LT4704B - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, acitivity - 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

Field of the invention:

The present invention relates to compounds and compositions for treating diseases associated with the activity of a serine protease, in particular tryptase.

Known state of the art:

As the predominant protease isolated from human stem cells, tryptase is thought to be involved in neuropeptide conversion and tissue inflammatory processes. Circulating levels of tryptase are elevated several hours after anaphylaxis (Schwartz et al. (1987). N. Engi. J. Med .. 316: 1622-1626), followed by increased nasal and pulmonary lavage fluid following specific antigen exposure to atopic subjects (Castells et al. et al., (1988), J. Allerg. Clin. Immunol., 141: 563-568) and there is increased lava lavage fluid after endobronchial allergic action in atopic asthmatics. Smokers in bronchoalveolar lavage fluid often have an impressive increase in tryptase levels, and the finding supports the hypothesis that release of proteinase from activated stem cells could provide some relief for smoker's emphysema-induced pulmonary destruction (Celenteron et al. (1988), Chest. 94: 119-123). . The appendix shows that tryptase is a potential mitogen for fibroplasts, suggesting that it is a cause of pulmonary fibrosis and interstitial lung disease (Ross et al. (1991), J. Clin. Invest. 88: 493-499).

Asthma is recognized as an inflammatory disorder (Hood et al. (1984), Benjamin-Cummings, ed. Immunology, 2nd ed.) And is usually characterized by the progressive development of tracheal and bronchial hyperresponsiveness due to both immunospecific allergens and common chemical and physical properties. exposure to stimuli. The disease is caused by many biochemical mediators, both in the acute and chronic stages. It is likely that the increased reactivity of asthmatic bronchiolar tissues is the result of chronic inflammatory reactions that irritate and damage the airway wall epithelial lining and promote pathologic lower tissue hardening. Bronchial biopsies in patients with mild asthma only show signs of airway inflammation.

Allergic responses to inhaled allergens can initiate an inflammatory sequence. For example, allergens can activate stem cells and basophilic leukocytes, which are located in the epithelium and lower smooth tissue cells, by binding to IgEs on the cell surface. Activated stem cells release a number of pre-formed or primary chemical mediators of the inflammatory response (e.g., histamine) and generate a number of other secondary inflammatory mediators (e.g., superoxide, protein derivative mediators, etc.) in situ. In addition, a number of large molecules (eg, proteoglycans, tryptase, chymase, etc.) are released during stem cell degranulation.

The release of these preformed mediators from the stem cells is the cause of the early allergic reaction of airborne allergens to the bronchioles. The peak phase of the asthmatic reaction is about fifteen minutes after allergen onset and is substantially reversible after one to two hours. Twenty-five to thirty percent of patients experience further deterioration of respiratory function, which is maximal between six and twelve hours after onset. This late phase of the reaction is accompanied by a significant number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating bronchial tissue. Infiltrated cells are attached to sites by releasing the stem cell, which produces chemotactic agents and is then activated during the late reaction phase. The late asthmatic response is likely to be a secondary inflammatory reaction, partially mediated by the activity of secreted granulocytes.

Tryptase is involved in the degradation of vasodilating and bronchodilating neuropeptides (Caughey et al. (1988). J. Pharmacol. Exp. Ther., 244: 133-137; Franconi et al. (1988). J. Pharmacol. Exp. Ther., 248: 947-951; and Tam et al. (1990), Am. J. Respir. Cell Mol. Biol. 3.27-32) and modulation of bronchial susceptibility to histamine (Sekizavva et al. (1989) J. Clin. Invest., 83: 175-179). These findings suggest that tryptase can increase bronchoconstriction in asthma by disrupting bronchodilating peptides. Tryptase cleaves fibrinogen fibrinogens and high molecular weight quininogen, indicating that heparin tryptase plays the same role as topical anticoagulants. Tryptase through MMP3 activates prostromelysin (pro-MMP-3) and prococolagenase, indicating that tryptase is involved in tissue inflammation and remodeling and combining destruction in rheumatoid arthritis. Further, administration of a tryptase inhibitor prevents allergen-exposed sheep from developing late and airway hyperreactivity (Clark et al. (1995), Am. J. Respir. Crit. Care Med. 152: 2076-2083) and inhibits direct allergic sheep. skin response to intracutaneous injection of allergen (Molinari et al. (1995), Amer. Physiol. Soc. 79 (6): 1966-1970). Both of the above findings clearly indicate the use of tryptase inhibitors as therapeutic agents in the treatment of asthma and other disorders associated with airway inflammation.

Disclosures of this and other documents, including patents and patent applications cited in this application, are incorporated herein by reference.

THE SUBSTANCE OF THE INVENTION

The present invention includes compounds of formula I:

(O, n1 is 0 or 1; n2 is O, 1,2, 3 or 4; n3 is 0, 1,2, 3 or 4;

A together with B forms a fused heterobicyclic radical containing from 8 to 12 ring atoms, each ring having from 5 to 7 ring members and each ring atom being optionally a heteroatom, X ¹ and X ^{2 being} adjacent ring members and X ¹ being a heteroatom moiety selected from -N =, NR ⁵ -, -O- and -S- wherein R ⁵ is hydrogen, (C _{4th 6)} alkyl or hetero (C _{2nd 6)} alkyl;

C forms a fused heteropolycyclic radical having from 8 to 18 ring members, each ring having from 5 to 7 ring members, each atom being optionally a heteroatom, X ⁴ and X ⁵ being adjacent members of the aromatic ring, X ⁵ being a heteroatom residue selected of -N =, -NR ⁶ -, -O-, and -S-, wherein R ⁶ is hydrogen, a group selected from (Ci. ₈₎ alkyl or hetero (C _{2nd 12)} alkyl, are optionally substituted with one or two substituents independently selected from (Ci-e) alkanoyloxy, (Cl-6) alkylamino, di (Ci-6) alkylamino, tri (Ci. ₆₎ alkylammonium (Ci. ₆₎ alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl (Ci. ₆₎ alkyloxy, (Ci. ₆₎ alkyloxycarbonyl, (Ci. ₆₎ alkiloksisulfonilo, amino, carboxy, carbamoyl, (C _6. i ₄₎ aryl, halogen, hetero (C5-i _4), aryl, hydroxy and sulfo groups as below; and any derivative thereof of carbocyclic ketone, thioketone and iminoketone;

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 s ₂₎ alkyl, or together with R ⁶ form a (C2.4) alkylene or hetero (C2.4) alkylene and R ⁸ is hydrogen, (Cl-6) alkyl, or hydroxyl or together with R ⁷ forms a (C 2 -C 6) alkylene or (C 1 -C 6) alkylidene wherein any aliphatic or alicyclic residue containing R ⁷ and / or R ^{8 is} optionally substituted with one to three substituents selected from (C .6) alkylamino, d ^ Cvejalkilamino, tritCveJalkilamonio (Ci. ₆₎ aikiloksi (Ci. ₆₎ a! kiloksikarbonilo (C₄) alkanoyloxy, amino, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci- 6) alkylcarbamoyl, halogen and hydroxyl groups;

R ¹ is amino (Ni 4) azohinyl, amino (Ni 4) azolyl, (Ni 4) azo (idinyl, (Ni 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 ¹¹ R ¹¹⁾ yNH2 and bonded to any ring atoms with free valence comprising B wherein x is 0 or 1, y is 0, 1, 2 or 3 and each R ^{9 is} independently hydrogen or (C _4-6 ) alkyl, each R ¹⁰ is are independently (Ci. ₆₎ alkyl, and each R is independently hydrogen, (Ci- ₃₎ alkyl, or together with another ^R11 and a carbon atom to which they are both attached form a cyclopropyl which any aliphatic or alicyclic moiety comprising R ¹ has been substituted with one to two substituents independently selected from (Ci-6) alkyloxycarbonyl, (Ci-C 6) alkanoyloxy, carboxy, carbamoyl, (Ci. ₆₎ alkylcarbamoyl, di (Ci-6) alkylcarbamoyl, (Ci. ₆ ) alkylsulfonyl and hydroxyl groups;

each R ² is independently a (Ci.6) alkyl, (Ci. ₆₎ alkyloxycarbonyl, (Ci-C 6) alkanoyloxy (C _{t. 6)} alkyloxy, carboxy, carbamoyl, (Ci. ₆₎ alkylcarbamoyl, di (C ,. ₆ ) alkylcarbamoyl, (C 1-6 alkylsulphinyl, (C _1-6 ) alkylsulphonyl, (C _1-6 ) alkylthio, halogen or hydroxyl and bonded to any free ring valence comprising B, wherein any aliphatic residue containing R ² is optionally substituted with one to two substituents independently selected from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxyl, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6 alkylsulfonyl) and hydroxyl groups;

each R ^{3 is} independently (C 1-6) alkyl, (C 1-6 alkyloxy, (C 1-6 alkylthio) cyano, halogen, perhalogen (C 1-6) alkyl or hydroxyl and bonded to any ring atoms with free valence comprising C ; 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 O 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) z} N ( R ¹³ ) C (O) N (R ¹³ ) R ¹² , OP (O) (OR ¹³ ) O r ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² and bonded to any ring atom with free valence comprising C in which:

z is 0,1 or 2,

R ¹² is -R ¹⁵ or -X ⁶ - (R ¹⁵ ) _n ¹⁵ , wherein _n ¹⁵ is 1 or 2, X ⁶ is (C ₁ -C 10) alkylene, cyclo (C ₃ -C ₁₀ ) alkylene, hetero (C ₂ -C _{10) 0} ) alkylene or heterocyclo (C ₃ .io) alkylene and kiekvienasR ¹⁵ independently are hydrogen, (C6-i4) aryl, cyclo (C _3-14) alkyl, polycycloalkanes (C6-i4) aryl, heteropolycycle (C ₆ -i4) aryl , heterocyclo (C ₃ -C ₁₄ ) alkyl, hetero (C ₅ -C ₁₄ ) aryl, or as defined below,

