JP2008520644A - Octahydropyrrolo [3,4-c] pyrrole derivative - Google Patents

Abstract

並びにそれらの製造方法、それらを含有する組成物及びそれらの使用に関する。The present invention provides an octahydropyrrolo [3,4-c] pyrrole derivative of formula (I):

And a method for producing them, a composition containing them, and their use.

Description

Detailed Description of the Invention

The present invention relates to octahydropyrrolo [3,4-c] pyrrole derivatives, as well as methods for producing these derivatives, compositions containing these derivatives, and the use of these derivatives.
The octahydropyrrolo [3,4-c] pyrrole derivatives of the present invention are histamine H ₄ receptor ligands and thus have numerous therapeutic uses, particularly in the treatment of asthma and allergic rhinitis.

Histamine H ₄ receptor has 390 amino is a 7-transmembrane G protein-coupled receptor comprising an amino acid homology of approximately 40% for the histamine H ₃ receptor. In contrast to H ₃ receptors, which are mainly present in the brain, H ₄ receptors are more highly expressed in inflammatory cells, especially eosinophils and mast cells. H ₄ receptor ligands should therefore be suitable for the treatment of various inflammatory disorders. Examples of diseases treated by H ₄ ligands are particularly suitable are inflammatory bowel disease, Crohn's disease, ulcerative colitis, dermatitis, psoriasis, conjunctivitis, rheumatoid arthritis, respiratory disease, for example, adult respiratory distress syndrome, acute Respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic ethmoid sinusitis, allergy, allergic inductive airway response, allergic rhinitis, viral rhinitis, Non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic hyperemia.

Recently, several histamine H ₄ receptor ligands have been developed. A review of the latest advances in H ₄ ligand research and patent status is given in Expert Opin. Ther. Patents (2003) 13 (6). Examples of histamine H ₄ receptor ligands can be found in WO 02/07548, WO 04/022537 and Terzioglu et al., J. Bioorg. Med. Chem. Lett. 14 (2004) , 5251-5256.

Although multiple H ₄ ligands are known, there is still a need to provide new H ₄ ligands that are good drug candidates. In particular, preferred compounds should show little affinity for other receptors while strongly bonded to the histamine H ₄ receptor. They should be well absorbed from the gastrointestinal tract, be metabolically stable and have favorable pharmacokinetic properties. They should be non-toxic and show few side effects.

  Accordingly, the present invention provides an octahydropyrrolo [3,4-c] pyrrole derivative of formula (I):

Or for pharmaceutically acceptable salts and solvates thereof, where:
R ¹ is H or (C ₁ -C ₄ ) alkyl optionally substituted with hydroxy;
X is N or CR ⁹ (where R ⁹ is H or methyl);
Y is O or NH;
R ⁶ is H or methyl; andR ² , R ³ , R ⁴ and R ⁵ are independently H, halo, cyano, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, (CH ₂ ) _n -C (O) OR ⁷ , (CH ₂ ) _n -O- (CH ₂ ) _m -R ⁸ and (CH ₂ ) _n -R is selected from ^8, this time n and m are 0 or 1 each independently, R ⁷ is H or (C ₁ -C ₄₎ alkyl, and R ⁸ is phenyl.

These compounds have proven to be a ligand of the histamine H ₄ receptor.
In the above formula, “halo” means a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, in particular fluoro or chloro.

(C ₁ -C ₄ ) alkyl radical means a straight chain or branched group containing 1, 2, 3 or 4 carbon atoms. This is also true if they have substituents such as hydroxy substituents or appear as substituents in other radicals such as (C ₁ -C ₄ ) alkoxy radicals. Suitable examples of (C ₁ -C ₄ ) alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl. Suitable examples of (C ₁ -C ₄ ) alkoxy radicals are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, s-butyloxy and t-butyloxy. Suitable examples of (C ₁ -C ₄ ) alkyl radicals substituted by hydroxy radicals are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, etc. is there.

The compounds of general formula (I) according to the invention can be prepared using conventional procedures, for example as described below (where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and Y is as defined above unless otherwise stated).

  A compound of formula (I) wherein Y is O is an acid of formula (II):

An amine of formula (III):

(At this time, 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 done with a conventional coupling agent (eg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, O -Benzotriazo-1-yl-N, N, N ^, N ^, -tetramethyluronium hexafluorophosphate or N, N ^, -dicyclohexylcarbodiimide) and optionally a catalyst (eg 1-hydroxybenzotriazole hydrate or 1- Hydroxy-7-azabenzotriazole) and optionally in the presence of a tertiary amine base such as N-methylmorpholine, triethylamine or N, N-diisopropylethylamine. The reaction can be carried out in a suitable solvent (eg pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate) and at a temperature between 10 ° C. and 40 ° C. (room temperature). Preferably, the coupling uses an excess of amine (1.2-1.5 equivalents) and O-benzotriazo-1-yl-N, N, N ^, N ^, -tetramethyluronium hexafluorophosphate as the coupling agent Implemented. Also preferably, this reaction is carried out using N, N-dimethylformamide as a solvent.

Amines of formula (III) can be prepared as described in the literature ( J. Heterocyclic. Chem 1983, 20, 321).
Acids of formula (II) in which X is CR ⁹ (where R ⁹ is as previously defined) are commercially available or prepared by well known methods described in the literature. obtain.

  The acid of formula (II) where X is N is an alcohol of formula (IV):

(At this time, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above).
The oxidation is generally carried out using a conventional oxidant (eg potassium permanganate), optionally in the presence of a base (eg NaOH), in a suitable solvent (eg water) between 40 ° C. and 100 ° C. Performed at a temperature between 0C. Preferably, this oxidation is carried out using potassium permanganate in the presence of sodium hydroxide using water as the solvent at a reaction temperature of 100 ° C. for 1 hour 30 minutes.

  The alcohol of formula (IV) is an aniline of formula (V):

(At this time, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) can be produced by condensing with glycolic acid.
The condensation is generally performed at a temperature between 40 ° C. and 100 ° C. in a suitable solvent (eg water) in the presence of an acid catalyst (eg HCl). Preferably, this condensation is carried out using a 6N aqueous hydrochloric acid solution as a solvent, at a temperature of 100 ° C. and for a reaction time of 16 hours.

  The anilines of formula (V) are commercially available or conventional methods well known to those skilled in the art as detailed in the experimental section (eg nitration, reduction, alkylation, chlorination). Can be produced from commercially available materials.

  Alternatively, the compound of formula (I) wherein X is N and Y is O is trichloromethylbenzimidazole of formula (VI):

An amine of formula (III):

(At this time, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) and can be produced by coupling.
Coupling generally involves using an excess of amine (III), optionally in the presence of a base (eg triethylamine, N, N-diethylisopropylamine, potassium carbonate), in a suitable aqueous solvent or solvent (eg (Acetonitrile, tetrahydrofuran, water) in a mixture at a temperature between 10 ° C. and 40 ° C. (room temperature).

  The compound of formula (VI) is an aniline of formula (V):

A trichloroacetimidic acid ester of the formula (VII):

Wherein R is methyl or ethyl and R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above.
Coupling is generally performed at a temperature between 10 ° C. and 40 ° C. (room temperature) in an appropriate solvent (eg AcOH) with an excess of acetimidate.

The aniline of formula (V) is prepared as described above and the trichloroacetimidate of formula (VII) is commercially available.
A compound of formula (I) wherein Y is NH and X is N is a trichloromethylbenzimidazole of formula (VI):

An ammonia source and an amine of formula (III):

(At this time, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) and can be produced by condensation.
The condensation is generally carried out using an equimolar amount of amine (III) and an ammonia source (eg ammonia / dioxane, ammonium acetate), optionally with a base (eg triethylamine, N, N-diisopropylethylamine, potassium carbonate). In the presence, it is carried out in a suitable solvent (eg acetonitrile, tetrahydrofuran) at a temperature between 10 ° C. and 40 ° C. (room temperature).

Preferably, the amine of formula (III) is reacted with trichloromethylbenzimidazole (VI) for 0.5-2 hours prior to the addition of ammonia equivalent.
Alternatively, a compound of formula (I) where X is N and Y is NH may be converted to an nitrile of formula (VIII) with an amine of formula (III):

(At this time, 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 amine (III), in a suitable solvent (isopropanol, methanol, tetrahydrofuran) and at a temperature between 60 ° C. and 85 ° C. (solvent reflux temperature). The Preferably, the reaction is carried out with 1.2 equivalents of amine in isopropanol at reflux for 3 hours.

  Nitriles of formula (VIII) can be prepared by reacting trichloromethylbenzimidazole of formula (VI) with aqueous ammonia followed by reaction with aqueous acid. The reaction is generally carried out with an excess of aqueous ammonia in a suitable solvent (eg ethanol, tetrahydrofuran) at a temperature between −7 ° C. and 0 ° C. for 0.5-2 hours. The resulting intermediate is then reacted with an aqueous hydrochloric acid solution at a temperature between 0 ° C and 5 ° C. Preferably, this reaction is carried out using tetrahydrofuran as a solvent.

A compound of formula (I) wherein X is CR ⁹ and Y is NH is a thioamide of formula (IX):

(At this time, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) can be produced by condensing with ammonia or an ammonia equivalent.
The condensation is generally carried out at −78 ° C. to 50 ° C. in an appropriate solvent (acetonitrile, tetrahydrofuran) with an excess of ammonia in the presence of an activator (eg methyl iodide, mercury acetate). Carried out at temperatures between.

Thioamides of formula (IX) can be prepared from amides of formula (I) where X is CR ⁹ and Y is O.
Conversion generally uses an excess of Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide). And in a suitable solvent (toluene, tetrahydrofuran) at a temperature between 50 ° C and 110 ° C.

  All of the above reactions and the methods of preparation of the starting materials used in the above-described methods are conventional and include appropriate reagents and reagents for carrying out or preparing the reaction, as well as procedures for isolating the desired product. Reaction conditions will be well known to those skilled in the art with reference to the prior literature and the examples and preparations described below.

