SK136799A3 - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity - Google Patents

Abstract

Novel compounds, compositions and methods effective for the prevention and treatment of mast-cell mediated inflammatory disorders are described. A preferred aspect of the invention are compounds of Formula (II) in which: the dashed lines independently represent optional bonds; each R<2> independently is (C1-6)alkyl, (C1-6)alkyloxy, halo or hydroxy; each R<3> independently is (C1-6)alkyl, (C1-6)alkyloxy, halo or hydroxy; X<3> is -C(O)- or -CR<7>R<8>-, X<8> is -CH(R<1>)n1- or -C(R<1>)n1=, wherein R<1> is amino(N1-4)azolidinyl, amino(N1-4)azolyl, (N1-4)azolidinyl, (N1-4)azolyl, -NHC(NH)NR<9>R<9>, -C(NR<9>)R<9>, -C(NH)NHR<10>, -C(NH)NR<10>R<10> or -(CR<11>R<11>)yNH2, or X<8> is -N= or -NH(R<1>)n1-, wherein R<1> is -C(NR<9>)R<9>, -C(NH)NHR<10> or -C(NH)NR<10>R<10>, wherein each R<9> independently is hydrogen or (C1-6)alkyl and each R<10> independently is (C1-6)alkyl; and X<9> is -CH(R<4>)- or -C(R<4>)=, wherein R<4> is -R<12>, -OR<12>, -N(R<13>)R<12>, -SR<12>, -S(O)R<12>, -S(O)2R<12>, -S(O)2OR<12>, -S(O)2N(R<13>)R<12>, -N(R<13>)S(O)2R<12>, -C(O)R<12>, -C(O)OR<12>, -C(O)N(R<13>)R<12>, -N(R<13>)C(O)R<12>, -OC(O)N(R<13>)R<12>, -N(R<13>)C(O)OR<12>, -(CH2)n4N(R<13>)C(O)N(R<13>)R<12>, -OP(O)(OR<13>)OR<12> or -C(O)N(R<14>)CH(COOH)R<12>, or X<9> is -N= or -N(R<4>)-, wherein R<4> is -C(O)R<12>, -C(O)OR<12>, -C(O)N(R<13>)R<12>, -OC(O)N(R<13>)R<12> or -C(O)N(R<14>)CH(COOH)R<12>, wherein R<12>, R<13> and R<14> are as defined in the Summary of the Invention; R<5> is hydrogen or (C1-4)alkyl, R<6> is hydrogen or (C1-4) alkyl, which alkyl optionally is substituted with one to two substituents independently selected from (C1-4)alkyloxy, hydroxy and sulfo, R<7> is hydrogen or methyl and R<8> is hydrogen, methyl or hydroxy. The compounds, compositions and methods are effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other types of immunomediated inflammatory disorders, such as rheumatoid arthritis, conjunctivitis and inflammatory bowel disease, various dermatological conditions, as well as certain viral conditions. The compounds comprise potent and selective inhibitors of the mast cell protease tryptase. The compositions for treating these conditions include oral, inhalant, topical and parenteral preparations as well as devices comprising such preparations.

Description

Compounds and compositions for treating diseases associated with serine protease activity, particularly tryptase

Technical field

This application is a continuation of Serial Number 08/833674 filed April 7, 1997, which is a continuation of Serial Number 08/357491 filed December 14, 1994, which is incorporated by reference, and relates to compounds and compositions for treating diseases associated with serine protease activity, especially tryptases.

BACKGROUND OF THE INVENTION

Tryptase is the predominant protease secreted from human mast cells and is involved in neuropeptide processes and tissue inflammation. Tryptase concentrations in the bloodstream are elevated hours after anaphylaxis (Schwartz et al., (1987) N. Eng. J. Med. 316: 1622-1626), are elevated in the lavage nasal and lung fluid present in atopic patients. exhibiting specific antigen stimulation (Castells et al., (1988) J. Allerg. Clin. Immunol. 141: 563-568) and are elevated in pulmonary lavage fluid in atopic asthma patients with endobronchial allergenic stimulation. Smokers often have a noticeable increase in tryptase levels in bronchoalveolar lavage fluid. This finding supports the hypothesis that proteinase release from activated mast cells is involved in lung destruction in smoking enphysema (Celenteron et al., (1988) Chest 94: 119-123). Tryptase is also an effective mitogen in fibroblasts and is involved in the development of pulmonary fibrosis and interstitial lung diseases (Ross et al., (1991) J. Clin. Invest. 88: 493-499).

Asthma is an inflammatory disease (Hood et al Benjamin-Cummings, Immunology, second edition), characterized by an increased response of trachea and bronchi to immunospecific allergens and generally to chemical or physical stimuli. Both acute and chronic disease include a number of biochemical mediators. The increased response of asthmatic bronchial tissue is the result of chronic inflammation that irritates and destroys the epithelium lining the bronchial pathways and changes it pathologically. Signs of inflammation in patients with mild asthma will be shown by biopsy of the bronchial tract.

The inflammatory process may trigger allergic responses to the inhaled allergen. For example, the allergens can activate mast and basophil cells that are present in the epithelium and the underlying smooth muscle tissue layer by binding IgEs that are on the surface of these cells.

mast cells release a number of precursors or chemical mediators of inflammation (e.g., histamine) and generate a number of other secondary mediators of inflammation directly at the site of inflammation (e.g., hyperoxide, lipid-derived mediators). In addition, some large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by mast cell degradation.

Mediator precursors contained in mast cells are likely to play a role in early bronchial spasm in asthma caused by aerial allergens. The peak of the early phase of the asthmatic reaction occurs about 15 minutes after exposure to the allergen, and is generally followed within 1 to 2 hours by a return to baseline. 25 to 35%

, / 1984 / in: which ones 3 ^e bronchi on the

The activated primary patient population has experience of subsequent respiratory function that lasts 6 to 12 hours after exposure. This late reaction phase is accompanied by an increased number of inflammatory cells (e.g. eosinophils, neutrophils, lymphocytes, etc.) that infiltrate bronchial tissue. Infiltrating inflammatory cells are chemotactically attracted by substances released from mast cells activated during the deterioration of the late reaction phase. The late asthmatic response is probably a secondary inflammatory response based on the secretively active granulocyte region.

Tryptase is involved in the degradation of vasodilatory and bronchorelaxant neuropeptides (Caughey et al., (1988) J. Pharmacol. Εαρ. Ther. 244: 133-137; Franconi et al., (1988)

J. Pharmacol. Exp. Ther. 248: 947-951; Tam et al., (1990) Am. J. Respir. Cell Mol. Biol. 3: 27-32) and modulates bronchial sensitivity to histamine (Sekizawa et al., (1989) J. Clin. Invest. 83: 147-179). These findings suggest that tryptase may increase bronchoconstriction in asthma through the destruction of peptides with bronchodilator effect. Tryptase cleaves fibrinogen chains and high molecular weight kininogen, suggesting that tryptase, together with heparin, has the role of a local anticoagulant. Tryptase activates prostromelysine (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, suggesting that tryptase is involved in tissue inflammation and remodeling, which are part of the destructive changes in rheumatoid arthritis. Administration of tryptase inhibitors prevents the development of a late respiratory hypersensitivity phase in sheep allergized and inhibits the immediate skin response after intradermal injection of allergen sheep allergen. All of the above teachings clearly point to the applicability of tryptase inhibitors as therapeutic agents in the treatment of asthma and other diseases associated with inflammation of the respiratory tract.

Descriptions of these and other documents, including patents and patent applications relating to this application, are set out in the Annex.

SUMMARY OF THE INVENTION

The invention relates to a compound of formula I:

(R ² ) "2

wherein n 1 is 0 or 1; n 2 is 0,1,2,3 or 4; n 3 is 0,1,2,3 or 4;

A together with B form a fused heterobicyclic group containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom optionally being a heteroatom, X ¹ and X ² are adjacent aromatic ring members and X ³ is a heteroatom selected of -N =, -NR ⁵ -, -O- and -S- wherein ^R5 is hydrogen, (Ci_6> alkyl or hetero (C ₂ -6) alkyl;

C is a fused heteropolycyclic group containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, wherein any ring atom may be a heteroatom, X ⁴ and X ⁵ are adjacent aromatic ring members, X ⁵ is a heteroatom selected from -N =, -NR ⁶ -, -O- and -S-, wherein R ⁶ is hydrogen, a group selected from (C ₈₎ alkyl or heteroaryl (C ₂ _ i ₂₎ alkyl, which group is optionally substituted with one to two substituents selected independently from one another of (C 1-6) alkanoyloxy, (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylammonium, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C 1-6) alkyloxy, (C 1-6) β) alkyloxycarbonyl, (C 6) alkyloxysulfonyl, amino, carboxy, carbamoyl, (n-Cg) aryl, halo, hetero (C ₄ -i ₅₎ aryl, hydroxy and sulfo, or as defined below; and any carbocyclic keto, thioketo and iminoketo derivative thereof;

X ³ is -O-, -S-, -S (O) -, -S (O) 2, -C (O) -, -NR ⁷ - or CR ⁷ R ⁸ -, wherein R ⁷ is hydrogen, ( Ci_6) alkyl, hetero (C ₂ _i ₂₎ alkyl or together with R ⁶ form a (C2-4) alkylene or hetero (C2-4) alkylene and R ⁸ is hydrogen, (Ci_6) alkyl or hydroxy or together with R ⁷ form a ( C ₂ _ ₆₎ alkylene or (C β) alkylidene, wherein any or alicyclic groups ^R7 and / or ^R8 are substituted by one to three substituents of (C ₆₎ alkylamino, di (C ₆₎ alkylamino, tri (C ( C _1-6 alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C 1-6 amino, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C _1-6 ) alkyl carbamoyl, halogen and hydroxy;

R ¹ is amino (N _1-4 ) azolidinyl, amino (Ni _1-4 ) azolyl, (Ni _1-4 ) azolidinyl, ( _{N 1-4} ) azolyl, carbamoyl, cyano, - (CH ₂ ) _X NHC (NR ⁹ ) R ⁹ , aliphatic selectively selected

6) alkylammonium, 6) alkanoyloxy, (CH ₂ ) _X NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , (CR ¹¹ R ¹¹ ) _y NH ₂ ,

-C (NH) NR ¹⁰ R ¹⁰ or a is bonded to any atom of cycle B with available valency, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R ⁹ independently of one another hydrogen or ( C 1-6 alkyl, each R ¹⁰ is independently from each other (C 1-6) alkyl and each R ¹¹ is independently from each other hydrogen, (C 1-3) alkyl, or together with another R ¹¹ and the carbon atom to which they are both attached form cyclopropyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one or two substituents selected independently of one another from (C 1-8) alkyloxycarbonyl, (C 1-8) alkanoyloxy, carboxy, carbamoyl, (C 1-8) alkyl carbamoyl, di (C 1-6) alkylcarbamoyl, (C _1-6 ) alkylsulfonyl and hydroxy;

each R ² is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxycarbonyl, (C _1-6 ) alkanoyloxy, (C _1-6 ) alkyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C 1-6) alkylsulfinyl, (C 1-6) alkylsulfonyl, (C 1-6) alkylthio, halogen or hydroxy, and is attached to any atom of cycle B with available valency, wherein any aliphatic group R ² is optionally substituted with one to two substituents selected independently of one another from (C 1-6) alkyloxycarbonyl, (C _1-6 ) alkanoyloxy, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy;

each R ³ is independently of one another (C _1-6 ) alkyl, (C _1-6 ) alkyloxy, (C 1-6) alkylthio, cyano, halogen, perhalogen (C _1-6 ) alkyl or hydroxy, and is bound to any atom of the C _5-6 cycle available valency; and

R ⁴ is -R ¹² , -OR ¹² , -N (R ¹³ ) R ¹² , -SR ¹² , -S (O) R ¹² , -S (O) 2 R ¹² , S (O) 2 OR ¹² , -S ( O) 2N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ¹² ,

-C (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) R ¹² , -OC (0) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (0) OR ¹² ,

- (CH ₂ ) _Z N (R ¹³ ) C (O) N (R ¹³ ) R ¹² , -0P (O) (OR ¹³ ) OR ¹² or -C (O) N (R ¹⁴ ) CH - (COOH) R ¹² , and is bonded to any ring C atom with available valency, wherein:

z is 0, 1 or 2,

R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ NI5 / NL5 which is 1 or 2, X ⁶ is (C io) alkylene, cyclo (C3_io) alkylene, hetero _(C2-IO) alkylene or heterocyclo (C ₃ _i ₀₎ alkylene and each ^R15 is independently is hydrogen, (C ₆ _i ₄₎ aryl, cyclo (C ₃ -i ₄₎ alkyl, polycyclo (CGI ₄₎ aryl, heteropolycyclo _(C6 -i ₄ ) aryl, heterocyclo (C ₃ _i ₄₎ alkyl, hetero (C5-1J or aryl as defined below;

R ¹³ is H, (C β) alkyl or hetero (C _2-6) alkyl;

R ¹⁴ is H, (Ci_e) alkyl or, together with X ⁶ and R ¹⁵ form a (C ₃ _ ₄₎ alkylene;

any aliphatic or alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C 1-6) alkyl, (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, (C _1-6 ) alkylcarbamoyl, di (C _1-6) ) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C 1-6) alkyloxycarbonyl, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, (C _1-6 ) alkylsulfonyl, (C _1-6 ) alkylsulfonyl, (C _1-6 ) alkylthio, amino, ( C _6-10 arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halogen, hydroxy, mercapto and ureido; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from cyano, guanidino, halogen, halogenated (C 1-8) alkyl, -R ¹⁶ , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , -S (O) ₂ R ¹⁶ ,

-S (O) ₂ N (R ¹³ ) R ¹⁶ , -C (O) R ¹⁶ , -C (O) OR ¹⁶ and -C (O) N (R ¹³ ) R ¹⁶ , wherein R ¹³ is as defined above, and R ^{1 S} is hydrogen, optionally mono-substituted with (C ₈₎ alkyl (wherein the optional substituent is (Cl-b alkyl) amino, di (C, β) alkylamino, tri (Ci_g) alkylammonio, (objective alkylcarbamoyl, di (C ^ g) alkyl carbamoyl, (C g) alkyloxycarbonyl, (C, g) alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C 3-6) alkyl, hetero (C ₈₎ alkyl, hetero (C ₅ _g) aryl, heterocyclo ( C3-6) alkyl or phenyl;

with the proviso that nl is 0 when n 2 is 0 or R ² is a (C) alkyl, or (Ci_6) alkoxy, n 3 is 0 and R ³ is a (C) alkyl or (C 1-6) alkyloxy and R ⁴ is hydrogen, (C 1-10) alkyl or (C 1-10) alkyloxy; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions of the compounds of the invention. These compositions may take various forms, oral dosage forms, inhalable forms, as well as injectable and infusible solutions. When an inhalation or aerosol form is used, the compounds of the present invention are used as a solution in a pharmaceutically acceptable carrier or as a dry powder which can be converted into an aerosol form. When the compounds of the present invention are used for oral administration, they are used similarly with pharmaceutically acceptable carriers suitable for oral administration. When used to treat immunologically induced skin inflammations, the compounds of the present invention are used in combination with non-toxic pharmaceutically acceptable ointment bases. The compounds of the present invention can be used in combination with anti-inflammatory drugs and other special anti-asthmatics such as βadrenergic agonists, corticosteroids, anticholinergics, bronchodilators such as methylxanthenes and the like.

The compounds described herein are useful for the prevention and treatment of immunologically induced inflammations primarily affecting pharmaceuticals, which include a combination for this respiratory tract, including asthma, particularly the hyperreactive phase accompanying chronic asthma and allergic rhinitis. The present invention further provides a method of treating immunologically induced inflammation, wherein a patient with immunologically induced inflammation is administered a therapeutically effective dose or amount of a compound of the present invention. Further disclosed herein are compounds useful for the treatment of syncytial viral infection.

DETAILED DESCRIPTION OF THE INVENTION

definitions

For purposes of this application, the following terms are defined and are used in the specification and claims, and unless otherwise indicated, have the following meanings:

Acanoyl means a -C (O) R group having the indicated total number of carbon atoms (e.g., (C 1-6) alkanoyl includes formyl, acetyl, propanoyl, butanoyl, isobutanoyl, crotonyl, isocrotonyl, etc.), wherein R is alkyl , which is defined below.

Alicyclic means any saturated or unsaturated, monocyclic or polycyclic moiety. Alicyclic means, for example, cycloalkyl (as defined herein) as well as alicyclic moieties including cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylcarbamoyl and the like.

Aliphatic means a linear or branched, saturated or unsaturated hydrocarbon moiety. Aliphatic means, for example, alkyl or heteroalkyl (as defined herein) as well as aliphatic moieties including alkyloxy, arylalkyl, heteroarylalkyl, alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroalkanoyl and the like.

Alkyl means, for the purposes of this application, a linear or branched, saturated or unsaturated aliphatic hydrocarbon group with the indicated number of carbon atoms and any keto, thioketo or iminoketo derivative thereof (e.g. (C _1-8 ) alkyl includes methyl, ethyl, propyl, isopropyl , butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylalyl, ethynyl, 1-propynyl, 2-propynyl, 3-oxopentyl , 3-thioxopentyl, 3iminopentyl, etc.).

Alkylene means a saturated or unsaturated divalent hydrocarbon group with the indicated number of carbon atoms and any keto-, thioketo-, iminoketo- or substitution derivative thereof (e.g. (C 1-10) alkylene includes methylene (-CH 2 -), ethylene (-CH ₂ CH ₂ - ), methylethylene, vinylene, ethynylene, trimethylene (-CH ₂ CH ₂ CH ₂ -), 2-oxotrimethylene (-CH 2 C (O) CH ₂ -), 2-thiatrimethylene (-CH ₂ C (S) CH ₂ -), 2-Iminotrimethylene (-CH ₂ C (NH) CH ₂ -), propenylene (-CH ₂ CH = CH- or -CH = CHCH ₂ -), propanylylidene (= CHCH ₂ CH ₂ -), propenediylene (= CHCH = CH -), 1-aminotetramethylene, pentamethylene, etc.).

Alkylidene means a group = CRR, wherein R is independently of one another hydrogen or alkyl (as defined above) having the total number of carbon atoms indicated (e.g. (C 1-6) alkylidene includes methylidene, ethylidene, propylidene, isopropylidene, etc.).

Alkyloxy means a -OR group wherein R is alkyl (as defined above) with the indicated number of carbon atoms (e.g., (C 1-6) alkyloxy includes methoxy, ethoxy, propoxy, isopropoxy, isopropenyloxy, butoxy, sec.butoxy, isobutoxy, tert-butoxy , vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylalyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.).

Alkylsulfinyl, alkylsulfonyl, and alkylthio are respectively -S (O) R, -S (O) ₂ R / and -SR, wherein R is alkyl (as defined above) with the indicated number of carbon atoms (e.g., (C 1 -b) ) alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propenylsulfonyl, isopropenylsulfonyl, 1-butenylsulfonyl, 2-butenylsulfonyl, 3-butenylsulfonyl, 3-butenylsulfonyl, , sulfonyl, 2-propynylsulfonyl, etc.).

Ammonio means -NH ₃ ⁺

Amidino is -C (NH) _NH2

1-propynylamine is -NH ₂

Animals include humans and other mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g., birds, etc.)

Aryl means an aromatic monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms, wherein each ring of the group is composed of six ring members (e.g. (C ₆ -i4) aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.).

Arylsulfonyl means the group -S (O) ₂ R, wherein R is aryl (as defined above) indicating the number of carbon atoms (e.g. (C _6-10 ) arylsulfonyl includes phenylsulfonyl, naphth-1-ylsulfonyl, etc.).

An aromatic group means any aromatic part of the group. An aromatic group includes, for example, aryl and heteroaryl (as defined herein), as well as aromatic moieties including arylalkyl, heteroarylalkyl, polycycloaryl, heteropolycycloaryl, and the like.

Azolidinyl means a saturated or unsaturated 5-membered monocyclic group with the indicated number of nitrogen atoms.

For example, ( _N-4 ) azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, triazolidinyl and tetraazolidinyl, dihydroII pyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.

Azolyl means an aromatic 5-membered monocyclic group containing the indicated number of nitrogen atoms. For example, (Ni- ₄ ) azolyl includes pyrrole, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.

Carbamoyl is -C (O) _NH2

Carboxy is -C (O) OH

Cyano is -CN

Cycloalkyl represents a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms, wherein each ring of the group comprising 3 to 8 ring members, and carbocyclic Any possible a keto, thioketone or iminoketoderivát (e.g., (C ₃ _i ₄₎ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5cyclohexadienyl, bicyclo [2.2.2] octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.).

Cycloalkylene means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon divalent group containing a designated number of carbon atoms, each ring of which includes 3 to 8 ring members, and any carbocyclic keto, thioketo or iminoketoderivative thereof (e.g. (C ₃ - ₁₀ ) cycloalkylene includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,4-cyclohexylene, 3-cyclohexen-1,2-ylene, 2 5-cyclohexadiene-1,4-ylene, 1,4-bicyclo [2.2.2] octylene, 5-oxo-1,3cyclohexylene, 2,5-dioxo-1,4-cyclohexylene, 5-thioxo-1,4-cyclohexylene , etc.).

Removal ”as used herein means the removal of any protecting group or groups present after the selective reaction.

In particular, the disease includes any non-physiological condition of individual organs that may be caused by iatrogenic medical or veterinary treatment, i. j. the side effects of such treatment or the individual.

A fused heteropolycyclic group includes a fused heterobicyclic group and means a heterocyclic group containing two to three fused rings having the indicated number of ring members, wherein at least two members of one ring are part of the other ring (e.g. heteropolycyclic group containing 8 to 18 ring atoms and their carbocyclic keto - and thioketo derivatives include 1H-benzimidazol-2-yl, 1H-naphtho [2,3-d] imidazol-2-yl, 1H-imidazo [4,5-f] quinolin-2-yl, 1H-imidazo [4, 5-b] pyridin-2-yl, 1H-phenantro [9,10-d] imidazol-2-yl, 1H-imidazo [4,5-g] quinoxalin-2-yl, 2,6-dioxo-2,3,6, 7-tetrahydro-1H-purin-8-yl, 7H-purin-8yl, 1,6-dihydrocyclopentaimidazol-2-yl, 4-quinolin-2-yl, etc.).

Guanidino means -NHC (NH) NH2

Halogen means -F, -Cl, -Br or -I

Heteroatom means an atom selected from N, O, S and P

Hetero means, unless otherwise indicated, a group selected from -N =, -NR ¹⁷ -, -O-, -S-, -S (O) -, -S (O) 2 -, P (O) (OR) ¹⁷ ) -, wherein R ¹⁷ is hydrogen or (C 1-6) alkyl.

Heteroalkyl means alkyl (as defined above) wherein one or more carbon atoms are replaced by a hetero group (as defined above), and any keto, thioketo, or iminoketo derivative thereof (e.g., hetero (C 2-12) alkyl includes methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 2- (Netyl-N-methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).

Heteroalkylene means an alkylene (as defined above) in which one or more carbon atoms are replaced by a hetero group (as defined above) or a suitable combination (e.g., -0S (O) ₂ -, -S (O) ₂ -, any -N (R) S (O) ₂ -, S (O) ₂ NR ¹⁷ -, -0P (O) (OR ¹⁷ ) O-, and the like, wherein R ¹⁷ is hydrogen or (C _1-6 ) alkyl), and any iminoketo - azaetylén derivative thereof (-CH ₂ -NH-), methylene (-CH ₂ CH ₂ O-), a keto, thioketone or (e.g., hetero (C ₂ _i ₀₎ alkylene includes 2-azapropylén (CH ₂ N = CH ₂ -, 1-oxatrio-2-oxo-3-azapentamethylene, 3-aza-2-thiopentamethylene, 2-oxa-3-oxopentamethylene, 3-aza-2-iminopentamethylene (-CH ₂ CH ₂ NH-C (NH) CH ₂ -), 2,4-aza-2-methyl-3,3-dioxo-3-thiapentamethylene (-CH ₂ NHS (O) ₂ N (CH 3) CH ₂ -), 3-hydroxy-2,4-oxa-3-oxo- 3-phosphapentamethylene (-CH ₂ OP (O) (OH) OCH ₂ -), 3-aza-2-oxo-4-carboxyhexanethylene, 4-aza-1-oxa-3-oxohexamethylene, 1-thia-3oxo-4-azahexamethylene , 1-thia-1,1,3-trioxo-4-azahexamethylene (CH ₂ CH ₂ NHC (O) CH ₂ S (O) 2 -), 3-aza-4-oxoheptam ethylene, 1,4,7-trioxaoctamethylene, 6-aza-1-oxa-2,5-dioxooctamethylene (-CH ₂ CH ₂ NHC (O) CH ₂ CH ₂ C (O) O-), 3-aza-4-oxodecamethylene, etc. .).

Heteroaryl means an aromatic monocyclic or fused polycyclic divalent group containing a marked number of ring atoms, each ring containing 5 to 6 ring members and one or more ring atoms being a hetero group selected from -N =, -NR ¹⁷ -, -O- or - S-, wherein R ¹⁷ is hydrogen or (CJ ₆₎ alkyl (e.g., a hetero (C5_i ₄₎ aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl -inyl, pterdinyl, perimidinyl, imidazolyl, pyridinyl, pyratolyl, pyrazinyl, quinolinyl, etc.).

Heterocycloalkyl is a cycloalkyl (as defined above), wherein one or more of the ring carbon atoms are replaced by a heteroatom moiety (as defined above), and any of keto, thioketone or iminoketone derivative thereof (e.g. the term heterocyclo (C ₄ -i ₅₎ alkyl group includes piperidyl , pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

Heterocycloalkylene represents a cycloalkylene (as defined above), wherein one or more of the ring carbon atoms are replaced by a heteroatom moiety (as defined above), and any of keto, thioketone or iminoketone derivative thereof (e.g. the term heterocyclo (C ₃ _ ₁₄₎ alkylene includes piperidinylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).

Heteropolycycloaryl means a polycycloaryl (defined below) in which one or more ring carbon atoms are replaced by a hetero group (as defined above) and any keto, thioketo- or iminoketo- derivative thereof (e.g., heteropolycyclo (C _8-10 ) aryl includes 3,4 dihydro-2H-quinolinyl,

5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H- [1,8] naphthyridinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, etc.).

Hydroxyl is -OH

Immunologically induced inflammation includes diseases in which a mediator is released from the mast cell. These disorders can be influenced by tryptase inhibitors (e.g., acute disease such as asthma, allergic rhinitis, urticaria and angioedema, anaphylactic eczema, atopic dermatitis, hyperproliferative skin disease, peptic ulcer, inflammatory bowel disorders, rheumatoid arthritis, conjunctivitis, conjunctivitis .).

The hypersensitivity response includes bronchoconstriction and airway hyperactivity, characteristic of the late phase of chronic asthma. Hypersensitivity of asthmatic bronchial tissue is probably the result of a chronic inflammatory reaction that irritates and destroys the epithelium lining the airways causing pathological weakening of the tissue under the lining.