R ¹³ is hydrogen, (CveJalkilas or hetero (C ₂ -6) alkyl;

R ¹⁴ is hydrogen, (C 1 -C ⁶ ) alkyl, or together with X ⁶ and R ¹⁵ form (C ₃ -C ₄ ) alkylene;

any aliphatic or alicyclic moiety comprising ^R4 optionally is substituted by one to five substituents independently selected from (Ci. ₆₎ alkyl, (Ci- ₆₎ alkylamino, di (Ci-6) alkylamino (Ci. ₆₎ alkylcarbamoyl di (Ci. ₆₎ alkylcarbamoyl, (Ci. ₆₎ alkyloxy, (Ci. ₆₎ alkyloxycarbonyl, (C? eJalkilsulfinilo (CveJalkilsulfonilo (Ci. ₆₎ alkylthio, amino, (C ₆ -io) arylsulfonyl, carbamoyl, carboxyl, cyano, guanidine, halogen, hydroxyl, mercapto and ureido groups; and any aromatic residue containing R ^{15 is} optionally substituted with one to three substituents independently selected from cyano, guanidine, halogen, 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 substituted with mono-substituted (C 1-8) ) alkyl (wherein the optional substituents is (Ci.6) alkylamino, di (Ci. ₆₎ alki lamin, tri {Ci. ₆₎ alkylammonium (C ,. ₆₎ alkylcarbamoyl, di (Ci-6) alkylcarbamoyl, (Ci. ₆₎ alkyloxycarbonyl, (Cvejalkiloksisulfonilas, amino, carboxy, carbamoyl, hydroxy or sulfo-group), cyclo (C ₃ - 6) alkyl, hetero (Ci. ₈₎ alkyl, hetero (C ₅ -6) aryl, heterocyclo (C ₃ .6) alkyl or phenyl;

with the proviso that n1 is not 0, when n2 is 0 or R ² is (Ci-6) alkyl or (Cvejalkiloksi, n3 is 0 or R ³ is (Ci-6) alkyl or (Ci-6) alkyloxy and R ⁴ is hydrogen, (C _b io) alkyl or _{(C1. 10)} alkyloxy, and / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

The present invention also provides pharmaceutical compositions containing the compounds of the present invention. The pharmaceutical compositions may take a variety of forms, including oral dosage forms, inhalation forms, and solutions for injection and infusion. When used in inhalation or aerosol dosage forms, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier solution or dry powder that can be converted into an aerosol formulation. In general, when used for oral administration, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used to treat immune-mediated inflammatory conditions of the skin, the compounds of the present invention are used in combination with non-toxic, pharmaceutically acceptable topical carriers. The compounds of the present invention may be used in combination with anti-inflammatory and other asthma medications such as β-adrenergic agonists, anti-inflammatory corticosteroids, anticholinergics, bronchodilators such as methylxanthenes and the like.

The compounds described herein are suitable for the protection and treatment of immune-mediated inflammatory disorders, and in particular those associated with the respiratory tract, including both asthma and specifically in the reactive phase of chronic asthma and allergic rhinitis. The present invention also provides the use of the compounds of the present invention in the manufacture of a medicament for the treatment of immune-mediated inflammatory disorders and syncytial viral infections.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 compares specific lung resistance (white squares) between control and 2- (5-aminomethyl-1A / benzoimidazol-2-ylmethyl) - N - (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 4; black squares). ) over a time period measured in hours.

Figure 3 is a graph depicting airway elevated reactivity (measured as PC400) in antigen-exposed sheep treated with compound 4 aerosol at three doses of 1 mg compared to control treated sheep.

DETAILED DESCRIPTION OF THE INVENTION

Terminology:

Unless otherwise stated, the terms used in the present invention and the definition have the following meanings:

"Alkanoyl means a radical of -C (O) R wherein R is alkyl as defined below having the total number of carbon atoms indicated (e.g., (C 1-6) alkanoyl includes formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonoyl etc. radical).

"Alicyclic residue" means any saturated or unsaturated, monocyclic or polycyclic moiety of a hydrocarbon radical. For example, an alicyclic moiety refers to cycloalkyl as defined herein, as well as to an alicyclic moiety including cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylcarbamoyl and the like.

"Aliphatic residue" means a linear or branched, saturated or unsaturated moiety of a hydrocarbon radical. For example, an aliphatic residue refers to alkyl or heteroalkyl as herein defined and also to an aliphatic moiety comprising alkyloxy, arylalkyl, heteroarylalkyl, alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl and the like.

"Alkyl" as used herein, means a linear or branched, saturated or unsaturated aliphatic hydrocarbon radical having the specified number of carbon atoms and any of its ketones, thioketones or iminoketones (e.g., (Cv 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-methylallyl, ethynyl, 1propynyl, 2-propynyl, 3-oxopentyl, 3-thiooxopentyl, 3-iminopentyl, etc.).

"Alkylene means a saturated or unsaturated divalent hydrocarbon radical having the specified number of carbon atoms and any ketone, thioketone, iminoketone or substituted derivative thereof (e.g., (CMo) 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-thiatromethylene (-CH ₂ -S ( O) CH ₂ -), 2iminotrimethylene (-CH ₂ -C (NH) CH ₂ -), propenylene (-CH ₂ -CH = CH- or * CH = CHCH ₂ -), propanylidene (= CHCH ₂ CH ₂ -). , propendylene (= CHCH = CH-, 1-aminotetramethylene, pentamethylene, etc.).

"Alkylidene" refers to a = CRR radical wherein each R is independently hydrogen or alkyl as above having the specified number of carbon atoms (e.g., (C 1-6) alkylidene includes methylidene, ethylidene, propylidene, isopropylidene, etc.).

"Alkyloxy" means a radical -OR "wherein R is alkyl as defined above having the indicated number of carbon atoms (eg .. (Ci. ₆₎ alkyloxycarbonyl radical include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy , tert -butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.).

"Alkylsulfinyl", "alkylsulfonyl and" alkylthio "denote the radicals -SOR, -S (O) ₂ R and -SR, respectively, wherein R is the above alkyl having the specified number of carbon atoms (e.g. (C 2 -alkylsulfonyl includes methylsulfonyl, ethylsulfonyl) , for example, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, anth-butylsulfonyl, isobutylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propensulfonyl, 2-butenylsulfonyl, 2-butenylsulfonyl, 2-butenylsulfonyl, - propynylsulfonyl, etc.).

"Ammonium" means the radical -NH ₃ ⁺ .

“Amidino means a radical of -C (NH) NH ₂ .

"Amino" refers to the radical -NH ₂ .

"Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, large cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g., birds, etc.).

"Aryl" refers to an aromatic or fused polycyclic hydrocarbon radical having the specified number of carbon atoms, wherein each ring herein is composed of 6 ring members (e.g., (C 6 -C 14) aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like). ).

"Arylsulfonyl" means a radical of -S (O) ₂ R wherein R is aryl as defined above having the specified number of carbon atoms (e.g. (C 6 -C 10) anlsulfonyl includes phenylsulfonyl, naphth-1-ylsulfonyl, etc.).

“Aromatic residue refers to any part of an aromatic radical. For example, the aromatic moiety refers to aryl or heteroaryl as defined herein, as well as an aromatic moiety including arylalkyl, heteroarylalkyl, polycycloaryl, heteropolycycloaryl and the like.

"Azolidinyl" means a saturated or unsaturated 5-membered monocyclic radical having the specified number of nitrogen atoms. For example, N, N-azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, trizolidinyl, tetrazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.

"Azolyl" means an aromatic 5-membered monocyclic radical having the specified number of nitrogen atoms. For example, (Ni ₄₎ azolyl include pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, and tetrazolyl.

"Carbamoyl" refers to the radical -C (O) NH ₂ .

"Carboxyl" refers to the radical -C (O) OH.

"Ciano" means a -CN radical.

"Cycloalkyl" means a saturated or unsaturated monocyclic or fused polycyclic hydrocarbon radical having the specified number of carbon atoms, each ring containing from 3 to 8 ring members and any carbocyclic ketone, its thioketone or aminoketone derivative (e.g. C ₃ - ( ₄ ) cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo [2.2.2] octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.).

"Cycloalkylene" means a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon radical having the specified number of carbon atoms, each ring containing from 3 to 8 ring members and any derivative of the carbocyclic ketone, its thioketone or the iminoketone (e.g. (C _3rd io) cycloalkylene includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2ciklopentileną, 1,3-cyclopentylene, 1,4-cyclopentylene, 1,4-cyclohexylene, cyclohexene -1,2-ylene, 2,5-cyclohexadien-1,4-ylene, 1,4-bicyclo [2.2.2] octylene, 5-oxo-1,3-cyclohexylene, 2,5-dioxo-1,4-cyclohexylene , 5-thiooxy-1,4-cyclohexylene, etc.).

“Unblocking means removing any existing blocking group by a selective reaction.