In some steps of the process for the preparation of the compound of formula (I) described above, it is possible to protect functional groups that are potentially reactive but not desired to react, and consequently to cleave the protecting groups. May be necessary. In such cases, any compatible protecting radical may be used. In particular, protection and deprotection methods such as those described by TW GREENE ( Protective Groups in Oraganic Synthesis , A. Wiley-Interscience Publication, 1981) or PJ Kocienski ( Protecting groups , Georg Thieme Verlag, 1994) may be used.

According to the invention, preferred compounds are those of formula (I), where:
- R ¹ is H or methyl, preferably methyl; and / or - R ⁶ is H; and / or - X is N or CH; and / or ^{- R 2, R 3, R} 4 and R ⁵ is independently from H, halo, methyl, hydroxy, phenyl and COOH, preferably from H, fluoro, chloro, bromo, methyl, hydroxy, phenyl and COOH, and more preferably H, fluoro, chloro , Bromo, hydroxy and methyl.

According to a further embodiment, R ¹ is H or methyl, and R ² , R ³ , R ⁴ and R ⁵ are independently selected from H, halo, methyl, hydroxy, phenyl and COOH, Compounds of I) are preferred.

According to a further aspect, R ¹ is methyl, R ⁶ is H, X is N or CH, and R ² , R ³ , R ⁴ and R ⁵ are independently H, fluoro, chloro More preferred are compounds of formula (I) selected from bromo, hydroxy and methyl.

According to a further aspect, Y is NH, R ¹ is methyl, R ⁶ is H, X is N or CH, and R ² , R ³ , R ⁴ and R ⁵ are independently Most preferred are compounds of formula (I) selected from, H, fluoro, chloro, bromo, hydroxy and methyl.

According to another embodiment, compounds of formula (I) as described above, wherein at least two of R ² , R ³ , R ⁴ and R ⁵ are H are preferred.
According to another preferred embodiment, the compound of formula (I) described above has a cis configuration, ie the following (3aR, 6aS) configuration:

(At this time, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and Y are as defined above).
More preferred compounds are Examples 1-68 and 6-bromo-4-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl. ] Carbonyl} -1H-benzimidazole and 6-fluoro-4-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl } -1H-benzimidazole.

The most preferred compounds are Examples 1, 3, 7, 15, 16, 17, 21, 22, 25, 26, 27, 41, 48, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 67 and 68.
Pharmaceutically acceptable salts of the compounds of formula (I) include their acid addition and base salts.

  Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include: acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, cansylate, citrate , Edsylate, Ethylate, Formate, Fumarate, Glucate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide , Hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, Nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharinate, stearate, succinate, tartrate, tosylate , And trifluoroacetic acid .

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

Acid and base half (hemi) salts such as hemisulfate and hemicalcium salts may also be formed.
For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of three methods:
(I) reacting a compound of formula (I) with the desired acid or base;
(Ii) removing the acid- or base-reactive protecting group from the appropriate precursor of the compound of formula (I) using the desired acid or base, or the appropriate cyclic precursor (eg lactone or lactam) Or (iii) converting one salt of a compound of formula (I) to another by reaction with a suitable acid or base, or a suitable ion exchange column.

  All three methods are typically performed in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of 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. As used herein, the term “solvate” describes a molecular complex consisting of a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg, ethanol). Used to do. The term “hydrate” is employed when the solvent is water.

The scope of the present invention includes complexes such as inclusion compounds, drug-host inclusion complexes, where the drug and host are stoichiometric or non-chemical in contrast to the solvates described above. Present in stoichiometric quantities. Also included are drug complexes containing two or more organic and / or inorganic components, which can be stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian (August 1975).

In the following, all references to compounds of formula (I) include references to salts, solvates and complexes thereof, and solvates and complexes of salts thereof.
The compounds of the present invention include compounds of formula (I) as defined above, including all polymorphs and crystal habits, prodrugs and isomers thereof (optical, geometric and tautomeric) as defined below. As well as isotope-labeled compounds of the compound of formula (I).

As mentioned above, so-called “prodrugs” of the compounds of formula (I) are also within the scope of the present invention. For example, certain derivatives of a compound of formula (I), which may have little or no pharmacological activity on their own, when administered in or on the body, have the formula (I ). Such derivatives are called “prodrugs”. For more information on the use of prodrugs, see Pro-drugs as Novel Delivery Systems , Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design , Pergamon Press, 1987 (EB Roche, Ed., American Pharmaceutical Association).

Prodrugs according to the present invention can be prepared, for example, by suitable functional groups present in the compounds of the formula (I) to those skilled in the art as described in, for example, Design of Prodrugs H. Bundgaard (Elsevier, 1985). It can be produced by replacing it with a specific part known as a “pro part”.

Some examples of prodrugs according to the present invention include:
(I) when the compound of formula (I) contains a carboxylic acid functional group (—COOH), the ester, eg the hydrogen of the carboxylic acid functional group of the compound of formula (I) is (C ₁ -C ₈ ) alkyl Replaced compound;
(Ii) when the compound of formula (I) contains an alcohol function (—OH), the ether, for example the hydrogen of the alcohol function of the compound of formula (I), is (C ₁ -C ₆ ) alkanoyloxymethyl And (iii) if the compound of formula (I) contains a primary or secondary amino function (—NH ₂ or —NHR, where R is not H), its amide, For example, a compound in which the hydrogen of the amino function of the compound of formula (I) is optionally replaced by one or both (C ₁ -C ₁₀ ) alkanoyl.

Further examples of substituents according to the above examples and examples of other prodrug types may be found in the aforementioned references.
Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the present invention include:
(I) when the compound of formula (I) contains a methyl group, its hydroxymethyl derivative (—CH ₃ → —CH ₂ OH);
(Ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (—OR → —OH);
(Iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (-NR ^a R ^b → -NHR ^a or -NHR ^b );
(Iv) if the compound of formula (I) contains a secondary amino group, its primary amino derivative (—NHR ^a → —NH ₂ );
(V) if the compound of formula (I) contains a phenyl moiety, its phenol derivative (-Ph → -PhOH); and (vi) if the compound of formula (I) contains an amide group, its carboxylic acid derivative (-CONR ^c R ^d → -COOH).

  Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where structural isomers are interconvertible via a low energy barrier, tautomerism (“tautomerism”) can occur. This can take the form of proton tautomerism, for example for compounds of formula (I) containing imino, keto or oxime groups, or so-called valence tautomerism for compounds containing aromatic moieties. Thus, a single compound may exhibit one or more isomeric forms.

  All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included within the scope of the present invention, including compounds exhibiting one or more isomeric forms, and one or more These mixtures are included. Also included are acid addition or base salts in which the counter ion is optically active, such as d-lactate or l-lysine, or racemates such as dl-tartrate or dl-arginine.

  Prior art techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or racemates (or salts using, for example, chiral high performance liquid chromatography (HPLC). Or resolution of the derivative racemate).

  Alternatively, the racemic compound (or racemic precursor) is reacted with a suitable optically active compound (eg alcohol), or when the compound of formula (I) contains an acidic or basic moiety, a base or acid (eg 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 enantiomers by means well known to those skilled in the art. it can.

  The chiral compounds of the present invention (and their chiral precursors) are prepared on an asymmetric resin with 0-50% by volume isopropanol (typically 2-20%) and 0-5% by volume alkylamine (typically Can be obtained in an enantiomer-enriched form using chromatography, typically HPLC, with a mobile phase consisting of a hydrocarbon containing 0.1% diethylamine, typically heptane or hexane. . Concentration of the eluate yields an enriched mixture.

Stereoisomer agglomerates can be separated by conventional techniques known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds EL Eliel and SH Wilen (Wiley, New York, 1994).

  The present invention includes all pharmaceutically acceptable compounds of the isotope-labelled compounds of formula (I), wherein one or more atoms have the same atomic number but are the predominant atoms in nature. It is replaced by an atom having an atomic mass or mass number different from the mass or mass number.

Examples of suitable isotopes for inclusion in the compounds of the present invention include the following isotopes: hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P and sulfur such as ³⁵ S .

Certain isotopically-labelled compounds of formula (I), such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes, such as deuterium, i.e. ² H, may result in certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, Therefore, it may be preferable in some situations.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be used in positron emission tomography (PET) studies to determine substrate receptor occupancy.
Isotopically-labelled compounds of formula (I) are generally used conventionally by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations. An appropriate isotope-labeled reagent can be used in place of the non-isotopically labeled reagent.

Pharmaceutically acceptable solvates in accordance with the present invention, the crystallization solvent is that isotopically substituted, e.g. D ₂ O, d ₆ - acetone, include those wherein d _6-DMSO.
The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained by methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying, for example as solid plugs, powders or films. Microwave or radio frequency drying may be used for this purpose.

  They can be administered alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or any combination thereof). In general, they will be administered as a formulation with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will to a large extent depend on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

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

  The compounds of the present invention can be administered orally. Oral administration involves swallowing, whereby the compound enters the gastrointestinal tract. Alternatively, buccal or sublingual administration can be employed, where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration include solid formulations such as tablets, particles, capsules containing liquids or powders, troches (including liquid filling), chewing agents, multiparticulates and nanoparticles, gels, solid solutions, liposomes, Films, oval tablets, sprays, and liquid formulations are included.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be employed as fillers in soft or hard capsules and typically contain a carrier (eg, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil) and one or more emulsifiers. And / or suspending agents. Liquid preparations can also be manufactured from solid sachets, for example from sachets.

The compounds of the present invention may also be used in fast-dissolving, fast-disintegrating dosage forms as described, for example, in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, Liang and Chen (2001). obtain.

  For tablet dosage forms, depending on dose, the drug may make up 1-80% by weight of the dosage form, more typically 5-60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate are included. Generally, the disintegrant will comprise 1-25% by weight of the dosage form, preferably 5-20%.

  Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, saccharides, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets are made of diluents such as lactose (monohydrate, spray-dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate 2 Hydrates can also be included.

  Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant can comprise 0.2-5% by weight of the tablet and the glidant can comprise 0.2-1% by weight of the tablet.

  Tablets may generally also contain a lubricant, for example magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally constitute 0.25-10% by weight of the tablet, preferably 0.5-3%.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.
Tablets can be, for example, up to about 80% drug, about 10 to about 90% by weight binder, about 0 to about 85% by weight diluent, about 2 to about 10% by weight disintegrant, and about 0.25 to about Contains about 10% by weight lubricant.