By syncytial viral infection is meant a virus infection, e.g. respiratory syncytial virus, which leads to the formation of cellular protoplasmic matter, i. syncytia due to infection.

Imino means = NH

Isomers are compounds of formula I having the same general formula but different in the nature or order of the bonds between their atoms or the arrangement of atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of one another are called diastereomers and stereoisomers that do not have compatible mirror images are called enantiomers or optical isomers. A carbon atom that carries four different substituents is called a chiral center. A compound with one chiral center has two enantiomeric forms of opposite chirality and is called a racemic mixture. A compound having more than one chiral center has 2 ^n-1 enantiomeric pairs, n being the number of chiral centers. Compounds with more than one chiral center may exist either as individual diastereoisomers or as a mixture of diastereoisomers, which is called a diastereomeric mixture. When a single chiral center is present, the stereoisomer may be characterized by the absolute configuration of the chiral center. The absolute configuration indicates the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center are categorized according to the sequence rules of Cahn, Ingold, and Prelog, and on this basis the corresponding descriptor R or S is assigned, enclosed in brackets before the compound name, separated by a hyphen. Compounds of formula I that contain a chiral center may exist as individual stereoisomers or as a mixture of stereoisomers. For the present invention, when a compound of formula I is defined by a name or formula and the configuration is not determined, it is meant that this name or formula denotes all possible configurations of the compound.

Optional or optional means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event occurs and instances where it does not. E.g. a phrase optionally substituted with one or three substituents means that within the scope of the present invention the group discussed is substituted with one or three substituents, but also a group that is not substituted.

N-oxide derivatives means derivatives of a compound of formula I in which the nitrogen atoms are in an oxidized state (i.e., O * -N) and which possess the desired pharmacological activity. N-oxide derivatives of a compound of formula I may be prepared by methods known to those skilled in the art.

Disease pathology refers to the development of disease changes, which includes the causal cause and sequence of disease changes, including structural and functional changes that result from disease processes.

Pharmaceutically acceptable means those used in the preparation of pharmaceutical compositions that are generally safe, non-toxic and not biologically or otherwise unsuitable, including those acceptable for both veterinary and pharmaceutical use in humans.

acceptable salts are salts of compounds I which are pharmaceutically acceptable and have the desired pharmacological activity. Such salts include acid salts formed with an inorganic acid such as e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like, or an organic acid such as e.g. acetic, propanoic, hexanoic, heptanoic, cyclopentanepropanoic, glycolic, pyruvic, lactic, malonic, succinic, malic,

Pharmaceutical of formula (described above) and maleic, fumaric, tartaric, lemon, benzoic, o- (4-hydroxybenzoyl) benzoic, cinnamon, almond, methanesulfone, ethanesulfone, 1,2-ethanedisulfone, 2-hydroxyethanesulfone, benzenesulfone, benzenesulfone, benzenesulfone, benzenesulfone, benzenesulfone, benzenesulfone; , p-toluenesulfone, gafrosulfone, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptane, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropane, trimethylacetic acid , t-butylacetic, lauryl sulfur, gluconic, glutamic, hydroxynaphtho, salicylic, stearic, muconic and the like.

Pharmaceutically acceptable salts also include salts with bases which may be formed in the presence of acidic protons capable of reacting with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine and the like.

Polycycloaryl means a fused polycyclic group with the indicated number of carbon atoms, wherein at least one carbon of the fused rings of the group, but not all, is aromatic and each ring present has 5 to 6 ring members. Also included is any keto- or thioceto-derivative thereof (e.g., polycyclo (C 8-10) aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, etc.).

Prodrug derivatives means derivatives of compounds of formula I that are converted in vivo to the corresponding compound of formula I. Suitable prodrug derivatives include compounds of formula I in which one or more nitrogen and / or oxygen atoms with available free valency is substituted with a readily leaving group in vivo processes.

For example, prodrug derivatives of compounds of Formula I may contain one or more N-substituted amino groups (e.g., -NH ₂ (R ¹⁸ )), N-substituted nitrogen atoms that are part of an aliphatic, alicyclic, or aromatic structure (e.g., -N (R 1) ¹⁸ ) -, N-substituted imino or imidino groups (e.g. -C (NR ¹⁸ ) H, -C (NR ¹⁸ ) NH 2 or C (NH) NHR ¹⁸ ), N-substituted guanidino groups (e.g.

NHC (NR ¹⁸ ) NHR ¹⁸ , -NHC (NH) NHR ¹⁸ or -NHC (NR ¹⁸ ) NH 2 and the like, wherein R ¹⁶ is (i) -C (O) R ¹⁹ or -CH (R ²⁰ ) OC ( 0) R ¹⁹ , where R ¹⁹ is (Cx_

10) alkyl, (Ci-io) alkoxy, carbamoyl, (Ci-io) alkylcarbamoyl, di (Ci-io) alkylcarbamoyl, cis-2- (Ci-io) alkanoyloxyfenylvinyl, 3 (C io) alkanoyloxybutanoyl, (C ₃ -io) cycloalkyl, hetero (C 3-10) cycloalkyl, (C 6-10) aryl or hetero (C 8-10) aryl and R ²⁰ is hydrogen or (C 1-10) alkyl; (ii) -X ⁷ -R ²¹ , wherein X ⁷ is (C 1-10) alkylene and R ²¹ is carboxy; or (iii) -C (O) OCH (R ²²⁾ OC (O) R ^23, wherein R ²² is H, (C 1-10) alkyl or (C3-10) cycloalkyl and R ²³ is (Ci_i0) - alkyl, or (C 3-10) cycloalkyl. Further, prodrug derivatives of compounds of formula I may contain one or more N-hydroxylated imino or imidino groups (e.g., -C (NOR ²⁴ ) H, -C (NOR ²⁴ ) NH 2 or -C (NH) NHOR ²⁴ ), N-hydroxylated guanidino groups ( e.g. -NHC (NOR ²⁴ ) NH ² , -NHC (NH) NHOR ²⁴ ), wherein R ²⁴ is hydrogen, methyl, -C (O) R ²⁵ or -CH (R ²⁶ ) OC (O) R ²⁵ , wherein R ²⁵ is (C 1-10) alkyl or (C 3-10) cycloalkyl and R ²⁶ is hydrogen or (C 1-10) -alkyl; O-substituted hydroxy groups (e.g., -OR ²⁷ ) wherein R ²⁷ is -C (O) R ¹⁹ or -CH (R ²⁰ ) OC (O) R ¹⁹ , wherein R ¹⁹ and R ²⁰ are as defined above; and / or esters of carboxyl groups (e.g. -C (O) OR ²⁸ ), wherein R ²⁸ is (C 1-10) alkyl or (C 3-10) cycloalkyl.

The protecting group has a meaning associated with a meaning in synthetic organic chemistry, i. a group that selectively blocks one reactive site in the multifunctional compound such that the chemical reaction can take place selectively at another unprotected reactive site and which can be easily removed after the selective reaction.

Protected derivatives means derivatives of the compounds of formula I in which the reactive site or sites are blocked by protecting groups. Protected derivatives of compounds of formula I are useful for preparing compounds of formula I. Suitable protecting groups for reactive nitrogen atoms include t-butoxycarbonyl, benzyloxycarbonyl and any other suitable protecting groups for amino groups (see, e.g., TWGreene, Protective Groups in Organic Synthesis, John Wiley &Amp; Sons, Inc. 1981). A particularly suitable protected derivative of the formula I is represented by the following compound: 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -4,5,6,7-tetrahydro -1H-benzimidazole-5-carboxylic acid.

A therapeutically effective amount is an amount that, when administered to an animal, is capable of effectively treating the disease.

By treatment or treatment is meant the administration of a compound of the invention and includes:

(1) preventing disease in an animal which is predisposed to developing disease but which has not yet shown symptoms of the disease;

2) stopping further progression of the disease, both its biological and clinical manifestations,

3) improving the disease, i. j. reduction of biological and clinical manifestations.

Sulfo is -S (O) OH

Ureido means -NHC (O) NH

The compounds of formula (I), intermediates and starting materials used in their preparation are named according to IUPAC nomenclature rules. For example, a compound of formula I wherein:

A together with B is guanidino-1H-benzoimidazol-2-yl, C is 5- (2-naphth-1-ylethylcarbamoyl) -1H-benzoimidazol-2-yl and X ³ is CH 2 - is called 2- (5-guanidino- H-benzoimidazol-2-ylmethyl) -N- (2-naphth-l-ethyl-lH-benzimidazole-5-carboxamide);

A together with B is 5-guanidino-1H-benzoimidazol-2-yl, C is

6- (2-naphth-1-ylethylcarbamoyl) -1-methyl-1H-benzoimidazol-2-yl; and

X ³ is -CH ₂ - is called 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl-3H-benzoimidazole-5-carboxamide);

A together with B is 5-guanidino-1H-benzoimidazol-2-yl, C is 6- (2- (2-carboxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1N-benzimidazol-2-yl and X ³ is - CH ₂ - it is named 2 - {2 - [2- (5 - guanidino-lH-benzoimidazol-2-ylmethyl) -3- (3-sulfopropyl) -3Hbenzoimidazol-5-ylcarbonylamino] ethyl} benzoic acid; and

A together with B is 5-guanidino-1H-benzoimidazol-2-yl, C is 6- [2- (2-methoxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1H-benzoimidazol-2-yl, and X ³ is - CH ₂ - is called 3- {2- (5-guanidinol-1-benzoimidazol-2-ylmethyl) -6- [2- (2-methoxyphenyl) ethylcarbonyl] benzoimidazol-1-yl] propane-1-sulfonic acid.

Certain compounds of Formula I exist in tautomeric equilibrium. For example, a compound of Formula I wherein C is 4,5,6,7-tetrahydro-3H-imidazo [4,5-c] pyridin-2-yl is in

and therefore graphically one of, thus, the compounds of the invention may be named, shown or otherwise described in this application as possible tautomers of such a name, drawing and description. The name ethyl-2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine (5-yl) -4-oxobutyl) benzoate also includes tautomers thereof; ethyl-2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4 oxobutyl) benzoate, ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 3,4,6,7-tetrahydroimidazo [4,5-c] pyridine -5-yl} -4-oxobutyl) benzoate and ethyl 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2-yl) ethyl] -3,4,6,7-tetrahydroimidazo [4] , 5-a] pyridin-5-yl} -4-oxobutyl) benzoate.

Preferred embodiments

While a rough definition of the invention is given in the summary of the invention, some embodiments of the invention are preferred. A preferred embodiment of the invention is a compound of formula I wherein A together with B is a fused heterobicyclic group, wherein A contains 5 ring members and B contains 6 ring members and X ⁴ and X ⁵ are adjacent oxazol-2-yl, 1H-imidazole members A 2-yl or thiazol-2-yl ring.

A preferred embodiment of the invention are compounds of formula II:

(II), (R ³ ) n 3 wherein the dotted lines represent, independently of one another, any bonds;

every R ^? are independently is (C _x _ ₆₎ alkyl, _(x e) alkyloxy, halo or hydroxy;

each R ³ is independently is (C, - _y) alkyl, (C _t) alkyloxy, halo or hydroxy;

X ³ is -C (O) - or -CR ⁷ R ⁸ -;

X ⁸ is -CHĺR ^ Ni or -CFR ¹⁾ =, wherein R ¹ is amino (Ni_ _4), and of 1 1 pyrrolidinyl, amino (Ni ₄₎ azolyl, (Ni ₄₎ azolidinyl, _(N - ₄ ) azolyl

NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ^1c , -C (NH) NR ¹⁰ R ¹¹ 'or (CR 4 R ¹¹ ) y NH 2, or X is ⁸ -NH or -N (R ¹⁾ add ^_, wherein R ¹ is C (NR ⁹⁾ R ^9, -C (NH) NHR ¹⁰ or -C (NH) NR ¹⁰ R ¹⁰ wherein each R ⁹ is independently one from the other is hydrogen or (C 1-6) alkyl and each R ¹⁰ is independently of one another (C _1-6 ) alkyl; and

X ⁹ is -CH (R ⁴ ) - or -C (R ⁴ ) =, wherein R ⁴ is -R ¹² , -OR ¹² , N (R ¹³ ) R ¹² , -SR ¹² , -S (O) R ¹² , -S (O) 2 R ¹² , -S (O) 2 R ¹² , -S (O) 2 N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ^12, -C (O) N (R ¹³⁾ R ^12,

N (R ¹³ ) C (O) R ¹² , -OC (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) OR ¹² , - (CH ₂ ) n ₄ N (R ¹³ ) C (0) N (R ¹³ ) R ¹² , -0P (O) (OR ¹³ ) OR ^12, or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , or X ^{9 is} -N = or -N (R ⁴ ) wherein R ⁴ is -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² , -OC (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , wherein R ¹² , R ¹³ and R ¹⁴ are as defined in the Summary of the Invention.

A preferred embodiment of the invention are compounds of formula I wherein:

R ⁵ is hydrogen or (C 1-4) alkyl, R ⁶ is hydrogen or (C 14) alkyl, wherein the alkyl is optionally substituted with one to two substituents selected independently of one another from (C 1-4) alkyloxy, hydroxy and sulfo, R ⁷ is hydrogen or methyl and R ⁸ is hydrogen, methyl or hydroxy;

^X8 is -CH ^(R4) - or -CÍR ¹⁾ ^ ^3, wherein R ¹ is aminomethyl, 1-amino-cyclopropyl, 2-Amino-imidazol-l-yl, 2-imino-l-dimethylethyl, imidazolyl, tetrazolyl, - ( CH ₂ ) NHC (NR ⁹ ) R ⁹ , (CH ₂ ) 3, NHC (NH) NR ⁹ R ⁸ and -C (NR ⁹ ) R ⁹ , wherein each R ⁹ is independently hydrogen or methyl, or X ⁸ is n (R ¹⁾ _n I ^_ out wherein R ¹ is -C ^{(NR9) R9,} -C (NH) NHR ¹⁰ or -C (NH) NR ¹⁰ R ^{I? j,} wherein each R is independently of one another hydrogen or methyl and each R ¹⁰ is methyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one to two substituents selected independently of one another from methylsulfonyl and carboxy;

X ⁹ is -C (R ¹ ) -, wherein R ⁴ is -R ¹² , -OR ¹² , -C (O) R ¹² , C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹¹ ', wherein R ¹³ and R ¹⁴ are independently from each other hydrogen or (C 1-6) alkyl; R ¹² is -R ¹⁵ or -X 0 - (R ¹⁵ ) n ¹⁵ , wherein X ⁶ is (C 1-10) alkylene or hetero (C 2-10) alkylene and each R ¹⁵ is independently from each other hydrogen, (C 6-14 aryl, cyclo) (C 3-14) alkyl, polycyclo (C 6 and ₄₎ aryl, heteropolycyclo _(C6 -i4) aryl, heterocyclo (C3-14) alkyl or hetero (C5-14) aryl;

any aliphatic and alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C _1-4 ) alkyloxy, (C 1-6) alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C 1-4) alkyl, (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C _3-6 ) alkyloxy, halo, hetero (Ci_e) alkyl, hetero (C _p) alkylcarbonyl, hetero (C5-6) aryl and trifluoromethyl; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof.

A preferred embodiment of the invention are compounds of formula I wherein:

A is taken together with B to form 4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl, wherein n 2 is 0 and R ¹ is -C (NR ⁹ ) R ⁹ , or A is together with B 1 H -benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1 H -benzoimidazol-2-yl, wherein R ¹ is aminomethyl or guanidino and each R ² is independently halogen or hydroxy;

C is 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl or 1H-benzoimidazol-2-yl, wherein R ⁴ is -C (O) X ^f, -R ^is ,

C (O) OX ⁶ -R ¹⁵ or -C (O) NHX ⁶ -R ¹⁵ , wherein X ^f is (C 1-6 alkylene or hetero (C 2-4) alkylene and R ¹⁵ is (C 6-10) aryl, ( _C6-IO) aryloxy, polycyclo (C -ic _c) aryl, hetero (C5-10) aryloxy or heteropolycyclo (Co-14) aryl;

any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C _1-4 ) alkyl, (C 1-4) alkyloxy, (C _1-4 ) alkyloxycarbonyl, carboxy, carbamoyl, halogen, hydroxy and tetrazole-1- yl; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof.

A preferred embodiment of the invention are compounds of formula I wherein n 1 is 0 and each R ² is independently from each other halogen or hydroxy, in particular:

2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid;

2- (2- {2- [1- (5,6, -Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid;

butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate;

propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; and isobutyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate.

A preferred embodiment of the present invention are compounds of formula I wherein R ^{1 is} guanidino or aminomethyl, in particular:

2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3-methyl-N- (2naft-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide;

ethyl-2- (4- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) -4-oxobutyl) benzoate;

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;

2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide;

2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide;

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide;

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide;

4-chloro-2- [2 - ((2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid;

5-chloro-2- [2- ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonyl (amino) ethoxy] benzoic acid;

2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide; and

2- (5-aminomethyl-4,5,6,7-Letrahydro-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide.

A preferred embodiment of the present invention are the compounds of formula I in which C is 4,5,6,7-tetrahydro imidazo [4,5-c] pyridin-2-yl and R ¹ is -C (NH) R ⁱ ' , in particular:

- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- 3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3-benzoimidazole-5-carboxamide;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1-ylethyl) -3-benzoimidazole-5-carboxamide;

2- (5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3Hbenzoimidazole- 5-carboxamide;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-hydroxy-2-naphtha) 1-ylethyl) 3H-benzoimidazole-5-carboxamide;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2-hydroxynaphthalen-1-yl)] -yl) ethyl] 3H-benzoimidazole-5-carboxamide;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4-hydroxynaphthalen- 1-yl) ethyl] 3H-benzoimidazole-5-carboxamide;

2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- (2- naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide;

ethyl-2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-y]] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) etosylberizole;

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl (-3- (2-Methoxyethyl) -3Hbenzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid;

ethyl-2- (2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl) - 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate;

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl] ethyl} -3-methyl-N- [2- (2-Tetrazolylphenoxy) ethyl] 3 H -benzoimidazole-5-carboxamide.

Pharmacology and use

The compounds of the invention are serine protease inhibitors and as such are useful in the treatment of diseases associated with increased serine protease activity. In particular, the compounds of the invention are tryptase inhibitors and are useful in the treatment of diseases associated with increased tryptase activity. Procedures for in vitro screening for potential inhibitors, i. procedures for verifying their ability to inhibit tryptase are known in the art (see, e.g., Sturzebecher et al., (1992) Biol. Chem. Hoppe-Seyler 373: 1025-1030). In general, these assays measure enzymatic hydrolysis of a peptide-type chromogenic substance. Details are described below in an exemplary tryptase inhibitor activity measurement procedure.

Further, the activity of the compounds of the invention can be determined in vivo in any of a number of animal models of asthma (see Larson, Experimental Models of Reversible Airway Obstruction, in The Lung: Scientific Eoundations, Crystal, ed. West et al., Raven Press, New York, 1991; Warner et al., (1990) Am Rev. Respir. Dis. 141: 253-257). The ideal animal model should have identical major clinical and physiological features of human asthma, including increased airway responses to chemical mediators and physical stimuli, airway obstruction with drugs applicable to human asthma (β-adrenergics, methylxanthines, corticosteroids, etc.). , airway inflammation with activated leukocyte infiltration, and chronic degenerative inflammatory changes such as basal membrane thinning, smooth muscle strengthening and epithelial destruction. Species used as animal models include mice, rats, guinea pigs, rabbits, dogs, and sheep. All models have some limitations and the choice of animal model depends on the questions to be answered.

The initial allergic response may be determined in guinea pigs and dogs, especially in a greyhound-basse hybrid, which exhibits a non-specific increased airway response to a number of non-allergenic substances such as methacholine and citric acid. Some sheep strains show a dual response after antigen challenge with Ascaris proteins. In animals with a dual response, the initial asthmatic response (IAR) is followed by a late asthmatic response (LAR), 6-8 hours after challenge. Hypersensitivity to the cholinergic agonist, carbachol, increases in animals showing LAR 24 hours after antigen stimulation.

The allergic sheep model (see below) was used to determine possible anti-asthmatic effects of the compounds of the present invention. Administration of the compositions comprising the compounds of the present invention to allergic sheep was carried out either orally or by inhalation or by aerosol, either before or after exposure to the specific allergen. The results demonstrate that the compositions substantially reduce or cancel the late asthmatic response and the consequent increased response.

The compounds of the invention are also useful for the treatment of other immunologically induced inflammations in which tryptase activity contributes to the pathological change. Such diseases, including inflammatory diseases associated with mast cells, include rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis and other arthritic changes, intestinal inflammatory diseases, peptic ulcer and a number of skin disease processes. The compounds of the present invention may further be used to treat syncytial viral infection.

The efficacy of the compounds of the present invention in the treatment of the vast majority of immunologically induced inflammations can be determined by in vitro or in vivo methods. The anti-inflammatory activity of the compounds of the present invention can be demonstrated by known assays in the art, e.g. Reversed Passive Arthus Reaction (RPAR) -PAW (see, e.g., Gangly et al., (1992) U.S. Patent No. 5,126,352). Assays for determining a therapeutic amount of a compound for the treatment of various skin diseases, e.g. proliferative skin changes are feasible, e.g. arachidonic acid test on mouse ear. The anti-ulcer activity of the compounds of this invention can be determined using the methods described (Chiu et al., Archives Internationales de Pharmacodynamie et de Therapie 270: 128140).

The efficacy of the compounds of the present invention in blocking cell fusion caused by syncytial viral infection can be determined by generally described methods (Tidwell et al. J. Med. Chem. 26: 294-298 (1983)).

Formulations and Administration

According to the invention, a therapeutically or pharmaceutically effective amount of a compound of the invention is administered to a patient suffering from immunolgically induced inflammation. In one embodiment, the compounds of the present invention are useful for preventing or ameliorating asthma. When using the compositions of the present invention in the treatment of asthma, the compounds may be administered prophylactically, i. j. before or after exposure to allergen or threatening conditions.

The compounds of the present invention are particularly useful for alleviating tissue damage that occurs in the late phase of seasonal and chronic rhinitis. Another embodiment of the present invention is directed to the prevention and treatment of other immunologically induced inflammation associated with mast cells such as urticaria, angioedema, atopic dermatitis and anaphylaxis, as well as proliferative skin changes, peptic ulcer and others. In another embodiment, the compounds of the present invention are used to treat syncytial viral infections, in particular respiratory-tract infections.

Compositions containing the compounds of the invention may be administered in therapeutic and / or prophylactic treatment. In therapeutic applications, the compositions are administered to a patient afflicted with the disease (see above) in an amount sufficient to treat or at least partially suspend the symptoms of the disease and its complications. An amount sufficient for this is defined as a therapeutically effective amount or dose. The effective amount for this use depends on the severity and course of the disease, the prior treatment, the patient's health, the response to the medicines and the experience of the attending physician.

In prophylactic applications, the compositions comprising the compounds of the invention are administered to a patient suspected of being at risk or to a patient immediately at risk of the disease in an amount sufficient to prevent or ameliorate the initial symptoms. Such an amount is defined as a prophylactically effective amount or dose. These may be administered orally or by inhalation. In this application, the exact amount again depends on the patient's health, weight, etc.

Upon improvement of the patient's discomfort and, if necessary, the maintenance dose is changed. Thus, depending on the symptoms, the doses or the frequency of their administration may be reduced to a level where the improved condition is maintained. Treatment may be discontinued after the severity of symptoms has decreased to an acceptable level. However, in the event of a relapse, the need to temporarily resume administration may be required.

Generally, a suitable effective dose of the compounds of the present invention is in the range of 0.05 to 1000 milligrams (mg) per person per day, more preferably 0.1 to 100 mg per day. The desired dosage is preferably accomplished by one, two, three, four or more smaller doses administered at appropriate intervals throughout the day. These smaller doses may be administered as unit dosage forms containing, for example, 0.01 to 1000 mg, more preferably 0.01 to 100 mg of active ingredient per unit dosage form.

The composition used in these therapies may be in a variety of forms. They are, for example, solid, almost solid and liquid dosage forms such as tablets, granules, pills, powders, liquid solutions or suspensions, liposomes, infused or injectable solutions. Another form is inhalable compositions such as aerosols. In view of the need for treatment, compositions for oral, intranasal, ointment and parenteral administration are preferred. Particularly preferred are aerosol formulations or for oral administration. Methods of preparing therapeutic compositions containing the compounds of this invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences and The Merck Index, 11th Edition, (Merck et al., 1989).

While the active ingredient of the present invention can be administered alone, it is preferred that it is part of a pharmaceutical composition. The compositions of the invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dose, together with a pharmaceutically acceptable carrier. The dosage form should contain the compounds of the invention in concentrations that guarantee the required dose. For example, if a daily dose of 0.05 mg is required, the concentration of the compound of the invention in the pharmaceutical composition should be 0.05 mg per dose, with a single daily dose being used. In the case of inhaled or aerosol formulations, the concentrations of the compounds of this invention will generally be dose-dependent. A typical concentration of the compounds of the invention in inhalation and aerosol formulations should be from 0.01 to 30 mg / ml. The composition may also contain other clinically useful compounds, such as βadrenergics (e.g. albuterol, terbutaline, formoterol, phenoterol and prenalin) and corticosteroids (e.g. beclomethasone triamcinolone, flunizolide and dexamethasone).

Chemistry of the present invention procedures and reagents, field. It should be

Generally, the compounds were prepared using standard ones used by those skilled in the art to note that bonds between different functional groups generally include carbon bonded to the amide or carbamate nitrogen, carbamate oxygen or carbonyl carbon. One skilled in the art will recognize that the methods and reagents forming these bonds are well known and readily available (see, e.g., March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Larock, Comprehensive Organic Transformations (VCH 1989); and Fumiss and et al., Vogel's Textbook of Practical Organic Chemistry, edition (Longman 1989), incorporated herein by reference).

5th

Compounds of formula I wherein X ⁴ and X ⁵ are adjacent members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring may be prepared by the methods represented by the following Reaction Scheme I:

Wherein L is a leaving group, D together with the vinyl group to which it is fused form a monocyclic or fused bicyclic divalent group containing 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring atom being optionally heteroatom, R ²⁹ is -OH, -NHR ⁶ or -SH, X ⁸ is -O-, -NR 0 - or -S- and n 2, n 3, n 4, A, B, X ¹ , X ² , X ³ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ^e are described in the Summary of the Invention.

Compounds of formula I wherein X ⁴ and X ⁵ are adjacent members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring (Formula I (a)) can be prepared (Scheme I) reacting Compound I or a protected derivative thereof with Compound 2 or a protected derivative thereof, followed by deprotection if necessary. The reaction of compounds 1 and 2 can be carried out in the substance, but is preferably carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU) or polyphosphoric acid at 160 to 200 ° C, preferably at 180 to 190 ° C, a reaction time of 1 to 5 hours being required to complete the reaction (see, e.g., Example 4 (d), 6 (h), 8 (k), 9 (d) and 10 ( d)). Deprotection may be accomplished by any method that deprotects and provides the desired product in a reasonable yield (see, e.g., Example 2 (g) below).