“Disease” specifically includes any unhealthy condition of an animal or part thereof and includes any unhealthy condition that may result from application of such medical or veterinary treatment to these animals, i. that is, the “side effect” of this therapy.

"Fused heteropolicyclic radical" includes a "fused heterobicyclic radical" and means a heterocyclic radical having two or three fused rings having a specified number of ring members in which at least two ring members of one ring share a second ring (e.g. 8 to 18 ring atoms and the carbocyclic ketone and its thioketone derivative include 17-benzimidazol-2-yl, 1 N -naphtho [2,3-d] imidazol-2-yl, 1H-imidazo [4,5-f] quinolin- 2-yl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-phenanthro [9,1 θά] imidazol-2-yl, 1H-imidazo [4,5-g] quinoxaline-2- 2,6-Dioxo-2,3,6,7-tetrahydro-1 H -purin-8-yl, 2,6-Dithiooxy-2,3,6,7-tetrahydro-1 H -purin-8-yl, 7A7- purin-8-yl, 1,6-dihydro-cyclopentoimidazol-2-yl, 4-quinolin-2-yl, etc.).

"Guanidino" refers to the radical-NHC (NH) NH ₂ .

"Halogen" means fluorine, chlorine, bromine or iodine.

"Heteroatom residue", unless taken generally, refers to a residue 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 an alkyl as defined above, except one or more of the carbon atoms is replaced by a heteroatom moiety as defined in the detailed description of the invention and any ketone, its tioketono or iminoketone derivative thereof (eg., Hetero (C ₂ .i ₂ ) alkyl includes methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 3-methoxymethoxycarbonylmethoxy, 2- (N-ethyl-N / methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).

"Heteroalkylene" means alkylene as defined above wherein, except for one or more of the indicated carbon atoms, it is substituted with a heteroatom residue as indicated in the "Detailed Description of the Invention" or any suitable combination thereof (e.g., -OS (O) ₂ -, -S (O) ₂ O-, -N (R) S (O) ₂ -, -S (O) ₂ NR ¹⁷ -, -OP (O) (OR ¹⁷ ) O- and the like, when R ¹⁷ is hydrogen or (C 1 -C 6) alkyl, and any ketone, its thioketone or iminoketone derivative (e.g., hetero (C ₂ -C 10) alkylene includes azaethylene (-CH ₂ NH-), _2- azapropylene (-CH ₂ N = CH ₂ -). ), 1-oksatrimetileną (-CH ₂ CH ₂ O-), 2-oxo-3azapentametileną, 3-aza2-tiopentametileną, 2-oxa-3-oksopentametileną, 3-aza2-iminopentametileną (-CH ₂ CH ₂ NHC ( NH) CH ₂ -), 2,4-aza-2-methyl-3,3-dioxo-3-thiopentamethylene (-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-carboxyhexamethylene, 4-aza-1-oxa-3-oxohexamethylene, 1-thia- 3-oxo-4-azahexamethylene, 1-thia-1,1,3-trioxy o-4-azahexamethylene (CH ₂ CH ₂ NHC (O) CH ₂ S (O) ₂ -), 3-aza-4-oxoheptamethylene, 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 radical having the specified number of ring atoms, wherein each ring herein consists of 5-6 ring members and one or more of the ring atoms is a heteroatom residue selected from -N =, -NR ¹⁷ - , -O- or -S-, wherein R ¹⁷ is hydrogen or (C 1 -C 6) alkyl and each ring herein is composed of 5-6 ring members (e.g., hetero (C ₅ -C ₄ ) aryl includes thienyl , furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl), pyrazolyl, pyrazolyl.

"Heterocycloalkyl" means cycloalkyl as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom residue as defined in the "Detailed Description of the Invention" and any carbocyclic ketone or its tipketone or iminoketone derivative (e.g. (C ₅ -C 14) alkyl includes piperidyl, pyrrolidinyl, pyrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

"Heterocycloalkylene" means cycloalkylene as defined above, except that one or more of the indicated ring carbon atoms is substituted with a heteroatom residue as defined in the "Detailed Description of the Invention" and any carbocyclic ketone or thioketone or iminoketone derivative thereof (e.g. (C _3. 14) alkylene includes piperidylene, pyrrolidinylene, pyrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).

"Heteropolycycloaryl" means polycycloaryl as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom residue as defined in the "Detailed Description of the Invention" and any carbocyclic ketone or thioketone or iminoketone derivative thereof (e.g. (C ₈ -C10) alkyl includes 3,4-dihydro-2/7-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" refers to the -OH radical.

"Immune-mediated inflammatory disorder" refers to diseases that are associated with the release of stem cell mediators and are susceptible to treatment with a tryptase inhibitor (e.g., a direct type of hypersensitivity disorders such as asthma, allergic rhinitis, urticaria and urticaria, eczema anaphylaxis, dermatitis, such as atopic dermatitis, dermatitis, gastric ulcer, inflammatory bowel disease, ocular and spring conjunctivitis, inflammatory skin condition of rheumatoid arthritis and the like).

"Increased reactivity" refers to the late phase of bronchial stenosis and airway hyperactivity associated with chronic asthma. It is likely that the increased reactivity of asthmatic bronchiolar tissues results from a chronic inflammatory reaction that annoys and damages the airway barrier epithelial walls and promotes thinning of underlying tissues.

"Syncytial viral infection" means infection by a virus, such as respiratory cytosolic virus, which causes the formation of a cellular protoplasmic mass, i. i.e., syncytia, through infection.

"Imino" means = NH radical.

"Isomer" means compounds of formula I having the same molecular formula but different structure, or atomic bond sequence, or different arrangement of their atoms in space. Isomers which differ in the arrangement of their atoms in space are called 'stereoisomers. Stereoisomers which are not mirror reflections of one another are called "diastereomers" and stereoisomers which are mirror reflections of one another are called "enantiomers" or sometimes "optical isomers". A carbon atom bound to four different substituents is called a "chiral center". A compound having one chiral center and having two enantiomeric forms of opposite chirality is called a "racemic mixture". A compound having more than one such center has 2 ⁿ ' ¹ enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist both as an individual diastereomer and as a mixture of diastereomers called a "diastereomeric mixture". When a single chiral center represents a stereoisomer, it may be characterized by the absolute configuration of that chiral center. The absolute configuration specifies the distribution of the substituents attached to the chiral center in space. Substituents joined to the chiral center are ranked according to Cahn, Ingold, and Prelog's Substitute Superiority Rule, and absolute descriptors P and S are quoted in the parenthesis followed by the chemical name. Compounds of formula I which have a chiral center may exist as individual stereoisomers or as a mixture thereof. For purposes of this application, when a compound name or formula of formula I is given and no configuration is specified, it is to be understood that reference is made to all possible configurations of the compound.

"Optional" or "optional" means that the event or conditions described below may or may not occur, and that the description includes instances where the event or conditions occur and events that do not occur. For example, the phrase "optionally substituted with one to three radicals" means that the specified group may or may not be substituted due to the order which forms within the scope of the invention.

"N -oxide derivative" means derivatives of a compound of formula I wherein the nitrogen is in the oxidized state (e.g., O <- N) and has the desired pharmacological activity. The N-oxides of the compounds of formula I may be prepared by methods known to those skilled in the art.

"Pathology" of a disease refers to an intrinsic property that arises and develops both as a result of the disease and as a result of structural and functional changes that occur in the course of the disease.

"Pharmaceutically acceptable" means one which is useful in the manufacture of pharmaceutical compositions, is intrinsically safe, non-toxic, is not biologically or otherwise undesirable and may be used for both veterinary and human purposes.

"Pharmaceutically acceptable salts" means salts of the compounds of the formula I which are pharmaceutically acceptable as defined above and which possess the desired pharmacological properties. Such salts include acid addition salts formed with non-acidic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2etandisulfonrūgštis, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, pchlorbenzensulfonrūgštis, 2-naphthalenesulfonic acid, p-toluenesulfonic kamforosulfonrūgštis, 4-methylbicyclo [2.2 .2] oct-2-en-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, butyl acetic acid, lauryl sulfonic acid, gluconic acid acid, glutamic acid, hydroxynaphthoic acid, salicylic acid s, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts which may be formed when a given acid proton can react with an inorganic or organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

"Polycycloaryl" means a fused polycyclic radical having the specified number of carbon atoms, wherein at least one, but not all, of the condensed rings contains an aromatic radical and each ring herein is composed of 5-6 ring members and any carbocyclic ketone and of its thioketone derivative (e.g.

₁₀ ) aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, etc.).