  Tablet blends are compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends can be wet, dry or melt granulated, melt solidified or extruded prior to tablet manufacture. The final formulation may include one or more layers and may be coated or uncoated and may be encapsulated.

Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets , Vol. 1, H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Oral films that can be ingested by humans or animals are typically water-soluble or water-swellable thin film dosage forms that can be laminated, which can be readily soluble or tacky, and typically have the formula (I ) Compounds, film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Some components of the formulation may perform more than one function.

  The compound of formula (I) may be water-soluble or insoluble. Water soluble compounds typically constitute 1-80% by weight of the solute, more typically 20-50%. Compounds with low solubility may constitute a greater percentage of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.

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

  Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva secretion promoters, cooling agents, co-solvents (including oils), softeners, extenders, Foams, surfactants and taste masking agents are included.

  Films according to the present invention are typically produced by evaporating and drying an aqueous film coated on a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze drying or vacuum drying.

  Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

Suitable modified release formulations for the purposes of the present invention are described in US Pat. No. 6,106,864. Details of other suitable release techniques such as high energy dispersion and osmotic and coated particles can be found in Pharmaceutical Technology On-line , 25 (2), 1-14, Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention can also be administered directly into the bloodstream, muscle or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, subarachnoid, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Devices suitable for parenteral administration include needles (including microneedles), syringes, needleless syringes and infusion methods.

  Parenteral preparations are typically aqueous solutions and can contain excipients such as salts, carbohydrates and buffering agents (preferably buffering the pH to 3-9), although depending on the application, sterile It is more suitably formulated as an aqueous solution or as a dry form for use with a suitable medium (eg, sterile, pyrogen-free water).

Production of parenteral preparations under aseptic conditions, such as lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased by appropriate formulation techniques such as incorporation of solubility enhancers.

  Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release. Thus, the compounds of the invention can be formulated as solids, semisolids or thixotropic liquids for administration as embedded reservoirs providing controlled release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-glycolic acid) (PGLA) microspheres.

The compounds of the present invention can also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, bandages, foams, films, skin patches, wafers, implants, Sponges, fibers, bandages and microemulsions are included. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white paraffin, glycerin, polyethylene glycol and propylene glycol. A penetration enhancer can also be incorporated. See, for example, J Pham Sci, 88 (10), 955-958, Finnin and Morgan (October 1999).

Other means of local administration include electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (eg Powderject ^™ , Bioject ^™, etc.) Delivery by injection is included.

  Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone or as a mixture, eg, in a dry blend with lactose, or as mixed component particles) From a dry powder inhaler, eg mixed with a phospholipid such as phosphatidylcholine, or as an aerosol spray, pressurized container, pump, nebulizer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist ) Or from a nebulizer with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane Can do. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, nebulizers, atomizers or nebulizers contain solutions or suspensions of the compounds of the invention, which may be used, for example, to disperse, dissolve or extend the release of ethanol, aqueous ethanol or active ingredients. Suitable alternatives include propellants as solvents, and optionally surfactants such as sorbitan trioleate, oleic acid or oligolactose.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing methods for nanoparticle formation, high pressure homogenization, or spray drying.

  Capsules (eg made from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or insufflators are suitable powder bases such as compounds of the invention, lactose or starch, and l- It may be formulated to contain a powder mixture of performance modifiers such as leucine, mannitol or magnesium stearate. Lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist can contain from 1 μg to 20 mg of the compound of the invention per actuation and the working volume is from 1 μl to It can vary in the range of 100 μl. A typical formulation may include 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 flavoring agents such as menthol and levomenthol, or sweetening agents such as saccharin or saccharin sodium may be added to these formulations of the present invention intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration can be formulated to be immediate and / or modified release using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Units according to the invention are typically prepared to administer a metered dose or “one puff” containing 1 μg to 4000 μg of the compound of formula (I). The total daily dose is typically in the range of 1 μg to 20 mg, which may be administered in a single dose or, more usually, as divided doses over the day.

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

  Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release and programmed release.

  The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of an instillation of a finely divided suspension or solution in isotonic pH adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg absorbable gels, sponges, collagen) and non-biodegradable (eg silicon) implants, wafers, lenses and particles or vesicle systems. For example, niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (eg hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose), or heteropolysaccharide polymers (eg gellan gum) with preservatives such as benzalkonium chloride Can be incorporated. Such formulations can also be delivered by iontophoresis.

  Formulations for ocular / ear administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, target release or programmed release.

  The compounds of the present invention may be used in any of the aforementioned modes of administration in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability, For example, it can be combined with cyclodextrin and appropriate derivatives thereof, or polyethylene glycol-containing polymers.

  For example, drug-cyclodextrin complexes have generally been found useful for most dosage forms and administration routes. Both encapsulated and non-encapsulated complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, ie carriers, diluents or solubilizers. The most commonly used for these purposes are alpha, beta, and gamma cyclodextrins, examples of which are in International Patent Application Nos. WO 91/11172, WO 94/02518, and WO 98/55148. Can be found in

  For example, for the purpose of treating certain diseases or conditions, it is desirable to administer a combination of active compounds, so that two or more pharmaceutical compositions (at least one of which contains a compound according to the invention) It is within the scope of the present invention that can be suitably combined in a kit form suitable for co-administration of the composition.

  Thus, the kit of the present invention comprises two or more separate pharmaceutical compositions (at least one of which contains a compound of formula (I) according to the present invention), and for holding said compositions separately Includes means such as a container, a divided bottle, or a divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

  The kits of the invention are particularly suitable for administering different dosage forms (eg oral and parenteral), for administering separate compositions at different dosing intervals, or for titrating separate compositions against each other. . To assist compliance, the kit typically includes directions for administration and may be provided with a so-called memory aid.

  For administration to human patients, the total daily dose of the compounds of the invention is typically from 0.001 mg to 2000 mg, depending of course on the mode of administration. For example, oral administration may require a total daily dose of 0.1 mg to 2000 mg, whereas an intravenous dose may only require 0.01 mg to 100 mg. The total daily dose can be administered in single or divided doses and, depending on the judgment of the physician, may deviate from the typical ranges given herein.

These dosages are based on an average human subject having a weight of about 60kg to 70kg. The dosage for subjects whose weight falls outside this range, such as infants and the elderly, will be readily determinable by the physician.
For the avoidance of doubt, references herein to “treatment” include references to therapeutic, palliative and prophylactic treatment.

According to another aspect of the present invention, the compound of formula (I), or a pharmaceutically acceptable salt, derivative or composition thereof, may be combined with a patient to obtain some particularly desirable therapeutic results. It can also be used in combination with one or more additional therapeutic agents for administration. The second and more additional therapeutic agents can also be a compound of formula (I), or a pharmaceutically acceptable salt, derivative or composition thereof, or one or more histamines known in the art. It may be an H ₄ receptor ligand. More typically, the second and more therapeutic agents will be selected from different classes of therapeutic agents.

As used herein, the terms “co-administration”, “co-administered” and “in combination with” with respect to the compound of formula (I) and one or more other therapeutic agents are intended to mean: And actually refers to and includes:
• Simultaneously administering such a combination of a compound of formula (I) (one or more) and a therapeutic agent (one or more) to a patient in need of treatment: these components are single agents Formulated together in form and the components are released to the patient substantially simultaneously;
Administering such a combination of a compound of formula (I) (one or more) and a therapeutic agent (one or more) substantially simultaneously to a patient in need of treatment: Formulated separately from each other in separate dosage forms and taken substantially simultaneously by the patient so that the components are released substantially simultaneously to the patient;
• Sequentially administering such a combination of a compound of formula (I) (one or more) and a therapeutic agent (one or more) to a patient in need of treatment: where the components are separate agents Formulated separately from each other in form and continuously taken by the patient with significant time intervals between each administration, so that the components are released to the patient at substantially different times And • sequentially administering such a combination of a compound of formula (I) (one or more) and a therapeutic agent (one or more) to a patient in need of treatment: these components Are formulated together in a single dosage form and the ingredients are released in a controlled manner so that they are simultaneously, sequentially and / or overlapped by the patient And / or administered at different time points;
In the above, each part may be administered by either the same or different routes.

Suitable examples of other therapeutic agents used in combination with one or more compounds of formula (I), or pharmaceutically acceptable salts, derivatives or compositions thereof include: But not limited to:
Histamine H ₁ receptor antagonists, in particular loratidine, desloratidine, fexofenadine and cetirizine,
Histamine H ₃ receptor antagonist,
Histamine H ₂ receptor antagonist,
· LTB _4, LTC _4, LTD comprising an antagonist of ₄ and LTE _4, leukotriene antagonists, in particular Montelukast (Montelukast),
Phosphodiesterase inhibitors, i.e. PDE4 inhibitors and PDE5 inhibitors,
Neurotransmitter reuptake inhibitors, especially fluoxetine, setraline, paroxetine, ziprasidone,
A 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,
An α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictive sympathomimetic agent for use as a decongestant,
A muscarinic M3 receptor antagonist or anticholinergic agent,
Β ₂ -adrenergic receptor agonist,
・ Theophylline,
・ Cromoglycate sodium,
-COX-1 inhibitor (NSAID) and COX-2 selective inhibitor,
Oral or inhaled glucocorticosteroids,
A monoclonal antibody active against endogenous inflammatory entities;
・ Anti-tumor necrosis factor (anti-TNF-α) agent,
-Adhesion molecule inhibitors including VLA-4 antagonists,
Kinin-B ₁ -and B ₂ -receptor antagonists,
・ Immunosuppressants,
An inhibitor of matrix metalloprotease (MMP),
Tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,
An elastase inhibitor,
Adenosine A2a receptor agonist,
An inhibitor of urokinase,
Compounds acting on dopamine receptors, such as D2 agonists,
A modulator of the NF _K b pathway, such as an IKK inhibitor,
Drugs that can be classified as mucolytics or antitussives,
·Antibiotics,
A modulator of cytokine signaling pathway, such as p38 MAP kinase inhibitor, syk tyrosine kinase inhibitor or JAK kinase inhibitor,
Prostaglandin D2 receptor antagonist (DP1 and CRTH2),
・ Inhibition of prostaglandin D synthase (PGDS),
An inhibitor of phosphoinositide-3-kinase, and an HDAC inhibitor.

