (1H, m), 4 , 15 (2H, bs), 3.85 (2H, bs), 3.14-3.07 (2H, m), 2.70-2.59 (4H, m), 2.35 (3H, 8) ) 15 ppm.

MS (APCI): m / z 288 [M + H] +, 286 [MH] +, 6-Bromo-4-methyl-2 - {[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -yl] carbonyl} -1H-benzimidazole and 6-fluoro-4-methyl-2- {[(3aR, 6aS) -5-methylhexahydropyrrolo-20 [3,4-c] pyrrole-2 (1 H) -yl] carbonyl} -1 H-benzimidazole have also been prepared using identical or similar methods.

Examples 61-64 were prepared from the trichloromethylbenzimidazole precursors indicated in the table below according to the following procedure: A solution of the trichloromethylbenzimidazole (0.75 mmol) in ethanol (3 ml) was cooled to 0 ° C and treated with a solution of 880 ammonia (3 ml) in water (3 ml). The resulting mixture was then allowed to gradually warm to room temperature. After 2 hours the pH became

adjusted to pH 1 by adding 2N hydrochloric acid. The reaction mixture was extracted with dichloromethane (2 x 20 ml) and the combined extracts were evaporated in vacuo. The resulting solid was dissolved in methanol (3 mL) and treated with N-acetyl cysteine (1 mmol) and (3aR, 6aS) -2-methyl octahydropyrrolo [3,4-c] pyrrole (0.8 mmol) ) and heated to 40 ° C for 2.5 hours. The reaction mixture 4 - 77 - was cooled to room temperature and purified on a strong cation exchange resin, eluting non-basic impurities with methanol and basic products with 2 M ammonia in methanol. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol / 880 ammonia (volume ratio 95: 5: 0.5 changing to 90: 10: 1) to provide the desired compounds .

10

Ex. Structure Precursor MS data 1 HNMR (400 MHz, ___ | (APCI) _ICDjOD) _ 61 1- (4,5-Difluoro-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5-methyl- hexahydropyrrolo [3,4-c] pyrrole-2 (1 H) -ylmethane imine

Preparation m / z δ 7.33-7.30 (1 H, m), c 1 10 306 [M + H] δ 6.97-6.90 (1 H, m). MH] 4.27-4.05 (2H, bm), T1 / T1 3.95-3.77 (2H, bm), 3.14-3.04 (2H, bm),

CH

3 2.70-2.57 (4H, m), 2.32 (3H, s) ppm.

62 1- (4-Methyl-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5-methylhexa-hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] methanimine

Preparation m / z 57.44 (1H, d), 7.10-11284 [M + H] +, 7.04 (1H, m), 6.99 nh 282 [MH] "6.95 (1H, m), 4.01 3.96, 12H, m), '3', 1 'CH3, A 3.68 (2H, m), 3.08 - 3.06 (2H, m), 2.73 -

CH

7.68 (2H, m), 2.61-2.57 (5H, m), 2.35 (3H, s) ppm.- 78 - 63 1- (4,6-Difluoro) 1H-benzimidazol-2-yl) -1- [(3aR, 6aS) -5-methyl-hexahydropyrrolo [3,4-c] pyrrole-2 (1H -yl-methanimine)

Preparation m / z 5 7.14-7.11 (1H, m), 13 288 [M + H], 6.73-6.67 (1H, m), TH. 286 [MH], 4.38-3.70 (4H, m), 3.19-3.10 (2H, bra), ch3 2.73-2.63 (4H, m), ____ 2.38 (3H s) ppm. 64 1- (6-Fluoro-7-methyl-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole- 2 (1 H) -yl] methane imine

Preparation m / z δ 7.40-7.37 (1H, m), 25 302 [M + H] *, 6.90-6.85 (1H, m), (PY'VVH 300 4/16-4 , 08 (2H, m), 3.85-3.75 (2H, ra), CH * V) 3.12-3.06 (2H, m), V 2.71-2.67 (2H, ra) ), 2.60-2.56 (2 H, m), 2.48 (3 H, s), 2.34 ____ (3 H, s) ppm.