"Prodrug derivatives" means derivatives of the compounds of the formula I which are converted in vivo to the corresponding non-derivatized forms of the compounds of the formula I. Suitable prodrug derivatives include those compounds of Formula I wherein one or more nitrogen and / or oxygen atoms with a possible free valence are replaced by a group that is readily degradable in vivo. For example, prodrug derivatives of compounds of formula I may have one or more N-substituted amino groups (e.g. NH ₂ (R ¹⁸ )), N-substituted nitrogen atoms {attached to an aliphatic, alicyclic, or aromatic structure (e.g., - N (R ¹⁸ ) -), N-substituted with imino or amidino groups (e.g. C (NR ¹⁸ ) H, -C (NR ¹⁸ ) NH 2 or -C (NH) NHR ¹⁸ ), N-substituted guanidine groups (e.g., -NHC (NR ¹⁸ ) NHR ¹⁸ , -NHC (NH) NHR ¹⁸ or -NHC (NR ¹⁸ ) NH 2) NH ₂ ) and the like, wherein R ¹⁸ is (i) -C (O) R ¹⁹ or -CH (R ²⁰ ) OC (O) R ¹⁹ wherein R ¹⁹ is (C 1-4 alkyl, (C b 10) alkoxy, carbamoyl, (C 1-10) alkylcarbamoyl, di (C 1-10) alkylcarbamoyl, cis-2). - (C 1-10) alkanoylphenyl vinyl, 3- (C 1-10) alkanoyloxybutyryl, (C 3-10) cycloalkyl, hetero (C 3-10) cycloalkyl, (C 6-10) aryl or hetero (C 5-10) aryl and R ²⁰ is hydrogen or (C ²⁰ ) io) alkyl; (ii) -X ⁷ -R ²¹ wherein X ⁷ is (C 1 -C 4 alkylene and R ²¹ is carboxyl) or (iii) -C (O) OCH (R ²² ) OC (O) R ²³ wherein R ²² is hydrogen, (Ci_10) alkyl or (C _3rd io ) cycloalkyl and R ²³ is (C 1-10) alkyl or (C 3-10) cycloalkyl. In the appendix, the prodrug derivatives of the compounds of formula I may have one or more N-hydroxylated imino or amidino groups (e.g., -C (NOR ²⁴ ) H, -C (NOR ²⁴ ) NH 2 or -C (NH) NHOR ²⁴ ). or N-hydroxylated guanidine 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 (Ci.10) alkyl or _{(C3. 10)} cycloalkyl and R ²⁶ is hydrogen or (Cnojalkilas; / V-substituted hydroxy groups (eg. ²⁷ -OR) 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 derivatives of carboxylic acid esters (e.g. -C (O) OR ²⁸ where R ²⁸ is (Ci-io) alkyl or (C ₃ .i ₀₎ cycloalkyl.

"Blocking group" has the meaning usually associated with synthetic organic chemistry, that is, a group that optionally blocks a single reactive site in a multifunctional compound to undergo a selected chemical reaction at an unblocked reactive site and which can be readily removed by a selective reaction. .

"Blocked derivatives" means derivatives of compounds of formula I wherein the reactive site or sites are blocked by protecting groups. Blocked derivatives of compounds of formula I are useful in the synthesis of compounds of formula I. Suitable protecting groups for the reactive nitrogen atom include tert-butoxycarbonyl, benzyloxycarbonyl, and any other suitable amino protecting group (e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, Ine. 1981). Specifically, examples of suitable blocked derivatives of Formula I include 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -4,5,6,7-tetrahydro-. 1H-benzoimidazole-5-carboxylic acid.

"Therapeutically effective amount" means an amount administered to an animal that is effective in treating a disease.

"Treatment" or "treat" refers to the administration of any compound of the present invention and includes:

(1) protection of an animal from a disease which is predisposed to the disease but not yet experienced or showing signs or symptoms of the disease, (2) suppressing the disease, i.e., arresting its pathology and / or symptoms, or (3) ) improvement in disease, i.e. that is, a return to its pathology and / or symptoms.

"Sulfo" means a radical of -S (O) OH.

"Ureido" refers to the radical -NHC (O) NH ₂ .

The compounds of formula I, intermediates and starting materials used in their synthesis are referred to as IUPAC nomenclature rules. For example, compounds of formula I wherein:

A together with B forms 5-guanidino-1A / benzoimidazol-2-yl, C includes 5- (2-naphth-1-yl-ethylcarbamoyl) -1,7-benzoimidazol-2-yl and X ³ is -CH ₂ - is referred to as 2 - (518 guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-yl-ethyl) -1H-benzoimidazole-5-carboxamide;

A together with B forms 5-guanidino-1H-benzoimidazol-2-yl, C includes 6- (2-naphth-1-yl-ethylcarbamoyl) -1-methyl-1/7-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 forms 5-guanidino-1/7-benzoimidazol-2-yl, C includes 6- [2- (2-carboxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl-1/7-benzoimidazol-2-yl) and X ³ is CH ₂ - is called 2- {2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino] ethyl} benzoic acid;

A together with B forms 5-guanidino-1H-benzoimidazol-2-yl, C includes 6- [2- (2-methoxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl-1/7-benzoimidazol-2-yl) and X ³ is CH ₂ - is called 3- {2- (5-guanidino-1/7-benzoimidazol-2-ylmethyl) -6- [2- (2-methoxyphenyl) ethylcarbamoyl] 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 [4,5c] pyridin-2-yl exists in equilibrium between the tautomers of the following formulas:

and thus, although the compounds of the present invention may be named, illustrated and described as one of the possible tautomers herein, it is to be understood that all the possible tautomers are to be referred to by the same names, illustrations and descriptions. Yes, the name 2- (4- {2- [1- (5-guanidino-1H19 benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl } -4-oxobutyl) ethyl benzoate means that its tautomers include 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5] -c] pyridin-5-yl} 4-oxobutyl) ethyl benzoate, 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] 3,4,6,7- tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) ethyl benzoate and 2- (4- {2- [1- (5-guanidino-3 H -benzoimidazol-2-yl) ethyl] -3, 4,6,7-Tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) ethyl benzoate.

Currently preferred implementations are:

Although the broadest definition of the present invention is set forth in the "Gist of the Invention", certain aspects of the invention are preferred. In a preferred aspect of the present invention there is provided a compound of formula I wherein A together with B forms a fused heterobicyclic radical wherein A has 5 ring members and X ⁴ and X ⁵ are oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl. Related members of 2nd ring.

In a preferred aspect of the invention are compounds having the formula IIi:

where:

dashed lines independently represent the selected connections; each R ² is independently (Ci. ₆₎ alki I (Ch ^ alkyloxy, halo or hydroxy;

each R ^{3 is} unsubstituted is (C 1-6) alkyl, (C 1-6) alkyloxy, halo or hydroxyl;

X ³ is -C (O) - or -CR ⁷ R ⁸ -;

X ⁸ is -CH (R ¹ ) ni - or -C (R ¹ ) ni = wherein R ¹ is amino (NM) azolidinyl, amino (Ni-4) azolyl, (Ni 4) azolidinyl, (Ni 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 ) y NH ₂ . or X ⁸ is -N = or NH (R ¹ ) _n i -, 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 hydrogen or (C _1-6 ) alkyl and each R ^{10 is} independently (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 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 ) _{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 wherein R ¹² , R ¹³ and R ¹⁴ are such as those set forth in the section of the Invention.

In a preferred aspect of the invention are compounds of formula I wherein:

R ⁵ is hydrogen or (C 1-4) alkyl, R ⁶ is hydrogen or (C 1-4) alkyl wherein alkyl is optionally substituted with one to two substituents independently selected from (C _1-4 ) alkyloxy, hydroxy and sulfo. , R ⁷ is hydrogen or methyl and R ⁸ is hydrogen, methyl or hydroxyl;

R ⁸ is -CH (R ⁴ ) - or -C (R ¹ ) ni = wherein R ¹ is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH 2) NHC (NR ⁹ ) R ⁹ , - (CH 2) x NHCH (NH) NR ⁹ R ⁹ and -C (NR ⁹ ) R ⁹ wherein each R ^{9 is} independently hydrogen or methyl, or X ⁸ is -N (R ¹ ) ni - 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 hydrogen or methyl and each R ¹⁰ is methyl, wherein any aliphatic or alicyclic residue containing R ^{1 is} optionally substituted with one or two substituents independently selected from methylsulfonyl and carboxyl;

X ⁹ is -CH (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 each independently hydrogen or (C 2 -alkyl); R ¹² is -R ¹⁵ or X ⁶ - (R ^15). ) ni 5 when X ⁶ is (C 1-10) alkylene or hetero (C 2-10) alkylene and each R ^{15 is} independently hydrogen, (C 6 -C 14) aryl, cyclo (C ₃ -C ₁₄ ) alkyl, polycyclic (C ₆ s ₄₎ aryl, heteropolycycle (C _{sixth 14)} aryl, heterocyclo (C _3-14) alkyl or hetero (C ₅ .i ₄₎ aryl;

any aliphatic or alicyclic moiety comprising ^R4 optionally substituted by one to five substituents independently selected from (Ci_ ₄₎ alkyloxy, (C _{b 4)} alkyloxycarbonyl, amino, carbamoyl, carboxyl, and hydroxyl; and any aromatic moiety comprising ^R15 optionally substituted with one to three substituents independently selected from (C _b4) alkyl, (C _b4) alkyloxy, (C _{b 4)} alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C _{3rd 6)} alkyloxy, halo, hetero (C _b 8) alkyl, hetero (C _b 8) alkylcarbonyl, hetero (C5-6) aryl and trifluoromethyl; and their N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

In a preferred aspect of the invention are compounds of formula I wherein:

A together with B forms 4,5,6,7-tetrahydro-1 H, -imidazo [4,5-c] pyridin-2-yl wherein n 2 is 0 and R ¹ is -C (NR ⁹ ) R ⁹ , or A together with B forms 1/7-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1/7-benzoimidazol-2-yl wherein R ¹ is aminomethyl or guanidine and each R ^{2 is} independently halo or hydroxyl ;

C includes 4,5,6,7-tetrahydro-1 H, -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 (O) NHX ⁶ R ¹⁵ where X ⁶ is (C 1-4) alkylene or hetero (C 2-4 alkyl) and R ¹⁵ is (C 6-10) aryl, (C6-io) aryloxy, polycycloalkanes (C ₆ -io) aryl, (C ₆ -io) aryloxy, polycycloalkanes (C5 ₁₀₎ aryl, hetero (C _5. io) aryl, hetero (C5-io) aryloxy or heteropolycycle (C ₆ s ₄₎ aryl; and any aromatic residue containing R ¹⁵ optionally substituted with one to three substituents independently selected from (C _1-4 ) alkyl, (C _1-4 ) alkyloxy, (C _1-4 ) alkyloxycarbonyl, carboxyl, carbamoyl, halo, hydroxyl, and tetrazol-1-yl; and their N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

In a preferred aspect of the invention are compounds of formula I wherein n 1 is 0 and each R ^{2 is} independently halogen or hydroxyl, in particular:

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

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

2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate;

2- (2- {2- [1- (5-Hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) propyl benzoate; and

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

In a preferred aspect of the invention are compounds of formula I wherein R ¹ is aminomethyl guanidine, in particular:

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide;

2- (4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} - 4-oxobutyl) ethyl 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-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide;

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl- N - (2-naphthylethyl) -3W-benzoimidazole-5-carboxamide;

2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3- (2-hydroxy) propyl- N - (2-naphthylethyl) -3 N -benzoimidazole-5-carboxamide;

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

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

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

5-Chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid ;

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-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-yl-ethyl) -3,7-benzoimidazol-5 -carboxamide.