Analogously, compounds of formula I wherein X ¹ and X ² are adjacent members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring may be prepared by the methods represented by the following Reaction Scheme II:

Wherein L is a leaving group, R ³⁰ is -OH, -NHR ⁵ or -SH, X ⁸ is -O-, -NR ⁶ - or -S- and n 2, n 3, n 4, B, C, X ¹ , X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁶ are described in the Summary of the Invention (see, e.g., Example 2 (e) and 7 (h) below).

The isolation and purification of the compounds and intermediates described herein may, if necessary, be accomplished by any suitable separation or purification method, e.g. filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, high performance liquid chromatography (HPLC), or a combination of these methods. Typical examples of suitable separation and isolation methods are in the examples below. Of course, another equivalent separation or isolation procedure may also be used. Nuclear magnetic resonance (NMR) spectra were measured on a General Electric QE Plus (300 MHz) spectrometer. Infrared spectra were measured on a Perkin-Elmer 1600 Fourier Transform IR (ETIR) instrument. Analytical HPLC was performed on an Ultrafast Microprotein Analyzer, by Michrom BioResuorces, Inc. with PLRP column, 1 mm x 150 mm. Preparative HPLC was performed on a Gilson LC using a Vydac 1 x 25 cm C _i8 reverse phase (RP) or a Waters Prep LC2000 using a Vydac 5 x 25 cm Cib DP. Mass spectra (MS) were measured on a Finnigan SSQ 710 with a direct input ESI source or HPLC MS (Ultrafast Microprotein Analyzer, C ₁₈ column 2 mm x 150 mm). Unless otherwise noted, all reagents and devices were prepared either according to published procedures or obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, WI); (St. Louis, MO) and ICN Chemical Co. (Irvine, Calif.). The methods used to perform the syntheses described below are routine to those skilled in the art (see, e.g., March, Larock, or Fumiss above).

Additional processes for the preparation of compounds of formula I

Compounds of formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of a compound of formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, compounds of Formula I may be prepared as pharmaceutically acceptable salts with a base, by reacting the free acid form of a compound of Formula I with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable compounds of formula I are defined in the definition section herein. Alternatively, the compounds of formula (I) may be prepared in the form of salts using salts as starting materials or intermediates.

The free acid or base forms of the compounds of formula I may be prepared from their corresponding base or acid salts. For example, compounds of formula I which are in the form of an acid salt may be converted to the corresponding free base by treatment with a suitable base (e.g., ammonia, sodium hydroxide, and the like). The compounds of formula (I) which are in the form of a salt with a base can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid and the like).

The N-oxides of the compounds of formula I may be prepared by methods known to those of ordinary skill in the art. For example, the N-oxides may be prepared by treating an unoxidized form of a compound of formula I in a suitable inert organic solvent (e.g., halogenated hydrocarbons, e.g. (methylene chloride) at about 0 ° C. Alternatively, the N-oxides of the compounds of formula I may be prepared from a suitable N-oxide starting material.

Compounds of formula I in non-oxidized form can be prepared from the N-oxides of compounds of formula I by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide and the like). a solvent (acetonitrile, ethanol, aqueous dicxane, etc.) at 0 to 80 ° C.

Prodrug derivatives of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (see, e.g., Example 12 below). For further details on prodrug derivatives and their preparation, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, 4: 1985).

Protected derivatives of compounds of formula I may be prepared by methods well known to those skilled in the art. A detailed description of the methods applicable to the introduction and removal of protecting groups can be found in T.W. Green, Protective Groups in Organic Synthesis, John Wiley & 1,981th

Compounds of formula I may be prepared as their individual stereoisomers by reacting a racemic compound with an optically resolving agent to form a pair of diastereomeric compounds, separating the diastereoisomers, and releasing the optically pure diastereoisomers. Although cleavage into individual enantiomers can be accomplished using covalent diastereomeric derivatives of compounds of Formula I, dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. Diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) by which they can be readily separated. The diastereomers may be separated by chromatography or, more preferably, by separation / resolution methods based on different solubilities. The optically pure enantiomers are subsequently obtained together with the resolving agent by any method that does not result in recemization. A more detailed description of the methods applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel J. Wilen, Enantomers, Racemates and Resolutions, Honh Wiley & (1981).

A general aspect of the invention is a process for the preparation of a compound of formula I, the process comprising: a) reacting compound 1

or a protected derivative thereof with compound 2

or a protected derivative thereof in which L is a leaving group, D together with the vinyl group to which it is fused form a monocyclic or fused bicyclic divalent group of 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each atom of the ring is optionally a heteroatom, R ²⁹ is -OH, -NHR ⁶ or -SH and n 1, n 2, n 3, A, B, X ¹ , X ² , X ³ , R ¹ , R ² , R ³ , R ⁴ and R ⁶ are described in the Summary of the Invention. If necessary to obtain a compound of formula I wherein X ⁴ and X ⁵ are adjacent members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring, deprotection is followed; or b) reacting compound 3

R ⁴ ( ^{R 3} ) n 3 or a protected derivative thereof with compound 4:

or with a protected derivative thereof, wherein L is a leaving group, R ³⁰ is -OH, -NHR ⁵ or -SH and n 1, n 2, n 3, B, C, X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in the Summary of the Invention.

If necessary to obtain a compound of formula I, wherein X ¹ and X ² are adjacent members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring, followed by deprotection; c) optionally, the compound of formula I is then converted into a pharmaceutically acceptable salt;

d) optionally converting a compound of Formula I from a salt form to a free form;

e) optionally, the compound of Formula I is then converted from the non-oxidized form to a pharmaceutically acceptable Noxide;

f) optionally, the N-oxidized form of a compound of Formula I is then converted to its non-oxidized form; g) optionally, the non-derivatized compound of Formula I is then converted to a pharmaceutical prodrug derivative; and h) optionally, the prodrug derivative of the compound of Formula I is then converted to its non-derivatized form.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 compares specific pulmonary resistance after application of control (open squares) and 2- (5 aminomethyl-1H-benzimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1H40 benzoimidazole-5-carboxamide (compound 4, solid squares) over time (in hours).

Figure 2 depicts a bar graph of airway hyperreactivity (measured as PC400) in an antigen stimulated sheep after administration of aerosolized compound 4 in three doses of 10 mg, compared to placebo.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided by way of illustration only and are not to be construed as limiting the scope of the present invention. One skilled in the art will readily recognize certain variations and modifications that may be made within the scope of the invention.

Example 1

2- (naphth-2-yl) -ethylamine

A solution containing 2- (naphth-2-yl) ethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) was mixed with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) and 1N under nitrogen. 8-diazabicyclo [5.4.0] undec-7-ene (0.47 mL, 3.14 mmol). The mixture was heated at 65 ° C for 3 hours and then partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3N hydrochloric acid and then with saturated sodium bicarbonate solution, dried (MgSO ₄ ), filtered and concentrated on a rotary evaporator. The residue was dissolved in THF (5 mL) and treated with triphenylphosphine (1 g, 3.81 mmol), stirred at room temperature for 2 h, diluted with water (0.100 mL), further stirred for 3 h, diluted with concentrated hydrochloric acid (0.33 ml) gave a precipitate. Addition of ethanol (5 mL) dissolved the precipitate and a white precipitate precipitated by slow addition of diethyl ether. Then, the precipitate was filtered off, washed with diethyl ether and dried under vacuum. There was thus obtained 2- (naphth-2-yl) ethylamine hydrochloride (0.447 g, 75% yield); ^! 1 H-NMR (300 MHz, DMSO-d ₆ ): 8.18 (br s, 3H), 7.82-7.88 (m, 3H),

7.74 (s, 1H); 7.38-7.48 (m, 3H); 3.07 (m, 4H)

The following amine intermediates were prepared as in Example 1:

2- (naphth-2-yl) ethylamine, yield = 56%, 1 H-NMR (300 MHz, DMSO-d 6): 8.26 (br s, 3H), 8.16 (d, 1H, J = 8, 1 Hz), 7.92 (dd, 1H, J = 1.5 and 7.8 Hz), 7.81 (dd, 1H, J = 1.2 and 7.5 Hz), 7.40-7, 56 (m, 4H), 3.37 (m, 2H), 3.05 (t, 2H, J = 7.4 Hz);

3-cyclohexylpropylamine, yield = 40%, 1 H-NMR (300 MHz,

CDC1 _3): 2.68 (t, 2H, J = 7.2 Hz), 2.17 (br s, 2H), 64-l, 71 (m,

5H), 1.46 (m, 2H), 1.18 (m, 6H), 0.87 (m, 2H);

3-phenyl-2-propenylamine, yield = 53%, 1 H-NMR (300 MHz, DMSO-d ₆ ): 8.39 (br s, 3H), 7.26-7.41 (m, 5H), 6 72 (d, 1 H,

J = 16.2 Hz), 6.29 (dt, 1H, J = 16.2 and 6.6) Hz) , 3.56 (d, 2H, J = 6.6 HZ), 3-phenyl-2-propynylamine, yield = 62 %, 1 H-NMR (300 MHz DMSO-d6): 8.67 (br s, 2H), 7.38-7.42 (m, 5H) 3.91 (m, 2H); and 3,3-diphenylpropylamine, yield = 50 %, 1 H-NMR (300 MHz

_DMSO-d6): 8.10 (br s, 3H), 7.30 (m, 8 H), 7.19 (m, 2H), 4, ll (t,

1H, J = 7.9Hz), 2.62 (m, 2H), 2.33 (m, 2H).

Example 2

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (4-phenylbutyl) 1H-benzoimidazole-5-carboxamide (Compound 1) (a) Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was treated with anhydrous ethanol (6 mL, 105 mmol) under a nitrogen atmosphere. The mixture was cooled to 10 ° C (ice / acetone) and bubbled dry hydrogen chloride gas for 20 minutes. The mixture was slowly warmed to room temperature, sealed, and stirred at room temperature for about 18 hours. The resulting solid was collected by filtration, washed several times with anhydrous diethyl ether, and dried in vacuo. There was thus obtained ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless crystalline solid; 1 H-NMR (300 MHz, CDCl ₃ ): 7.84 (d, 1H,

J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H,

J = 5.7 Hz), 2.73 (t, 2H, J = 6.5 Hz), 1.89 (m, 4H).

(b) A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-iminopropionate and glacial acetic acid (15 mL) was stirred for 30 minutes at 110 ° C under a nitrogen atmosphere. The mixture was poured onto crushed ice and stirred for 30 minutes to give a dark yellow oil. The mixture was stirred and after addition of diethyl ether (25 ml) a gray precipitate was obtained. The precipitate was collected by filtration, washed several times with anhydrous diethyl ether and dried in vacuo. 2-Ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid was obtained (12.6 g, 83% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 12.77 (br s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7, 57 (d, 1H, J = 8.4Hz), 4.1 (q, 2H, J = 7.1Hz), 4.02 (s, 2H), 1.17 (t, 3H, J = 7) l

Hz).

(c) A mixture of dinitrophenylmethanol (22 g, 111 mmol), triphenylphosphine (34.5 g, 131 mmol) and phthalimide (17.6 g, 119 mmol) in THF (450 mL) was stirred at -10 ° C (ice / acetone) under nitrogen and diethyl azodicarboxylate (20.7 mL, 131 mmol) was added dropwise. The mixture was stirred at -10 ° C for 2 hours and then diluted with diethyl ether (900 mL) and held at -20 ° C for about 18 hours. The precipitated crystalline material was filtered off and washed. There was thus obtained 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (24.6 g, 67% yield) as an off-white crystalline solid; 1 H-NMR (300 MHz, DMSO-d 6): 7.87-7.94 (m, 5Η), 7.74-7.82 (m, 2H), 4.96 (s, 2H).

(d) A mixture of 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (8 g,

24.4 mmol) prepared in Example 2c and 10% Pd / C (300 mg) were mixed with anhydrous ethanol (200 mL), anhydrous THF (100 mL with glacial acetic acid (30 mL) under a constant stream of nitrogen). . The mixture was then stirred vigorously at room temperature under a hydrogen atmosphere for 15 hours, filtered and concentrated to a volume of about 30 ml on a rotary evaporator. The mixture was diluted with water (100 mL) and the addition of aqueous ammonia gave an orange precipitate. The precipitate was isolated by filtration

There was thus obtained 2- (3.4g, 91% yield); ^H-NMR

4H), 6.31 to 6.43 (m, 3H), and washed several times with water, diaminobenzyl) isoindole-1,3-dione (6 (300 MHz, _DMSO-d6): 7.76-7.85 (m,

4.51 (br s, 4H); 4.47 (s, 2H).

(e) A mixture of finely divided 2- (3,4-diaminobenzyl) isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated at 185 ° C and under nitrogen atmosphere for 1 hour. The mixture was suspended in 20 mL of methylene chloride with ethanol (1: 1) and stirred vigorously for 1 hour. The solid was filtered off, washed with methylene chloride and ethanol (1: 1, 3 x 20 mL) and dried. There was obtained 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 12.45 (br s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H),

7.51 (d, 1H, J = 7.5Hz), 7.43 (s, 1H), 7.1 (d, 1H, J = 7.2Hz),

4.82 (s, 2H); 4.48 (s, 2H).

(f) 2- [5- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.05 g, 0.111 mmol) was dissolved in anhydrous dimethylformamide (0.5 mL) and this solution was treated with 1hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate methyl (0.063 g, 0.126 g, 0.126 g, 0.126, 0.126 mmol, 0.126 mmol). 0.013 mL, 0.118 mmol). After 2 minutes, 4-phenylbutylamine (0.02 mL, 0.127 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel containing 20% ethanol / ethyl acetate solution (7 mL), 0.2 N HCl (3.5 mL) and saturated aqueous NaCl (3.5 mL). The aqueous phase was extracted once with 20% ethanol / ethylene acetate solution (7 mL).

The combined organic phases were washed with a solution containing 0.2 N HCl (3.5 mL) in saturated aqueous NaCl (3.5 mL) and then washed with saturated sodium bicarbonate solution (7 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered and evaporated to dryness by rotary evaporation. Crude 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -N- (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide was obtained (0.14 g).

(g) 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -N- (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (0.14) g, crude) was dissolved in anhydrous ethanol (0.5 mL) and treated with anhydrous hydrazine (0.15 mL, 0.48 mmol). The mixture was heated under reflux for 1 hour under nitrogen and then concentrated on a rotary evaporator. Excess hydrazine was removed from the residue by placing under a vacuum of 20 Pa (0.15 torr) for 2 hours. The residue was diluted with 3 M HCl (0.5 mL) and heated to 50 ° C for 20 min. The reaction mixture was cooled to room temperature and stirred for an additional 20 minutes. The resulting precipitate was collected by filtration and washed with water (4 x 1.5 mL). The filtrates were combined and washed with 20% ethanol / ethyl acetate solution (2 x 7 mL). The combined aqueous phases were lyophilized to give the crude product as the hydrochloride. The crude product was purified by reverse phase preparative HPLC to give 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzimidazol-2-ylmethyl] -N- (3-phenylpropyl) 1H-benzoimidazole-5-carboxamide (0.04 g, 0.07 mmol) as a white solid; 1 H-NMR (300 MHz, CD ₃ OD): 8.24 (s, 1H), 7.84-7.89 (m, 2H), 7.77 (d, 1H, J = 8.1 Hz) 7.71 (d, 1H, J = 8.1 Hz), 7.56 (d, 1H, J = 8.1 Hz), 7.12-7.27 (m, 5H), 4.29 ( s, 2H), 3.43 (t, 2H, J = 7.2 Hz), 2.66 (t, 2H, J = 7.2 Hz), 1.69 (m, 4H).

The following compounds of the invention were prepared as in Example 2:

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-naphth-1-ylmethyl-1H-benzoimidazole-5-carboxamide (Compound 2), 1 H-NMR (300 MHz, CD ₃ OD): 8 13 (m, 2H); 7.88 (m, 2H); 7.80 (m, 2H);

7.73 (d, 1H, J = 7.9Hz), 7.67 (d, 1H, J = 7.9Hz), 7.38-7.54 (m,

5H), 5.01 (s, 2H), 4.26 (s, 2H);

2- (5-aminomethyl-lHbenzoimidazol-2-ylmethyl) -N-benzyl-lHbenzoimidazol-5-carboxamide (Compound ^3); H-NMR (300 MHz, CD 3 OD): 8.18 (s, 1H). 7.91 (d, 1H, J = 7.9Hz), 7.82 (s, 1H),

7.76 (d, 1H, J = 7.9Hz), 7.72 (d, 1H, J = 7.9Hz), 7.54 (d, 1H,

J = 7.9 Hz), 7.23-7.38 (m, 5H), 4.60 (s, 2H), 4.28 (s, 2H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 4), 1 H-NMR (300 MHz, CD 3 OD): 8.14 ( s, 1H), 7.87 (d, 1H, J = 8.6 Hz), 7.8 (s, 1H), 7.76 (d, 1H, J = 8.6 Hz), 7.71 ( d, 1H, J = 8.6 Hz), 7.54 (d, 1H, J = 8.6 Hz), 7.24 (m, 4H), 7.16 (m, 1H), 4.28 ( s, 2H), 3.46 (t, 2H, J = 7.9 Hz), 2.95 (t, 2H, J = 7.9 Hz), 1.62 (kv, 2H, 7.9 Hz) ;

2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -N- (2-phenylmethyl) -lH-benzoimidazole-5-carboxamide (Compound 5) H-NMR (300 MHz, _DMSO-d6): 8 12 (s, 1 H), 7.83 (m, 2 H), 7.78 (d, 1 H,

J = 9.3 Hz), 7.71 (d, 1H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz),

7.29 (m, 4H), 7.22 (m, 1H), 4.29 (s, 2H), 3.65 (t, 2H, J = 7.9 Hz), 2.9 (t, 2H) J = 7.9 Hz);

2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -N- (3-aminomethyl) benzyl-lH-benzimidazole-5-carboxamide (Compound ^6),? (300 MHz, _DMSO-d6): 9.31 (t, 1 H, J = 5.7 Hz), 8.58 (br s,

3H), 8.41 (br s, 3H), 8.28 (s, 1H), 7.97 (m, 2H), 7.79 (d, 1H,

J = 9.3 Hz), 7.75 (d, 1H, J = 9.3 Hz), 7.59 (d, 1H, J = 9.3 Hz),

7.43 (s, 1H), 7.35 (s, 3H), 5.07 (s, 2H), 4.50 (m, 2H), 4.18 (m,

2H), 3.97 (m, 2H);

2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -N- (2-aminoetyJ j-1-methyl-1-ΙΗ-benzimidazole-5-carboxamide H (Compound ^7): H-tJMR (300 MHz, DMSO-d6: 8.86 (br. 1H), 8.50 (br s, 3H),

8.24 (s, 1H), 8.08 (br s, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J = 8.7)

Hz), 7.55 (d, 1H, J = 9.2 Hz), 5.02 (br s, 2H), 4.16 (m, 2H),

3.94 (s, 2H); 3.50 (m, 2H); 2.96 (m, 2H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-aminoethyl) -1H-benzoimidazole-5-carboxamide (Compound 8), ¹ H-NMR (300 MHz, DMSO-d 6): δ 97 (t, 1H, J = 4.3Hz), 8.58 (br s, 3H),

8.31 (s, 1H), 8.16 (br s, 3H), 7.97 (m, 2H), 7.79 (d, 1H, J = 10.0 Hz), 7.73 (d, 1H, J = 10.0 Hz), 7.59 (d, 1H, J = 10.0 Hz), 5.09 (s, 1H), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H);

2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -N- (4-aminobutyl) -lH-benzoimidazole-5-carboxamide (Compound 9), ³ ΗNMR (300 MHz, _DMSO-d6): 8, 77 (t, 1H, J = 5.7Hz), 8.61 (br s, 3H), 8.24 (s, 1H), 7.90-8.02 (m, 5H), 7.78 ( d, 1H, J = 9.3 Hz), 7.74 (d, 1H, J = 9.3 Hz), 7.60 (d, 1H, J = 9.3 Hz), 5.09 (s, 1H), 4.18 (m,

2H), 3.28 (m, 2H), 2.78 (m, 2H), 1.12 (m, 4H);

2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -lH-benzoimidazole-5-carboxamide (Compound 10); H-NMR (300 MHz, _DMSO-d6): 8 9 (t, 1H, J = 5.0Hz), 8.53 (brs, 3H),

8.23 (s, 1H), 7.97 (br s, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.78 (d, 1H, J = 8.6Hz), 7.71 (d, 1H, J = 8.6Hz), 7.57 (d, 1H, J = 8.6Hz), 5.03 (s, 2H) 4.40 (m, 2H); 3.34 (m, 2H); 2.81 (m, 2H); 1.81 (m, 2H); and

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-cyclohexylmethyl-1H-benzoimidazole-5-carboxamide (compound 11), ³ Η "

NMR (300 MHz, CD ₃ OD): 8.15 (s, 1H), 7.88 (d, 1H, J = 7.6 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 7.6 Hz), 7.72 (d, 1H, J = 7.6 Hz), 7.54 (d, 1H, J = 7.6Hz) 4.29 (s, 2H), 3.26 (d, 2H, J = 7.2 Hz),

1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).

Example 3

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole-5-carboxamide (Compound 12) (a) A mixture containing 3-nitro-4- chlorobenzoic acid (1.3 g, 6.45 mmol), 10%, a solution of methylamine in water (10 mL) was heated in a sealed vial at 100 ° C for 1 h, concentrated to 1.0 mL and then diluted with concentrated hydrochloric acid formation of a yellow precipitate. The precipitate was collected by filtration, washed with water, diethyl ether and dried. There was thus obtained 3-nitro-4-methylaminobenzoic acid (2.1 g, 86% yield); 1 H-NMR (300 MHz, CDCl ₃ ): 8.56 (d, 1H, J = 2.1)

Hz), 8.52 (q, 1H, J = 2.1 Hz), 8.52 (q, 1H, J = 8.6 Hz), 7.94 (dd, 1H, J = 9.3 and 2 Hz) 1 Hz), 7.00 (d, 3H, J = 8.6 Hz).

(b) Ethanol (100 mL) was added to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09 g, 10.7 mmol) and 10% Pd / C (30 mg) under a constant stream of nitrogen. The mixture was stirred under a nitrogen atmosphere for 16 hours, filtered through a filter disc (Milipore 0.22 µm, type GV) and concentrated on a rotary evaporator. The residue was dried in vacuo to give 3 amino-4-methylaminobenzoic acid (1.1 g, 61% yield).

(c) Ethyl 3-ethoxy-3-iminopropanoate, prepared as in Example 2 (a), was reacted with 3-amino-4-methylaminobenzoic acid under similar conditions to Example 2 (b) to give 2- ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid (71% yield); ^J (300 MHz, _DMSO-d6): 7.18 (dd, 1 H, J = 8 Hz), 7. 11 (d, 1 H,

J = 1.2 Hz), 6.33 (d, 1H, J = 8.1 Hz), 5.28 (br s, 1H), 4.67 (br s, 1H), 3.34 (br s 1 H, 2.72 (s, 3H).

(d) 2- (3,4-diaminobenzyl) isoindole-1,3-dione, prepared as in Example 2 (d), was reacted with 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid under similar conditions as in Example 2 (e) to give 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-1H-benzoimidazole-5 -carboxylic acid (48% yield); 1 H-NMR (300 MHz, DMSO-d 6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J = 10.0)

Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s,

2H), 3.79 (s, 3H).

(e) 2- [5- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-1H-benzimidazole-5-carboxylic acid (0.05 g) , 0.108 mmol), 1-hydroxy-benztriazole (0.016 g, 0.118 mmol), 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and propane-1,3-diamine with one amino protected group group of Boe (t-butyloxycarbonyl) were dissolved at 0 ° C in methylene chloride (1 mL) and DMF (minimum amount necessary to form a solution). The pH of the solution was adjusted to approximately 8 with N-methylmorpholine, and the mixture was slowly warmed to room temperature and stirred for 20 hours. The mixture was transferred to a separatory funnel, dissolved in methylene chloride, washed with 0.1 N HCl and then saturated NaHCO ₃ , dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (10% methanol / ethyl acetate) to give 2- [6- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-N- (3-aminopropyl) -1H-benzoimidazole-5-carboxamide (0.02 g, 28% yield); 1 H-NMR (300 MHz, CDCl ₃ ): 7.757.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (br s, 1H), 7.27 (d, 1H) .

J = 8.6 Hz), 7.15 (d, 1H, J = 9.3 Hz), 5.10 (br t, 1H), 4.90 (br s, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J = 7.2 Hz), 3.24 (q, 2H, J = 7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H);

(f) Under similar conditions to Example 2 (g), 2- [6- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-N- ( 3-aminopropyl) -1H-benzoimidazole-5-carboxamide removed the protecting group to give 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole-5 -carboxamide (20% yield); ^H-NMR (300 MHz, _DMSO-d): 8.85 (t, 1 H, J = 5.7 Hz), 8.55 (br s, 3H), 8.20 (s, 1H), 8 1.01 (br s, 3H), 7.74 (m, 2H), 7.80 (d, 1H, J = 6.6)

Hz), 5.07 (s, 2H), 4.16 (m, 2H), 3.96 (s, 3H), 3.32 (m, 2H), 2.79 (m, 2H), 1, 80 (m. 2H).