According to the invention, a combination of a compound of formula (I) with:
Histamine H ₁ receptor antagonists, especially loratidine, desloratidine, fexofenadine and cetirizine,
Histamine H ₃ receptor antagonist,
Histamine H ₂ receptor antagonist,
• Leukotriene antagonists, particularly montelukast, including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ; • Phosphodiesterase PDE4 inhibitors.

Compounds of formula (I) has the ability to interact with H ₄ receptor, therefore have a wide range of therapeutic applications. As described further below, the H ₄ receptor plays an essential role in the physiology of all mammals. According to the present invention, H ₄ ligand is meant to include H ₄ receptor antagonists, agonists and inverse agonists. For the preferred indications to be treated by the present invention, H ₄ antagonist is considered to be the most appropriate.

Therefore, a further aspect of the invention involves the use of a compound of formula (I) or a pharmaceutically acceptable salt, derivative or composition thereof as a medicament, more specifically the H ₄ receptor. For use in the treatment of certain diseases, disorders and conditions. More particularly, the present invention relates to the treatment of diseases, disorders and conditions selected from the group consisting of the compounds of formula (I) or pharmaceutically acceptable salts, derivatives or compositions thereof: Also related to use:
Inflammatory diseases,
・ Respiratory diseases (eg adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic ethmoid sinusitis), allergy, allergy Inductive airway response, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic hyperemia,
・ Female and male sexual dysfunction,
Skin diseases such as dermatitis, psoriasis,
Cardiac dysfunction, such as myocardial ischemia and arrhythmia,
・ Gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, ulcerative colitis,
·cancer,
Rheumatoid arthritis,
·Low blood pressure,
Pain, and overactive bladder condition.

  The compounds of formula (I) according to the invention are used for the treatment of asthma, allergies, allergic inductive airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic hyperemia. Especially suitable.

Still further aspect of the present invention, for the manufacture of a medicament is H ₄ ligand, compound or a pharmaceutically acceptable salt of formula (I), also relates to the use of a derivative or a composition thereof. In particular, the present invention is for the manufacture of a medicament for treating diseases and / or conditions, diseases and / or conditions listed particularly above mediated by H _4, compound or a pharmaceutically acceptable of the formula (I) The use of possible salts, derivatives thereof or compositions thereof.

As a result, the present invention provides a particularly interesting method of treating mammals, including humans, with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, derivative or composition thereof. More precisely, the present invention is a particularly interesting method of treating diseases and / or conditions mediated by H _{4 in} mammals, including humans, in particular the diseases and / or conditions listed above, A method comprising administering an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof and / or a derivative thereof.

The following examples illustrate the preparation of compounds of formula (I) according to the present invention.
In all cases, ¹ H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structure. Characteristic chemical shifts (δ) are conventional abbreviations to define the main peaks: eg s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q ( Quartet, quadruple), m (multiplet multiple), and br (broad) are used to provide a low magnetic field in parts per million (ppm) from tetramethylsilane. Mass spectra (m / z) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Purification by SCX indicates the use of a strong cation exchange resin.

Examples section
Production Example 1: (5-Methoxy-1H-benzimidazol-2-yl) methanol
A solution of 4-methoxybenzene-1,2-diamine (1.13 g, 8.18 mmol) and hydroxyacetic acid (1.85 g, 24.5 mmol) in 6N hydrochloric acid (25 ml) was heated at 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 collected by filtration and dried in vacuo to give the title compound as a pale yellow solid (638 mg).

Production Example 2: (5-Fluoro-1H-benzimidazol-2-yl) methanol
Prepared from 4-fluorobenzene-1,2-diamine using the method of Preparation Example 1 to give the title compound as a brown crystalline solid.

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

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

Production Example 5: 5-Methoxy-1H-benzimidazole-2-carboxylic acid
A suspension of (5-methoxy-1H-benzimidazol-2-yl) methanol (Production Example 1) (638 mg, 3.58 mmol) in 1N aqueous sodium hydroxide (0.95 ml) and water (40 ml) was heated to reflux. And an aqueous solution of potassium permanganate (848 mg, 5.36 mmol) was added dropwise over 30 minutes. The reaction mixture was refluxed for an additional hour and cooled to room temperature. The reaction mixture was acidified to pH 4 by 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).

Production Example 6: 5-Fluoro-1H-benzimidazole-2-carboxylic acid Prepared from the alcohol of Preparation Example 2 using the method of Preparation Example 5 to give the title compound as a light brown solid.

Production Example 7: 5-Methyl-1H-benzimidazole-2-carboxylic acid Prepared from the alcohol of Production Example 3 using the method of Production Example 5, and the title compound was obtained as a pale yellow solid.

Preparation Example 8: 5-Chloro-1H-benzimidazole-2-carboxylic acid Prepared from the alcohol of Preparation Example 4 using the method of Preparation Example 5 to give the title compound as a pale yellow solid.

Production Example 9: 6,7-Dimethyl-2- (trichloromethyl) -1H-benzimidazole
A solution of 3,4-dimethylbenzene-1,2-diamine (1.0 g, 7.34 mmol) in acetic acid (10 ml) is reacted 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 (˜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 (360 mg) was isolated by filtration as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 10: 6,7-Difluoro-2- (trichloromethyl) -1H-benzimidazole
Reaction of 3,4-difluorobenzene-1,2-diamine (274 mg, 1.90 mmol) in acetic acid (4 ml) with methyl-2,2,2-trichloroacetimidate (0.25 ml, 2.09 mmol) and formation The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was poured onto ice (˜50 g) and the resulting precipitate was filtered and dried in vacuo to give the title compound as a brown solid (496 mg). This material was used as the crude product in the next step without further characterization.

Production Example 11: 7-Methyl-2- (trichloromethyl) -1H-benzimidazole
Prepared from 3-methylbenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 12: 5,6-Difluoro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 5,6-difluorobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 13: 5,7-Difluoro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 3,5-difluorobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 14: 5-Chloro-7-methyl-2- (trichloromethyl) -1H-benzimidazole
Prepared from 5-chloro-3-methylbenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a yellow solid. This material was used as the crude product in the next step without further characterization.

Production Example 15: 7-Chloro-5-methyl-2- (trichloromethyl) -1H-benzimidazole
Prepared from 3-chloro-5-methylbenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 16: 5-iodo-2- (trichloromethyl) -1H-benzimidazole
Prepared from 4-iodobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step.

Production Example 17: Production from methyl-2- (trichloromethyl) -1H-benzimidazole-5-carboxylatemethyl -3,4-diaminobenzoate using the method of Production Example 10 to obtain the title compound as a brown solid It was. This material was used as the crude product in the next step.

Production Example 18: 5-Chloro-6-fluoro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 4-chloro-5-fluorobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 19: 5,6-Dimethyl-2- (trichloromethyl) -1H-benzimidazole
Prepared from 4,5-dimethylbenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 20 5,6-Dichloro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 4,5-dichlorobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown solid. This material was used as the crude product in the next step without further characterization.

Production Example 21: 2- (Trichloromethyl) -5- (trifluoromethyl) -1H-benzimidazole
Prepared from 4- (trifluoromethyl) benzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a pale yellow solid. This material was used as the crude product in the next step.

Production Example 22: 4-Chloro-6-fluoro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 3-chloro-5-fluorobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as an orange solid. This material was used as the crude product in the next step without further characterization.

Production Example 23: 4,6-Dichloro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 3,5-dichlorobenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a yellow solid. This material was used as the crude product in the next step without further characterization.

Production Example 24: The title compound was obtained as a brown oil from 5-phenyl-2- (trichloromethyl) -1H-benzimidazolebiphenyl -3,4-diamine using the method of Production Example 10. This material was used as the crude product in the next step without further characterization.

Production Example 25: 5-Fluoro-4-methyl-2- (trichloromethyl) -1H-benzimidazole
Prepared from 4-fluoro-3-methylbenzene-1,2-diamine using the method of Preparation Example 10 to give the title compound as a brown oil. This material was used as the crude product in the next step without further characterization.

Production Example 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 reacted with a solution of acetic anhydride (1.50 ml, 15.9 mmol) in dichloromethane (50 ml). The resulting mixture was allowed to warm slowly to room temperature over 1 hour. Saturated aqueous sodium bicarbonate solution (50 ml) is added and the organic phase is separated, washed with additional saturated aqueous sodium bicarbonate solution (50 ml), dried (sodium sulfate) and the solvent reduced by reduced pressure to give the title compound. Was obtained as a colorless solid (2.26 g).

Preparation 27: 2-Fluoro-4-methyl-6-nitroaniline Preparation 26 Acetamide (1.0 g, 5.9 mmol) in nitric acid (70%, 10 ml) was cooled to 0 ° C. and the reaction temperature <0 ° C. Was reacted with fuming nitric acid (90%, 10 ml). The reaction was stirred at 0 ° C. for 1 hour and then poured onto ice and allowed to warm slowly to room temperature. The resulting precipitate was collected by filtration and dried in vacuo to give a colorless solid (1 g, mixture of isomers). This 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 additional dichloromethane (50 ml) and the combined organic phases were dried (sodium sulfate) and reduced by reduced pressure. Purification by flash column chromatography on silica gel eluting with pentane: ethyl acetate (volume ratio changed from 80:20 to 20:80) gave the title compound as a yellow solid (124 mg).

Preparation 28: 3-Fluoro-5-methylbenzene-1,2-diamine Preparation 27 A solution of nitroaniline (124 mg, 0.72 mmol) in ethanol (5 ml) was reacted with 10% Pd / C and 4 at 50 psi. Hydrogenated for hours at room temperature. The reaction mixture was filtered and the solvent removed in vacuo to give a colorless solid (79 mg).

Production Example 29: 4-chloro-3-methylbenzene-1,2-diamine
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 iron powder (900 mg, 16.0 mmol) And reacted. The reaction mixture was heated at 90 ° C. for a further 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 was reduced by reduced pressure. Purification by flash column chromatography on silica gel eluting with pentane: ethyl acetate (volume ratio changed from 70:30 to 30:70) gave the title compound as a brown oil (213 mg).