In a preferred aspect of the invention are compounds of formula I wherein C has 4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl and R ¹ is -C (NH) R ⁹ , specifically:

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

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

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

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

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

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

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

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

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] ethyl 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) -3W-benzoimidazol-5-ylcarbonylamino) ethoxybenzoic acid;

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] ethyl benzoate, and

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

Pharmacology and application:

The compounds of the present 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 present invention are tryptase inhibitors and are useful in the treatment of diseases associated with increased tryptase activity. In vitro protocols for the selection of potential inhibitors as well as their ability to inhibit tryptase are already known. See, e.g., Sturzebecher et al. (1992) Biol. Chem. Hoppe-Seyler, 373: 1025-1030. Typically, these assays measure peptide-based enzyme-induced hydrolysis of chromogenic substances. Exemplary methods of measuring tryptase inhibition activity are described below.

In addition, the activity of the compounds of the present invention can be assessed by one of the in vivo animal models of asthma. See Larson, "Experimental Models of Reversible Airway Obstruction", in THE LUNG: SCIENTIFIC FOUNDATIONS, Crystal, West et al., Eds., Raven Press, New York, 1991; Varner et al. (1990) Am. Rev. Respir. Dis., 141: 253-257. The ideal animal model should replicate the basic clinical and physiological signs of human asthma, including: increased respiratory responsiveness to chemical mediators and physical stimuli;

reversible airway obstruction with drugs used to treat asthma in humans (β-blockers, methylxanthines, corticosteroids and the like); respiratory tract inflammation with activated leukocyte inflammation; and chronic inflammatory lesions such as hardening of the basement membrane, hypertrophy of smooth muscle, and epithelial damage. Animal species as animal models include mice, rats, guinea pigs, rabbits, dogs and sheep. Everyone has some limitations, so choosing the right animal model depends on what issue needs to be addressed.

The primary asthmatic reaction can be assessed with guinea pigs, dogs, and especially with the basset-greyhound hybrid, which develops nonspecific respiratory reactivity to a series of non-allergenic substances such as methacholine and citric acid. Some selected sheep show a double reaction when exposed to antigen with Ascaris proteins. In double-reactive animals, the primary asthmatic reaction is accompanied by a (IAR) late asthmatic reaction (LAR) after 6-8 hours of exposure. Hypersensitivity to the cholinergic agonist carbachol increases 24 hours after subcutaneous antigen in animals showing LAR.

An allergic sheep model (see below) was used to evaluate the potential antistatic effect of the compounds of the present invention. Administration of compositions containing the compounds of the present invention to oral allergic sheep, as well as inhalation or aerosol administration, prior to or during exposure to specific allergens, demonstrates that such compositions substantially reduce or eliminate late asthmatic response and consequent increased reactivity.

The compounds of the present invention are useful in the treatment of other immunomediated inflammatory disorders in which tryptase activity causes a pathological condition. Such diseases include inflammatory diseases involving stem cells such as rheumatoid arthritis, conjunctivitis, rheumatic spondylosis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, gastric ulcer and various skin conditions. Further, the compounds of the present invention can be used to treat syncytial viral infections.

The efficacy of the compounds of the present invention in the treatment of a variety of immune-mediated inflammatory disorders can be evaluated by both in vitro and in vivo methods. Yes, the anti-inflammatory efficacy of the compounds of the present invention can be demonstrated by well known tests, such as the Reverse Passive Joint Reaction (RPAR) -PAVV technique (see, e.g., Gangly et al. (1992), U.S. Patent No. 5,126,352). Attempts to determine the therapeutic value of compounds in the treatment of various skin conditions, such as highly advanced skin conditions, are well known in the art, the test for arachidonic acid in the mouse ear (ld). The compounds of this invention may be evaluated for their anti-opine activity according to the methods described by Chiu et al. (1984), Archives Internationales de Pharmacodynamie et de Therapie, 270: 128-140.

The efficacy of the compounds of the present invention in blocking cell fusion due to syncytial viral infection can be assessed by the methods essentially provided by Tidwell et al., J. Med. Chem., 26: 294-298 (1983).

Compositions and assignments:

According to the present invention, a therapeutically or pharmaceutically effective amount of the compounds of the present invention is administered to patients suffering from immune-mediated inflammatory disorders. In one embodiment of the invention, the compositions of the present invention are useful for the protection or alleviation of asthma. When used in the treatment of asthma, the compounds of the present invention may be administered prophylactically before or after exposure to an allergen or other accelerating factor. The compounds of the present invention are particularly effective in improving the late phase of tissue destruction observed in both seasonal and persistent rhinitis. Another aspect of the present invention is directed to the prophylaxis of other immune-mediated inflammatory disorders associated with stem cells such as urticaria (urticaria) and angioedema, and eczema dermatitis (atopic dermatitis) and anaphylaxis, as well as highly advanced skin disease, gastric ulcer and the like. and treatment. In yet another embodiment, the compounds of the present invention are used to treat syncytial viral infections, in particular respiratory syncytial viral infections.

Compositions containing these compounds may be administered for therapeutic and / or prophylactic treatment. In therapeutic use, the compositions are administered to patients already suffering from the disease, as described above, in amounts that can cure or at least partially ameliorate the symptoms or complications of the disease. The corresponding amount is referred to as a "therapeutically effective amount or dose." The amounts effective for such use will depend upon the severity and course of the disease, the prior treatment, the patient's state of health and response to the medications, and the competence of the attending physician.

In prophylactic applications, the compositions comprising the compounds of the invention are administered to a patient who is susceptible or, more generally, to an amount of a particular disease risk that may protect or ameliorate the onset of symptoms. Such stated amount should be the "prophylactically effective amount or dose". It can be administered by boom or by inhalation. Again, in such applications, the exact amount again depends on the patient's state of health, body weight, and the like.

Once the patient's condition has been corrected, only a maintenance dose can be administered if necessary. Accordingly, the dose or frequency of administration, or both, as a function of symptoms, may be reduced to a level at which improvement is maintained. When symptoms reach the desired level, treatment may be »interrupted. However, over a long period of time, the patient may require intermittent treatment because the symptoms of the disease may recur.

Generally, a suitable effective dosage for the recipient of the present invention is in the range of 0.05 to 1000 milligrams (mg) per day, preferably 0.1 to 100 mg per day. two, three, four or more times (sub-dose) per day. Subdoses may be administered as a unit dosage form, for example, 0.01 to 1000 mg, more preferably 0.01 to 100 mg of active ingredient per unit dosage form.

The compositions used for treatment may take various forms. These include, for example, solid, semi-solid and liquid dosage forms such as enteric-coated tablets, pills, powders, liquid solutions or suspensions, liposomes, solutions for injection or infusion. Inhaled preparations such as aerosols are also used. Preferred dosage forms are those suitable for oral, nasal, topical or parenteral administration, but it is desirable to have a dosage form which has a convenient therapeutic use. Particularly desirable formulations would be those suitable for nasal or aerosol administration. Methods for preparing the dosage form and pharmaceutical compositions containing the compounds of this invention are well known and described, for example, by REMINGTON'S PHARMACEUTICAL SCIENCES and THE MERCK INDEX, 11th Edition (Merck & Co. 1989).

Since the active ingredient of the present invention can be administered alone, it is desirable that it be presented as part of a dosage form. The dosage forms of the present invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dosage form, together with a pharmacologically acceptable carrier. The pharmaceutical compositions will also contain compounds of the present invention at concentrations substantially equivalent to the appropriate dosage. For example, if the corresponding dose is 0.05 mg / day, the pharmaceutical composition of the invention would be 0.05 mg / dose when taken at a single daily dose. In formulations for inhalation or aerosol formulation, the concentrations of the compounds of this invention will be substantially dose dependent. Typical concentrations of the compounds of the present invention for inhalation or aerosol formulation will range from about 0.01 to about 30 mg / ml. The formulations may contain other clinically useful compounds such as β-adrenergic blocking agents (e.g., albuterol, terbutaline, formoterol, phenoterol and prenaline) and corticosteroids (e.g., beclomethasome, triamcinolone, flunisolide and dexamethasone).