Examples 65-68 were prepared from the bis-aniline precursors indicated in the table below according to the following procedure: A solution of the aniline precursor (79 mg, 0.50 mmol) in acetic acid (3 ml) was treated with | methyl 2,2,2-trichloroacetimidate (0.55 mmol) and the resulting solution was stirred at room temperature for 16 hours. Water (ml ml) was added and the reaction was stirred for another hour. The trichloromethyl benzimidazole intermediate was filtered and dried under vacuum prior to processing as described for Examples 61-64 to provide the desired compounds.

, * - 79 -

Ex. Structure precursor - data 1 H NMR (400 MHz, ____ | (APCI) - CD3OD) - 65 1- (6-Chloro-7-methyl-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5- methyl hexahydropyrrolo [3,4-c) pyrrole-2 (1 H) -yl] methanimine

Preparation tn / z 5 4.21-4.08 (1H, d), | ΡγΥ_ ^ ΝΗ 29 318/320 7.08 (1H, d), 4.21- α>] Η [* ~ \ [M + H] *, 4.08 (2H, m), 3.89- 316/318 3.78 (2H, m), 3.12-CH '[MH] *. 3.06 (2H, m), 2.71-2.58 (7H, m), 2.35 ____ (3H, a) ppm. 66 1- (7-Fluoro-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5-methylhexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -yl] methanimine m / z δ 7.45 (1H, d), 7.10-306 [M + H] *, 7.04 ≤ 1 H, m)., 6.84-γ-≤ M 304 [»->), S.'3« H, rn), 4.31-pn CX (2H, m, , Y) F 3.83 (2H, m), 3.20 - η, 3.1K2H, m), 2.75 - 2.63 (4H, m), 2.39 _____ (3H, 3) ppm, 67 1 - [(3aR, 6aS) -5-Methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl] -1- (4,5,6-trifluoro-1H-benzimidazol-2-yl) ) methane imine // NH tn / z δ 7.24-7.20 (1H, m), F '^ STf} Ρ-Λ 324 [M + H] *, 4.47-3.44 (4H, m) , Y> 322 W-HJ "3.16-3.04 (2H, m), ^ CHS F 2.69-2.60 (4H, m), ______________ 2.34 (3H, s) ppm.68 - {5-Chloro-1H-benzimidazol-2-yl) -1 - [(3aR, 6aS) -5-methylhexahydro-pyrrolo [3,4-c] pyrrole-2 (1H) -yl] methanimine-m / z δ 7.57 (1H, d), 7.54 304/306 (1H, s), 7.08 (1H, ^ 0 \ "tr [M + HI +"). 4.16 (2H, bra), 302/304 3.86 (2H, m), 3.11 013 [MH] '(2H, m), 2.62 (4H, ______L___J__tn), 2.35 (3H, s) ppm.

♦ j - 80 - φ

BIOLOGY SECTION

H4 binding

Cell pellets from CHO cells expressing the histamine H4 receptor were homogenized in ice-cold 50 mM Tris-HCl / 0.5 mM CaCl2 buffer containing a protease inhibitor cocktail (Roche®, UK) using a ground glass homogenizer. Homogenates were centrifuged for 30 minutes at 48,000 g at 4 ° C. The membrane pellet was resuspended in fresh buffer and the centrifugation step was repeated as described above. The membrane pellet was resuspended in 50 mM Tris-HCl in the same volume as the original cell pellet. Amounts of membrane preparation were stored at -80 ° C and were used for [3 H] Histamine binding experiments.