Production Example 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) is reacted with methyl-2,2,2-trichloroacetimidate (1.5 ml, 12.2 mmol), The resulting solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in methanol (100 ml) and heated to reflux for 4 hours. The solvent was removed under reduced pressure 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 by reduced pressure. Purification by flash column chromatography on silica gel eluting with pentane: ethyl acetate (volume ratio changed from 90:10 to 50:50) gave the title compound as a yellow solid (963 mg).

Production Example 31 5,6-difluoro-1H-benzimidazole-2-carboxylic acid A solution of the ester of Production Example 30 (963 mg, 4.53 mmol) in tetrahydrofuran (10 ml) was mixed with lithium hydroxide (9.0 ml of 1M aqueous solution, 9.0 mmol). And stirred at room temperature for 16 hours. Hydrochloric acid (9.0 ml of 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 (700 mg).

Production Example 32: 5,6-difluoro-2- (trichloromethyl) -1H-benzimidazole
Prepared from 4-fluorobenzene-1,2-diamine using the method of Preparation 10 to give the title compound as a brown solid that was used in the next step as a crude product without further characterization. .

Production Example 33: 5,6-Difluoro-1H-benzimidazole-2-carbonitrile A solution of trichloromethylbenzimidazole (5 g, 18.4 mmol) in Production Example 12 in tetrahydrofuran (25 ml) was cooled to 880 ammonia (10 ml) in water. To the (30 ml) solution was added dropwise, maintaining the internal temperature <-5 ° C. The reaction mixture was stirred at 0 ° C. for 2 hours and then poured onto ice and acidified to pH 5 by the 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 dissolved in 50 ml water). The aqueous phase was separated, poured onto ice and acidified to pH 5 by the slow addition of concentrated hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo to give the title compound as a pale yellow solid (2.63 g).
¹ H NMR (400MHz, CD ₃ OD): δ7.62-7.58 (2H, m) ppm.
MS (APCI): m / z 180 [M + H] ⁺ , 178 [MH] ^-
Example 1: 2-{[(3aR, 6aS) 5-Methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

A solution of 1H-benzimidazole-2-carboxylic acid (456 mg, 2.81 mmol) in N, N-dimethylacetamide (5 ml) was added to (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (322 mg 2.55 mmol), triethylamine (0.71 ml, 5.11 mmol) and O-benzotriazo-1-yl-N, N, N′N′-tetramethyluronium hexafluorophosphate (1.16 g, 3.06 mmol) and The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was purified directly on SCX resin; the non-basic compound was eluted with methanol and the basic compound was eluted with 1N ammonia / methanol. Concentrate the basic wash under reduced pressure and purify by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (volume ratio changed from 99: 1: 0.1 to 90: 10: 1) to give the title compound Was obtained as a pale yellow solid (499 mg).
¹ H NMR (400MHz, CD ₃ OD): δ7.71-7.69 (2H, m), 7.39-7.34 (2H, m), 4.42-4.30 (2H, 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 (3H, s) ppm.
MS (electrospray method): m / z 271 [M + H] ⁺ , 269 [MH] ^-
Example 2: 5-methoxy-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from 5-methoxy-1H-benzimidazole-2-carboxylic acid (Production Example 5) using the method of Example 1 to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.55 (1H, d), 7.09 (1H, s), 6.95 (1H, d), 4.36-4.24 (2H, 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 (3H, s) ppm.
MS (APCI) m / z 301 [M + H] ⁺ , 299 [MH] ^-
Example 3: 5-Fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from 5-fluoro-1H-benzimidazole-2-carboxylic acid (Production Example 6) using the method of Example 1 to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.65 (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, m), 2.51-2.48 (2H, m), 2.32 (3H, s) ppm.
MS (APCI) m / z 289 [M + H] ⁺ , 287 [MH] ^-
Example 4: 5-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from 5-methyl-1H-benzimidazole-2-carboxylic acid (Production Example 7) using the method of Example 1 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.54 (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 (3H, s) ppm.
MS (APCI) m / z 285 [M + H] ⁺ , 283 [MH] ^-
Example 5: 5-Chloro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from 5-chloro-1H-benzimidazole-2-carboxylic acid (Production Example 8) using the method of Example 1 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.64 (1H, d), 7.60 (1H, s), 7.29 (1H, d), 4.37-4.25 (2H, 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 [MH] ^-
Example 6: 5-Chloro-2-[(3aR, 6aS) -hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -ylcarbonyl] -1H-benzimidazole

A solution of 5-chloro-1H-benzimidazole-2-carboxylic acid (Production Example 8) (100 mg, 0.50 mmol) in N, N-dimethylacetamide (5 ml) was added to tert-butyl (3aR, 6aS) -hexahydropyrrolo [ 3,4-c] pyrrole-2 (1H) -carboxylate (108 mg, 0.51 mmol) and O-benzotriazo-1-yl-N, N, N′N′-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, dried (sodium sulfate) and the solvent reduced by reduced pressure. The residue was reacted with 1M HCl / methanol solution (15 ml) and stirred at room temperature for 16 hours. 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 changed from 99: 1: 0.1 to 90: 10: 1) to give the title The compound was obtained as a colorless solid (50 mg).
¹ H NMR (400MHz, CD ₃ OD): δ7.69-7.65 (2H, m), 7.34 (1H, d), 4.45-4.40 (1H, 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 [MH] ^-
Example 7: 5-Chloro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5-chloro-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.67 (1H, s), 7.46 (1H, d), 7.24 (1H, dd), 6.97 (1H, 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 (3H, s) ppm.
MS (APCI) m / z 304/306 [M + H] ⁺ , 302/304 [MH] ^-
Example 8: 5-Chloro-2-{[(3aR, 6aS) -hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

A solution of 5-chloro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol) in N, N-dimethylacetamide (5 ml) was added to tert-butyl (3aR, 6aS) -hexahydropyrrolo [3,4-c] Reacting with pyrrole-2 (1H) -carboxylate (108 mg, 0.51 mmol) and O-benzotriazo-1-yl-N, N, N′N′-tetramethyluronium hexafluorophosphate (256 mg, 0.67 mmol); 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 reduced by reduced pressure. The residue was reacted with 1M HCl / methanol solution (15 ml) and stirred at room temperature for 16 hours. 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 changed from 99: 1: 0.1 to 90: 10: 1) to give the title The compound was obtained as a pale yellow solid (42 mg).
¹ H NMR (400MHz, DMSO _d6 ): δ11.77 (1H, bs), 7.69 (1H, bs), 7.45 (1H, d), 7.20 (1H, d), 6.93 (1H, s), 4.13-3.45 (4H, m), 2.99-2.63 (6H, m), 2.52 (3H, s) ppm (low resolution spectrum).
MS (APCI) m / z 290/292 [M + H] ⁺ , 288/290 [MH] ^-
Example 9: 5-Methoxy-3-methyl-2-{[(3aR, 6aS) -5-methylhexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H- Indole

Prepared from 5-methoxy-3-methyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CDCl ₃ ): δ9.42 (1H, bs), 7.28 (1H, d), 6.99 (1H, s), 6.92 (1H, 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) ppm.
MS (APCI) m / z 314 [M + H] ⁺ , 312 [MH] ^-
Example 10: 5- (Benzyloxy) -2-{[(3aR, 6aS) -5-methylhexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5- (benzyloxy) -3-methyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ): δ9.39 (1H, bs), 7.47 (2H, d), 7.39 (2H, dd), 7.30 (2H, d), 7.13 (1H, s), 7.05 (1H , d), 6.76 (1H, s), 5.10 (2H, s), 4.15-4.03 (2H, 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-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5-methyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CDCl ₃ ): δ9.69 (1H, bs), 7.54 (1H, d), 7.23 (1H, s), 6.98 (1H, 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-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 4-methoxy-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ): δ9.38 (1H, bs), 7.21 (1H, t), 7.05 (1H, d), 6.96 (1H, s), 6.51 (1H, s), 4.14-4.04 (2H, m), 3.97 (3H, s), 3.89-3.78 (2H, m), 3.12-3.00 (2H, 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 [MH] ^-
Example 13: 6-Chloro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 6-chloro-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CDCl ₃ ): δ10.24 (1H, bs), 7.55 (1H, d), 7.46 (1H, s), 7.06 (1H, d), 6.81 (1H, s), 4.16-4.08 (m, 2H), 3.83-3.76 (m, 2H), 3.14-2.91 (m, 2H), 2.68-2.59 (4H, m), 2.36 (s, 3H) ppm.
MS (APCI) m / z 304/306 [M + H] ⁺ , 302/304 [MH] ^-
Example 14: 5-Methoxy-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5-methoxy-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ): δ9.68 (1H, bs), 7.34 (1H, d), 7.06 (1H, s), 6.96 (1H, dd), 6.77 (1H, s), 4.15-4.02 (2H, m), 3.85 (3H, s), 3.83-3.75 (2H, m), 3.11-2.91 (2H, m), 2.71-2.65 (2H, m), 2.59-2.53 (2H, m), 2.35 (3H, s) ppm.
MS (APCI) m / z 300 [M + H] ⁺ , 298 [MH] ^-
Example 15: 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole-5-ol

Prepared from 5-hydroxy-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.33 (1H, d), 7.02 (1H, d), 6.86 (1H, dd), 6.83 (1H, 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 [MH] ^-
Example 16: 5-Fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5-fluoro-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ): δ7.37 (1H, dd), 7.28 (1H, dd), 7.08-7.02 (1H, m), 6.81 (1H, 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 (2H, m), 2.37 (3H, s) ppm.
MS (APCI) m / z 288 [M + H] ⁺ , 286 [MH] ^-
Example 17: 5-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5-methyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CDCl ₃ ): δ7.43 (1H, s), 7.33 (1H, d), 7.12 (1H, d), 6.77 (1H, 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 (2H, m), 2.44 (3H, s), 2.38 (3H, s) ppm.
MS (APCI) m / z 284 [M + H] ⁺ , 282 [MH] ^-
Example 18: 3,5-dimethyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 3,5-dimethyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.32 (1H, s), 7.23 (1H, d), 7.03 (1H, d), 3.79-3.74 (2H, 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 [MH] ^-
Example 19: 5-chloro-3-methyl-2-{[(3aR, 6aS) -5-methylhexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H- Indole