Chemistry:

In general, the compounds of the present invention are synthesized using standard techniques and reagents known to those skilled in the art. It is noted that the bonds between the various functional groups usually include a carbon bond to the nitrogen of the amide or urea groups, the oxygen of the carbamate group or the carbon atom of the carbonyl group. Those skilled in the art will recognize that the methods and reagents for making these linkages are well known and readily available. See, e.g., March, ADVANCED ORGANIC CHEMISTRY, 4th ed. (Wiley. 1992), Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH 1989); and Furniss et al., VOGEL'S OF PRACTICAL ORGANIC CHEMISTRY, 5th Edition (Longman 1989), each of which is incorporated herein by reference.

Compounds of formula I wherein X ⁴ and X ⁵ are adjacent members of oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl may be synthesized according to the following reaction scheme:

scheme

wherein L is a leaving group, D together with the vinylene residue to which it is fused include a monocyclic or fused bicyclic divalent radical having from 5 to 15 ring atoms, each ring having from 5 to 7 ring atoms and each ring atom being optionally is a heteroatom, R ²⁹ is -OH, NHR ⁶ , or -SH, X ⁸ is -O-, -NR ⁶ - 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 ⁵ are as defined in the Summary of the Invention.

Compounds of formula I wherein X ⁴ and X ⁵ are adjacent members of oxazol-2-yl, 1 W -imidazol-2-yl or thiazol-2-yl (Formula I (a)) may be synthesized by reacting a compound of formula I or a block thereof. with a compound of formula 2 or a blocked derivative thereof followed by deprotection if necessary. The reaction between the compounds of formulas I and II can be carried out readily, but is preferably carried out in the presence of 1,3-dimethyl-3,4,5-tetrahydro-2 (1W) -pyrimidinone (DMPU) or polyphosphoric acid, 160-200 ° C, more preferably 180-190 ° C. ° C, and it takes 1 to 5 hours for the reaction to complete (e.g., see Examples 4 (d), 6 (h), 8 (k), 9 (d) and 10 (d) below). The deprotection may be accomplished by any means which removes the protecting group and yields the desired product with acceptable yield (e.g., see Example 2 (g) below).

Similarly, compounds of formula I wherein X ¹ and X ² are oxazol-2-yl,

The 1H-imidazol-2-yl or thiazol-2-yl contiguous members may be synthesized according to the procedure outlined in the following reaction scheme:

scheme

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

Isolation and purification of the compounds and intermediates described herein can be carried out, if desired, by any suitable separation or purification techniques such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, high-performance liquid chromatography ( HPLC) or a combination of the two. Specific illustrations of suitable separation and isolation techniques may be provided by reference to the examples below. However, other appropriate methods of separation and isolation may of course be used. Nuclear Magnetic Resonance (NMR) spectra were recorded on a General Electric QE Plus spectrometer (300 MHz).

Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR) spectrometer. Analytical HPLC was performed on an ultrafast protein microanalyzer, Michrom BioResources, Ine. with PLRP column fitted, 1 mm χ 15 mm. Preparative HPLC was performed on a Gilson LC using a VYDAC 1 χ 25 cm C ™ Reverse Phase (RP) column or a Vaters Prep LC2000 system using a VYDAC 5 χ 25 cm C ^ RP column. Mass spectra (MS) were obtained on a Finnigan SSQ 710 equipped with an ESI source by direct infusion or by HPLC MS (Ultra-High Speed Microanalyzer, Cie 2mm x 150mm column). Unless otherwise stated, all reagents and equipment were either manufactured according to published procedures or commercially available from Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (St. Louis MO) and INC Chemical Co. (Irvine, CA). Methods used to carry out the syntheses described below will be recognized by those of ordinary skill in the art (see, for example, March, Larock, or Furniss, supra).

Additional methods for preparing the compounds of formula I:

Compounds of formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting a compound of formula I in free base form with a pharmaceutically acceptable inorganic or organic acid. Accordingly, the pharmaceutically acceptable addition salts of the bases of the compounds of the formula I can be obtained by reacting the compounds of the formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of formula I are provided in the references section of the application. Accordingly, the salt forms of the compounds of formula I may be prepared using the salts of the starting materials or intermediates.

The free acids or free bases of the compounds of the formula I may be obtained from the corresponding base addition salts or acid addition salts thereof. For example, the compounds of formula I in the acid addition form may be converted into the corresponding free bases by treatment with an appropriate base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds of formula I in the form of the base addition may be converted to the corresponding free acids by treatment with the appropriate acid (e.g., hydrogen chloride, etc.).

The A / V-oxides of the compounds of the formula I may be obtained by methods known to those skilled in the art. For example, N-oxides can be obtained by treating the unoxidized form of a compound of formula I with an oxidizing agent (e.g., trifluoro-peroxyacetic acid, peroxy-lactic acid, benzenperoxycarboxylic acid, peroxyacetic acid, methachlorperoxybenzoic acid, etc.) in a suitable inert organic solvent such as methylene chloride) at about 0 ° C. Also, the V-oxides of the compounds of formula I may be obtained from the corresponding starting materials / V-oxides.

The compounds of formula I in unoxidized form may be prepared from the compounds of formula I / V-oxides by treatment with a reducing agent (e.g. sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (e.g. ., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 ° C.

Prodrug derivatives of the compounds of the formula I may be prepared by methods known to one of ordinary skill in the art (e.g., see Example 12 below). For more details on prodrugs and how to obtain them, see: Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, 4: 1985).

Blocked derivatives of the compounds of Formula I may be prepared by methods known to one of ordinary skill in the art. A detailed description of procedures for the creation and deprotection of blocking groups can be found in T, W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Ine. 1981.

Compounds of formula I may be synthesized as individual stereoisomers thereof by reacting a racemic mixture of the compound with an optically active cleavage agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. Since the separation of enantiomers can be accomplished using covalent diastereomeric derivatives of the compounds of formula I, preference is given to dissociating complexes (e.g., crystalline diastereoisomeric salts). Diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated due to such differences. The diastereomers may be separated by chromatography or, better still, by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is recovered via the cleavage agent by any practical means that does not result in racemization. Further methods for describing and suitable stereoisomers of compounds from racemic mixtures can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Ine. (1981).

In a general aspect, the present invention provides a process for the preparation of compounds of formula I which comprises:

(a) a compound of formula 1 or a blocked derivative thereof

with a compound of formula 2 or a blocked derivative thereof:

wherein L is a leaving group, D together with the vinylene residue to which it is condensed include monocyclic or fused bicyclic divalent radicals having from 5 to 15 ring atoms, each ring having from 5 to 7 ring atoms and each ring atom being optionally is 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 as defined in the Summary of the Invention, and thereafter, if necessary, deprotection to provide a compound of formula I wherein X ⁴ and X ⁵ are adjacent rings of oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl; or (b) a compound of formula 3 or a blocked derivative thereof:

with a compound of formula 4 or a blocked 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 'Substance of the Invention' section followed by deprotection if necessary to give a compound of Formula I wherein X ¹ and X ² are oxazol-2-yl, 1H-imidazol-2-yl or thiazole. Related members of the -2-yl rings;

(c) optionally further converting a compound of Formula I into a pharmaceutically acceptable salt;

(d) optionally further converting the salt form of the compound of formula I into a non-salt form;

(e) optionally further converting the non-oxidized form of the compound of formula I into a pharmaceutically acceptable N-oxide;

(f) optionally further converting the N-oxide form of the compound of Formula I into an unoxidized form;

(g) optionally further converting the non-derivatized form of the compound of formula I into a pharmaceutical prodrug derivative; and (h) optionally further converting the prodrug derivative of the compound of formula I to its non-derivatized form.

Examples:

The following examples are provided for purposes of illustration only and are in no way intended to limit the scope of the invention. Those skilled in the art will appreciate that some variations and modifications may be made within the scope of the present invention.

EXAMPLE 2-Naft-2-ylethylamine

A solution of 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) under nitrogen was combined with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) and 1.8 mL. -Diazabicyclo [5.4.0] undec-7-enu (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, then saturated sodium bicarbonate, dried (MgSO ₄ ), filtered and concentrated by rotary evaporation. The precipitate was dissolved in THF (5 mL) and the resulting solution was combined with triphenylphosphine (1 g, 3.81 mmol), stirred at room temperature for 2 hours, diluted with water (100 mL), stirred for 3 hours, diluted with concentrated hydrochloric acid (0 33 ml) gives a precipitate which, after treatment with ethanol (5 ml), dissolves the precipitate, followed by slow addition of diethyl ether to give a white precipitate. This white precipitate was titrated, washed with diethyl ether and dried in vacuo to give 2-naphth-2-ylethylamine hydrochloride (0.447 g, 75% yield);

¹ H-NMR (300 MHz, DMSO-d 6): 8.18 (bs, 3H), 7.82-7.88 (m, 3H), 7.74 (s, 1H), 7.38-. 7.48 (m, 3H), 3.07 (m, 4H).