The following compounds of the invention were prepared as in Example 3:

3- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1H-benzoimidazole-5-carboxamide (Compound 13); 1 H-NMR (300 MHz, CD ₃ OD): 8.25 (d, 1H, J = 8.1 Hz), 8.09 (s, 1H),

7.67-7.86 (m, 6H), 7.37-7.54 (m, 5H), 4.27 (s, 2H), 3.73 (t, 2H, J = 7.4 Hz) 3.41 (t, 2H, J = 7.4Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3,3-diphenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 14); ^X H-NMR (300 MHz, CD ₃ OD): 8, ll (s, 1H), 7.77-7.86 (m, 3H),

7.70 (d, 1H, J = 9.3 Hz), 7.56 (d, 1H, J = 9.3 Hz), 7.23-7.39 (m,

8H), 7.13-7.19 (m, 2H), 4.30 (s, 2H), 4.07 (t, 1H, J = 7.2 Hz),

3.40 (t, 2H, J = 7.2 Hz), 2.44 (q, 2H, J = 7.2 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-2-ethyl) -1H-benzoimidazole-5-carboxamide (Compound 15); 1 H-NMR (300 MHz, CD 3 OD): 8.10 (s, 1H), 7.67-7.86 (m, 8H), 7.55 (d, 1H,

J = 10.0 Hz), 7.38-7.44 (m, 3H), 4.28 (s, 2H), 3.72 (t, 2H, J = 7.2 Hz), 3.10 ( t, 2H, J = 7.2Hz);

2- (1H-benzoimidazol-2-ylmethyl) -N- [2- (1H-indol-3-yl) ethyl] -1H-benzoimidazole-5-carboxamide (Compound 16); 1 H-NMR (300 MHz, CD 3 OD): 8.09 (s, 1H), 7.81-7.84 (m, 2H), 7.74 (d, 1H, J = 8.6 Hz), 7, 67 (d, 1H, J = 8.6Hz), 7.52-7.58 (m, 2H), 7.30 (d,

1H, J = 7.9Hz), 7.01-7.08 (m, 2H), 6.94 (t, 1H, J = 7.9Hz),

4.26 (s, 2H), 3.68 (t, 2H, J = 6.8 Hz), 3.06 (t, 2H, O = 6.8 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- [2- (5-methoxy) indol-3-yl] -1H-benzoimidazole-5-carboxamide (Compound 17); 1 H-NMR (300 MHz, CD ₃ OD): 8.10 (s, 1H), 7.81-7.85 (m, 2H),

7.76 (d, 1H, O = 8.2 Hz), 7.69 (d, 1H, J = 8.2 Hz), 7.54 (d, 1H,

Δ = 8.2 Hz), 7.20 (d, 1H, δ = 8.2 Hz), 7.07 (m, 2H), 6.70 (dd, 1H,

Δ = 10.0 and 2.2 Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3.04 (t, 2H,

J = 7.2 Hz);

2- (5-aminomety1-benzoimidazol-2-ylmethyl) -N- (2,3,4,

5,6-pentahydroxyhexyl) -1H-benzoimidazole-5-carboxamide (compound 18); 1 H-NMR (300 MHz, CD ₃ OD / D ₂ O (1/1)): 8.15 (s, 1H),

7.86-7.90 (m, 2H), 7.83 (d, 1H, J = 9.6Hz), 7.77 (d, 1H, J = 9.6)

Hz), 7.61 (d, 1H, J = 9.6 Hz), 4.32 (s, 2H), 4.01 (m, 1H), 3.473, 55 (m, H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenyloxyethyl) -1H-benzoimidazole-5-carboxamide (Compound 19); H-NMR

(300 MHz, CD ₃ OD): 8.16 (s, 1H). 7.88 (d, 1H, J = 9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 9.3) Hz), 7.71 (d, 1H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3Hz), 7.23 (2H, J = 7.9 Hz), 6, 85 to 6.96 (m, 3H), 4.27 (s,

2H), 4.16 (t, 2H, J = 6.1 Hz), 3.78 (t, 2H, J = 6.1 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-phenylprop-2-ynyl) -1H-benzoimidazole-5-carboxamide (Compound 20); ^X H-NMR (300 MHz, CD ₃ OD): 8.18 (s, 1H), 7.91 (d, 1 H, J = 9, 3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 9.3 Hz), 7.71 (d, 1H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.38-7 43 (m, 2H); 7.28-7.32 (m, 3H);

4.40 (s, 2H); 4.27 (s, 2H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (E-3-phenylalyl) -1H-benzoimidazole-5-carboxamide (Compound 21); ^ -

NMR (300 MHz, CD ₃ OD) 8.19 (s, 1H). 7.92 (d, 1 H, J = 9.3 Hz), 7.86 (s, 1H), 7.76 (d, 1 H, J = 9.3 Hz), 7.71 (d, 1 H, J = 9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.33-7.39 (m, 2H), 7.18-7, 30 (m, 3H), 6.60 (d, 1H, J = 15.8 Hz), 6.34 (dt, 1H, J = 15.8 and 6.1 Hz), 4.27 (s, 2H), 4.17 (d, 2H (J = 6.1 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-cyclohexylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 22);

1 H-NMR (300 MHz, CD ₃ OD): 8.13 (s, 1H), 7.86 (d, 1H, J = 9.3 Hz), 7.81 (s, 1 H) 7.74 (d, 1H, J = 9.3) Hz), 7.69 (d, 1H, J = 9.3 Hz), 7.53 (d, 1 H, J = 9.3 Hz), 4.27 (s, 2H), 3.36 (t, 2H, J = 7.2 Hz),

1.61-1.78 (m, 7H), 1.19-1.32 (m, 6H), 0.90 (m, 2H);

3- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-oct-1-yl-1H-benzoimidazole-5-carboxamide (Compound 23); H H-NMR (300 MHz)

MHz, CD ₃ 0D): 8.13 (s, 1H), 7.86 (d, 1 H, J = 9.7 Hz), 7.82 (s, 1H).

7.74 (d, 1H, J = 9.7 Hz), 7.69 (d, 1H, J = 9.7 Hz), 49.4 (d, 1H,

J = 9.7 Hz), 4.27 (s, 2H), 3.39 (t, 2H, J = 7.2 Hz), 1.64 (m, 2H), 1.26-1.43 ( m, 11H ', 0.88 (m, 2H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-methyl-N (2-phenylethyl) -1H-benzoimidazole-5-carboxamide (Compound 24); ^H-NMR (300 MHz, CD ₃ OD): 7.76 (s), 7.69 (d), 7.63 (d), 7,447,55 (m), 7.20-7.28 (m ), 7.09-7.14 (m), 6.97 (d), 6.85 (br s),

4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3.08 (s), 2.87 (t),

2.7 6 (t); and

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (1-methyl-3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 25); 1 H-NMR (300 MHz, CD ₃ OD): 8.05 (s, 1H), 7.79 (d, 1H, J = 9.3 Hz), 7.75 (s, 1H), 7.68 ( d, 1H, J = 9.3 Hz), 7.63 (d, 1H, J = 9.3 Hz), 7.46 (d, 1H, J = 9.3 Hz), 7.09-7, 17 (m, 4H), 7.03 (m, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 2.61 (t, 2H, J = 7.9 Hz), 1.17-1.93 (m, 2H);

1.18 (d, 3H, J = 7.2Hz).

Example 4

C - {2- [5- (4-phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazol-5-yl} methylamine (compound 26) (a) 4-phenyl-1-butanol (1 mL, 6.49 mmol) in THF (3 mL) was treated with a 60% dispersion of sodium hydride in mineral oil (0.26 g, 6.5 mmol) under dry nitrogen. The mixture was stirred vigorously for 5 minutes. 3,4-Dinitrochlorobenzene (1.3 g, 6.42 mmol) was then added and the mixture was stirred at room temperature for 10 hours. The mixture was partitioned between diethyl ether and 3 hydrochloric acid. The aqueous layer was separated and extracted with diethyl ether. Combined organic dried (MgSO4), filtered and concentrated by evaporation. The residue was purified by flash chromatography (9: 1 hexane / diethyl ether) to give 4- (4-phenylbutoxy) 1,2-dinitrobenzene (1.16 g, 72% yield); ³ H-NMR (300 MHz,

CDCl 3: 7.84 (d, 1H, J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.007.06 (m, 2H), 4.10 (t, 2H, J = 5.7 Hz), 2.73 (t, 2H, J = 6.5 Hz),

1.89 (m, 4 H).

The N acid several times the layers were reacted on the rotary (b) Ethyl 3-ethoxy-3-iminopropanoate prepared as in Example 2 (a) under similar conditions to Example 2 (b) with 2- (3,4- diaminobenzyl) isoindole-1, 3-dione to give ethyl 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-yl acetate (71% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J = 9) 43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J = 7 , 2 Hz).

(c) 4- (4-phenylbutoxy) -1,2-dinitrobenzene was reduced under similar conditions to Example 3 (b) to give crude 4- (4-phenylbutoxy) benzene-1,2-diamine (86%). yield).

(d) A mixture of 5- (4-phenylbutoxy) benzene-1,2-diamine (0.06 g, 0.234 mmol) and ethyl 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H- of benzoimidazol-2-yl acetate (0.1 g, 0.234 mmol) was heated at 185 ° C under nitrogen for 1 h. The mixture was suspended in diethyl ether and stirred vigorously for 1 hour. The solid was filtered off, washed with diethyl ether and dried. There was thus obtained 2- {2- [5- (4-phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3H-benzoimidazol-5-ylmethyl} isoindole-1,3-dione (0.1 g, 0.18 mmol). .

(e) Under similar conditions to Example 2 (g), 2- {2- [5- (4-phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3H-benzoimidazol-5-ylmethyl} isoindole-1,3 the dione was removed by a protecting group to give C - {2- [5- (4-phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazol-5-yl} methylamine (0.05 g, 55% yield) ); 1 H-NMR (300 MHz, CD ₃ OD): 7.83 (d, 1H, J = 8.6 Hz),

7.76 (s, 1H), 7.69 (d, 1H, J = 10.0 Hz), 7.48 (d, 1H, J = 8.6 Hz),

6.99-7.16 (m, 5H), 6.92 (d, 1H, J = 10.0 Hz), 6.80 (t, 1H, J = 7.2 Hz), 4.44 (s H, 3.39 (t, 2H, J = 6.5 Hz), 2.56 (t, 2H, J = 7.2 Hz), 1.72 (m, 2H).

Example 5

2-Phenylethyl 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzimidazole-5-carbamate (Compound 27)

2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.06 g, 0.133 mmol) in Phenylethanol (0.16 mL, 1.34 mmol) was mixed with diphenylphosphoryl azide (0.034 mL, 0.158 mmol) and triethylamine (0.022 mL, 0.158 mmol) at room temperature and under nitrogen atmosphere. The mixture was stirred at 120 ° C for 1 hour, cooled to room temperature, and ethanol (0.5 mL) and hydrazine (0.02 mL, 0.637 mmol) were added. The mixture was stirred at 95 ° C for 45 minutes, cooled to room temperature and diluted with 3 N hydrochloric acid (0.5 mL). The mixture was stirred at 55 ° C for 20 minutes and then filtered. The filtered solid was washed with 3 N hydrochloric acid and the combined filtrates were washed with ethyl acetate (15 mL) and lyophilized. The residue was purified by reverse phase preparative HPLC to give the desired product (0.008 g, 11% yield); ¹ H-NMR (300 MHz, CD ₃ OD): 8.10 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 7.63 (d, 1H, J = 9, 3 Hz), 7.38-7.44 (m, 2H), 7.197.32 (m, 5H), 4.36 (t, 2H, J = 6.8 Hz), 4.23 (s, 2H) 1.98 (t, 2H, J = 6.8 Hz).

Example 6

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 28) (a) Solution containing 2- nitro-1,4-phenylenediamine (21.0 g, 137 mmol) in ethanol (350 mL) and 4.0 M hydrogen chloride in dioxane (30.8 mL, 123 mmol) were stirred at room temperature for 15 min and then added diethyl ether (1.0 L). The resulting precipitate was filtered off, then washed with diethyl ether and dried in vacuo. There was thus obtained 2-nitro-1,4-phenylenediamine hydrochloride (23.3 g, 100% yield).

(b) A mixture of 2-nitro-1,4-phenylenediamine hydrochloride (15.0 g, 79.1 mmol), cyanamide (25.0 g, 595 mmol) and water (5 mL) was stirred at room temperature for 1.5 hours. 60 ° C, allowed to cool to room temperature and then excess diethyl ether was slowly added. The resulting precipitate was filtered off, then washed with diethyl ether and dried in vacuo. There was thus obtained N- (4-amino-3-nitrophenyl) guanidine hydrochloride (18.0 g, 98% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 9.7 (s), 7.8 (s), 7.6 (s),

7.5 (s), 7.3 (d), 7.1 (d).

(c) A mixture containing N- (4-amino-3-nitrophenyl) guanidine hydrochloride (12.0 g, 51.8 mmol), 10% Pd / C (1.0 g), tetrahydrofuran (100 mL) and methanol ( 100 ml) was hydrogenated at 101 kPa (atm), filtered and concentrated in vacuo.

Thus, (d) A mixture containing phenyl) guanidine (9.9 g, additional precipitate with diethyl ether and hydrochloride) gave N- (3,4-diaminophenyl) guanidine hydrochloride as a dark solid; 1 H-NMR (300 MHz, DMSO d ₆ ): 9 4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).

N- (3,4-diamino49 mmol) hydrochloride, ethylethoxycarbonimidoylacetate hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL) were stirred and heated in an oil bath at 110 ° C for 1.5 h, cooled to room temperature. temperature and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) and addition of ethyl acetate (10 mL) resulted in a suspension of the precipitate. The suspension was filtered and excess ethyl ether was obtained. The precipitate was filtered off, then washed and dried in vacuo. There was thus obtained ethyl 5-guanidino-1H-benzoimidazol-2-yl acetate (14.1 g, 94% yield) as an off-white solid; 1 H-NMR (300 MHz, DMSO-d 6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 (q), 1.2 (t).

(e) A mixture containing 4-nitro-3-methoxybenzoic acid (5.0 g, 25.4 mmol) and an aqueous solution of methylamine (40%, 15 mL) was heated in a sealed vial to an oil bath for 12 hours.

100 ° C, allowed to cool to room temperature and then poured into a stirred slurry of 1 M aqueous hydrochloric acid and ice to give an orange precipitate,

The precipitate was filtered off, washed with water and recrystallized from hot ethanol. There was thus obtained 3-methylamino-4-nitrobenzoic acid as a bright red crystalline solid (3.6 g, 73% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3, 0 (d).

(f) A mixture containing 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxynenztriazole hydrate (9.9 g, 73.0 mmol) , dimethylformamide (100 mL) and N-methylmorpholine (18.3 mL) were stirred at room temperature for 15 min before 2-naphthylethylamine (13.8 g, 66.3 mmol) was added. The mixture was stirred for an additional 30 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, 0.1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo by crystallization from hot ethanol. .

methylamino-N- (2-naphth-1-ylethyl) -4-nitrobenzamide as a bright red crystalline solid (21.3 g, 92% yield); 1 H-NMR (300 MHz, DMSO-d 6): 8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d),

7.8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 ( d).

(g) A mixture containing 3-methylamino-N- (2-naphth-1-ylethyl) -4-nitrobenzamide (21.3 g, 61 mmol), 10% Pd / C (1.0 g), tetrahydrofuran (100 mL) and methanol (100 mL) was hydrogenated at 101 kPa (atm), filtered and concentrated in vacuo

4-amino-3-methylamino-N- (2-naphth-1g, 95% yield) as a colorless amorphous solid; 1 H-NMR (300 MHz, DMSO-d 6): 8.3 (d),

8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 (m), 7.1 (d), 6.9 (s), 6.5 ( d),

5.0 (s), 3.5 (q), 3.2 (t), 2.7 (s).

The residue was purified. There was thus obtained ylethyl) -4-benzamide (18.4 (h) mixture containing ethyl 5-guanidino-1H-isoisoimidazol-2-ylacetate hydrochloride (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N-). (2-naphth-1-ylethyl) -4-benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 mL) were heated in an oil bath at 185 ° C and stirred for 3.5 hours under a nitrogen atmosphere, The reaction mixture was cooled to room temperature and poured into stirred acetonitrile (150 mL) and the resulting precipitate was washed with acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo to give an off-white solid which was purified by reverse phase preparative HPLC. 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -3-methyl-3H-benzoimidazole-5-carboxamide was obtained as a white solid (0.5 g, LRMS (ESI): calcd for C30H2BN8O: 516.6, found (MH ⁺ ): 517.2.

Example 7 ethyl-2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5- yl} -4-oxobutyl) benzoate (compound 29) (a) A solution containing ethyl 2-cyanopropanoate (100 g, 0.29 mol) in ethanol (65 mL) was cooled to 0 ° C and then saturated with dry hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred for 24 hours, cooled to 0 ° C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred for an additional 24 hours. Diethyl ether / hexane (1/1) was then added to the mixture. The resulting precipitate was collected by filtration and dried under vacuum. There was thus obtained ethyl 2- (N-ethoxyamidino) propanoate hydrochloride (119.6 g, 73% yield) as a white solid; 1 H-NMR (300 MHz, DMSO-d 6): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1, 2 C (t, 3 H).

(b) A mixture containing 3,4-diaminopyridine (51.7 g, 0.46 mmol), ethyl 2- (N-ethoxyamidino) propanoate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 g). ml) was warmed to ° C and stirred for 18 hours. It was then heated to 120 ° C and stirred for an additional hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized by the addition of 5 M aqueous ammonia and the organic layer of sodium bicarbonate, and the mixture was washed with sodium and dried and extracted with ethyl acetate. saturated aqueous solution saturated aqueous solution (MgSO ₄ ), filtered and concentrated in vacuo. There was thus obtained ethyl 1H-imidazo [4,5c] pyridine-2-carboxylate (60.4 g, 58% yield); 1 H-NMR (300

MHz, CDC1 _3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q,

2H), 3.90 (q, 2H), 1.75 (d, 3H), 1.25 (t, 3H).

(c) A mixture containing ethyl 1H-imidazo [4,5-c] pyridine-2-carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 mL) and platinum oxide (2.5 g) in a Parra hydrogenation apparatus. was hydrogenated at 50 psi for 24 h, filtered, and concentrated in vacuo. The oily residue was dissolved in a minimum amount of ethanol. To this solution was added a solution of dry hydrogen chloride in dioxane (4M, 120 mL, 475 mmol). Excess diethyl ether was then added to the solution. The resulting precipitate was filtered off and dried in vacuo. There was thus obtained ethyl 1,4,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2-carboxylate dihydrochloride (30.7 g, 66% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 10.00 (bs, 2H), 4.35 (q, 1H), 4.20 (bs,

2H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (bs, 2H), 1.55 (d, 3H), 1.15 (t, 3H).

(d) A mixture containing ethyl 1,4,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2-carboxylate dihydrochloride (60.2 g, 0.20 mol), acetonitrile (500 mL) and diisopropylethylamine (100 mL, 0.60 mol) was cooled to 0 ° C. Benzyl chloroformate (58 mL, 0.40 mol) was added slowly with stirring. The mixture was slowly warmed to room temperature, stirred for an additional 16 hours, and concentrated in vacuo. The residue was dissolved in diethyl ether (500 mL) and the solution was washed with 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This gave a colorless oil, which was dissolved in ethanol (320 mL) and cooled to 0 ° C. A solution of sodium ethoxide in ethanol (2.6 M, 85 mL, 0.22 mol) was then added slowly. The mixture was stirred at 0 ° C for 1 hour and then a solution of hydrogen chloride in dioxane (4 M, 50 mL) was added. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Thus it was obtained

5-benzyl-2-ethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-2,5-dicarboxylate as a yellow amorphous substance (52 g, 72% yield); ¹ HNMR (300 MHz, DMSO-d ₆ ): _δ , 75 (bs, 1H), 7.30 (s, 5H), 5.10 (s,

2H); 4.40 (bs, 2H); 4.05 (m, 2H); 3.75 (q, 1H); 3.65 (bs, 2H); 1.40 (d, 3H); 15 (t, 3 H).

(e) A mixture containing 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), t-butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g, 8, 2 mmol) was heated at 50 ° C under a nitrogen atmosphere for 12 hours. The resulting white suspension was partitioned between diethyl ether (250 mL) and water. The organic layer was separated and washed repeatedly with water followed by 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The obtained colorless oil was distilled at 66 Pa (0.5 mmHg) at 51 ° C. There was thus obtained t-butyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); 1 H-NMR (300 MHz, CDCl 3 -J: 3.60 (t,

2H), 2.40 (t, 2H), 2.10 (m, 2H), 1.45 (s, 9H).

(f) A mixture containing ethyl saicyclate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 mL), and t-butyl 4-chlorobutyrate (4, 2 mL). 08 g (22.8 mmol) was heated at 70 ° C and stirred for 12 hours. The mixture was then partitioned between diethyl ether (100 mL) and water. The organic layer was separated and washed with water (3x) and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The colorless oil obtained was purified by chromatography on silica gel using neat hexane to hexane / ethyl acetate (10/1). There was thus obtained ethyl 2- (3-t-butoxycarbonylpropoxy) benzoate (3.6 g, 62% yield) as a colorless oil; 1 H-NMR (300 MHz, CDCl ₃ ): 7.80 (d, 1H), 7.49 (t, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (t,

2H), 2.50 (t, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).

(g) Ethyl 2- (3- t -butoxycarbonylpropoxy) benzoate

11.7 mmol) was stirred with excess trifluoroacetic acid at room temperature for 1 hour.

The residue was chromatographed on silica gel using hexane / ethyl acetate (10/1) to neat diethyl ether. There was thus obtained 4- (2-ethoxycarbonylphenoxy) butanoic acid (2.81 g, 95% yield) as a colorless crystalline solid; ¹ H-NMR (300 MHz, CDCl ₃ ): 7.80 (d, 1H), 7.50 (t, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4, 15 (t,

2H), 2.65 (t, 2H), 2.20 (m, 2H), 1.40 (t, 3H).

(h) A mixture comprising benzyl-2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (1.7 g, 4.8 mmol), N- (3, 4, 5-carboxylate) hydrochloride. 4-Diaminophenyl) guanidine (0.8 g, 4.0 mmol) and dimethylformamide (2 mL) were heated in an oil bath at 185 ° C under a nitrogen atmosphere for 2.5 hours. Then, the mixture was room temperature and poured into stirred (150 mL). The resulting precipitate was washed with diethyl ether (150 ml), filtered and dried in vacuo. The off-white solid was purified by reverse phase HPLC. There was thus obtained benzyl-2- [] - (5-guarudino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetra (3.6 g, acid). The solution was concentrated and purified by flash cooling on acetonitrile with acetonitrile. dihydroimidazo [4,5-c] pyridíη-5-carboxylate as a white solid (1.0 g, 55% yield); LRMS (ESI): calcd for CzqHzeNsOz: 458.5 found (M-H ⁴⁾ 4 59. second

(i) A mixture comprising benzyl 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (1) 1.0 g, 2.2 mmol), 10% Pd / C (0.5 g), tetrahydrofuran (50 mL) and methanol (50 mL) were hydrogenated at 101 kPa (atm), filtered and concentrated in vacuo. There was thus obtained N- {2- [1- (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2-yl) ethyl] -1H-benzoimidazol-5-yl} guanidine (0.69 g, 97% yield); LRMS (ESI) Οΐ6Η ₂ οΝ ₈ Calculated: 324.4; found (MH +): 325.2.

(j) A mixture containing 4- (2-ethoxycarbonylphenoxy) butanoic acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenztriazole hydrate (87 mg, 0.64 mmol), N-methylmorpholine (0.16 mL, 0.92 mmol) and dimethylformamide (2.5 mL) was stirred at room temperature for 10 min before N- {2- [1- (4,5,6,7-tetrahydroimidazo [4, 5-c] pyridin-2-yl) ethyl] -3H-benzoimidazol-5-yl} guanidine (203 mg, 0.63 mmol). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product was purified by reverse phase preparative HPLC. The combined pure fractions were then lyophilized. There was thus obtained ethyl 2- (4- {2 [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-one; yl} -4-oxobutyl) benzoate; LRMS (Bioión): for C 29 H ₃₄ N ₈ O4 Calculated: 558.6; found: 559, 3.

Example 8

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 30) ( a) A solution containing t-butyl 2-hydroxyethylcarbamate (25 mL, 161.1 mmol) in dichloromethane (60 mL) was cooled to 0 ° C and stirred. Diisopropylethylamine (33.8 mL, 193.9 mmol) was added first followed by dropwise addition of mesyl chloride (13.7 mL,

177.8 mmol). The mixture was allowed to warm to 23 ° C, stirred for 18 h, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3 M, 3 x 25 mL) and saturated aqueous sodium bicarbonate (2 x 25 mL). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. There was thus obtained t-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI): calcd for C 8 H 17 NO 5 S: 239.08; found 240 (MH ⁺ ).

(b) Lithium bromide (136.0 g, 1.56 mol) was dissolved in tetrahydrofuran (600 mL) at 0 ° C. The mixture was allowed to warm to 23 ° C and then t-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 156 mmol) was added dropwise. The mixture was stirred at 23 ° C for 18 hours and concentrated in vacuo. The residue was dissolved in hexane and the organic layer was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. There was thus obtained t-butyl 2-bromomethyl carbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI): calcd for C ₇ H ₁₄ BrNO ₂ : 224.10; found 225 (MH ⁺ ).

(c) A mixture of 2-methoxyphenol (9.8 mL, 89.3 mmol), dimethylformamide (100 mL) and potassium carbonate (61.5 g, 445 mmol) was stirred at 23 ° C and t-butyl 2 - was added. bromomethyl carbamate (20.0 g, 89.3 mmol). The mixture was stirred for 24 hours and then poured into diethyl ether / hexane (1/1, 400 mL) and washed with water (5 x 50 mL). The aqueous layer was extracted with diethyl ether / hexane (1/1, 3 x 40 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. There was thus obtained t-butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.22 g, 97 yield) as a yellow oil; MS (PB-PCI): calcd for C ₁₄ H ₁₄ NO ₄ : 267.32; found 268 (MH +).

(d) t-Butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 ° C and a mixture of three fluoroacetic acid and dichloromethane (1/1, 40 mL) was added dropwise with stirring. The mixture was allowed to warm to 23 ° C, stirred for 2 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and the solution was washed with saturated aqueous sodium bicarbonate (3 x 20 mL) and aqueous sodium hydroxide solution (10%, 3 x 20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. There was thus obtained 2- (2-methoxyphenoxy) ethylamine (13.0 g, 88% yield) as a light yellow solid; MS (PB-PCI): calcd for C 8 H 13 NO ₁ : 167.21; found 168 (MH ⁺ ).

(e) A heterogeneous mixture containing 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 mL, 391 mmol) was heated at reflux for 1 h. Excess thionyl chloride was removed by distillation and the residue was concentrated in vacuo. There was thus obtained 3-methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a light yellow solid; MS (PB-PCI): calcd for C ₈ H ₆ ClNO ₄ : 215.59; found (MH ⁺ ): 216.

(f) A mixture containing 2- (2-methoxyphenoxy) ethylamine (10.0 g,

59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) were cooled to 0 ° C and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g,

54.4 mmol) in dichloromethane (50 mL). The mixture was warmed to 23 ° C over 2 hours, aqueous hydrochloric acid (3 M, 20 mL) was added, washed with water (3 x 20 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. There was thus obtained N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (14.0 g, 74% yield) as an off-white solid; MS (PB-PCI): for C 17 H; ₈ N; O. calculated: 34.6, 34; found 347.

(g) A mixture of N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40 mL) and DMSO (2 mL). was heated in a sealed ampoule for 4 hours

1. '

110 ° C, cooled and poured into water (25 mL). Addition of 3 M aqueous hydrochloric acid to the solution gave an orange solid which was isolated by filtration. There was thus obtained N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 89% yield) as an off-white solid; MS (PB-PCI): calcd for C17H19N3O5: 345, 35; found 346 (MH ⁺ ).

(h) A mixture containing N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), Pd / C suspension (10%, 0.5 g) in methanol (100 mL) and tetrahydrofuran (50 mL) was stirred under an atmosphere of hydrogen at room pressure for 2.5 hours. The mixture was filtered and the solution was concentrated in vacuo. There was thus obtained 4-amino-N- [2- (2-methoxyphenoxy) ethyl] -3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PBPCI): calcd for C17H21N3O3: 315.37; found (MH ⁺ ): 316.

(i) A mixture of 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), Pd / C (10%, 1.0 g) and methanol (50 mL) in a Parra apparatus was hydrogenated for 3 hours at 50 psi, filtered through celite and concentrated in vacuo. There was thus obtained 3,4-diaminophenol (4.02 g, 91% yield) as a dark solid; MS (PB-PCI): calcd for C ₆ H ₈ N ₂ O: 124.16; found ( ⁺ ): 125.