Prepared from 5-chloro-3-methyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.53 (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, s) ppm.
MS (APCI) m / z 318/320 [M + H] ⁺ , 316/318 [MH] ^-
Example 20: 1-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 1-methyl-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.60 (1H, d), 7.42 (1H, d), 7.28 (1H, t), 7.10 (1H, 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 (2H, m), 2.55-2.33 (2H, m), 2.32 (3H, m) ppm .
MS (APCI) m / z 284 [M + H] ⁺
Example 21: 5-Bromo-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5-bromo-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ 7.79 (1H, s), 7.37 (1H, d), 7.31 (1H, dd), 6.92 (1H, 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 (3H, s) ppm.
MS (APCI) m / z 348/350 [M + H] ⁺ , 346/348 [MH] ^-
Example 22: 7-Fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 7-fluoro-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.47 (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 [MH] ^-
Example 23: 5,6-dimethoxy-2-{[(3aR, 6aS) -5-methylhexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared from 5,6-dimethoxy-1H-indole-2-carboxylic acid by the method of Example 1 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.16 (1H, s), 7.04 (1H, s), 6.91 (1H, s), 4.20-3.93 (2H, m), 3.92 (3H, s), 3.89 (3H, s), 3.86-3.77 (2H, m), 3.15-2.98 (2H, 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-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

A solution of trichloromethylbenzimidazole (Production Example 9) (100 mg, 0.37 mmol) in a mixture of acetonitrile (3 ml) and water (1 ml) was dissolved in (3aR, 6aS) -2-methyloctahydropyrrolo [3,4- c] Pyrrole (95 mg, 0.76 mmol) was reacted with a solution 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 under reduced pressure and the residue was partitioned between dichloromethane (5 ml) and saturated aqueous sodium bicarbonate (5 ml). The organic phase was separated, dried (sodium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (volume ratio changed from 100: 0: 0 to 93: 7: 0.7) gave the title compound as a pale yellow solid (48 mg) .
¹ H NMR (400MHz, CD ₃ OD): δ7.43-7.35 (1H, m), 7.17 (1H, d), 4.43-4.27 (2H, 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 (2H, m), 2.43 (3H, s), 2.37 (3H, s) ppm.
MS (Electrospray): m / z 299 [M + H] ⁺ , 297 [MH] ^-
Example 25: 6,7-difluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Production Example 10 by the method of Example 24 in a reaction time of 2 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.43-7.39 (1H, m), 7.32-7.25 (1H, m), 4.45-4.33 (2H, m), 3.95-3.76 (2H, m), 3.15 -2.98 (2H, m), 2.83-2.76 (2H, m), 2.58-2.53 (2H, m), 2.37 (3H, s) ppm.
MS (electrospray): m / z 307 [M + H] ⁺ , 305 [MH] ^-
Example 26: 7-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Production Example 11 by the method of Example 24 in a reaction time of 2 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.45 (1H, d), 7.20 (1H, t), 7.09 (1H, d), 4.37-4.24 (2H, m), 3.90-3.71 (2H, m ), 3.09-2.91 (2H, m), 2.79-2.71 (2H, m), 2.59 (3H, s), 2.49-2.44 (2H, m), 2.32 (3H, s) ppm.
MS (APCI): m / z 285 [M + H] ⁺ , 283 [MH] ^-
Example 27: 5,6-difluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

A solution of the acid of Preparation Example 31 (700 mg, 3.53 mmol) and (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (490 mg, 3.88 mmol) in N, N-dimethylformamide (35 ml) was added. , O-benzotriazo-1-yl-N, N, N′N′-tetramethyluronium hexafluorophosphate (1.60 g, 4.24 mmol) was reacted and the resulting solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate. Under reduced pressure
¹ H NMR (400MHz, DMSO _d6 ): δ13.29 (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 [MH] ^-
Example 28: 5,7-difluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Production Example 13 by the method of Example 24 in a reaction time of 2 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.15-7.12 (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 (3H, s) ppm.
MS (APCI): m / z 307 [M + H] ⁺
Example 29: 5-chloro-7-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from the trichloromethylbenzimidazole of Production Example 14 by the method of Example 24 in a reaction time of 2 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.44 (1H, s), 7.10 (1H, s), 4.39-4.27 (2H, m), 3.90-3.71 (2H, 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 (3H, s) ppm.
MS (APCI): m / z 319/321 [M + H] ⁺ , 317/319 [MH] ^-
Example 30: 7-Chloro-5-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from the trichloromethylbenzimidazole of Production Example 15 by the method of Example 24 in a reaction time of 16 hours to give the title compound as a pale orange solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.31 (1H, s), 7.19 (s, 1H), 4.42-4.26 (2H, m), 3.92-3.71 (2H, m), 3.15-3.03 (2H , m), 2.82-2.72 (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-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Production Example 16 by the method of Example 24 in a reaction time of 3 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ8.07 (1H, s), 7.65 (1H, d), 7.51 (1H, d), 4.42-4.31 (2H, 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 (3H, s) ppm.
MS (APCI): m / z 397 [M + H] ⁺ , 395 [MH] ^-
Example 32: Methyl 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-carboxylate

Prepared from the trichloromethylbenzimidazole of Preparation Example 17 by the method of Example 24 in a reaction time of 3 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ8.41 (1H, s), 8.03 (1H, d), 7.73 (1H, d), 4.44-4.34 (2H, 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, m), 2.37 (3H, s) ppm.
MS (APCI): m / z 329 [M + H] ⁺ , 327 [MH] ^-
Example 33: 5-Chloro-6-fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from the trichloromethylbenzimidazole of Preparation Example 18 by the method of Example 24 in a reaction time of 1.5 hours to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.76 (1H, d), 7.48 (1H, d), 4.38-4.28 (2H, 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] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Preparation Example 19 by the method of Example 24 in a reaction time of 1.5 hours to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.41 (2H, s), 4.34-4.21 (2H, m), 3.88-3.70 (2H, m), 3.08-2.92 (2H, m), 2.79-2.72 (2H, m), 2.49-2.45 (2H, m), 2.37 (6H, s), 2.32 (3H, s) ppm.
MS (APCI): m / z 297 [M + H] ⁺ , 299 [MH] ^-
Example 35: 5,6-Dichloro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Preparation Example 20 by the method of Example 24 in a reaction time of 16 hours to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.81 (2H, s), 4.39-4.28 (2H, m), 3.92-3.72 (2H, m), 3.15-2.94 (2H, m), 2.79-2.70 (2H, m), 2.56-2.48 (2H, m), 2.35 (3H, s) ppm.
MS (APCI): m / z 339/341 [M + H] ⁺ , 337/339 [MH] ^-
Example 36: 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -5- (trifluoromethyl) -1H-benz Imidazole

2- (Trichloromethyl) -5- (trifluoromethyl) -1H-benzimidazole (Production Example 21) (100 mg, 0.33 mmol) dissolved in a mixture of acetonitrile and water (3.2 ml, volume ratio 3: 1) Was reacted with (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (83 mg, 0.66 mmol) and potassium carbonate (0.24 ml of 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, dried (sodium sulfate) and the solvent removed in vacuo. Purification on silica gel by flash column chromatography eluting with dichloromethane: methanol: 880 ammonia (95: 5: 0.5 by volume) gave the title compound as a colorless solid (20 mg).
¹ H NMR (400MHz, CD ₃ OD): δ8.00 (1H, s), 7.80 (1H, d), 7.59 (1H, d), 4.42-4.30 (2H, m), 3.93-3.74 (2H, m ), 3.14-2.95 (2H, m), 2.79-2.72 (2H, m), 2.55-2.51 (2H, m), 2.34 (3H, s) ppm.
MS (APCI): m / z 339 [M + H] ⁺ , 337 [MH] ^-
Example 37: 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-carboxylic acid

Methyl 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-carboxylate (1.6 g, 5.0 mmol) in a mixture of water (8 ml) and 1,4-dioxane (60 ml) was reacted with sodium hydroxide (0.6 g, 15.0 mmol) and the resulting suspension was heated to reflux 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, filtered, and the solvent removed in vacuo to give the title compound as a colorless solid (1.41 g).
¹ H NMR (400MHz, CD ₃ OD): δ8.33 (1H, bs), 7.98 (1H, d), 7.64-7.60 (1H, m), 3.50-3.41 (2H, m), 3.20-3.12 (4H , m), 2.90-2.88 (2H, m), 2.68-2.60 (2H, m), 2.48 (3H, s) ppm.
MS (APCI): m / z 315 [M + H] ⁺ , 313 [MH] ^-
Example 38: 4-Chloro-6-fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from the trichloromethylbenzimidazole of Production Example 22 by the method of Example 24 in a reaction time of 16 hours to give the title compound as a pale yellow foam.
¹ H NMR (400MHz, CD ₃ OD): δ7.32-7.29 (1H, dd), 7.24-7.22 (1H, dd), 4.45-4.33 (2H, 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 (3H, s) ppm.
MS (APCI): m / z 323/325 [M + H] ⁺ , 321/323 [MH] ^-
Example 39: 4,6-dichloro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Production Example 23 by the method of Example 24 in a reaction time of 16 hours to give the title compound as a pale yellow foam.
¹ H NMR (400MHz, CD ₃ OD): δ7.60 (1H, s), 7.38 (1H, s), 4.44-4.32 (2H, m), 3.95-3.75 (2H, m), 3.17-2.99 (2H , m), 2.84-2.77 (2H, m), 2.58-2.54 (2H, m), 2.37 (3H, s) ppm.
MS (APCI): m / z 339/341 [M + H] ⁺ , 337/339 [MH] ^-
Example 40: 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -5-phenyl-1H-benzimidazole

Prepared from the trichloromethylbenzimidazole of Production Example 24 by the method of Example 24 in a reaction time of 16 hours to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.88 (1H, s), 7.75 (1H, d), 7.69-7.67 (2H, m), 7.63-7.61 (1H, 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 (3H, s) ppm.
MS (APCI): m / z 347 [M + H] ⁺ , 345 [MH] ^-
Example 41: 5-Fluoro-4-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from the trichloromethylbenzimidazole of Production Example 25 by the method of Example 24 in a reaction time of 16 hours to give the title compound as a yellow foam.
¹ H NMR (400MHz, CD ₃ OD): δ7.49-7.46 (1H, m), 7.13-7.08 (1H, m), 4.43-4.31 (2H, 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 (3H, s) ppm.
MS (APCI): m / z 303 [M + H] ⁺ , 301 [MH] ^-
Example 42: 5-chloro-2-{[(3aR, 6aS) -5-ethylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