Cell membranes (20-35 / xg / well) were incubated 90 min with shaking at room temperature with 3nM [3 H] -Histamine (23 Ci / mmol) in 50 mM Tris-HCl (pH 7.4), with or without competing H4- ligands. The reaction was terminated by rapid filtration through 0.5% polyethyleneimine-soaked Unifilter GF / B plates (Packard) followed by three washes with 1 ml of ice-cold 50 mM Tris-HCl. The filters were dried at 45 ° C for 45 minutes and bound radioactive marking was determined using scintillation counting techniques. Non-specific binding was defined with 5 μΜ clobenpropit. For competitive binding studies, Ki values were calculated from the IC50 value based on an experimentally determined ligand Ka of 3.5 nM and a ligand concentration of 3 nM according to the Cheng-Prussoff equation 30 where K ± - (IC 50) / (1 + ([L] / Kd))

The compounds of the Examples have been tested in the H4 binding assay described above and found to have a K * value of less than 13 μΜ in the H * cell-based binding assay. Preferred examples have a Kj-35 value of less than 1 μΜ in the H4 binding assay. The most preferred examples have a Ki value of less than 120 nM in the H4 cell-based binding assay as given in the table below:

Example N ° K ± (nM) _ Example N ° K ± (nM) _ 1_91_48_91_ 3 _82_58__100 _ 7_16_59_7_ 15 _28_60 _6_, 16 _20_61_24_ 17 _84_62_7_ 21 _43 63_47_ 22 _20__64_4_ 25 _67_65_12_ 26_67_10_6_10_6_10_6_10_6_6_10_6_6_10_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_6_10

Claims (10)