The following intermediate amines were synthesized according to the procedure of Example 1:

2-naphth-1-ylethylamine, yield = 56%; 1 H-NMR (300 MHz, DMSO-d ₆ ): 8.26 (ppm s, 3H), 8.16 (d, 1H, J = 8.1 Hz), 7.92 (dd, 1H, J = 1.5, 7.8 Hz), 7.81 (dd, 1H, J = 1.2, 7.5 Hz), 7.40-7.56 (m, 4H), 3.37 (m, 2H), 3.05 (t, 2H, 3 = 7.4 Hz);

3-cyclohexylpropylamine, yield = 40%; ¹ H-NMR (300 MHz, CDCl 3): 2.68 (t, 2H, J = 7.2 Hz), 2.17 (pi, s, 2H), 1.64-1.71 (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 (bs, 3H), 7.26-7.41 (m, 5H), 6.72 (d, 1H, J = 16, 2Hz), 6.29 (dt, 1H, J = 16.2, 6.6Hz), 3.56 (d, 2H, J = 6.6Hz);

3-phenyl-2-propynylamine, yield = 62%; 1 H-NMR (300 MHz, DMSO-d ₆ ): 8.67 (bs, 2H), 7.38-7.42 (m, 5H), 3.91 (m, 2H); and

3,3-diphenylpropylamine, yield = 50%; ¹ H-NMR (300 MHz, DMSO-d 6): 8.10 (bs, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1H, J = 7.9 Hz), 2.62 (m, 2H), 2.33 (m, 2H).

EXAMPLE

2- (5-Aminomethyl-1,7-benzoimidazol-2-ylmethyl) -N-4-phenylbutyl) -1,7-benzoimidazole-5-carboxamide trifluoroacetate (Compound 1) (a) Ethyl cyanoacetate (8 mL, 75 mmol) anhydrous benzene (100 mL) was combined with anhydrous ethanol (6 mL, 105 mmol) under nitrogen. The mixture was cooled to 10 ° C (ice / acetone) and bubbled with dry hydrogen chloride gas for 20 minutes. The mixture was slowly warmed to room temperature, sealed and stirred for about 18 hours. The mixture was diluted with diethyl ether (400 mL) and left to stand at room temperature for 5 hours to give a crystalline precipitate. The precipitate was filtered off, washed several times with anhydrous diethyl ether and dried to give 3-ethoxy-3-iminoethylpropionate (13.2 g, 90% yield) as a solid 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), 3-ethoxy-3-iminoethylpropionate and glacial acetic acid (15 mL) was stirred under nitrogen at 110 ° C for 30 min. The mixture was poured onto crushed ice (50 mL) and stirred for another 30 minutes to give a dark yellow oil. The mixture was stirred until diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was filtered off, washed several times with diethyl ether and dried in vacuo to give 2-ethoxycarbonylmethyl-1/7-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 12.77 (pi s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7.57 (d, 1H, J = 8.4 Hz), 4.11 (quart, 2H, J = 7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J = 7.1 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) stirred under a nitrogen atmosphere of -10 ° C (ice / acetone) until azodicarboxylate (20.7 mL, 131 mmol) was added dropwise. The mixture was stirred for 2 hours at -10 ° C and then diluted with diethyl ether (900 mL) and kept at -20 ° C for about 18 hours to give a crystalline solid. The material was filtered off and washed to give 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 ): 7.877.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H).

(d) 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (8 g, 24.4 mmol) obtained in Example 1 and 10% palladium on carbon (300 mg) was combined with anhydrous ethanol (200 g) ml), anhydrous THF-nu (100 ml) and glacial acetic acid (30 ml). The mixture was then stirred vigorously for 15 hours at room temperature under a hydrogen atmosphere, filtered and concentrated on a rotary evaporator to a volume of about 30 ml. The mixture was diluted with water (100 mL) and the addition of ammonium hydroxide gave an orange precipitate. The precipitate was filtered off and washed several times with water containing 2- (3,4-diaminobenzyl) isoindole-1,3-dione (6 g, 91% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ); 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H), 4.51 (pi, 4H), 4.47 (s, 2H).

(e) Fine trituration of 2- (3,4-diaminobenzyl) isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1Z7-benzimidazole-5-carboxylic acid (0.93 g,

The mixture (3.75 mmol) was heated at 185 ° C for 1 h under nitrogen. The mixture was suspended in a 1: 1 mixture of methylene chloride / ethanol (200 mL) and stirred vigorously for 1 hour. The resulting solid was filtered, washed with methylene chloride / ethanol 1: 1 (3 x 20 mL) and dried to give 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); ¹ H-NMR (300 MHz, DMSOd ₆ ): 12.45 (pi s, 1H), δ , 07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J = 7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J = 7.2 Hz), 4.82 (s, 2H), 4.48 (s, 2H).

(f) 2- (5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -1,7-benzoimidazole-5-carboxylic acid (0.05 g, 0.111 mmol) was dissolved in anhydrous dimethylformamide (0.5 mL) and the solution was combined under dry nitrogen at room temperature with 1-hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (0.063 g, 0.121 mmol) (0.013 mL, 0.118 mmol) After 2 min add

Of 4-phenylbutylamine (0.02 mL, 0.127 mmol) 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 / ethyl acetate solution (7 mL), and the combined organic layers were washed with 0.2 N HCl (3.5 mL) in saturated aqueous NaCl (3.5 mL), followed by finally washed with saturated aqueous bicarbonate solution (7 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness in a rotary evaporator to give 2- [5 (1,3-dioxo-1,3-dihydro-doloizol-2-ylmethyl) -1H-benzoimidazole. -2-ylmethyl] - N - (3-phenylpropyl) -1,7-benzoimidazole-5-carboxamide as a crude material (0.14 g).

(g) 2- (5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -N- (3-phenylpropyl) -1- 7-Benzoimidazole-5-carboxamide (0.14 g, crude) was dissolved in anhydrous ethanol (0.5 mL) and the resulting solution was combined with anhydrous hydrazine (0.15 mL, 0.48 mmol). The reaction mixture was concentrated in a vacuum (0.2 bar) for 2 hours to remove hydrazine, diluted with 3 M HCl (0.5 mL) and heated at 50 ° C for 20 minutes. The mixture was cooled to room temperature and stirred for a further 20 minutes to give a solid precipitate. The precipitate was filtered off and washed with water (4 χ 1.5 ml). The filtrates were combined and washed with 20% ethanol / ethyl acetate solution (2x7 ml). yields the crude product as the hydrochloride salt. The crude product is purified by preparative reverse phase HPLC gives 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -N- (3-phenylpropyl) -1,7-benzoimidazole-5-carboxamide (O). , 04 g, 0.07 mmol) as a white solid: ¹ H-NMR (300 MHz, CD ₃ OD): 8.14 (s, 1H), 7.84 to 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).

Synthesis according to the procedure of Example 2 gave the following compounds:

2- (5-aminomethyl-1 Hbenzoimidazol-2-ylmethyl) -N-naphth-1-ylmethyl-1 Hbenzoimidazol-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 = 7.9 Hz), 7.67 (d, 1H, J = 7.9 Hz), 7.38-7.54 (m, 5H), 5.01 (s, 2H), 4.26 (s, 2H);

2- (5-Aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N-benzyl-1/7-benzoimidazole-5-carboxamide (Compound 3); ¹ H-NMR (300 MHz, CD ₃ OD): 8.18 (s, 1H), 7.91 (d, 1H, J = 7.9 Hz), 7.82 (s, 1H), 7.76 (d, 1H, J = 7.9), 7.72 (d, 1H, J = 7.9 Hz), 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-1 H -benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1,7-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 , 6Hz), 7.71 (d, 1H, J = 8.6Hz), 7.54 (d, 1H, J = 8.6Hz), 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 ( quintet, 2H, 7.9 Hz);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenylethyl) -1H-benzoimidazole-5-carboxamide (Compound 5); ¹ H-NMR (300 MHz, DMSO-d _s): 8.12 (s, 1H), 7.83 (m, 2H), 7.78 (d, 1H, 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), 2.95 (t, 2H, J = 7.9 Hz);

2- (5-aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N- (3-aminomethyl) benzyl-1 H -benzoimidazole-5-carboxamide (Compound 6); ¹ H-NMR (300 MHz, DMSO-d 6): 9.31 (t, 1H, J = 5.7 Hz), 8.58 (pi, s, 3H), 8.41 (pi, 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-1 N-benzoimidazol-2-ylmethyl) -N- (2-aminoethyl) -1-methyl-1 N-benzoimidazole-5-carboxamide (Compound 7); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.86 (m.s, 1H), 8.50 (ppm s, 3H), 8.24 (s, 1H), 8.08 (ppm) , s, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J = 8.7 Hz), 7.55 (d, 1H, J = 9.2 Hz), 5.02 (pi s, 2H), 4.16 (m, 2H), 3.94 (s, 2H),

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

2- (5-aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N- (2-aminoethyl) -1 H -benzoimidazole-5-carboxamide (Compound 8); ¹ H-NMR (300 MHz, DMSO-d 6): 8.97 (t, 1H, J = 4.3 Hz), 8.58 (pi s, 3H), 8.31 (s, 1H), δ , 16 (pi s, 3H), 7.97 (m, 2H), 7.79 (d, 1H, J = 10 Hz), 7.73 (d, 1H, J = 10 Hz), 7.59 (d, 1H, J = 10Hz), 5.09 (s, 1H),

4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (4-aminobutyl) -1,7-benzoimidazole-5-carboxamide (Compound 9); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.77 (t, 1H, J = 5.7 Hz), 8.61 (ppm 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-1H-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1,7-benzoimidazole-5-carboxamide (Compound 10); ¹ H-NMR (300 MHz, DMSO-d ₆ ):

8.9 (t, 1H, J = 5.0 Hz), 8.53 (pi, 3H), 8.23 (s, 1H), 7.97 (pi, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.78 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8, 6), 7.57 (d, 1H,

J = 8.6 Hz, 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-benzimidazole-5-carboxamide (Compound 11); ¹ H-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 = 7.6 Hz), 4.29 ( s, 2H), 3.26 (d, 2H, J = 7.2 Hz), 1.6430 1.86 (m,

EXAMPLE

2- (5-Aminomethyl-1,7-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole-5-carboxamide (Compound 12) (a) Mixture of 3-nitro -4-Chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine and water (10 mL) in a sealed tube was heated at 100 ° C for 11 h, concentrated to 1 mL and then diluted with concentrated hydrochloric acid to give a yellow precipitate. . The precipitate was separated by filtration, washed with water, then with diethyl ether and dried to give 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 (quartet, 1H, J = 8.6 Hz), 7.94 (dd, 1H, 9.3, 2.1 Hz), 7.00 (d, 1H, J = 9.3 Hz), 2.97 (d, 3H, J = 8.6 Hz).