(j) A mixture of 3,4-diaminophenol (3.661 g, 29.5 mL), ethyl 2- (N-ethoxyamidino) propanoate (7.423 g, 38.4 mmol) and ethanol (30 mL) was heated at rt for 6 h. reflux and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated aqueous sodium bicarbonate solution (3 x 20 mL) and brine (1 x 20 mL), dried (MgSO 4 and concentrated in vacuo to give ethyl 2- (5). hydroxy-1H-benzoimidazol-2-yl) propanoate (6.3 g, 91% yield) as a dark solid The material was further purified by flash chromatography on silica gel (100% ethyl acetate); MS (PBPCI): for C] HHN-Ό; calculated: 234.28; found (MH + ^1): 235th

(k) A mixture containing ethyl 2- (5-hydroxy-1H-benzoimidazol-2-yl) propanoate (148.0 mg, 0.63 mmol), 4-amino-N- [2- (2-methoxyphenoxy) ethyl] -3- methylaminobenzamide (200.0 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (0.5 mL) were stirred at room temperature until homogeneous of the solution, which was degassed under vacuum and the solution was concentrated by heating at 170 ° C for 2 hours, under a stream of N ₁ . The residue was cooled to room temperature and washed with excess diethyl ether. The amorphous material obtained was taken up in 50% aqueous acetonitrile and purified by reverse phase preparative HPLC (2-50% CH 3 CN / H 2 O). There was thus obtained 2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxy-phenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (40 mg, 13% yield) as a pale pink solid; MS (Biolone) calcd for C 27 H 27 N 5 O 4 485, 59; found 486.5 (MH ⁺ ).

The following compounds of the invention were prepared as in Example 8:

methyl 2- {2- {2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 31), MS (Biolone ): Calcd. for C28H26N5O4F: 515.54; found 516 (MH ⁺ );

2- (2- {2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 32), MS (Biolone ): Calcd. for C27H24N5O4F: 501.52; found 502.1 (MH ⁺ );

ethyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 33), MS (Biolone ): Calcd for C29H29N5O5 527.58; found 528.1 (MH +);

2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 34), MS (BioTone) for C12H25N5O5: 499.53; Found (MH ^4): 500, 1;

N-ethyl-2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (compound 35), MS (BioIon): calcd for C20H21N5O2: 363, 42; Found (MH ^4): 364, 1;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 36), MS (Biolone): Calcd for C21H23N5O3: 393.45; found 394.1 (MH ⁺ );

butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino-ethoxy) benzoate (Compound 37), MS (Biolone) for C31H33N5O5: 555.64; Found (MH ^4): 555.7;

- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] -benzimidazol-1-yl (propane-1-sulfonic acid) (compound 38), MS (LCMS): the C ₃ oH35N ₈ 0 ₆ S Calc'd: 635, 72, found: (MH ^4): 635, 4;

N- [2- (2-ethoxyphenoxy) ethyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 39), MS (Biolone) calcd for C28H29N5O4: 499.58; found 500.4 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 40), MS (Biolon) ₂ C 9 H ₃ iN5O ₄ calculated: 513.61; Found (MH ^4): 514.5;

- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 41), MS ( Biolone): calcd. Found (MH + ^1): 514.2;

2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl]] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} crude oil ( ethoxy) benzoate.

(Compound 42), MS (ESI) for C ₃ oH ₃₁ N c, 0 ₅ calculated: 541.61; found 542.2 (MH ⁺ );

Isobutyl 2- (2- (2- (1- (5-hydroxy-1H-benzoimidazol-2yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 43), MS (Bione) Calcd for C 31 H 33 N 5 O 5: 555.64, found (MH ⁺ ): 556.3;

ethyl 4- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} butanoate (compound 44), MS (Biolone): calcd for C24H27N5O4 : 449, 51; found 449.9 (MH ⁺ );

4- (2- (1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} butanoic acid (compound 45), MS (Biolone): for C ₂₂ H ₂₃ N ₅ O ₄ calculated: 421.46, found (MH ⁺ ): 422.1;

Isopropyl 2- (2- (2- (1- (5-hydroxy-1H-benzoimidazol-2yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 46), MS (ESI) ) for C ₃ oH ₃ and _{5 5} 0 calculated: 541.61; found (MH ^+): 542.2;

N- {2- [2- (1-ethyl-propoxy) -phenoxy] -ethyl} -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) -ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (compound 47), MS (Biolon) C ₃ H ₃₅ N ₅ O ₄ calculated: 541.65; found 542.5 (MH ⁺ );

ethyl 2- (2- (2- (1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino (ethoxy) benzoate (compound 48), MS (Biolone) ) for C ₂ 9H ₂₈ N ₅ O ₄ F calcd: 529, 57, found (MH ^+): 529.5;

2-Methoxyethyl 2- (2- (2- (1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino (ethoxy) benzoate (Compound 49), MS (BioIon) 0 _{3 31} οΗ _Ν5θ Γ, calculated: 557, 61, found (MH +): 558.2;

N- (3-methoxypropyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (compound

501, MS (Biolone): calcd for C22H25N5O3: 407.47; found 408.0 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 51), MS ( Biolone: calcd for C28H29N5O4: 499.57; found 499.8 (MH ⁺ );

N- [2- (2-ethoxymethylphenoxy) ethyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 52), MS (Biolone): calcd for C29H31N5O4: 513.60; found 514.1 (MH ⁺ );

ethyl 2- {2- {2- [1- (6-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 53) MS (ESI) calcd for C 29 H 28 N 5 O 5 F: 545.57; found 546.3 (MH ⁺ );

ethyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) cyclohexanecarboxylate (compound 54), MS (Biolone ): Calcd for C29H35N5O5 533.63; found 534 (MH ⁺ );

2- [1- (5-hydroxy-ΙΗ-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxymethylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 55), MS (Biolone): calcd for C30H33N5O4: 527.62; found 527.6 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 56), MS (Biolon) C3 _{0 5} H 3 N ₃ O4 calculated: 527.62; found 527.9 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxyjetyl} -3-methyl-3H-benzoimidazole-568 carboxamide (Compound 57), MS (Biolone): calcd. For C30H33N5O5: 543.62; found 543.4 (MH +);

2- [1- (1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (compound

58), MS (Biolone): calcd for C28H29N5O3: 483.57, found (MH ⁺ ): 484;

N- [2- (2-ethoxymethylphenoxy) ethyl] -2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (compound

59), MS (Biolone): calcd for C29H31N5O3: 497.6; found 498.3 (MH ⁺ );

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxymethylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (compound

60), MS (Biolone): calcd. For C30H33N5O3: 511.62; found 511.5 (MH ⁺ );

- [1- (1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 61), MS (Biolone): calcd for C30H33N5O3: 511.62; found 511.6 (MH ⁺ );

2- [1- (1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 62 MS (Biolone) calcd. For C30H33N5O4: 527.62; found 527.7 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (compound 63), MS (Biolone): calcd. For C ₃₀ H ₃ N ₆ O ₄ : 540.73; found 541.8 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (compound 64), MS (Biolone):

503, 59; found 504.2 (MH +);

Calcd for C ₂₆ H ₂₅ N ₆ O ₄ S:

2- (2- (2- (1- (6-fluoro-5-hydroxy-4-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy) benzoic acid; 65), MS (ESI): calcd for C 51 H 51 N ₅ O ₅ F: 517.52, found (MH +): 518.2;

ethyl 2-hydroxy-5- (2- (1- (5-hydroxy-6-benzoimidazol-2yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} benzoate; (Compound 66), MS (Biolone Calcd: for C27H25N5O5: 499.52, found (MH ⁺ ): 500.2;

2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (compound 67), MS (Biolone) calcd for C 30 H 31 N 6 O 3 F: 542.62; found 543.4 (MH ⁺ );

N- (2-phenylsulfonylethyl) -2- (1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 68), MS (Biolone): for C26H24N5O3FS found 506.5 (MH ⁺ );

ethyl 2- (2- (2- (1- (4,6-difluoro-5-hydroxy-ΙΗ-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; ( Compound 69), MS (Biolone): calcd for C29H27N5O5F2: 563.52, found (MH ⁺ ): 563.4;

2- (2- (2- (1- (4,6-Difluoro-5-hydroxy-4-benzoimidazol-2yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 70), MS (Bione): for

C27H23N5O5F2 calculated: 536.51; found 563 (MH ⁺ );

ethyl-2- (2- (2- (1- (4,6-difluoro-5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) (ethoxy) benzoate (compound 71), MS (Bione): for

C32H11N / O4F2 calculated: 613.62; found 614.3 (MH ⁺ );

2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) -3-methyl-N {2- [2- (3-methyl | 1,2,4] oxadiazol-5-yl) f -3H-benzo70 imidazole-5-carboxamide (compound 72), MS (Biolone): for

C3CH30N10O3 requires 578.63; found (MI-1 '): 579.4; and - [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2- (3-methyl- [1,2,4] oxadiazole-5-] - yl) phenoxy] ethyl} -3H-benzoimidazole-5-carboxamide (compound 73), MS (Biolone) calcd for C32H29N9O3: 587.64; found 588.2 (MH ⁺ ).

Example 9

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl] ethyl} -3-methyl -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; (compound 47) (a) A solution containing 3,4-diaminopyridine (51.7 g, 0.46 mol) in acetic acid (400 mL) was heated to 85 ° C and then added over three hours with three equal portions of diethyl methyl 1-iminomalonate (125 g, 0.60 mol). The mixture was heated at 85 ° C for 12 hours and at 120 ° C for an additional hour, cooled and concentrated under reduced pressure. The residue was cooled to 0 ° C and neutralized with 5 N aqueous ammonia. The aqueous layer was extracted several times with ethyl acetate. The combined extracts were washed sequentially with sodium bicarbonate and sodium chloride, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. There was thus obtained ethyl 2- (1H-imidazo [4,5c] pyridin-2-yl) propanoate (60.4 g, 58%) as an amber yellow solid;

(b) A solution containing ethyl 2- (1H-imidazo [4,5-c] pyridin-2-yl) propanoate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 mL) was hydrogenated at 244 kPa for 2 days. (50 psi) in the presence of PtO ₂ (5 g). The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0 ° C, treated with 4 M HCl / dioxane, suspended in diethyl ether, filtered and dried. Solutions containing the residue (15-20 g each) were hydrogenated in fresh trifluoroacetic acid (50 mL each) at 24 psi (50 psi) for 24 hours in the presence of PtO.- (5 g each). The mixtures were filtered and concentrated under reduced pressure. The residues were azeotroped with toluene / ethanol -1: 1, with 4 M HCl / dioxane, suspended in diethyl ethers, collected by filtration, and dried on a vacuum line. There was thus obtained ethyl 2- (4,5,6,7-tetrahydroimidazo [4,5c] pyridin-2-yl) propanoate dichloride (61.80 g, 75% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 10.00 (bs, 2H), 4.35 (q, 1H, J = 7.1 Hz),

4.25 (bs, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (bs, 2H), 1.60 (d, 3H, J = 7.1 Hz) 1.22 (t, 3H, J = 6.9 Hz).

(c) A solution containing ethyl 2- (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2-yl) propanoate (60.2 g, 0.20 mol) in acetonitrile (400 mL) was added. under nitrogen atmosphere cooled to 0 ° C. Then, N, N-diisopropylethylamine (35.0 mL, 0.20 mol) was added and the solution was cooled to about -5 ° C (ice / acetone) and then benzyl chloroformate (58.0 mL, 0.41 mol) and N, N-diisopropylethylamine (70.0 ml, 0.40 mol). The mixture was cooled to -5 ° C for 1 hour and allowed to warm to 20 ° C. After 16 hours, it was concentrated under reduced pressure. The residue was suspended in diethyl ether and the suspension was subsequently washed with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 mL) and the solution was cooled to -5 ° C under a nitrogen atmosphere. Sodium ethoxide (21 wt%, 85 mL, 0.22 mol) was then added dropwise over 1 hour while maintaining the temperature of the reaction mixture below 0 ° C. The mixture was cooled to -5 ° C for 1 hour, 50 mL of 4 M hydrochloric acid was adjusted to pH neutral, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate and sodium chloride, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate). There was thus obtained benzyl 2- (letloxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (52.0 g, 72% yield) as a light yellow oil; ^X H-NMR (300 MHz, _DMSO-d6): l, 72 (bs, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (bs, 2H); 4.02 (q, 2H, J = 9.3 Hz), 3.77 (q, 1H, J = 8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H, J = 8.3 Hz), 1.13 (t, 3H, J = 9.3 Hz).

(d) A mixture containing benzyl 2- (1-ethoxycarbonylethyl) 1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino-3 - (N-methylamino) benzoic acid (2.70 g, 0.016 mol) and DMPU (20 mL) were briefly degassed on a vacuum line, heated to 185 ° C under nitrogen atmosphere for 4 hours, cooled and added to an equal volume of benzene . Subsequent addition of diethyl ether gave a precipitate. The precipitate was isolated by filtration, briefly dried on a vacuum line, and purified by recrystallization from hot, isolated by filtration and ethanol / water mixtures. dried. This is how

The precipitate recovered

2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) -ethyl] -3-methyl-3H-benzoimidazole-5-carboxylic acid (4, 73 g, 58% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 12.70 (bs, 1H), 11.70 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H, J = 8.3 Hz), 7.64 (d, 1H, J = 8.3 Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (q, 1H, J = 5.2 Hz), 4.32 (bs, 2H), 3.78 (s, 3H),

3.65 (bs, 2H), 2.52 (bs, 2H), 1.73 (d, 3H, J = 5.2 Hz).

(e) A mixture comprising 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5- carboxylic acid (0.75 g, 1.6 mmol), methyl 2- (2-aminoethoxy) benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) were cooled under nitrogen at -40 ° C, EDC (0.32 g, 1.6 mmol) and N, N-diisopropylethylamine (0.29 mL, 1.6 mmol) were added and after 15 minutes more N, Ndiisopropylethylamine (0 , 29 ml). The mixture was allowed to warm to 20 ° C and stirred for 16 hours. The mixture was then cooled to -40 ° C and EDC (0.080 g) and N, N-diisopropylethylamine (0.050 mL) were added, stirred for 15 minutes at -40 ° C and 2 hours at 20 ° C, and concentrated by shortpath distillation. The residue was partitioned between chloroform and sodium bicarbonate. The organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl ₃ / MeOH / AcOH 95/5/1). There was thus obtained benzyl 2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] ] pyridine-5-carboxylate (0.69 g, 66%) as a brown glassy foam; ¹ H-NMR (300 MHz, DMSO-d ₆ ): 11.92 (s, 1H), 8.49 (t, 1H,

J = 5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H, J = 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1H, J = 9.9 Hz),

6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J = 8.8 Hz),

4.30 (bs, 2H), 4.20 (t, 2H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s,

3H), 3.63 (m, 4H), 2.55 (bs, 2H), 1.67 (d, 3H, J = 8.8 Hz).

(f) A solution containing benzyl-2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (0.69 g, 1.1 mmol) in THF (2.0 mL) and water (2.0 mL) was cooled to 0 ° C under a nitrogen atmosphere, added 2 N lithium hydroxide (1.1 mL, 2.2 mmol) was allowed to warm to 20 ° C and stirred for 8 hours. Then the mixture was cooled to 0 ° C, 2 N lithium hydroxide (1.1 ml) was added, allowed to warm to 20 ° C, stirred for 6 hours, pH was adjusted to 7 with 1M hydrochloric acid and the mixture was concentrated under reduced pressure. He concentrated. The residue was carefully washed with cold sodium chloride and water and then dried on a vacuum line. There was thus obtained 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1H-benzoimidazo [4,5-c] pyridin-2-yl) ethyl] -3H- benzoimidazol-5-ylcarbonylamino-ethoxy) -benzoic acid (0.56 g, 83%) as a glassy residue; 1 H-NMR (300 MHz, DMSO-d ₆ ): _δ , 87 (bs,

(g) A solution containing 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1H-benzoimidazo [4,5-c] pyridin-2-yl) ethyl] 3 H -Benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.561 g, 0.90 mmol) in glacial acetic acid (2 mL) was heated to 10 ° C under a nitrogen atmosphere in a water bath. To the mixture was added hydrogen bromide in acetic acid (2.0 mL of a 30% solution) and the mixture was allowed to warm to 20 ° C. After an hour, the mixture was concentrated with a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the solution was added dropwise to stirred diethyl ether. The resulting pale brown precipitate was collected by filtration and dried. 2- (2- {3-Methyl-2- [4,5,6,7-tetrahydro-1H-benzoimidazo [4,5-c] pyridin-2-yl) ethyl] -3H-benzoimidazole- 5-ylcarbonylamino} ethoxy) benzoic acid (0.651 g); ¹ H-NMR (300 MHz, DMSO-d 6):?

9.31 (bs, 2H), 8.63 (m, 1H), 8.24 (s, 1H), 7.79 (d, 1H, J = 7.9)

Hz), Hz), 2H)

7.63 (m, 7.00 (t, 4.21 (s,

2H), 7.47 (t, 1H, J = 7.9Hz), 7.21 (d, 1H, J = 7.9)

1H, J = 7.9Hz), 5.21 (q, 1H, J = 6.3Hz), 4.29 (s,

2H), 3.91 (s, 3H), 3.68 (m, 2H), 3.43 (m, 2H),

2.89 (s, 2H), 1.79 (d, 3H, J = 6.3 Hz) and (h) 2- (2- {3-methyl-2 [4,5,6,7] hydrobromide solution) -tetrahydro-1H-benzoimidazo [4,5-c] pyridin-2-yl) ethyl] 3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.30 g, 0.46 mmol) in DMF (1.5 mL) was cooled to 0 ° C under a nitrogen atmosphere, ethyl acetimidate (0.12 g, 0.92 mmol) and N, N-diisopropylethylamine (0.25 mL, 1.4 mmol) were added. The solution was cooled to 0 ° C in minutes and then allowed to warm to 20 ° C and stirred for 20 hours. Then the mixture was cooled to 0 ° C, additional ethyl acetimidate (0.06 g) and N, N-diisopropylethylamine (0.16 mL) were added, allowed to warm to 20 ° C and stirred for 2 hours. The mixture was cooled to 0 ° C, additional ethyl acetate imidate (0.03 g) was added, allowed to warm to 20 ° C and stirred for 2 hours. The mixture was then added dropwise to stirred diethyl ether. The resulting precipitate was collected by decantation and dried on a vacuum line. The residue was precipitated from ethanol / ether and purified by preparative RP-HPLC: 2-50% MeCN / FhO (20 mM HCl) for 50 minutes. Fractions were lyophilized. This gave 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (0.145 g, 52% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 9.77 (s, 1H), 9.34 (2s, 1H), 8.81 (m, 1H),

8.36 (s, 1H), 7.89 (d, 1H, J = 8.6Hz), 7.71 (d, 1H, J = 8.6Hz), 7.60 (d, 1H, J) = 7.7 Hz), 7.49 (t, 1H, J = 7.7 Hz), 7.21 (d, 1H, J = 7.7 Hz), 6.99 (t, 1H, J = 7 7 Hz), 5.37 (m, 1H), 4.71 (2s, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.82 (s, 1H), 3.66 (m, 2H), 2.83 (m, 2H), 2.49 (s, 1H), 2.40 (d, 3H, J = 3.5 Hz), 1.85 (d, 3H) J = 5.1

Hz); MS (ESI): calcd for C28H31N7O4: 529.61; found (MH ⁺ ): 530.3.

Example 10 ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) benzoate (compound (A) A solution containing 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5 M, 7.5 mmol) was stirred at room temperature for 3 hours. at room temperature to give a white precipitate. To dissolve the white precipitate, the mixture was diluted with an equal volume of water to give yellow crystals. The crystals were separated and dried. There was thus obtained 2,3,5-trifluoro-6-nitroaniline (307.0 mg, 51% yield) as yellow needles; 1.1. 66 [deg.] C .; 1 H-NMR (CDCl ₃ ): 6.4 (1H, m),

6.0 (2 H, s).

(b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300.0 mg, 1.56 mmol) and Pd / C in absolute ethanol was hydrogenated at room pressure overnight, filtered under a nitrogen atmosphere and concentrated. There was thus obtained 1,2-diamino-3,4,6-trifluorobenzene (219.0 mg, 87% yield) as a violet crystalline solid; MS: M ⁺ 162.7, +41, +82 (+ ACN, + 2 ACN) (calcd for C ₆ H ₅ F ₃ N 2: 162.11).

(c) A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g,

11.8 mmol), ethyl 2-ethoxycarbonimidoyl propanoate (3.1 g, 14.7 mmol) and absolute ethanol (6 mL) were heated at reflux until completion of the reaction indicated by TLC, filtered from NH 4 Cl and concentrated. The residue was purified by silica gel chromatography (hexane / methylene chloride / ethyl acetate 5: 5: 1) to give ethyl 2- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) propanoate (1.37 g, 42% yield) as a brownish crystalline solid; NMR (CDCl 3): 10.35 (s, 1 / 2H), 7.05 (s, 1 / 2H), 6.7 (m, 1H), 4.25 (dd, 2H), 4.15 (dd) 1 H, 1.73 (d, 3H), 1.31 (t, 3H); (calcd for C12H11F3N2O2: 272.23).

(d) ethyl 2- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) propanoate (988 mg, 3.63 mmol) and ethyl 2- [2- (4-amino-3-methylaminobenzoylamino) of ethoxy] benzoate (1.3 g, 3.63 mmol) was combined and kept under vacuum for 4 hours. DMPU (4.0 mL) was then added and the mixture was stirred to dissolve and evacuated by evacuation under high vacuum overnight. The mixture was heated to 195 ° C under a stream of nitrogen for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (stepwise gradient from 100% hexane to 100% ethyl acetate) followed by crystallization from MeOH / THF / water. There was thus obtained ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) benzoate ( 1.0 g (49% yield) as a white crystalline solid; ¹ H-NMR (300 MHz, CDCl ₃ ): 6.84-8.07 (m, 8H), 4.93 (dd, 1H), 4.34 (dd, 2H), 4.27 (m, 2H) 1.95 (m, 2H), 3.9 (s, 3H), 1.93 (d, 3H), 1.78 (s, 2H), 1.38 (t, 3H); LCMS M ⁺ 566.2 Biolone

Biolon M ⁺ 565, 7 (for C ₂₉ H 6 F _{2 3 4} N5O Calcd: 565, 55).

The following compounds of the invention were prepared as in Example 10:

ethyl 2- (2- {2- [1- (5,6-difluoro-ΙΗ-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 76), MS (Biolon) ₂ C 9 H ₂₇ F ₂ N5O ₄ calculated: 547.56; found 548.1 (MH ⁺ );

ethyl 2- (2- {2- [1- (4,6-difluoro-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 77), MS (LCMS): for C 9 H ₂₇ F _{2 2} N5O ₄ calculated: 547.56; found 548.3 (MH ⁺ );

ethyl 2- (2- {2- [1- (4,5,6-trifluoro-1H-benzoimidazol-2yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 78) MS (LCMS): for C 9 H ₂ 6 F _{2 3 4} N5O calcd: 565, 55; found 566.2 (MH ⁺ ); and ethyl 2- {2- [3-methyl-2- (4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl) -3H-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (Compound 79), MS (Biolone ) for C 8 H ₂₄ F _{2 3 4} N5O calculated: 551.52; found 551.2 (MH ⁺ ).

Example 11

2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 80)

Ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) -ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino-ethoxy) -benzoate (118.0) mg, 0.21 mmol), methanol (4.0 mL) and 2 N sodium hydroxide (2.1 mL) were stirred at room temperature for 4 hours, neutralized with 2 N hydrochloric acid (2.1 mL) and partitioned between ethyl acetate and saturated chloride solution The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The remaining white solid was dissolved in hot ethanol (10.0 mL) and a 4 M solution of hydrogen chloride in dioxane. This solution was diluted with diethyl ether and the resulting precipitate was collected and dried. There was thus obtained 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid. in the form of a white solid; MS (LCMS) calcd for C27H22F3N5O4: 537.50; found 538.4 (MH ⁺ );

The following compounds of the invention were prepared as in Example 11:

2- (2- {2- [1- (5,6-Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 81), MS ( LCMS): calcd. For C27H23F2N5O4: 519.51; found 520.2 (MH ⁺ );

2- (2- {2- [1- (4,6-Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 82), MS ( LCMS): calcd. For C27H23F2N5O4: 519.51; found 520.2 (MH ⁺ ); and

2- (2- {2- [1- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 83), MS (Biolone) calcd for C27H22F3N5O4: 537.5; found 537.7 (MH ⁺ ).

Example 12

Ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino-ethoxy) benzoate (Compound 84)

Ethyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) benzoate (0.50) g, 0.95 mmol), dimethylformamide (5.0 mL), cesium carbonate (0.93 g, 2.85 mmol) and isobutyric anhydride (0.17 mL, 1.05 mmol) were stirred for 2 hours, then diluted with dichloromethane (50.0 mL) and filtered through a pad of celite. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (5.0 mL). Diisopropylethylamine (0.47 mL, 2.7 mmol) and methyl chloroformate (0.1 mL, 1.3 mmol) were added to the solution and stirred for 1 h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography using ethanol and dichloromethane as eluent. This gave ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (0.20 g, 32% yield) as an amorphous colorless solid; MS (Biolon) C35H3 ₇ N ₅ 0e Calculated: 655.72; found 656.1 (MH ⁺ ).

The following prodrug derivatives of the invention were prepared as in Example 12:

methyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-hydroxybenzoimidazole-1-carboxylate (Compound 85), MS (ESI): for C31H31N5O7 requires 585.62; found 586.2 (MH ⁺ );

ethyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-methoxycarbonyloxybenzoimidazole-1-carboxylate (Compound 86), MS (ESI) for C33H33N5O7: 643.66; found 644.2 (MH ⁺ );

ethyl 2- (2- {2- [1- (5-hydroxy-1-isobutyryl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} 80 ethoxy) benzoate ( compound 87), MS (ESI): calcd for C33H35N5O6: 597.68; found 598.2 (MH ⁺ );

ethyl 2- (2- {2- [1- (1-benzoyl-5-hydroxy-1H-benzoimidazol-2yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 88) MS (ESI) calcd for C ₃₆ H ₃₃ N ₅ O ₆ 631.69; found 632.3 (MH ⁺ );

ethyl 2- (2- {2- [1- (1-dimethylcarbamoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 89), MS (ESI): calcd. For C ₃₂ H ₃₄ N ₆ O ₆ : 598.66; found 599.3 (MH ⁺ );

ethyl 2- (2- {2- [1- (1-acetoxymethyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 90), MS (Biolone): calcd for C ₃ H ₃₃ N ₅ O 7 599, 65; found 600.7 (MH ⁺ );

ethyl 2- [2- (2- {1- [1- (2,2-dimethylpropanoyloxymethyl) -5-hydroxy-1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate (compound 91), MS (ESI): for C ₃₅ H ₃ 9 N ₅ O7 calculated: 641.74; found 642.3 (MH ⁺ );

ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino-ethoxy) benzoate (compound 92), MS (Biolone) ) for C ₃ 5 H ₃ 7NsO ₈ calcd: 655, 72; found 656.1 (MH ⁺ );

ethyl 5-ethoxycarbonyloxy-2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) benzoimidazole-1-carboxylate (Compound 93), MS (ESI): for C 5 H ₃ 7 N _{3 S} O9 calculated: 671.72; found 672.4 (MH ⁺ );

Isopropyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-isopropoxycarbonyloxybenzoimidazole-1-carboxylate (Compound 94), MS ( ESI): calcd for C ₃₇ H ₄₁ N ₅ O ₉ 699, 79; found 700.4 (MH ⁺ ); and ethyl 2- {2- {2- [1- (1-acetyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 95 ), MS (ESI) C3iH ₃ and ₅ O ₆ calculated: 569.62; found 570.1 (MH ⁺ ).