A compound of formula (I): 5 f nrv α 10 N R 1 or pharmaceutically acceptable salts and solvates thereof, wherein: 15. R 1 is H or (C 1 -C 4) alkyl optionally substituted with a hydroxy; X is N or C-R9, wherein R9 is H or methyl; Y is O or NH; R 6 is H or methyl; and 20. R 2, R 3, R 4, and R 5 are independently selected from H, halogen, cyano, (C 1 -C 4 alkyl, (C 1 -C 4) alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, (CH 2) 0 -C (O) 0 - R 7, (CH 2) n-O- (CH 2) r 0 -R 8 and (CH 2) n-R 8, wherein n and m are both independently 0 or 1, R 7 is H or (C 1 -C 4) alkyl and R 8 is phenyl. A compound of formula (I) or salts and solvates thereof according to claim 1 wherein R 1 is H or methyl. A compound of formula (I) or salts and solvates thereof according to claims 1 or 2 wherein R 6 is H. A compound of formula (I) or salts and solvates thereof according to any of claims 1 to 3 wherein X is N or CH. R 2 / cl TT y-fa (VI) β'Ύ'ί, c 1 R 5 R 10 with an ammonia source and an amine of formula (III) wherein R 1, R 2, R 3, R 4, R 5 and R 6 are as defined in one of claims 1 to 10; or 3. when Y is NH and X is N: reacting an amine of formula (III) with a nitrile of formula (VIII) R2 2 ° Try = N w * 1 'Fis r' wherein R1, R2, R3 , R4, R5 and Re are as defined in any one of claims 1 to 10; 4. when Y is NH and X is CR 9: condensing a thioamide of formula (VIII): R 2 R 9 3 // s nrv α R1 with ammonia or an ammonia equivalent in which R1, R2, R3, 4. - 86 - R4, R5 and R6 are as defined in any one of claims 1 to 10. 16. Combination of a compound of formula (I) as defined in any one of claims 1 to 10 and another pharmacologically active agent selected from: • Histamine Hi-receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine • Histamine H3 receptor antagonists • Histamine H2 receptor antagonists 10. Leukotriene antagonists, including antagonists of LTB4, LTC4, LTD4 and LTE4 / in particular Montelukast • Phosphodiesterase inhibitors, namely PDE4 inhibitors and PDE5 inhibitors • neurotransmitter reuptake inhibitors, in particular fluoxetine, setraline, paroxetine , ziprasidone • 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxy-genase-activating protein (FLAP) antagonists, αχ- and α2-adrenoceptor-agonist-vasoconstrictor-sym-pathomimetic agents for use as decongestant, • Muscarinic M3 receptor antagonists or anticholinergic agents, • S2 adrenoceptor agonists, • Theophylline, 25. Sodium cromoglycate, • COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors, • Oral or inhaled glucocorticosteroids, • Monoclonal antibodies active against endogenous inflammatory entities, • Anti-tumor necrosis factor (anti-TNF-a-) ) agents, • Adhesion molecule inhibitors comprising VLA-4 antagonists, • Kinine B1 and B2 receptor antagonists, 35. Immunosuppressants, • Inhibitors of matrix metalloproteases (MMPs), • Tachykinin NKX, NK2 and NK3 receptor antagonists, - 87 - »** *. • Elastase inhibitors, • Adenosine A2a receptor agonists, • Inhibitors of urokinase, • Compounds that act on dopamine receptors, for example D2 agonists, • Modulators of the NFidD pathway, for example IKK inhibitors, • Agents that can are classified as tmico-lytica or anti-cough agents, A compound of formula (I) or salts and solvates thereof according to any of claims 1 to 4 wherein R 2, R 3, R 4 and R 5 are independently selected from H, halogen, methyl, hydroxy, phenyl and COOH. A compound of formula (I) or salts and solvates thereof according to claim 5, wherein R 2, R 3, R 4 and R 5 are independently selected from H, fluorine, chlorine, bromine, methyl, hydroxy, phenyl and COOH. A compound of formula (I) or salts and solvates thereof according to any one of claims 1 to 6 wherein at least two of R 2, R 3, R 4 and R 5 are H. A compound of formula (I) or salts and solvates thereof according to any of claims 1 to 7 which has the cis configuration (3aR, 6aS). A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 8, together with a pharmaceutically acceptable excipient. A compound of formula (I) as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof, for use in the form of a medicament. 11. Use of a compound of formula (I) as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of a disease for which an H 4 ligand is indicated. 12. Use of a compound of formula (I) according to claim 11, for the preparation of a medicament for the treatment of a disease selected from inflammatory diseases, respiratory diseases (e.g. respiratory distress syndrome in adults, acute respiratory distress syndrome, bronchitis, chronic bronchitis , chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis), allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic obstruction, sexual dysfunction in women and men, skin diseases such as dermatitis and psoriasis, cardiac dysfunctions such as myocardial ischemia and arrhythmia, diseases of the gastrointestinal tract such as bowel disease, Crohn's disease and ulcerative colitis, cancer, rheumatoid arthritis, hypotension , pain and over-ative bladder conditions. A method for the treatment of a mammal comprising a human suffering from a disease for which an H4 ligand is indicated, comprising administering to said mammal an effective amount of a compound of the formula (I) as defined in one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate or preparation thereof. The method of claim 13 wherein the disease is selected from that of claim 12. A process for obtaining a compound of formula (I) and salts or solvates thereof as described in any one of claims 1 to 8, which comprises the following steps: 1. when Y is 0: coupling an acid of formula ( II): R 2 T 1 H (ii> OH R 5 R 25 with an amine of formula (III): H H - N, R 1 wherein R 1, R 2, R 3, R 4, R 5, R 6 and X are as defined in any one of claims 1 to 10 / or 4 · - 85 - ί 2. when Υ ΝΗ is xs and X Ν: condensing a trichloromethylbenzimidazole of formula (VI): 10. Antibiotics, • Modulators of cytokine signaling pathways such as p38 MAP kinase inhibitors, syk tyrosine kinase inhibitors or JAK kinase inhibitors • Prostaglandin D2 receptor antagonists (DPI and CRTH2) • Inhibition of Prostaglandin -D synthase (PGDS) • Inhibitors of phospho-inositide-3-kinase and • HDAC inhibitors. 1030503