A solution of the compound of Example 8 (170 mg, 0.58 mmol) in dichloromethane (5 ml) was reacted with acetaldehyde (66 l, 1.18 mmol), acetic acid (33 l, 0.58 mmol) and sodium triacetoxyborohydride (147 mg, 70 mmol). And the resulting mixture was stirred at room temperature for 16 hours. Additional dichloromethane (20 ml) and saturated aqueous sodium bicarbonate (20 ml) were added and the organic phase was separated. The aqueous phase was extracted with additional dichloromethane (20 ml) and the combined organic phases were dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (volume ratio changed from 99: 1: 0.1 to 90: 10: 1) to give the title compound as a pale yellow solid (60 mg ).
¹ H NMR (400MHz, CD ₃ OD): δ7.67 (1H, s), 7.46 (1H, d), 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) ppm.
MS (APCI): m / z 318/320 [M + H] ⁺ , 316/318 [MH] ^-
Example 43: 5-chloro-2-{[(3aR, 6aS) -5-isopropylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-indole

Prepared by the method of Example 42 using the compound of Example 8 and acetone to give the title compound as a colorless solid.
¹ H NMR (400MHz, DMSO _d6 ): δ11.75 (1H, s), 7.69 (1H, s), 7.46 (1H, dd), 7.21 (1H, 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-ethylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared by the method of Example 42 using the compound of Example 6 and acetaldehyde to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.70-7.68 (1H, m), 7.66 (1H, s), 7.30 (1H, d), 4.42-4.33 (2H, m), 3.93-3.79 (2H , m), 3.13-2.90 (4H, m), 2.61-2.53 (4H, m), 1.17 (3H, t) ppm.
MS (APCI): m / z 319/321 [M + H] ⁺ , 317/319 [MH] ^-
Example 45: 5-chloro-2-{[(3aR, 6aS) -5-isopropylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared by the method of Example 42 using the compound of Example 6 and acetone to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.70-7.67 (2H, m), 7.36-7.34 (1H, m), 4.43-4.31 (2H, m), 3.92-3.80 (2H, m), 3.13 -2.98 (4H, m), 2.56-2.46 (3H, m), 1.17 (6H, d) ppm.
MS (APCI): m / z 333/335 [M + H] ⁺ , 331/333 [MH] ^-
Example 46: 2-[(3aR, 6aS) -5-[(5-Chloro-1H-benzimidazol-2-yl) carbonyl] hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl ]ethanol

Prepared by the method of Example 42 using the compound of Example 6 and 1,4-dioxane-2,5-diol to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.70-7.65 (2H, m), 7.36-7.33 (1H, m), 4.38-4.36 (2H, m), 3.94-3.78 (2H, m), 3.70 (2H, t), 3.13-2.92 (4H, m), 2.73-2.65 (4H, m) ppm.
MS (APCI): m / z 335/337 [M + H] ⁺ , 333/335 [MH] ^-
Example 47: 7-Fluoro-5-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

A solution of the aniline of Preparation 28 (79 mg, 0.56 mmol) in acetic acid (3 ml) was reacted with methyl-2,2,2-trichloroacetimidate (77 l, 0.62 mmol) and the resulting solution was allowed to react at room temperature for 16 Stir for hours. Water (10 ml) was added and the reaction was stirred for an additional hour. The precipitate was collected by filtration and dried in vacuo. The resulting solid was suspended in a mixture of acetonitrile and water (volume ratio 3: 1, 4 ml) and (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (148 mg, 1.17 mmol) Was reacted with a solution dissolved 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 × 15 ml), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (volume ratio changed from 99: 1: 0.1 to 93: 7: 0.7) gave the title compound as a colorless solid (133 mg).
¹ H NMR (400MHz, CD ₃ OD): δ7.19 (1H, s), 6.87-6.84 (1H, d), 4.39-4.27 (2H, m), 3.90-3.84 (1H, m), 3.75-3.71 (1H, m), 3.09-2.95 (2H, m), 2.79-2.72 (2H, m), 2.51-2.40 (2H, m), 2.46 (3H, s), 2.33 (3H, 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] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from the diamine of Preparation Example 29 using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.43 (1H, d), 7.30 (1H, d), 4.40-4.29 (2H, m), 3.90-3.85 (1H, m), 3.76-3.72 (1H , m), 3.08-2.95 (2H, m), 2.80-2.73 (2H, m), 2.62 (3H, s), 2.51-2.47 (2H, m), 2.33 (3H, s) ppm.
MS (APCI): m / z 319 [M + H] ⁺ , 317 [MH] ^-
Example 49: 4-Fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from 3-fluorobenzene-1,2-diamine using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.41 (1H, d), 7.31-7.26 (1H, m), 7.03-6.98 (1H, m), 4.40-4.28 (2H, m), 3.91-3.85 (1H, m), 3.77-3.73 (1H, m), 3.11-2.95 (2H, m), 2.80-2.73 (m, 2H), 2.52-2.49 (m, 2H), 2.33 (3H, s) ppm.
MS (APCI): m / z 289 [M + H] ⁺ , 287 [MH] ^-
Example 50: 4,6-Dimethyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole

Prepared from 3,5-dimethylbenzene-1,2-diamine using the method of Example 47 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.22 (1H, s), 6.94 (1H, s), 4.37-4.24 (2H, m), 3.89-3.84 (1H, m), 3.76-3.71 (1H , m), 3.09-2.92 (2H, m), 2.81-2.73 (2H, m), 2.55 (3H, s), 2.49-2.44 (2H, m), 2.42 (3H, s), 2.33 (3H, s ) ppm.
MS (APCI): m / z 299 [M + H] ⁺ , 297 [MH] ^-
Example 51: 4,5,6,7-tetrafluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl}- 1H-benzimidazole

Prepared from 3,4,5,6-tetrafluorobenzene-1,2-diamine using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, DMSO _d6 ): δ4.22-4.17 (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 [MH] ^-
Example 52: 6-Fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -4- (trifluoromethyl) -1H-benzimidazole

Prepared from 5-fluoro-3- (trifluoromethyl) benzene-1,2-diamine using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.57 (1H, d), 7.42 (1H, d), 4.39-4.33 (2H, m), 3.91-3.72 (2H, m), 3.10-2.97 (2H , m), 2.80-2.73 (2H, m), 2.54-2.50 (2H, m), 2.34 (3H, s) ppm.
MS (APCI): m / z 357 [M + H] ⁺ , 355 [MH] ^-
Example 53: 6-Fluoro-4-iodo-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from 5-fluoro-3-iodobenzene-1,2-diamine using the method of Example 47 to give the title compound as a yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.53 (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, m), 2.80-2.74 (2H, m), 2.54-2.50 (2H, m), 2.34 (3H, s) ppm.
MS (APCI): m / z 415 [M + H] ⁺ , 413 [MH] ^-
Example 54: 6-chloro-4-fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from 5-chloro-3-fluorobenzene-1,2-diamine using the method of Example 47 to give the title compound as a yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.76 (1H, d), 7.50-7.48 (1H, m), 4.38-4.28 (2H, 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 (2H, m), 2.33 (3H, s) ppm.
MS (APCI): m / z 323 [M + H] ⁺ , 321 [MH] ^-
Example 55: 6-chloro-5-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benz Imidazole

Prepared from 4-chloro-5-methylbenzene-1,2-diamine using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.67 (1H, s), 7.55 (1H, s), 4.37-4.25 (2H, m), 3.90-3.84 (1H, m), 3.75-3.71 (1H , m), 3.09-2.95 (2H, m), 2.79-2.72 (2H, m), 2.51-2.49 (2H, m), 2.47 (3H, s), 2.33 (3H, s) ppm.
MS (APCI): m / z 319 [M + H] ⁺ , 317 [MH] ^-
Example 56: 2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole-5-carbonitrile

Prepared from 3,4-diaminobenzonitrile using the method of Example 47 to give the title compound as a light brown solid.
¹ H NMR (400MHz, CD ₃ OD): δ8.09 (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 [MH] ^-
Example 57: 6-Fluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -5- (trifluoromethyl) -1H-benzimidazole

Prepared from 4-fluoro-5- (trifluoromethyl) benzene-1,2-diamine using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ8.01-8.00 (1H, d), 7.54-7.51 (1H, d), 4.41-4.30 (2H, m), 3.92-3.86 (1H, m), 3.77 -3.72 (1H, m), 3.10-2.96 (2H, m), 2.79-2.72 (2H, m), 2.55-2.51 (2H, m), 2.34 (3H, s) ppm.
MS (APCI): m / z 357 [M + H] ⁺ , 355 [MH] ^-
Example 58: 4,5,6-trifluoro-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H- Benzimidazole

Prepared from 3,4,5-trifluorobenzene-1,2-diamine using the method of Example 47 to give the title compound as a colorless solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.33-7.30 (1H, m), 4.40-4.30 (2H, m), 3.90-3.71 (2H, m), 3.11-2.95 (2H, m), 2.79 -2.73 (2H, m), 2.55-2.50 (2H, m), 2.34 (3H, s) ppm.
MS (APCI): m / z 325 [M + H] ⁺ , 323 [MH] ^-
Example 59: 1- (5,6-difluoro-1H-benzimidazol-2-yl) -1-[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H ) -Il] methanimine

A suspension of trichloromethylbenzimidazole (1.17 g, 4.3 mmol) of Preparation Example 12 and 4A molecular sieve (1 g) in acetonitrile (15 ml) was added to (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c It was reacted with a solution of pyrrole (598 mg, 4.74 mmol) in acetonitrile (2 ml). The resulting mixture was stirred at room temperature for 30 minutes before ammonium acetate (397 mg, 5.16 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate (20 ml) and this mixture were extracted with dichloromethane (3 × 20 ml). The combined organic phases were dried (sodium sulfate) and reduced by reduced pressure. Purification by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (volume ratio changed from 98: 2: 0.2 to 90: 10: 1) gave the title compound as a light brown solid (155 mg) .
¹ H NMR (400MHz, CD ₃ OD): δ7.37 (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.
MS (APCI): m / z 306 [M + H] ⁺ , 304 [MH] ^-
Alternative to Example 59: 1- (5,6-difluoro-1H-benzimidazol-2-yl) -1-[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole- 2 (1H) -yl] methanimine Preparation Example 33 nitrile (8.66 g, 48.3 mmol) and (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (7.32 g, 58.0 mmol) isopropanol The (100 ml) solution was heated to reflux for 3 hours. The reaction mixture was slowly cooled to room temperature and the resulting precipitate was collected by filtration, washed with additional 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-[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H)- Il] methanimine

Prepared from the trichloromethylbenzimidazole of Preparation Example 32 using the method of Example 59 to give the title compound as a pale yellow solid.
¹ H NMR (400MHz, CD ₃ OD): δ7.58-7.54 (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, s) ppm.
MS (APCI): m / z 288 [M + H] ⁺ , 286 [MH] ^-
6-bromo-4-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole and 6- Fluoro-4-methyl-2-{[(3aR, 6aS) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] carbonyl} -1H-benzimidazole is the same or similar It was manufactured using the method.