The following compounds of the invention were prepared by the procedures described in this application or by methods known to those skilled in the art:

C- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3H-benzoimidazol-5-yl] methylamine (Compound 96);

C- [2- (1H-naphtho [2,3-d] imidazol-2-ylmethyl) -1H-benzoimidazol-5-yl] methylamine (compound 97), MS (Biolone): calcd for C20H17N5 327.4; found 328.1 (MH ⁺ );

C- [2- (5-methyl-lH-benzoimidazol-2-ylmethyl) -lH-benzoimidazol-5-yl] methylamine (Compound 98), MS (Biolon) Ci7Hi ₇ N ₅ Calculated: 291.4; found 292.3 (MH ⁺ );

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazole-5-carboxylic acid (Compound 99);

3- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] propanoic acid (Compound 100), ¹ H-NMR (300 MHz, CD ₃ OD): 1.92 (m, 2H, J = 7.2Hz), 2.38 (t, 2H, J = 7.2Hz), 3.47 (t, 2H, J = 7.2Hz), 4.30 (s (2H), 7.54 (d,

1H, J = 10.0Hz), 7.69 (d, 1H, J = 8.6Hz), 7.75 (d, 1H, J = 10.0)

Hz), 7.81 (s, 1H), 7.87 (d, 1H, J = 8.6 Hz), 8.12 (s, 1H);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphthylethyl) -1H-benzoimidazole-5-carboxamide (Compound 101), 1 H-NMR (300 MHz, CD ₃ OD): 3.42 (t, 2H, J = 7.5Hz); 3.75 (t, 2H, J = 7.5)

Hz), 7.39-7.81 (m, 12H), 8.08 (s, 1H), 8.27 (d, 1H, J = 10.0 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (compound 102), 1 H-NMR (300 MHz, CD ₃ OD): 3.41 (t, 2H, J = 7.4 Hz), 3.72 (t, 2H, J = 7.4 Hz), 3.96 (s, 3H), 4.27 ( s, 2H), 7.37-7.54 (m, 5H),

7.67 (d, 1H, J = 8.7 Hz), 7.71-7.77 (m, 2H), 7.80-7.85 (m, 2H),

8.70 (d, 1H, J = 0.9 Hz); 8.24 (d, 1H, J = 8.1 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N (2-naphth-1-ylethyl) -3H-benzoimidazole-4-carboxamide (Compound 103), ¹ H-NMR (300 MHz) CD ₃ OD): 3.45 (t, 2H, J = 7.2 Hz), 3.74 (s, 3H), 3.83 (t, 2H, J = 7.2 Hz), 4.27 (s, 2H), 7.36-7.55 (m, 7H);

7.71-7.77 (m, 3H), 7.83-7.86 (m, 2H), 8.24 (d, 1H, J = 8.1 Hz);

(S) -2- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-ylpropanoic acid (Compound 104), ¹ H-NMR (300 MHz) , CD ₃ OD): 3.36 (dd,

1H, J = 14.6 and 8.1 Hz), 3.53 (dd, 1H, J = 14.6 and 5.0 Hz), 3.92 (s, 3H), 4.27 (s, 2H 6.97 (t, 1H, J = 7.4 Hz), 7.07 (t, 1H, J = 7.4

Hz), 7.16 (s, 1H), 7.33 (d, 1H, J = 7.8 Hz), 7.51 (dd, 1H, J = 8.4 and 1.5 Hz), 7, 60-7.66 (m, 2H), 7.73-7.80 (m, 3H), 7.96 (d, 1H,

J = 0.9 Hz), 8.39 (d, J = 7.5 Hz, partially replaced);

(R) -2- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-ylpropanoic acid (Compound 105), 1 H-NMR (300 MHz, CD ₃ OD): 3.35 (dd,

1H, J = 14.5 and 8.1 Hz), 3.51 (dd, 1H, J = 14.4 and 4.8 Hz), 3.90 (s, 3H), 4.23 (s, 2H 6.96 (t, 1H, J = 7.4 Hz), 7.06 (t, 1H, J = 7.4

Hz), 7.14 (s, 1H), 7.31 (d, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 7.8)

Hz), 7.58-7.74 (m, 5H), 7.94 (s, 1H), 8.33 (d, J = 8.1 Hz, partially replaced);

2- (1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1H-benzoimidazole-5-carboxamide (Compound 106), ¹ H-NMR (300 MHz, CD ₃ OD): 3.42 (t, 2H, J = 7.4Hz), 3.76 (t, 2H, J = 7.4Hz), 3.97 (s, 3H), 7.38-7, 60 (m, 5H) 7.65 (d, 1H, J = 8.7 Hz), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, J = 8.6 and 1.5 Hz), 8.04 (d, 1H, J = 1.2 Hz), 8.26 (d, 1H, J = 8.4 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N (4-aminobutyl) -3H-benzoimidazole-4-carboxamide (compound 107), MS (Bioion): calcd for C22H27N7O: 405, 4; found 406.5 (MH ⁺ );

2- [1- (5-Aminomethyl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 108), MS (Bione) ) for C ₃ H ₃₀ N ₆ O calculated: 502.6; found 503.3 (MH ⁺ );

2- (1H-imidazo [4,5-c] pyridin-3-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 109), MS (Biolone) for C ₂₈ H ₂₄ N ₆ O: 460.5; found 461.3 (MH ⁺ );

2- (5-Aminomethyl-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 110), MS (Biolone): for C ₃ H ₂₆ N ₆ 02 Calcd: 502.6; found 503.6 (MH ⁺ );

2- (5-carbamoyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphthylethyl) -1H-benzoimidazole-5-carboxamide (Compound 111);

2- (5-aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 112), ¹ H-NMR (300 MHz, CD ₃ OD): 1.67 (m,

1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd, 1H, J = 15.3 and 9.3 Hz), 2.76 (m, 2H), 2.90 (dd, 1H, J = 15.7 and 7.5 Hz), 3.41 (t, 2H, J = 7.4 Hz), 3.75 (t, 2H, J = 7.4 Hz) 3.90 (s, 3H), 7.35-7.53 (m, 5H),

7.61 (d, 1H, J = 8.4 Hz), 7.72-7.75 (m, 2H), 7.85 (dd, 1H, J = 8, 1 and 1.2 Hz), 7, 99 (d, 1H, J = 0.9Hz), 8.26 (d, 1H, J = 8.4Hz);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N (3-phenylpropyl) -3H-benzoimidazole-5-carboxamide (compound

113), ¹ H-NMR (300 MHz, CD ₃ OD): 1.98 (m, 2H), 2.72 (t, 2H, J = 7.6 Hz), 3.46 (t, 2H, J = 7.2 Hz), 4.01 (s, 3H), 4.29 (s, 2H), 7.127.17 (m, 1H), 7.21-7.28 (m, 4H), 7.56 (d, 1H, J = 8.1 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.85-7 88 (m, 2H);

8.16 (s, 1H, J = 1.0 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 114),

1 H-NMR (300 MHz, CD ₃ OD): 3.80 (t, 2 H, J = 5,0 Hz), 3,99 (s, 3H), 4.17 (t, 2H, J = 5.0Hz); 4.27 (s, 2H). 6.88 (t, 1H, J = 7.5) Hz), 6.92 (d, 2H, J = 7.5Hz); 7.22 (t, 2 H, J = 7.5Hz, 7.55 (d, 1H,

J = 8.7 Hz), 7.68 (d, 1H, J = 6.6 Hz), 7.77 (d, 1H, J = 8.4 Hz),

7.84 (s, 1H); 7.88 (d, 1H, J = 8.7 Hz); 8.18 (s, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1-ylethyl) ) -3H-benzoimidazole-5-carboxamide (compound ^115); H-NMR (300 MHz,

CD ₃ OD): 2.45 (2.43, s, 3H), 2.96 (m, 2H), 3.42 (t, 2H, J = 7.4

Hz), 3.75 (t, 2H, J = 7.4 Hz), 3.93 (s, 3H), 3.98 (m, 2H),

4.70 (4.80, s, 2H), 7.38-7.53 (m, 4H), 7.63-7.87 (m, 4H),

8.04 (d, J = 1.5 Hz), 8.08 (s, 1H), 8.26 (d, 1H, J = 8.0 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1-ylethyl) ) -3H-benzo

(compound 116), ^X H-NMR (300 MHz 3H), 3.03 (m, 2H). 3.41 (t, 2 H, J = 7.4 Hz), 3.97 (m, 2H). 4.18 (4.18, s, 3H), 38-7.54 (m, 4H); 7.72-7.92 (m, 4H),

8.04 (s, 1H); 8.26 (d, 1H, J = 7.8 Hz);

2- (5-imino-methyl-4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-l-yl-ethyl) -3 H benzoimidazole-5-carboxamide (Compound 117), ¹ H-NMR (300 MHz, CD 3 OD): 2.95 (m, 2H), 3.40 (t, 2H, J = 7.4 Hz), 3.74 ( t, 2H, J = 7.4 Hz), 3.90 (3.89, s, 3H), 3.98 (m, 2H), 4.70 (4.82, s, 2H), 7.387.39 -7.52 (m, 4H), 7.63-7.84 (m, 4H), 8.03 (s, 1H), 8.16 (8.18, s, 1H), 8.24 (d (1H, J = 8.4 Hz);

2- (5-aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 118), ¹ H-NMR (300 MHz, CD 3 OD): 1.69 (m, 1H), 2.15 (m, 1H), 2.20 (m, 1H), 2.55 (dd, 1H, J = 15, 0 and 11.4

Hz), 2.81-3.08 (m, 5H), 3.44 (t, 2H, J = 7.5 Hz), 3.74 (m, 2H),

4.23 (s, 3H), 7.39-7.52 (m, 4H), 7.75 (dd, 1H, J = 6.1 and 3.2 Hz), 7.83-7.88 ( m, 2H), 7.97 (d, 1H, J = 8.7 Hz), 8.10 (s, 1H), 8.27 (d, 1H, J = 8.1 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-phenoxyethyl) -3H- benzoimide 85 zole-5-carboxamide (compound 119), 1 H-NMR (300 MHz, CD ₃ OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (t (2H, J = 5.6Hz),

3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, J = 5.6 Hz), 4.71 (4.81, s, 2H), 6.89 (t, 1H, J = 7.3Hz), 6.93 (d, 2H, J = 8.6Hz),

7.23 (dd, 2H, J = 8.6 and 7.3 Hz), 7.66 (d, 1H, J = 7.8 Hz), 7.85 (d, 1H, J = 7.8 Hz) 8.13 (s, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-benzo [1,3] ] dioxol-4-ylethyl) 3H-benzoimidazole-5-carboxamide (compound 120), 1 H-NMR (300 MHz, CD ₃ OD): 2.45 (2.43, s, 3H), 2.89-2, 97 (m, 4H), 3.65 (t, 2H, J = 7.1 Hz), 3.94 (s, 3H), 3.98 (m, 2H), 4.71 (4.81, s) , 2H),

5.83 (s, 2H), 6.65-6.74 (m, 3H), 7.64 (d, 1H, J = 7.8 Hz), 7.767.79 (m, 1H), 8.06 (m, 1 H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (benzoimidazol-1-ylethyl) - 3 H -benzoimidazole-5-carboxamide (compound 121), 1 H-NMR (300 MHz, CD 3 OD): 2.46 (2.44, s, 3H), 2.96 (m, 2H), 3.92 (s, 3H) 3.954.01 (m, 4H), 4.73 (4.79, s, 2H), 4.80 (m, 2H), 7.54-7.64 (m,

4H), 7.83 (dd, 1H, J = 6.5 and 2.2 Hz), 7.93 (s, 1H), 7.98 (dd,

J = 6.5 and 2.1 Hz), 9.49 (s, 1H);

N- [2- (5-hydroxy-1H-indol-2-yl) ethyl] -2- [5- (1-iminoethyl) 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 122), ¹ H-NMR (300 MHz, CD 3 OD): 2.42 (2.39, s, 3H), 2.90 ( m, 2H), 2.99 (t, 2H, J = 7.1 Hz), 3.67 (t, 2H, J = 7.1 Hz), 3.75 (s, 3H), 3.93 ( m, 2H), 4.66 (4.76, s, 2H), 6.61 (dd, 2H, J = 8.5 and 2.3 Hz), 6.94 (d, 1H, J = 2, 3 Hz), 7.06 (s, 1H), 7.12 (d, 1H, J = 8.5 Hz), 7.59 (d, 1H, J = 8.4 Hz), 7.76 (dd) 1 H, J = 8.4 and 1.2 Hz), 7.87 (d, 1H, J = 1.2 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2-chlorophenoxy)] ethyl] -3H-benzoimidazole-5-carboxamide (compound 123), MS (Biolone ₎ calcd for C 26 H 28 ClN ₇ O ₂ : 506.0; found 506.3 (MH ⁺ );

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- [2- (3-chlorophenoxy)] ethyl] -3H-benzoimidazole-5-carboxamide (compound 124), MS (Biolone) calcd for C26H28ClN7O2: 506.0; found 506.7 (MH ⁺ );

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1-ylethyl) 13H-benzoimidazole-5-carboxamide (Compound 125), ¹ H-NMR (300 MHz, CD ₃ OD): 2.48 (2.46, s, 3H), 3.00 (m, 2H), 3 60 (t, 2H, J = 6.6 Hz), 3,904.05 (m, 7H), 4.76 (4.76, s, 2H), 6.64 (6.66, s, partially exchanged) 7.45-7, 95 (m, 9H), 8.02 (m, partially replaced),

8.17 (d, 1H, J = 8.1 Hz), 8.96 (s, partially replaced);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-hydroxy-2-naphtha) 1-ylethyl) 3H-benzoimidazole-5-carboxamide (Compound 126), ¹ H-NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.94 (m, 2H), 3.55 (dd, 1 H,

J = 13.6 and 8.3 Hz), 3.91-3.99 (m, 6H), 4.70 (4.80, s, 2H),

5.78 (dd, 1H, J = 8.3 and 3.6 Hz), 7.44-7.54 (m, 3H), 7.66 (d, 1H, J = 8.4 Hz), 7 76-7.88 (m, 4H), 8.08 (m, 1H), 8.39 (d, 1H, J = 8.4)

Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2- hydroxynaphth-1-yl) ethyl] -3H-benzimidazole-5-carboxamide (Compound 127), ¹ H-NMR (300 MHz, CD 3 OD): 2.43 (2.41, s, 3H), 2.92 (m, 2H ), 3.41 (t, 2H, J = 7.1)

Hz), 3.69 (t, 2H, J = 7.1 Hz), 3.85 (s, 3H), 3.93-3.96 (m, 2H),

4.68 (4.78, s, 2H), 7.1 (d, 1H, J = 8.7 Hz), 7.21 (d, 1H, J = 7.5 Hz), 7.38 (dt 1 H, J = 1.2 and 7.6 Hz), 7.50-7.61 (m, 2H), 7.697.75 (m, 2H), 7.93 (s, 1H), 8.07 ( d, 1H, J = 8.4Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4- hydroxynaphth-1-yl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 128), ¹ H-NMR (300 MHz, CD ₃ OD): 2.42 (2.40, s, 3H), 2.89 (m (2H), 3.27 (m, 2H), 3.69 (t, 2H, J = 7.2 Hz), 3.82 (3.83, s, 3H), 3.93 (m, 2H) , 4.64 (4.76, s,

2Η), 6.72 (d, 1H, J = 7.8Hz), 7.17 (d, 1H, J = 7.5Hz), 7.37 (t,

1H, J = 7.5Hz), 7.46 (dt, 1H, J = 0.9 and 6.9Hz), 7.62 (d, 1H, J = 8.5Hz), 7.77 ( d, 1H, J = 8.5 Hz), 7.95 (s, 1H), 8.12 (d, 1H, J = 8.4 Hz), 8.17 (d, 1H, J = 8.4 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2- methoxyphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 129), ¹ H-NMR (300 MHz, CD ₃ OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.80 (m, 5H), 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, J = 5.4 Hz), 4.71 (4.81) s, 2H), 6.85-7.00 (m, 4H), 7.66 (d, 1H, J = 8.7 Hz), 7.84 (m, 1H), 8.13 (s, 1H);

2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N-naphth-ylmethyl- 3H-benzoimidazole-5-carboxamide (Compound 130), 1 H-NMR (300 MHz, CD ₃ OD):

2.44 (2.42, s, 3H), 2.92 (m, 2H), 3.91 (s, 3H), 3.95 (m, 2H),

4.68 (4.78, s, 2H), 4.77 (s, 2H), 7.41-7.44 (m, 2H), 7.50 (dd,

1H, J = 8.6 and 1.1 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.78-7.83 (m, 4H),

7.90 (m, 1H); 8.16 (m, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (3-pyridin-4) -ylpropyl) -3H-benzimidazole-5-carboxamide (Compound 131), 1 H-NMR (300 MHz, CD 3 OD): 2.1 (m, 2H), 2.46 (2.43, s, 3H), 2.96 ( m, 2H), 3.06 (t, 2H, J = 7.7 Hz), 3.51 (t, 2H, J = 6.8 Hz), 3.98 (m, 5H), 4.72 ( 4.82, s, 2H), 7.67 (d, 1H, J = 8.5 Hz), 7.83 (dd, 1H, J = 8.5 and 1.3 Hz), 8.00 (d (2H, J = 6.6 Hz), 8.15 (d, 1H, J = 1.3 Hz), 8.70 (d, 2H,

J = 6.6 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 132), MS (Biolone ): Calcd. for C32H32N8O3: 576.6; found 577.5 (MH ⁺ ); ¹ H-NMR (300 MHz,

CD 3 OD): 3.41 (t, 2H, J = 7.5 Hz), 3.58-3.76 (m, 4H), 4.05 (m, 1H), 4.45 (dd, 1H, J) = 14.9 and 8.5 Hz), 4.61 (dd, 1H, J = 14.9 and 3.2 Hz),

7.36-7.52 (m, 4H), 7.66-7.85 (m, 4H), 8.14 (s, 1H), 8.25 (d,

1H, J = 7.8Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4- methoxyphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 133), 1 H-NMR (300 MHz, CD ₃ OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3 70 (m, 2H), 3.77 (t, 2H, J = 5.6 Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.12 (t, 2H, J = 5.6 Hz), 4.71 (4.81, s, 2H), 6.78-6.89 (m, 4H), 7.66 (d, 1H, J = 8.4 Hz), 7.84 (m, 1H); 8.13 (d, 1H, J = 1.2 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 134), MS (Biolone ): Calcd for C32H30N7O4: 590.6; found 590.7 (MH ⁺ ); ¹ H-NMR (300 MHz,

CD 3 OD): 3.42 (t, 2H, J = 7.4 Hz), 3.74 (t, 2H, J = 7.4 Hz), 4.00 (d, 2H, J = 4.2 Hz) 4.38 (t, 1H, J = 11.7 Hz), 4.56 (dd, 1H, J = 12.5 and 3.5 Hz), 7.34-7.51 (m, 5H), 7.61-7.65 (m, 2H); 7.72-7.86 (m, 2H)

4H), 8.05 (d, 1H, J = 1.2 Hz), 8.25 (d, 1H, J = 8.1 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- 2,3,4-tetrahydronaphthyl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 135), ¹ H NMR (300 MHz, CD 3 OD): 1.69-2.1 (m, 6H), 2.45 (2.43, s, 3H),

2.73 (m, 2H), 2.88 (m, 1H), 2.95 (m, 2H), 3.52 (t, 2H, J = 7.4 Hz), 3.97 (m, 5H) 4.72 (4.81, s, 2H), 6.99-7.06 (m, 3H), 7.157.18 (m, 1H), 7.67 (d, 1H, J = 8.7) Hz), 7.82-7.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (3- methoxyphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 136), 1 H-NMR (300 MHz, CD 3 OD): 2.45 (2.42, s, 3H), 2.95 (m, 2H), 3.71 (s, 3H), 3.78 (t,

2H, J = 5.6 Hz), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 (t, 2H, J = 5.6 Hz), 4.71 (4.80, s, 2H). 6.46 to 6.54 (m, 3H), 7, 12 (t, 1H, J = 8.0 Hz), 7.66 (d, 1H, J = 8.4) Hz), 7.83 (m, 1H), 8.12 (d. 1H, J = 2 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 137);

2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide

(compound 138), 1 H-NMR (300 MHz CD 3 OD): 2.09 (m, 2H), 3.44 (t, 2H, J = 7.4) Hz), 3.58 (t, 2H, J = 5.6 Hz), 3.77 (t, 2H, J = 7.4 Hz), 4.55 (t, 1H, J = 7.1 Hz), 7 32 (dd, 1H, J = 8.6 and 1.9 Hz), 7.37-7.55 (m, 4H), 7.61 (d, 1H, J = 1.9 Hz), 7.69 (d, 1H, J = 8.4 Hz), 7.73-7, 88 (m, 4H), .delta. II (p. 1H), 8.28 (d, 1H, J = 8.1) Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide (Compound 139), MS ( Biolone: calcd for C29H32N8O5: 572.62; found 573.3 (MH ⁺ ); ¹ H-NMR (300 MHz,

CD ₃ OD): 3.58 to 3.69 (m, 2H), 3.80 (m, 5 H), 4.07 (m, 1H), 4.17 (t,

2H, J = 5.3 Hz), 4.47 (dd, 1H, J = 15.0 and 8.4 Hz), 4.64 (dd, 1H,

J = 15.0 and 3.0 Hz), 6.66-7.00 (m, 4H), 7.38 (dd, 1H, J = 8.6 and 1.7 Hz), 7.66 (d 1 H, J = 1.7 Hz), 7.70 (d, 1H, J = 8.6 Hz), 7.78 (d,

1H, J = 8.6 Hz), 7.87 (dd, 1H, J = 8.6 and 1.5 Hz), 8.24 (d, 1H,

J = 1.5 Hz);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 140) , MS (Biolon) for C ₃₃ H 3 N ₄ O 3 calcd _8: 590.7; found 591.3 (MH ⁺ );

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) -N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 141), MS (Biolone ): for _C2 9H3 ₀ N ₈ O6 Calc'd: 586, 6; found 587.5 (MH ⁺ ); ¹ H-NMR (300 MHz,

CD 3 OD): 3.33 (m, 1H), 3.81 (m, 5H), 3.98 (d, 2H, J = 4.5 Hz),

4.18 (t, 2H, J = 5.4 Hz), 4.38 (t, 1H, J = 12.0 Hz), 4.57 (dd, 1H,

J = 12.0 and 3.5 Hz), 6.85-7.00 (m, 4H), 7.30 (dd, 1H, J = 8.7 and 2.2 Hz), 7.60 (d 1 H, J = 2.2 Hz), 7.64 (d, 1H, J = 8.4 Hz), 7.74 (d,

1 J, J = 8.7 Hz), 7.80 (dd, 1H, J = 8.4 and 1.5 Hz), 8.14 (d, 1H,

J = 1.5 Hz);

2- [5- (1-Iminoethyl) aminomethyl-1H-benzoimidazol-2-ylmethyl] -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3Hbenzoimidazole-5-carboxamide (compound 142), ¹ H-NMR (300 MHz, CD ₃ OD): 2.28 (s, 3H), 3.64 (m, 2H), 3.80 (s, 3H), 3.79-3 85 (m,

2H), 4.05 (m, 1H), 4.18 (t, 2H, J = 5.4 Hz), 4.46 (dd, 1H, J = 15.0 and 8.7 Hz), 4, 62-4.66 (m, 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H,

J = 8.7 and 1.2 Hz), 7.70 (d, 1H, J = 8.4 Hz), 7.77-7.80 (m, 2H), 7.84 (dd, 1H, J = 8.4 and 1.4 Hz), 8.21 (d, 1H, J = 1.4 Hz);

methyl 2- {2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) 3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy (benzoate (compound 143), MS (Biolone): for C ₂₈ H ₂₈ N ₈ O ₄ calculated: 540.56, found (MH ⁺ ): 541.4;

{2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy (benzoic acid (Compound 144);

methyl 3- {2- [2- (5-guanidino-1H-benzoimidazol-5-ylmethyl) 3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy (benzoate (compound 145), MS (Biolone): for C28H28NgO ₄ calcd: 540.5, found (MH ⁺ ): 541.4;

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2 (2,6-dimethoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide (Compound 146), ¹ H-NMR (300 MHz, CD ₃ OD): 3.71 (t, 2H, J = 5.3 Hz), 3.73 (s, 6H), 4.01 (s, 3H), 4.13 (t, 2H J = 5.3 Hz), 6.63 (d, 2H, J = 8.4 Hz), 6.99 (t, 1H, J = 8.4 Hz), 7.33 (dd, 1H, J = 8.6 and 1.9

Hz), 7.63 (d, 1H, J = 1.9 Hz), 7.74 (d, 1H, J = 8.7 Hz), 7.75 (d,

1H, J = 8.6 Hz), 7.90 (dd, 1H, J = 8.7 and 1.5 Hz), 8.21 (d, 1H,

J = 1.5 Hz);

2- (5-guanidinomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 147), - NMR (300 MHz, CD ₃ OD): 3.5791

3.69 (m, 2H), 3.80 (m, 5H), 4.05 (m, 1H), 4.17 (t, 2H, J = 5.4 Hz), 4.45 (dd, 1H) J = 15.0 and 8.7 Hz), 4.58-4.65 (m, 3H), 6.85-7.00 (m, 4H), 7.50 (dd, 1H, J = 8) 7 and 1.5 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.72 (d, 1H, J = 1.5 Hz), 7.76 (d, 1H, J = 8.7 Hz), 7.82 (dd, 1H, J = 8.5 and 1.4 Hz), 8.19 (d, 1H, J = 1.4 Hz);

2- (5-Iminomethylaminomethyl-1H-benzoimidazol-2-ylmethyl) -3 (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide (Compound 148) 1 H-NMR (300 MHz, CD ₃ OD): 3.58-3, 70 (m, 2H), 3.81 (m, 5H), 4.06 (m, 1H), 4.19 (t,

2H, J = 5.4 Hz), 4.46 (dd, 1H, J = 15.0 and 8.7 Hz), 4.64 (dd, 1H, J = 15.0 and 3.0 Hz), 4.69 (4.73, s, 2H), 6.86-7.01 (m, 4H), 7.51 (dd, 1H, J = 8, 1 and 1.5 Hz), 7.69 (d 1H, J = 8.6 Hz), 7.767.79 (m, 2H), 7.84 (dd, 1H, J = 8.6 and 1.3 Hz), 7.96 (8.12, s, 1H), 8.21 (d, 1H, J = 1.3Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-hydroxy-2-quinol-4-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 149), ¹ H-NMR (300 MHz, CD ₃ OD): 3.60 (dd, 1 H, J = 13.8 and 7.5 Hz), 3.97-4.06 (m, 4H), 5.99 (dd, 1 H, J = 7.5 and 3.6 Hz),

7.35 (dd, 1H, J = 8.7 and 2.0 Hz), 7.65 (d, 1H, J = 2.0 Hz), 7.69 (d, 1H, J = 8.7 Hz) ), 7.77 (d, 1H, J = 8.7 Hz), 7.84 (dd, 1H, J = 8.7 and

1.5 Hz), 7.99 (m, 1H), 8.1-8.18 (m, 2H), 8.26 (d, 1H, J = 8.4

Hz), 8.33 (d, 1H, J = 5.7 Hz), 8.88 (d, 1H, J = 8.7 Hz), 8.15 (d,

1H, J = 5.7Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-methyl-2,4-dioxoquinazolin-1-yl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 150 MS (Biolone) calcd for C 29 H 28 N 10 O 3 564.6; found 565.5 (MH ⁺ );

methyl 2- {2- [2- (5-guanidino-ΙΗ-benzoimidazol-2-ylcarbonyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (compound 151), MS (Biolone): for C ₂₈ H ₂ 6N8O5 calculated: 554.5; found 554.8 (MH +);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carbox92 amide (Compound 152); NMR (300 MHz, CD ₃ OD): 3.44 (t, 2H,

J = 7.4 Hz), 3.77 (t, 2H, J = 7.4 Hz), 3.95 (t, 2H, J = 4.9 Hz),

4.56 (t, 2H, J = 4.9 Hz), 7.32 (dd, 1H, J = 8.7 and 1.5 Hz), 7.407.54 (m, 4H), 7.61 (d 1 H, J = 1.8 Hz), 7.67-7.89 (m, 5H), 8.09 (d, 1H, J = 1.2 Hz), 8.28 (d, 1H, J = 8.1 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3H -benzoimidazole-5-carboxamide (compound 153);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2-hydroxyethyl) -N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 154); 300 MHz, CD ₃ OD): 3.42 (t, 2H,

J = 7.3 Hz), 3.75 (t, 2H, J = 7.3 Hz), 4.48-4.51 (m, 2H), 7.29 (dd, 1H, J = 8.6) and 1.9 Hz), 7.38-7.52 (m, 4H), 7.58 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.7 Hz) 7.71-7.76 (m, 3H), 7.86 (d, 1H, J = 8.6)

Hz), 8.06 (s, 1H), 8.26 (d, 1H, J = 8.1 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 155);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (3-hydroxypropyl) -N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 156);

2- (5-Imidazol-1-yl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (compound

157);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (compound

158), MS (Biolone) calcd for C 31 H 30 N 8 O: 530.6; found 531.1 (MH ⁺ );

2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 159) MS (Biolone) calcd. For C19H18N3O: 539.6; found 540.1 (MH +);

2-] 1- [5- (2-Aminoimidazol-1-yl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 160), MS (Biolone): calculated for 553.7 for _{33 33} Η ₃ οΝ _δ θ; Found (MH ^+): 555.2;

1- (5-guanidino-1H-benzoimidazol-2-yl) -3-hydroxy-1-methyl-N- (2-naphth-1-ylethyl) -3,4-dihydro-1H-2-oxa-4a, 9- diazafluorene-6-carboxamide (compound 161);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (4-hydroxybutyl) -N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 162) MS (Biolone) calcd for C 34 H 36 N 8 O 2 588.7; found 589.3 (MH ⁺ );

3- [2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-ylethylcarbamoyl) benzoimidazol-1-yl] propane-1-sulfonic acid (Compound 163), MS (Biolone ₎ calcd for C ₃₃ H ₃₄ N ₈ O ₄ S: 638.7; found 639.2 (MH ⁺ );

3- {2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6 (2-naphth-1-ylethylcarbamoyl) benzoimidazol-1-yl} propane-1-sulfonic acid (compound 164), MS (Biolon) C35H ₃₃ N7O ₄ S calculated: 647.8; found 648.2 (MH ⁺ );

2- [1- (5-guanidino-1-yl-1H-benzoimidazol-2-yl) -2-methylpropyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide ( compound 165), MS (Biolon) for C ₃₃ H 3 N ₄ O ₈ calculated: 558.7; found 559.6 (MH ⁺ );

2- [1- (1H-imidazo [4,5-c] -2-yl) ethyl] -3-methyl-N- (2-naphthyl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 166), MS (Biolon) for C ₂₉ H 6 N ₂ O ₆ calculated: 474.6; found (MH ⁺ ):

475.2;

2- {5- [1- (N-methylimino) ethyl] -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl} -3-methyl-N- (2- Naphth-1-ylethyl) 3H-benzoimidazole-5-carboxamide (Compound 167), MS (Biolone): Calcd. for C31H3-1N / O: 519.71; found 520.9 (MH +);

imino (2- {1- [1-methyl-6- (2-naphthyl-ethylcarbamoyl) -1H-benzoimidazol-2-yl] ethyl} -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine -5-yl) acetic acid (Compound 168), MS (Biolone) calcd for C 31 H 31 N 7 O 3 549.6; found 550.2 (MH ⁺ );

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl] ethyl} -3-methyl-N- (2- Naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 169), MS (Biolone): Calcd. for C31H33N7O: 519.6; found 520.3 (MH ⁺ );

2- {1- [5- (N-methylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- ( 2-Naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 170), MS (Biolone): Calcd for C31H34N8O: 534.7; found 535.1 (MH ⁺ );

- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) -5-methoxybenzoic acid (Compound 171), MS ( Biolon) ₂ C 9 H ₃₀ N ₈ O5 calcd: 570, 6; found 571.2 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 172), MS (Biolone) : for C ₂₉ H ₃ oN ₈ 0 ₅ calculated: 570.6; found 571.3 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -1-hydroxyethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} -ethoxy) -6-methoxybenzoic acid (compound 173), MS (Biolon) ₂ C 9 H _{6 3} oNb0 calcd: 586, 6; found 587.2 (MH ⁺ );

ethyl 2- [2- (2- {1- [5- (N-acetylguanidino) -1H-benzimidazol-2yl] ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate (Compound 174) MS (Biolone): calcd. For C ₃₁ H ₃₂ N ₈ O ₅ : 596.6; found 597.2 (MH ⁺ );

- {1- [5- (N, N-dimethylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- (2 -naphth-1-ylethyl) 3H-benzoimidazole-5-carboxamide (compound 175);

- {1- [5- (2-Amino-1,1-dimethylethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide ( Compound 176);

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl] ethyl} -N-ethyl-3-methyl-3H -benzoimidazole-5-carboxamide (compound 177);

2- [2- (2- {1- [5- (N-acetylguanidino) -1H-benzimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 178 MS (Biolone) calcd. For C30H30N8O5: 582.6; found 583.3 (MH ⁺ );

2- [2- (2- {1- [5- (1-Aminocyclopropyl) -1H-benzimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 179), MS (Biolon) C ₃ oH ₃ oN ₆ 0 ₄ calculated: 538.6; found 539.3 (MH ⁺ );

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (3-methylbutyl) -3H-benzoimidazole-5-carboxamide (Compound 180), MS (Bione) ): calcd for C26H29N7O: 455.6; found 456.2 (MH ⁺ );

2- (1H-benzoimidazol-2-ylethyl) -3-methyl-N- (2-phenoxyethyl) 3H-benzoimidazole-5-carboxamide (Compound 181), MS (Biolone): calcd for C26H25N5O2: 439.5; found 440.2 (MH ⁺ );

ethyl-2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3 -methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (compound 182);

2- (1- (5-guanidino-lH-benzoimidazol-2-yl) ethyl) -3-methyl-N- [2- (2,4-dioxo-3,4-dihydro-2H-quinazolin-l-yl) ethyl] -3H-benzoimidazole-5-carboxamide (compound 183);

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl] ethyl} -N- (3-methoxypropyl) -3 -methyl-3H-benzoimidazole-5-carboxamide (compound 184);

N-Ethyl-2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 185), MS (Biolone): calcd for C23H23N7O: 413.5; found (MH ⁺ ):

414.1;

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 186), MS (Bione) ): Calcd. for C24H25N7O2: 443.5; found 444.2 (MH ⁺ );

1- {2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) -4-methylpentanoic acid (Compound 187), MS ( Biolone: Calcd for C27H29N7O3 499.6; found 500.3 (MH ⁺ );

2- (2- {2- [1- (5-Imidazol-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy) benzoic acid (Compound 188), MS (Biolone) for C 30 H 27 N 7 O 4 calculated: 549.6; found 550.2 (MH ⁺ );

2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- 3H-Benzoimidazol-5-ylcarbonylamino) -4-methylpentanoic acid (Compound 189);

2- {l- [5- (N, N-dimetylimidino) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-3H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (compound 190), MS (Biolone): calcd for C39H34N8O4: 558.6; found 559.3 (MH ⁺ );

2- [2- (2- {1- [5- (2-carboxy-1-iminoethyl) -4,5,6,7-tetrahydrol-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (compound 191), MS (Biolone): calcd. found (MH *):

530.3 - CO ₂ loss;

2- (2- {2-fl- (5-imidazol-l-yl-benzoimidazol-H] -2-yl) ethyl] -3- (2-methoxy-ethyl) -3H-benzoimidazol] -5-ylcarbonylamino (ethoxy) benzoic acid acid (compound 192), MS (Biolone): calcd for C ₃ H ₃₁ N ₇ O ₅ 593.6, found (MH ⁺ ): 594.2;

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -N- (2-methoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 193) , MS (Biolon) ₂ C 6 H 9 N ₂ O _{7 3} calculated: 487.6; found 488.2 (MH ⁺ );

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3 - (2-methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (compound 194);

3- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 195), MS (Biolone) for C ₂ H ₂ BN ₈ O 4 calculated: 540.6; found 541.3 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 196), MS (Biolone) calcd for C 30 H 32 NBO 5: 584.6; found 585.3 (MH ⁺ );

- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (3sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 197), MS (Biolon) for C ₃₀ H ₃₂ N8O7S calculated: 648.7; found 649.6 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] 3- (3-sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 198), MS (Biolone): calcd for C32H31N7O7S: 657.7; found 658.4 (MH ⁺ );

2- (2- {2- [1- (5-Imidazol-1-yl-3-methyl-3H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid ( Compound 199), MS (Biolone): calcd. for C 31 H ₂₉ N ₂ O ₁ : 563.6; found 564.2 (MH +);

- (2- {2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] 3- (2-hydroxypropyl) -3H-benzoimidazol-5-ylcarbonylamino} 98 ethoxy) benzoic acid (Compound 200), MS (Biolone): Calcd for C ₃₂ H ₁₁ N ₅ O: 593.6; found 594.3 (MH ⁺ );

- {2- [2- (1- {5- [1- (N-hydroxyimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl}} ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoic acid (compound 201);

ethyl 2- {2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 202), MS ( Biolon) for C ₃₀ H ₃₂ N ₈ O ₄ calculated: 568.6; found 569.5 (MH ⁺ );

ethyl-2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1 4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (compound

203), MS (Biolone): calcd for C ₂₈ H ₃₆ N ₈ O ₄ 549.0; Found (M-H ^T): 548.2;

ethyl 4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} butanoate (compound

204), MS (Biolon) for C ₂₅ H ₃ ON ₈ 0 ₃ Calculated: 490.57; found 491.3 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N [2- (2-tetrazol-1-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (compound 205), MS (Biolone): calcd. For C ₂₈ H ₂₈ N ₁₂ O ₂ : 564.56; found 565.3 (MH ⁺ );

2- [2- (2- {1- [5- (1-Iminoethylamino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 206 ), MS (Biolon) C ₃ H ₃₃ N ₇ O ₄ calculated: 567.6; Found (MH ^4): 568.4;

ethyl 4- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) 3-methyl-3H-benzoimidazol-5-ylcarbonylamino (ethoxy) benzoate (compound 207)), MS (Biolon) C _{{ί0 Η,} Ν Ο _{8 4} calculated: 568.6; found (MH +): 569.4;

5- (2-12- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 208), MS (Bione): calcd for CTgHcgN5Of: 584.6; found 585.3 (MH ⁺ );

4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 209), MS (Biolone) for: Ο28Η2θΝ ₈ Ο ₄ calculated: 540.6; found 541.2 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 210), MS (Biolone): calcd for C30H32N8O5: 584.6; found 585.4 (MH ⁺ );

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 211 MS (Biolone) calcd. For C30H29N7O2: 535.6; found 536.3 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 212), MS (Biolone) for C27H26N8O4: 526.6; found 527.2 (MH ⁺ );

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 213), MS (Bione) ): calcd for C29H27N7O2: 505.6; found 506.2 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 214), MS (Biolone ) for C 9 H _{2 2} 5N7O ₄ calculated: 535.6; found 536.4 (MH +);

ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) -4-methyl100 benzoate (Compound 215 MS (Biolone) calcd. For C ₃₁ H ₃₄ N ₈ O ₄ : 582.7; found 583.5 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methylbenzoimidazol-5-ylcarbonylamino} ethoxy) -4-methylbenzoic acid (Compound 216), MS (Biolone): for C 2 _{9H 30} N ₈ O ₄ calculated: 554.6; found 555.5 (MH ⁺ );

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1 , 4,6, 7-tetrahydro-imidazo [4,5-c] pyridin-5-ylcarbonylamino) etoxyjbenzoát (compound 217), MS (Biolon) C26H32N ₈ O ₄ Calc'd: 520, 58; found 521.3 (MH ⁺ );

ethyl 2- (2- {2- [5- (N-methylamidino) -1H-benzoimidazol-2-ylmethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 218), MS (Biolone) : for C 3 _{0 4} H3iN7O calcd: 553, 6; found 554.3 (MH ⁺ );

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3 - (3-sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (compound 219), MS (Biolone): calcd for C30H35N7O7: 637.7; found 638.3 (MH ⁺ );

ethyl-2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3- methyl 3H-benzoimidazol-5-ylcarbonylamino) -4-methylvalerate (compound 220);

ethyl-2- {2- [2- (1- {5- [1- (N-hydroxyimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl} ethyl -3-methyl-3H-benzoimidazol-5-ylcarbonylamino-ethoxy (benzoate (compound 221);

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 222), MS (Biolone) for C 8 H 11 N 4 O 3 calculated: 469.5; found 469.5 (MH +);

ΙΟΙ

2- (2-ethoxycarbonylphenoxy) ethyl 2- (1- (6-guanidino-1H-benzimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate ( Compound 223), MS (Bioion): Calcd for C28H32N8O5: 560.62, found (MH ⁺ ): 561.3;

4- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} butanoic acid (Compound 224), MS (Bioion): Calculated for C23H26N8O3: Found (MH ⁺ ): 462.8;

2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- [2- (2-Tetrazolylphenoxy) ethyl] 3H-benzoimidazole-5-carboxamide (Compound 225) MS (ESI) calcd for C28H31N11O2: 553.6, found (MH ⁺ ): 553.5;

Isopropyl 2- (2- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 226) MS (Bioion): Calcd for C 33 H 33 N 7 O 4 591.3, found (MH ⁺ ): 591.4;

2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- [2- (3-Tetrazolylphenoxy) ethyl] 3H-benzoimidazole-5-carboxamide (Compound 227), MS (Bioion): Calcd for C28H31N11O2: 553.59, Found (MH ⁺ ): 553.5;

2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- (2- (4-Tetrazolylphenoxy) ethyl] 3H-benzoimidazole-5-carboxamide (Compound 228), MS (Bioion): Calcd for C28H31N11O2: 553.59, found (MH ⁺ ): 553.5;

Cyclohexyl 2- (2- (2- (1- (5-imidazol-1-yl) -1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxybenzoate (Compound 229 ), MS (ESI): C 3 to C ₆ H37N _7> 4 calculated: 631.3; found (MH + ^1): 631.5;

2- (2- (1- (5- (N-methylamidino) -1H-benzoimidazol-2-yl) ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy) 102 benzoic acid (compound 230), MS (Biolone): calcd: 525.6, found (MH +): 525.5;

2- [2- (2- {1- [5- (1-Iminoethylamino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 231 ), MS (Biolon) C 29 H _L and N-> 0 ₄ calculated: 539.6; found 539.8 (MH ⁺ );

2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonyl} propoxy) benzoic acid (compound 232), MS (Biolon) Οξ7Η οΝ _{3 8} 0 ₄ calculated 530, 6; found 531.7 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylformyloxy} ethoxy) benzoic acid (compound 233), MS (Biolone) calcd for C 26 H 28 N 8 O 5 532.56; found 533.2 (MH ⁺ );

2-Methoxyethyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 234), MS (Biolone): for

C33H33N7O5 requires 607.3; found 607.4 (MH ⁺ );

Isobutyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 235) MS (Biolone): calcd for C34H35N7O4: 605.3; found 605.4 (MH ⁺ );

2- (2-methoxyethoxy) ethyl-2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy) benzoate (compound 236), MS (Biolon) C35H37N ₇ O ₈ calculated: 651.3; found 651.3 (MH ⁺ );

butyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 237) MS (Bione): Calcd .: 605.3; found 605.4 (MH +);

103

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3H- benzimidazole-5-carboxamide (compound 238), MS (Biolon) C t H _{2; rn} O3 calculated: 494.2; found 494.5 (MH ⁺ );

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-fluorophenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 239);

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-fluorophenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 240);

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-isopropoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 241), MS (Biolone) : for C 9 H ₃₁ N5O _{2 3} calculated: 497.2; found 497.6 (MH ⁺ );

- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 242), MS (Biolone) : for C ₅ H ₂ 7H27N ₂ calculated: 453.2; found 453.5 (MH ⁺ );

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-ethoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 243), MS (Biolone) : for C ₂₈ H ₂ 9N5O ₃ calculated: 483.2; found 483.5 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 244), MS (BioIon) ₂ C 8 H 03 _{8 3} on calcd: 526, 6; found 526.8 (MH ⁺ );

ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino} ethoxy) benzoate ( Compound 245), MS (Biolone): calcd for C 18 H 18 N 6 O 2: 559.6; Found (MH ^4): 559.6;

ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino-104 ethoxy) benzoate (Compound 246), MS (Biolone): Calcd for C28H33N9O4: 559.6; found 559.6 (MH +);

ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 247), MS ( Biolone): calcd for C ₂₉ H ₃₀ N ₈ O ₄ : 554.6; found 555.4 (MH ⁺ );

ethyl 2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 248), MS (BioIon) 0 ₂₈ Η2 Ν _{8 8} 0 ₄ calculated 540, 6 found (MH ^+): 541.3;

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 249), MS (Biolon) for C ₂₈ H 9 N ₂ O 3 calculated _9: 539, 6; found 540.5 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 250 ), MS (Biolon) C2eH ₂₈ ClN ₉ O 3 calculated: 574.0; found 574.2 (MH ⁺ );

4-Chloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 251 ), MS (Biolon) ₂₈ C ₈ H27C1N O4 Calc'd: 575, 0; found 575.2 (MH ⁺ );

5-Chloro-2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 252 ), MS (Biolone): calcd. For Ο ₂₈ Ο ₂ 7Ν1Ν ₈ Ο4: 575.0, found (MH ⁺ ): 575, 2;

6-chloro-2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 253), MS (Biolone): calcd: 575.0 for C ₁₈ H 2701 ₈ 04 04 (MH +): 575.2;

105

4,6-Dichloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 254 ), MS (Bione): for

C28H26Cl2N8O4 requires 609.5; found 609.1 (MH ⁺ );

ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) benzoate (Compound 255), MS (Biolone): for C29H29N5O4 calcd, 511.6; found 512.2 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N {2- [2,4-dioxo-3- (2-trimethylsilanylethyl) -3,4-dihydro- 2H-quinazolin-1-yl] ethyl} -3H-benzoimidazole-5-carboxamide (compound

256), MS (Biolone ₎ : calcd for C ₃₄ H ₄₀ N ₁₀ O ₃ Si: 664.8; found 665.4 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N {2- [2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl] ethyl} -3H-benzoimidazole-5-carboxamide (compound 257), MS (Biolon) ₂ C 9 H ₂₈ Nio0 ₃ calculated: 564.6; found 565.2 (MH ⁺ );

2- [1- (1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-cyanophenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 258), MS (Biolone) : for C 7 H ₂₄ N ₂ O _{6 2} calculated: 454.5; found 465.1 (MH ⁺ );

5- (2- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 259), MS (Biolone): for C ₂₈ H25N ₆ O ₅ calcd: 527, 5; found 528.4 (MH ⁺ );

2- (2-methoxyethoxy) ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 260) MS (Biolone): calcd: 585.7; found (MH '): 585.4;

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyrimidin-5-ylcarbonylamino} 106 ethoxy) benzoic acid (Compound 261), MS (Biolone): for C 29 H 29 N 9 O .; calcd, 531.6; found 531.5 (MH ⁺ );

2- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide ( compound

262), MS (Biolone): calcd for C26H26N6O3: 470.54; found 471.4 (MH ⁺ );

2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (compound

263), MS (Biolone): calcd for C27H26FN5O3: 487.54; found 488.1 (MH ⁺ );

2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-tetrazol-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 264) , MS (ESI): calcd for C24H23NHO: 481.47; found 482.6 (MH ⁺ );

2- [1- (4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 265), MS ( Biolone): calculated for C27H27N5O4:

485, 59; found 486.3 (MH ⁺ );

2- [1- (4-aminobenzoxazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 266), MS (Biolone) for C27H27N5O4: 485.59; found (MH ⁺ ):

486, 1;

- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid (Compound 267), MS (BioIon) C29H3iN5O _e S calculated: 577.66; found 577.4 (MH ⁺ );

3- {2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1sulfonic acid ( Compound 268), MS (Biolone): for

C? H33N ₇ 0ES Calcd: 643, 72; found 644.6 (MH +);

107 Ethyl 2- [2- (2- {1- [1- (2-methoxyethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazole-5-carbonylamino) ethoxy] benzoate (Compound 269 MS (Biolone) calcd for C 32 H 35 N 5 O 5 569.66; found 570.5 (MH ⁺ );

benzyl 2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (compound 270), MS (Biolon) for C 9 H ₃ oN ₂ 0 _{8 6} calcd: 586.6 found (MH ^+): 587.2;

ethyl 2- (4- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutoxy) benzoate (compound 271);

1- (2- (1- (1H-benzoimidazol-2-yl) ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4- (2-methoxyphenoxy) butan-1-one (Compound 272);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphthylethyl) imidazo [1,2-a] pyridine-6-carboxamide (Compound 273);

N- [3- (2-ethoxyphenyl) propyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 274), MS (Biolone) calcd for C29H31N5O3: 497.62; found 497.4 (MH ⁺ );

N- [3- (2-butoxyphenyl) propyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 274), MS (Biolone) calcd for C31H35N5O3: 525.65; found 526.3 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [3- (2-propoxyphenyl) propyl] -3H-benzoimidazole-5-carboxamide (Compound 276), MS (Biolone): calcd. For C30H33N5O3: 511.62; found 512.3 (MH ⁺ );

2- (1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl) -N- {2- [2- (3-methyl- [1,2,4] oxadiazol-5-yl) phenoxy] ethyl} - 3-methyl-3H-benzo108 imidazole-5-carboxamide (Compound 277) MS (Biolone) calcd for C29H27N7O4: 538.1, found (M-1 '): 537.58;

ethyl 2- (2- {2- [1- (4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino-ethoxy) benzoate (Compound 278), MS (ESI): calcd for C29H28FN5O5: 545, 57; found 545.6 (MH ⁺ );

2- (2- {2- [1- (4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 279), MS (ESI) for C 7 H _{2 2 5} 4FN O5 calculated: 517.52; found 517.4 (MH ⁺ );

ethyl 2- (2- {2- [1- (6-fluoro-4-hydroxy-1H-benzoimidazol-2yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 280) MS (Biolone) calcd for C29H28FN5O5: 545.57; found 545.9 (MH ⁺ );

2- (2- {2- [1- (6-fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 281 MS (ESI): calcd. For C27H24FN5O5: 517.52; found 517.6 (MH ⁺ );

ethyl 2- (2- {2- [1- (4,5-difluoro-7-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 282), MS (Biolone): calcd for C29H27F2N5O5: 563, 56; found 563.9 (MH ⁺ ); and

2- (2- (2- [1- (4,5-Difluoro-7-hydroxy-4-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 283 MS (ESI) calcd for C27H23F2N5O5: 536.1, found (MH ⁺ ): 535.51.

Example 13

Determination of tryptase inhibition in vitro

A tryptase solution (60 g / ml) was prepared by dissolving tryptase purified from human lung or skin tissue preparations or from. human mast cell cultures (BMC109

1) or obtained from commercial sources, e.g. ICN Biomeidals, Irvine, Calif., Athens Research & Technology, Athens, Georgia, etc., in a mixed solvent comprising: 10 mM 2-N-morpholinoethanesulfonic acid, 2 mM CaCl ₂ , 20% glycerol and 50 g / ml heparin. A substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys-p-nitroanilide) was obtained from Sigma. Test compound solutions were prepared by diluting the stock solution ten times (1 mg of test compound in 200 µl dimethylsulfoxide (DMSO)) in buffer (containing: Tris-HCl (pH 8.2), 50 mM; NaCl, 100 mM; 0.05% polyoxyethylene sorbitan monolaurate (Tween-20®) and zinc chloride, 150 μΜ) and then 7 consecutive triplicate dilutions in 10% DMSO in the above buffer.

Aliquots (60 µL) from each of the eight dilutions of the test compound solution were added to individual wells of a 96-well LJ-day microtiter plate. Tryptase solution (25 μί) was added to each well and the solutions were stirred at room temperature for 1 hour. To start the enzymatic reaction, substrate solution (25 µL) was added and the microtiter plates were subsequently transferred to a UV / MAX Kinetic Microplate Reader (Molecular Devices). Hydrolysis of the chromogenic substrate was followed spectrophotometrically for 5 minutes at 405 nm. The initial measurement rate was calculated from the measured hydrolysis story curves by a kinetic analysis program (BatchKi; Peter Kuzmic, University of Wisconsin, Madison, WI). The apparent inhibition constants (Ki) were calculated from the measured hydrolysis curves using standard mathematical models.