  Examples 61-64 were prepared from the trichloromethylbenzimidazole precursor shown in the table below by the following procedure: A solution of trichloromethylbenzimidazole (0.75 mmol) in ethanol (3 ml) was cooled to 0 ° C. It was then reacted with a solution of 880 ammonia (3 ml) in water (3 ml). The resulting mixture was then allowed to warm slowly to room temperature. After 2 hours, the pH was adjusted to pH 1 by the addition of 2N hydrochloric acid. The reaction mixture was extracted with dichloromethane (2 × 20 ml) and the combined extracts were reduced by reduced pressure. The resulting solid is dissolved in methanol (3 ml) and reacted with N-acetylcysteine (1 mmol) and (3aR, 6aS) -2-methyloctahydropyrrolo [3,4-c] pyrrole (0.8 mmol), and Heated at 40 ° C. for 2.5 hours. The reaction was cooled to room temperature and purified on a strong cation exchange resin by eluting non-basic impurities with methanol and eluting the basic product with 2M ammonia / 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 changed from 95: 5: 0.5 to 90: 10: 1) to give the desired A compound was obtained.

Examples 65-68 were prepared from the bisaniline precursors shown in the table below by the following procedure: A solution of the aniline precursor (79 mg, 0.50 mmol) in acetic acid (3 ml)
Reacted with methyl-2,2,2-trichloroacetimidate (0.55 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 trichloromethylbenzimidazole intermediate was collected by filtration, dried under reduced pressure, and the desired compound was then obtained by the steps described for Examples 61-64.

Biology section
Cell pellets from CHO cells expressing H ₄ binding histamine H ₄ receptor were ice-cold, 50 mM Tris-HCl / 0.5 mM CaCl ₂ containing protease inhibitor cocktail (Roche®, UK) Homogenized in a buffer using a ground glass homogenizer. The homogenate was centrifuged at 48000 g for 30 minutes at 4 ° C. The membrane pellet was resuspended in fresh buffer and the above centrifugation step was repeated. The membrane pellet was resuspended in the same volume of 50 mM Tris-HCl as the original cell pellet. An aliquot of the membrane preparation was stored at −80 ° C. and used for [ ³ H] -histamine binding experiments.

Cell membranes (20-35 μg / well) were shaken with 3 nM [ ³ H] -histamine (23 Ci / mmol) in 50 mM Tris-HCl (pH 7.4) in the presence or absence of competing H ₄ ligands. And incubated for 90 minutes at room temperature. The reaction was stopped by rapid filtration through a unifilter GF / B plate (Packard) soaked in 0.5% polyethyleneimine, and then washed 1 ml x 3 times with ice-cold 50 mM Tris-HCl. Filters were dried at 45 ° C. for 45 minutes and bound radiolabel was determined using scintillation counting techniques. Nonspecific binding was defined using 5 μM clobenpropit. For competition binding studies, Cheng-Prussoff _{equation: K i = (IC 50)} / according (1 + ([L] / K d)), the ligand K _d = 3.5 nM and a ligand concentration = 3 nM were determined experimentally Based on the IC ₅₀ value, the Ki value was calculated.

Compounds of the Examples were tested in the above H ₄ binding assay, and found to have a smaller K _i values than 13μM in binding assays based on H ₄ cells. Preferred embodiments have K _i values of less than 1 μM in the H ₄ binding assay. As shown in the table below, the most preferred example has a K _i value of less than 120 nM in a binding assay based on H ₄ cells.

Claims (16)

Compound of formula (I):

(At this time:
R ¹ is (C ₁ -C ₄ ) alkyl optionally substituted with H or hydroxy;
X is N or CR ⁹ (where R ⁹ is H or methyl);
Y is O or NH;
R ⁶ is H or methyl; andR ² , R ³ , R ⁴ and R ⁵ are independently H, halo, cyano, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, (CH ₂ ) _n -C (O) OR ⁷ , (CH ₂ ) _n -O- (CH ₂ ) _m -R ⁸ and (CH ₂ ) _n -R ^And n and m are each independently 0 or 1, R ⁷ is H or (C ₁ -C ₄ ) alkyl, and R ⁸ is phenyl)
Or a pharmaceutically acceptable salt and solvate thereof. The compound of formula (I) or a salt and solvate thereof according to claim 1, wherein R ¹ is H or methyl. The compound of formula (I) or a salt and solvate thereof according to claim 1 or 2, wherein R ⁶ is H. The compound of formula (I) or a salt and solvate thereof according to any one of claims 1 to 3, wherein X is N or CH. R ^2, R ^3, R ⁴ and R ⁵ are independently H, halo, methyl, hydroxy, phenyl and COOH, the compounds of formula (I) according to any one of claims 1 to 4 Or salts and solvates thereof. R ^2, R ^3, R ⁴ and R ⁵ are independently H, fluoro, chloro, bromo, methyl, hydroxy, phenyl and COOH, compound of the formula (I) according to claim 5 And solvates. At least two are H, the compound or salts and solvates thereof of formula (I) according to any one of claims 1 to 6 of R ^2, R ^3, R ⁴ and R ^5. The compound of formula (I) or a salt and solvate thereof according to any one of claims 1 to 7, having a cis configuration (3aR, 6aS). A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient. 9. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined in any one of claims 1-8 for use as a medicament. H ₄ ligand for the manufacture of a medicament for treating a disease that is required, the compound or a pharmaceutically acceptable salt or solvate of formula as defined in any one of claims 1 to 8 (I) Use of Japanese products. Inflammatory diseases, respiratory diseases (eg adult respiratory distress syndrome, acute dyspnea syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic ethmoid sinusitis), Allergies, allergen-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic hyperemia, female and male sexual dysfunction, skin diseases such as dermatitis and psoriasis Selected from: cardiac dysfunction such as myocardial ischemia and arrhythmia, gastrointestinal disorders such as inflammatory bowel disease, Crohn's disease and ulcerative colitis, cancer, rheumatoid arthritis, hypotension, pain and overactive bladder condition Use of a compound of formula (I) according to claim 11 for the manufacture of a medicament for the treatment of certain diseases. H ₄ suffering from a disease ligand is required, a method of treating a mammal, including a human, to said mammal, formula as defined in any one of claims 1 to 8 (I) A method comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt, solvate or composition thereof. 14. The method of claim 13, wherein the disease is selected from the diseases of claim 12. A process for obtaining a compound of formula (I) as defined in any one of claims 1 to 8 and a salt or solvate thereof, comprising the following steps:
1) When Y is O
Acid of formula (II):

An amine of formula (III):

(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 2) When Y is NH and X is N,
Trichloromethylbenzimidazole of formula (VI):

Is condensed with an ammonia source and an amine of formula (III) (where R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are defined in any one of claims 1 to 10) Or 3) when Y is NH and X is N,
An amine of formula (III) is converted to a nitrile of formula (VIII):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in any one of claims 1 to 10);
4) When Y is NH and X is CR ⁹
Thioamide of formula (IX):

Is condensed with ammonia or an ammonia equivalent (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in any one of claims 1 to 10). . A 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 H ₁ receptor antagonists, especially loratidine, desloratidine, fexofenadine and cetirizine,
Histamine H ₃ receptor antagonist,
Histamine H ₂ receptor antagonist,
Leukotriene antagonists, including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ , especially montelukast,
Phosphodiesterase inhibitors, i.e. PDE4 inhibitors and PDE5 inhibitors,
・ Neurotransmitter reuptake inhibitors, especially fluoxetine, cetraline, paroxetine, ziprasidone,
A 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,
An α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictive sympathomimetic agent for use as a decongestant,
A muscarinic M3 receptor antagonist or anticholinergic agent,
Β ₂ -adrenergic receptor agonist,
・ Theophylline,
・ Cromoglycate sodium,
-COX-1 inhibitor (NSAID) and COX-2 selective inhibitor,
Oral or inhaled glucocorticosteroids,
A monoclonal antibody active against endogenous inflammatory units,
・ Anti-tumor necrosis factor (anti-TNF-α) agent,
-Adhesion molecule inhibitors including VLA-4 antagonists,
Kinin-B ₁ -and B ₂ -receptor antagonists,
・ Immunosuppressants,
An inhibitor of matrix metalloprotease (MMP),
Tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,
An elastase inhibitor,
Adenosine A2a receptor agonist,
An inhibitor of urokinase,
Compounds acting on dopamine receptors, such as D2 agonists,
Modulators of · NF _K b pathway, e.g. IKK inhibitors,
Drugs that can be classified as mucolytics or antitussives,
·Antibiotics,
A modulator of cytokine signaling pathway, such as p38 MAP kinase inhibitor, syk tyrosine kinase inhibitor or JAK kinase inhibitor,
Prostaglandin D2 receptor antagonist (DP1 and CRTH2),
・ Inhibition of prostaglandin D synthase (PGDS),
An inhibitor of phosphoinositide-3-kinase, and an HDAC inhibitor.