The following compounds of the invention were tested for tryptase inhibition activity by the procedure described in this application or by methods commonly known to those skilled in the art:

110 Compound 1, K! = 0.09 μΜ; Compound 12, K i = 29 μΜ; Compound 26, K _L = 33 μΜ; Compound 27, K i = 0.06 μΜ; Compound 28, K i = 0.00007 μΜ; Compound 29, K ₂ = 0.00008 μΜ; Compound 30, Κχ = 0.009 μΜ; Compound 37, K _x = 0.002 μΜ; Compound 42, Ki = 0.008 μΜ; Compound 43, Ki = 0.002 μΜ; Compound 74, K _x = 0.006 μΜ; Compound 75, K _x = 0.03 μΜ; Compound 80, Ki = 0.01

μΜ; compound 84. K i = 2.6 μΜ; Compound 102 Ki = 0.00007 μΜ; Compound 112 r Ki: = 0.00005 μΜ ; Compound 115 , K i = 0,003 μΜ; Compound 116 , Ki = 0.006 μΜ; Compound 117 Ki = 0.008 μΜ; Compound 126 , Ki = 0.008 μΜ; Compound 127 Ki = 0.00 6 μΜ; Compound 128 , Ki = 0.002 μΜ; Compound 169 Ki = 0.001 μΜ; Compound 132 , Ki = 0.00002 μΜ; Compound 134, ν = 0.00002 μΜ; compound 138 Ki = 0.0002 μΜ; compound 152, Ki = 0.0005 μΜ; compound 182, , Ki = 0.004 μΜ; compound 194, Ki = 0.009 μΜ; compound 203. , Ki = 0.008 μΜ; compound 225, Ki = 0.008 μΜ; compound 249. Ki = 0.0007 μΜ; compound 250, Ki = 0.0004 μΜ; compound 251. Ki = 0.0008 μΜ and compound 252, Ki = 0.0004 μΜ. Example 14 Sheep model of asthma For in vi vo rating of the compounds of the invention as

Antiasthmatic model of allergic sheep asthma was used. These methods have been published (see Abraham et al., (1983) Am. Rev. Respir. Dis. 128: 839-844; Allegra et al., (1983) J. Appl. Physiol. 55: 726-730; Russi (1985) J. Appl. Physiol. 59: 1416-1422; Soler et al., J. Appl. Physiol. 67: 406-413). The weight of these animals ranged from 20 to 50 kg.

In these studies, 1 mg of compound 13 was dissolved in 3.0 mL of distilled water and the whole solution was dosed as an aerosol 0.5 h before, 4 h after, and 24 h after antigen challenge (total

III dose = 1.0 mg; n = 3). The results of these experiments are shown in Figure 1.

hours after antigen challenge, both in the active and placebo trials, the sheep showed airway hyperreactivity. This hyperreactivity was expressed as PC400, i. concentration of carbachol which causes a 400% increase in SRL. Thus, a decrease in PC400 is indicative of hyperreactivity. Compound 13 blocked the development of hyperreactivity. As shown in Figure 2, this compound maintained the PC400 at a baseline level of 15 breath units. The number of respiratory units in the control group, on the other hand, decreased to 7. Thus, administration of Compound 13 resulted in a significant improvement in airway function in antigen-stimulated sheep.

Accordingly, the present invention provides compounds and compositions that are useful for the prevention and treatment of immunolgically induced inflammations, particularly respiratory tract diseases, including asthma, and airway hyperreactivity in chronic asthma and further allergic rhinitis. The present invention also provides a method of treating immunologically induced inflammations that are treatable by the compounds of the invention.

It should be noted that the above description is illustrative only and not exhaustive. Other connections not mentioned here will be apparent to those skilled in the art. It should be understood that the scope of the invention is not defined only by the above description, but that it is defined by the above description together with the claims and all equivalents to which these claims may apply.

Industrial usability

The compounds, compositions and methods are effective in preventing and treating inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other types

112 immunologically induced inflammatory disorders such as rheumatoid arthritis, conjunctivitis and intestinal inflammation, various skin diseases as well as certain viral diseases. The compounds are potent and selective inhibitors of mast cell tryptase.

Claims (26)

PATENT CLAIMS 1. A compound of formula I: ( ^R2 ) n2 ( ^R3 ) n3 (I) wherein n1 is 0 or 1; n 2 is 0,1,2,3 or 4; n 3 is 0,1,2,3 or 4; A together with B form a fused heterobicyclic group containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom being optionally a heteroatom, X ¹ and X ² are adjacent aromatic ring members and X ³ is a heteroatom selected of -N =, -NR ⁵ -, -O- and -S- wherein ^R5 is hydrogen, (C β) alkyl or hetero (C ₂ -6) alkyl; C is a fused heteropolycyclic group containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, each ring atom may optionally be a heteroatom, X ⁴ and X ⁵ are adjacent aromatic ring members, X ⁵ is a heteroatom selected from -N =, -NR ⁶ -, -O- and -S-, wherein R ⁶ is hydrogen, a group selected from (C _1-8 ) alkyl or hetero (C 2-12) alkyl, which group is substituted with one to two substituents selected independently one from the other of (C _1-6 ) alkanoyloxy, (C _1-6 ) alkylamino, di (C 1-6) alkylamino, tri (C _1-6 ) alkylammonium, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C _1-6 ) ₆₎ alkyloxycarbonyl, (C e) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6 and ₄₎ aryl, halo, hetero (C ₄ -i ₅₎ aryl, hydroxy and sulfo, or as defined below; and any keto, thioketo, and iminoketo derivative thereof; 114 crV-, X is -0-, -S-, -S (0) -, -S (0) _2, -C (0) -, -NR -, or wherein R is hydrogen, _(C, - _s alkyl, hetero (C 2-6) alkyl or together with R ^b form (C 2-4) alkylene or hetero (C 1-4) alkylene and R ^b is hydrogen, (C 1-6) alkyl or hydroxy or together with R ⁷ they form (C _2-6 ) alkylene or (C _1-6 ) alkylidene, wherein any aliphatic or alicyclic group R ⁷ and / or R ^e is optionally substituted with one to three substituents from (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C 1 -C 6) alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C _1-6 amino, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, halogen and hydroxy; R ¹ is amino (N-4) azolidinyl, amino (N! _4) azolyl, (N! _4) azolidinyl, (N-4) azolyl, carbamoyl, cyano, - (CH 2) X NHC (NR ⁹⁾ R ^9, ( CH 2) _X NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , selected ε) alkylammonium, et) alkanoyloxy, -C (NH) NR ¹⁰ R ¹⁰ or (CR 1 R ¹¹ ) _y NH ₂ , and is bonded to any atom of cycle B with available valency, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R ⁹ is independently from each other hydrogen or (C 1-0) alkyl, each R ¹⁰ is independently from each other (C 16) alkyl, and each R ¹¹ is independently from each other hydrogen, (C 13) alkyl, or together with another R ¹¹ and s the carbon atom to which they are both attached cyclopropyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one or two substituents selected independently of one another from (C 1-6) alkyloxycarbonyl, (C _1-6 ) alkanoyloxy, carboxy, carbamoyl, (C 1-6) ₆ ) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy; each R ² is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, (C 1-6) alkyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1) alkylsulfinyl, ( C 1-6 alkylsulfonyl, (C 1-6) alkylthio, halogen or hydroxy, and is bonded to any ring B atom with available valency, wherein any aliphatic R ² group is optionally substituted with one to two substituents selected independently of one another from ( C3a1 cyloxycarbonyl, 115 (Cι-θ), and 1 1 alkanoyl oxy, carboxy, carbamoyl, (C ₆₎ alkylcarbamoyl, di (C _t) alkylcarbamoyl, (C _S) alkylsulfonyl and hydroxy; each R ³ is independently of one another (C _1-6 ) alkyl, (C 1-6 alkyloxy, (C _1-6 ) alkylthio, cyano, halogen, perhalogen (C _1-6 ) alkyl or hydroxy) and is bonded to any atom of the C ring with available valency ; and R ⁴ is -R ¹² ,> 12 -OR -N (R ¹³ ) R ¹² , -SR ^12, -S (O) R ^12, -S (O) 2 R ^12, S (O) 2 OR, -S (O) ₂ N (R ^ij) R, -C (O) N (R ^lj) R -N (R ¹³ ) S (O) ₂ R ¹² , -C (O) R ¹² , -C (O) OR ¹² , -N (R ^ij) C (0) R ^IZ, -OC (O) N (R ¹³⁾ R ^12, - (CH ₂ ) _Z N (R ¹³ ) C (O) N (R ¹³ ) R ¹² , -0P (0) (OR ¹³ ) OR ^12, or -N (R ¹³ ) C (O) OR ¹² , -C (O) N (R ¹⁴ ) CH 12 - (COOH) R a is bonded to an available valency, wherein: z is 0, 1 or 2, any atom of the C>12> 15 ring is -R ¹⁵ or -X ° - (R ¹³ ) _n is where _n 15 is 1 or 2, X ^c is (C io) alkylene, cyclo (C3-10) alkylene, hetero (C -i _{2 0)} alkylene or heterocyclo (C3-3.0) alkylene and each ^R15 is independently is hydrogen, , (C ₆ -i ₄₎ aryl, cyclo (C3-14) alkyl, polycyclo (C ₆ and ₄₎ aryl, heteropolycyclo _(C6 -i ₄₎ aryl, heterocyclo (C ₃ _i ₄₎ alkyl, hetero (C 5 ₄ ) aryl or as defined below; R ¹³ is H, (C1-6) alkyl or hetero (C ₂ _ ₆₎ alkyl; > 14 is hydrogen, (C _1-6 ) alkyl or together with X ⁶ and R ¹⁵ form (C _3-4 ) alkylene; any aliphatic or alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C 1-6) alkyl, (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, (C _1-6 ) alkylcarbamoyl, di (C _1-6) ) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C 1-6) alkyloxycarbonyl, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkylsulfonyl, (C _1-6 ) alkylsulfonyl, (C _1-6 ) alkylthio, amino, ( C _6-10 arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halogen, hydroxy, mercapto and ureido; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from cyano, guanidino, halogen, 116 halogenated (C 1-8) alkyl, -R ¹⁶ , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , S (O) ₂ R ¹⁶ , -S (O) ₂ N (R ¹³ ) R ¹⁶ , -C (O) R ¹⁶ , -C (O) OR ^16, and -C (O) N (R ¹³ ) R ¹⁶ wherein R ¹³ is as defined above and R ¹⁶ is hydrogen, optionally mono-substituted (C _1-8 ) alkyl (wherein the optional substituent is (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, tri (C _1-6 ) alkylamino, (C _1-6 ) -6) alkylcarbamoyl, di (C 1-8) alkylcarbamoyl, (C 1-8) alkyloxycarbonyl, (C 1-8 alkyloxycarbonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C 3-6) alkyl, hetero (C _1-8) ) alkyl, hetero (C ₅ _6) aryl, heterocyclo (C 3-6) alkyl or phenyl; except that n 1 is not 0 when n 2 is 0 or R ² is (C 1-6) alkyl or (C 1-6) alkyloxy, n 3 is 0 or R ³ is (C 1-6) alkyl or (C 1-6) alkyloxy and R ⁴ is hydrogen, (C1-10) alkyl or (C1-10) alkyloxy; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 1, wherein A contains 5 ring members and B contains 6 ring members and X ¹ and X ⁵ are adjacent members of the oxazol-2-yl, h-imidazol-2-yl or thiazol-2-yl ring; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. A compound according to claim 2 which satisfies formula II: wherein the dotted lines represent, independently of one another, any bonds; 117 each R ² is independently of one another (C _1-6 ) alkyl, (C 1-6) alkyloxy, halogen or hydroxy; each R ³ is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxy, halogen or hydroxy; X ³ is -C (O) - or -CR ⁷ R ⁸ -; X ⁸ is -CH ² R ^11, -, or -C (R ¹ ) n X =, wherein R ¹ is amino (Ni 4) azolidinyl, amino ( _{N 1-4} ) azolyl, (Ni _1-4 ) azolidinyl, (Ni _1-4 ) azolyl , NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , -C (NH) NR ¹⁰ R ¹⁰ or (CR ¹ R ¹¹ ) y NH 2, or X ⁸ - N = or -NH ⁽ R ¹ ) ¹ -, wherein R ¹ is C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ or -C (NH) NR ¹⁰ R ¹⁰ , wherein each R ⁹ is independently one from a second hydrogen or (C 1-6) alkyl and each R ¹⁰ is independently from the other (C 1-6) alkyl; and X ⁹ is -CH (R ⁴ ) - or -C (R ⁴ ) =, wherein R ⁴ is -R ¹² , -OR ¹² , N (R ¹³ ) R ¹² , -SR ¹² , -S (O) R ¹² , -S (O) 2 R ¹² , -S (O) 2 R ¹² , -S (O) 2 N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ^12, -C (0) N (R ¹³⁾ R ^12, N (R ¹³ ) C (O) R ¹² , -OC (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) OR ¹² , - (CH ₂ ) n ₄ N (R ¹³ ) C (O) N (R ¹³ ) R ¹² , -OP (O) (OR ¹³ ) OR ^12, or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , or X ^{9 is} -N = or -N (R ⁴ ) wherein R ⁴ is -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² , -OC (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² . The compound of claim 3, wherein: R ⁵ is hydrogen or (C 1-4) alkyl, R ⁶ is hydrogen or (C 14) alkyl, wherein the alkyl is optionally substituted with one to two substituents selected independently of one another from (C _1-4 ) alkyloxy, hydroxy and sulfo, R ⁷ is hydrogen or methyl and R ⁸ is hydrogen, methyl or hydroxy; X ⁸ is -C (R ¹ ) n 1 = z wherein R ¹ is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-imino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH 2) XNHC (NR ⁹ ) R ⁹ , (CH 2) _X NHC (NH) NR ⁹ R ⁹ and -C (NR ⁹ ) R ⁹ , wherein each R ⁹ is independently from each other hydrogen or methyl, or X ^{8 is} -N (R ¹ ) 4 -, wherein R 9 is ¹ is -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ or -C (NH) NR ¹⁰ R ¹⁰ , wherein each R ⁹ is independently from each other hydrogen or methyl, and each R ¹⁰ is methyl, wherein any aliphatic or 118 the alicyclic group R ¹ is optionally substituted with one to two substituents selected independently of one another from methylsulfonyl and carboxy; X ⁹ is -C (R ^{4 *} ) =, wherein R ⁴ is -R ¹² , -OR ¹² , -C (O) R ¹² , C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , wherein R ¹³ and R ¹⁴ are independently from each other hydrogen or (C 1-6) alkyl; R ¹² is -R ¹⁵ or -X ^{5 6 * *} - (R ¹⁵ ) n ¹⁵ , wherein X ⁶ is (C 1-10) alkylene or hetero (C 2-10) alkylene and each R ¹⁵ is independently from each other hydrogen, (C 6-14 ₎ ) aryl, cyclo (C3-14) alkyl, polycyclo (C ₆ -i ₄₎ aryl, heteropolycyclo (C6-14) aryl, heterocyclo (C ₃ _i ₄₎ alkyl or hetero (C5-14) aryl; any aliphatic and alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C _1-4 ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C _1-4 ) alkyl, (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C 3-8) alkyloxy, halo, hetero (C ₈₎ alkyl, hetero (C ₆₎ alkylcarbonyl, hetero (C ₅ _ ₆₎ aryl and trifluoromethyl; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 4, wherein: A together with B form 4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl, wherein n 2 is 0 and R ¹ is -C (NR ⁹ ) R ⁹ , or A together with B is 1H-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl, wherein R ¹ is aminomethyl or guanidino and each R ² is independently halogen or hydroxy; 119 C is 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl or 1H-benzoimidazol-2-yl, wherein R ⁴ is -C (O) X ⁶ -R ¹⁵ , C (O) OX ⁶ -R ¹⁵ or -C (0) NHX ⁶ -R ¹⁵ wherein X ⁶ is a (C ₄₎ alkylene or hetero (C _2-4) alkylene and R ¹⁵ is a (C6-io) aryl, , (C 6-10) aryloxy, polycyclo (C 6-10) aryl, hetero (C 5-10) aryloxy or heteropolycyclo (C 6-14) aryl; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C _1-4 ) alkyl, (C _1-4 ) alkyloxy, (C _1-4 ) alkyloxycarbonyl, carboxy, carbamoyl, halogen, hydroxy and tetrazole-1- yl; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 5, wherein A together with B form 1 H -benzoimidazol-2-yl and each R ² is independently from each other halogen or hydroxy; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 6, wherein n 1 is 0; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 7, wherein it is selected from compounds; 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5,6, -Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 120 butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; and isobutyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 5, wherein R ¹ is guanidino or aminomethyl, and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 9, wherein the compound is selected from: 2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3-methyl-N- (2naft-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide; ethyl-2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) benzoate; 2- (5-guanidino-lH-benzoimidazol-2-ylcarbonyl) -3- (2,3dihydroxy) propyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide; 2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide; 2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide; 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide; 121 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide; 4-chloro-2- [2- ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonyl] amino) ethoxy] benzoic acid; 5-chloro-2- [2- ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid; 2- (5-aminomethyl-lH-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-l-yl-ethyl) -3H-benzoimidazole-5-carboxamide; and 2- (5-aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 5, wherein A together with B form 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl and R ¹ is C (NH) R ⁹ ; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 11, wherein it is selected from: 2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3-benzoimidazole-5-carboxamide; 122 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1-ylethyl) -3Hbenzoimidazole 5-carboxamide; 2- (5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3Hbenzoimidazole- 5-carboxamide; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- (2-hydroxy-2-naphtha) 1-ylethyl) 3H-benzoimidazole-5-carboxamide; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2-hydroxynaphthyl) 1-yl) ethyl] 3 H -benzoimidazole-5-carboxamide; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4-hydroxynaphthalen- 1-yl) ethyl] 3 H -benzoimidazole-5-carboxamide; 2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl] ethyl} -3-methyl-N- (2- naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; ethyl-2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3 methyl 3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate; 2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3- (2- methoxyethyl) -3Hbenzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; ethyl-2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1,4,6 7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate; and 2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl-ethyl} -3-methyl-N- [2- (2-tetrazolylphenoxy) 3-ethyl-3H-benzoimidazole-5-carboxamide; and N-oxide derivatives thereof, for 123 drug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts. The compound of claim 12, wherein the compound is 2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2] -yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. 14. A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 14, further comprising a compound that is a β-adrenergic agonist. The pharmaceutical composition of claim 14, wherein the compound that is a βadrenergic agonist is selected from the group consisting of albuterol, terbutaline, formoterol, phenoterol, and prenalin. 17. A pharmaceutical composition according to claim 14 comprising a pharmaceutically acceptable carrier for administration as an ointment. A pharmaceutical composition according to claim 14 comprising a pharmaceutically acceptable carrier for oral administration. 124 19. A pharmaceutical composition according to claim 14 comprising a pharmaceutically acceptable carrier for aerosol administration. An aerosol inhaler comprising the compound of claim 1 in a pharmaceutically acceptable carrier, i. j. in solution or dry powder, and means for converting the solution or dry powder into an aerosol form suitable for inhalation. A method of treating immunologically induced inflammation in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method of treating rheumatoid arthritis in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method of treating conjunctivitis in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method of treating a syncytial viral infection in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of claim 1. A method of treating immunologically induced inflammation in the respiratory tract of a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. 26. A process for the preparation of a compound of formula I: 125 where nl is a 0 or 1; n2 is a 0,1,2,3 or 4; n3 is a 0,1,2,3 or 4; A together with B forms a fused heterobicyclic group containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom optionally being a heteroatom, X ¹ is a heteroatom group selected from -N =, -O- and -S- , and X ¹ and X ² are adjacent members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring, wherein the 1H-imidazol-2-yl ring member is optionally -NR ⁵ -, wherein R ⁵ is hydrogen, (C 6) alkyl or hetero (C ₂ -6) alkyl; or C forms a fused heteropolycyclic group containing 8 to 18 ring atoms, each ring atom being optionally a heteroatom, X ⁵ is a heteroatom group selected from -N =, -O- and -S-, and X ⁴ and X ⁵ are adjacent oxazol-2 members an -yl, 1H-imidazol-2-yl or thiazol-2-yl ring, wherein the 1H-imidazol-2-yl ring member is optionally -NR ⁶ -, wherein R ⁶ is hydrogen, a group selected from (C _1-8 ) alkyl, or hetero (C _2nd and ₂₎ alkyl, wherein alkyl is optionally substituted with one to two substituents selected, independently of one another, from (C, ₆₎ alkanoyloxy, (C ₆₎ alkylamino, di (C ₆₎ alkylamino, tri (C 6 ) alkylammonium, (C 1-6) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C 1-6) alkyloxycarbonyl, (C _1-6 ) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-6) aryl, halogen, hetero (C ₅ _ n) aryl, hydroxy and sulfo, or as described below; and any keto, thioketo, and iminoketo derivative thereof; 126 X ³ is -O-, -S-, -S (O) -, -S (O) ₂ , -C (O) -, -NR ⁷ - or CR ⁷ R ⁸ -, wherein R ⁷ is hydrogen, ( Ci_6) alkyl, hetero (C2, 2) alkyl or together with R ⁶ form a (C2. ₄₎ alkylene or hetero (C ₂ _ ₄₎ alkylene and R ⁸ is hydrogen, (C β) alkyl or hydroxy or together with R ⁷ form a (C ₂ _ ₆₎ alkylene or (Ci_e) alkylidene, wherein any aliphatic optionally selected δ) alkylammonium, ₆ ) alkanoyloxy, or an alicyclic group R ⁷ and / or R ⁸ is substituted with one to three substituents from (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, tri (C 1 - (C _1-6 ) alkyloxy, (C _1-6 ) ₆ ) alkyloxycarbonyl, (C 1-6 amino, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, halogen and hydroxy; R ¹ is amino (Ni_4) azolidinyl, amino (Ni_4) azolyl, (Ni_4) azolidinyl, (Νχ.4) azolyl, carbamoyl, cyano, - (CH 2) X NHC (NR ⁹⁾ R ^9, (CH 2) _x NHC (NH ) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , -C (NH) NR ¹⁰ R ¹⁰ or (CR ¹ R ¹¹ ) y NH 2, and is attached to any atom of ring B, which has an available valency, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R ⁹ is independently from each other hydrogen or (C 1-6) alkyl, each R ¹⁰ is independently of one another (C 1-8) ) alkyl and each R ¹¹ is independently from each other hydrogen, (C 1-3) alkyl, or together with the other R ¹¹ and the carbon to which they are both attached to form cyclopropyl, wherein any aliphatic or alicyclic group R ¹ is independently from each other optionally substituted with one to two substituents selected independently of one another from (C 1-6) alkyloxycarbonyl, (C _1-6 ) alkanoyloxy, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy; each R ² is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxycarbonyl, (C _1-6 ) alkanoyloxy, (C _1-6 ) alkyloxy, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkylsulfinyl, (C _1-6 ) alkylsulfonyl, (C _1-6 ) alkylthio, halogen or hydroxy, and is attached to any atom of ring B with available valency, wherein any aliphatic group R ² is optionally substituted with one to two substituents, independently one a second selected from (C _1-6 ) alkyloxycarbonyl, 127 (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy; each R ³ is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxy, (C 1-6) alkylthio, cyano, halogen, perhalogen (C 1-6) alkyl or hydroxy, and is bonded to any ring C atom with available valence; and R ⁴ is -R ¹² , -OR ¹² , -N (R ¹³ ) R ¹² , -SR ¹² , -S (O) R ¹² , -S (O) ₂ R ¹² , S (O) ₂ OR ¹² , -S (O) 2 N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) R ¹² , -OC (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) OR ¹² , - (CH ₂ ) _from N (R ¹³ ) C (O) N (R ¹³ ) R ¹² , -0P (0) (OR ¹³ ) OR ¹² or -C (O) N (R ¹⁴ ) CH- (COOH) R ¹² , and is bonded to any ring C atom with available valency, wherein: z is 0, 1 or 2, R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ ηΐ5, the NL5 is 1 or 2, X ⁶ is (C io) alkylene, cyclo (C3_io) alkylene, hetero (C ₂ _i ₀₎ alkylene or heterocyclo (C3-10) alkylene and each ^R15 is independently is hydrogen, (C 6 and ₄₎ aryl, cyclo (C ₃ _i ₄₎ alkyl, polycyclo (C ₆ and ₄₎ aryl, heteropolycyclo _(C6 -i ₄ ) aryl, heterocyclo (C ₃ _i ₄₎ alkyl, hetero (C5-14) aryl or as defined below; R ¹³ is H, (C β) alkyl or hetero _(C2 _6) alkyl; R ¹⁴ is hydrogen, (C 1-6) alkyl or together with X ⁶ and R ¹⁵ form (C _3-4 ) alkylene; any aliphatic or alicyclic R ⁴ is optionally substituted with one to five substituents selected independently of one another, from (Ci_e) alkyl, (C ₃ _ ₆₎ alkylamino, di (C ₆₎ alkylamino, (C ₁ _ ₆₎ alkylcarbamoyl, di ( C _1-6 alkylcarbamoyl, (C _1-6 ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, (C 1-6) alkylsulfinyl, (C 1-6) alkylsulfonyl, (C _1-6 ) alkylthio, amino, ( C _6-10 arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halogen, hydroxy, mercapto and ureido; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from cyano, guanidino, halogen, 128 halogen substituted (C _1-8 ) alkyl, -R ¹⁶ , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , -S (O) 2 R ¹⁶ , -S (O) 2 N (R ¹³ ) R ¹⁶ , -C (O) R ¹⁶ , -C (O) OR ¹⁶ and -C (O) N (R ¹³ ) R ¹⁶ , wherein R ¹³ is as defined above and R ¹⁶ is hydrogen, optionally monosubstituted (C _1-8 ) alkyl ( wherein the optional substituent is (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylamino, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkyloxycarbonyl, (C _1-6 ) alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C 3-6) alkyl, hetero (C ₈₎ alkyl, hetero (C5-6) aryl, heterocyclo (C _{3. 6)} alkyl or phenyl; with the proviso that nl is 0, when n2 is 0 or R ² is (C ε) alkyl or (C1-6) alkyloxy, n3 is 0 and R ³ is (C ₆₎ alkyl or (C ₆₎ alkyloxy and R ⁴ is hydrogen, (C 1-10) alkyl or (C 1-10) alkyloxy; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof; wherein the method comprises: a) reacting compound 1 or a protected derivative thereof with compound 2: or a protected derivative thereof, wherein L is a leaving group, D together with the vinyl group to which it is fused form a monocyclic or fused bicyclic divalent group of 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring member is a 129 is optionally heteroatom, R ²⁹ is -OH, -NHR ⁶ or -SH, wherein R ⁶ is hydrogen or a group selected from (C 1-8) alkyl or hetero (C 2-12) alkyl, wherein the group is optionally substituted with one to two substituents selected independently from one of the other of (C _1-6 ) alkanoyloxy, (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylammonium, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C ₆₎ alkyloxycarbonyl, (C ₆₎ alkyloxysulfonyl, amino, carboxy, carbamoyl, (C _6-n) aryl, halo, hetero (cs_ n) aryl, hydroxy and sulfo; and nl, n2, n3, A, B, X ^1, X ^2, X ^3, R ^1, R ^2, R ^3, R ⁴ and R ⁶ are as defined above, and if necessary, further comprises removing the protecting group; or b) reacting compound 3 or a protected derivative thereof, wherein L is a leaving group, R ³⁰ is -OH, -NHR ⁵ or -SH and n 1, n 2, n 3, B, C, X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above and, if necessary, further include deprotection; c) optionally further comprising converting a compound of Formula I into a pharmaceutically acceptable salt; d) optionally further comprising converting a compound of Formula I in salt form to its free form; 130 e) optionally further comprising converting the non-oxidized form of a compound of Formula I to a pharmaceutically acceptable N-oxide; f) optionally further comprising converting the N-oxidized form of a compound of Formula I to its non-oxidized form; g) optionally further comprising converting the non-derivatized form of a compound of Formula I into a pharmaceutical prodrug derivative; and h) optionally further comprises converting a prodrug derivative of a compound of Formula I to its non-derivatized form.