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

(c) 3-Ethoxy-3-iminoethylpropionate, obtained as in Example 2 (a), under close conditions to Example 2 (b), reacts with 3-aminomethylaminobenzoic acid to give 2-ethoxycarbonylmethyl-1-methyl-1 H / benzoimidazole-5 -carboxylic acid (71% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.18 (dd, 1H, J = 8.1 Hz), 7.11 (d, 1H, J = 1.2 Hz), 6.33 ( d, 1H, J = 8.1 Hz), 5.28 (pi, 1H), 4.67 (pi, 1H), 3.34 (pi, 2H), 2.72 (s) , 3H).

(d) 2- (3,4-Diaminobenzyl) isoindole-1,3-dione, obtained as in Example 2 (d), under conditions close to Example 2 (e), reacts with 2-ethoxycarbonylmethyl-1-methyl-1, 7-benzoimidazole. -5-carboxylic acid to give 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-1H-benzoimidazole-5-carboxylic acid (48% 1 H-NMR (300 MHz, DMSO-d 6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.58 (d, 1H, J = 10, 0 Hz), 7.40 (s, 2H), 7.10 (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) -1,7-benzoimidazol-2-ylmethyl] -1-methyl-1/7-benzoimidazole-5-carboxylic acid (O) , 05 g, 0.108 mmol), 1-hydroxybenzotriazole (0.016 g, 0.118 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and mono-BOC-blocked 1,3-diaminopropane were dissolved at 0 ° C. methylene chloride (1 ml) and DMF-de (in a minimal amount giving a solubility effect). The solution was boiled with N-methylmorpholine to pH about 8, and the mixture was allowed to warm slowly to room temperature and then stirred for 20 hours. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with 0.1 N HCl solution, followed by NaHCO ₃ solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (TLC) (10% methanol / ethyl acetate) to give 2- [6- (1,3-dioxo-1,3-dihydro-isoindol-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 ): 7.75-7.81 (m, 4H) , 7.61-7.68 (m, 3H), 7.33 (s, 1H), 7.27 (d, 1H, J = 8.6 Hz), 7.15 (d, 1H, J) = 9.3 Hz),

5.10 (pi, t, 1H), 4.90 (pi, s, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (quartet, 2H, J = 7.2 Hz), 3.24 (quartet, 2H, J = 7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H).

(f) 2- [6- (1,3-Dioxo-1,3-dihydroisolindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl-N- (3-aminopropyl) The 1H-benzoimidazole-5-carboxamide is deprotected under similar conditions as in Example 2 (g) to give 2- (5-aminomethyl-1, 7-benzoimidazol-2-ylmethyl) - N - (3-aminopropyl) -1-methyl-1H benzoimidazole-5-carboxamide (20% yield); ¹ H-NMR (300 MHz, DMSO-d 6): 8.85 (t, 1H, J = 5.7 Hz), 8.55 (ppm, 3H), 8.20 (s, 1H), δ , 01 (pi 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).

Synthesized as in Example 3, the following compounds of the present invention were obtained: 3- [2- (5-Aminomethyl-1/7-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethyl) -1,7-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 = 7.4 Hz);

2- (5-aminomethyl-1 H -benzoimidazol-2-ylmethyl) - N - (3,3-diphenylpropyl) -1 N -benzoimidazole-5-carboxamide (Compound 14); ¹ H-NMR (300 MHz, CD3OD)

8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J = 9.3), 7.56 (d, 1H, J = 9.3). Hz), 7.237.39 (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 (quartet, 2H, J = 7.2 Hz);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-2-ylethyl) -1,7-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 , 2 Hz);

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), 7.817.84 (m, 2H), 7.74 (d, 1H, J = 8.6 Hz), 7.67 (d, 1H, J = 8.6 Hz), 7.52-7.58 (m, 2H), 7.30 (d, 1H, J = 7.9), 7.01-7.08 (m , 2H), 6.94 (t, 1H, J = 7.9 Hz), 4.26 (s, 2H), 3.68 (t, 2H, J = 6.8 Hz), 3.06 (t , 2H, J = 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, J = 8.2 Hz), 7.69 (d, 1H, J = 8.2 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.20 (d, 1H, J = 8.2 Hz), 7, 07 (m, 2H), 6.70 (dd, 1H, J = 10.0, 2.2 Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3 , 04 (t, 2H, J = 7.2 Hz);

2- (5-aminomethyl-1H-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 = 9.6 Hz), 7.77 (d, 1H, J = 9.6 Hz), 7.61 (d, 1H, J = 9.6 Hz), 4.32 (s, 2H) , 4.01 (m, 1H), 3.62-3.86 (m, 6H), 3.47-3.55 (m, 1H);

• 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenoxyethyl) -1H-benzoimidazole-5-carboxamide (Compound 19); ¹ 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 = 9.3 Hz), 7.23 ( 2H, J = 7.9 Hz), 6.85-6.96 (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); ¹ H-NMR (300 MHz, CD ₃ OD): 8.18 (s, 1H), 7.91 (d, 1H, J = 9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J = 9.3), 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-1 H -benzimidazol-2-ylmethyl) -N- (E-3-phenylallyl) -1 H -benzimidazole-5-carboxamide (Compound 21); ¹ H-NMR (300 MHz, CD ₃ OD): 8.19 (s, 1H), 7.92 (d, 1H, J = 9.3 Hz), 7.86 (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), 7.33-7 , 39 (m, 2H), 7.18-7.30 (m, 3H), 6.60 (d, 1H, J = 15.8 Hz), 6.34 (dt, 1H, J = 15.8 , 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) -1 H -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, 1H), 7.74 (d, 1H, J = 9.3 Hz), 7.69 (d, 1H, J = 9.3 Hz), 7.53 (d, 1H, 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-1A / benzoimidazol-2-ylmethyl) -N-oct-1-yl-1A-benzoimidazole-5-carboxamide (Compound 23); ¹ H-NMR (300 MHz, CD ₃ OD): 8.13 (s, 1H), 7.86 (d, 1H, J = 9.7 Hz), 7.82 (s, 1H), 7.74 (d, 1H, J = 9.7 Hz), 7.69 (d, 1H, J = 9.7 Hz), 7.49 (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-benzimidazole-5-carboxamide (Compound 24); ¹ H-NMR (300 MHz, CD ₃ OD): 7.76 (s), 7.69 (d), 7.63 (d), 7.44-7.55 (m), 7.20-7 , 28 (m), 7.09-7.14 (m), 6.97 (d), 6.85 (pi), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3.08 (s), 2.87 (t), 2.76 (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 = 7.2 Hz).

EXAMPLE

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) THF-not combined under dry nitrogen atmosphere with sodium hydride (0.26 g, 6.5 mmol) in a 60% mineral oil dispersion. The mixture was stirred vigorously for 5 minutes, combined with 3,4-dinitrochlorobenzene (1.3 g, 6.42 mmol) and then stirred at room temperature for 10 hours. The mixture was partitioned between diethyl ether and 3N hydrogen chloride. The aqueous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO ₄ ), filtered and concentrated on a rotary evaporator. 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): 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) 3-Ethoxy-3-iminoethyl propionate obtained as in Example 2 (a) is reacted with 2- (3,4-diaminobenzyl) isoindole-1,3-dione under conditions similar to Example 2 (b) to give 5 - (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1H-benzoimidazol-2-yl-ethyl acetate (71% yield): ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.787.9 (m , 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J = 9.43 Hz), 4.82 (s, 2H), 4.07 (quartet, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J = 7.2 Hz).

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

(d) A mixture of 5- (4-phenylbutoxy) benzene-1,2-diamine (0.06 g, 0.234 mmol) and 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-Benzoimidazole-2-ethyl acetate (0.1 g, 0.234 mmol) was heated at 185 ° C for 1 h under a nitrogen atmosphere. The mixture was suspended in diethyl ether and stirred vigorously for 1 hour. The solid was filtered, washed with diethyl ether and dried to give 2- {2- [5- (446 phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3,7-benzoimidazol-5-ylmethyl} isoindole-1,3-dione (0, 1 g, 0.18 mmol).

(e) 2- {2- [5- (4-Phenylbutoxy) -1,7-benzoimidazol-2-ylmethyl] -3F-benzoimidazol-5-ylmethyl} isoindole-1,3-dione deprotected under conditions similar to 2 ( g) in the example gives C- {2- [5- (4-phenylbutoxy) -1 H -benzoimidazol-2-ylmethyl] -1 H -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, 2H), 3.93 (t, 2H, J = 6.5 Hz), 2.56 (t, 2H, J = 7, 2 Hz), 1.72 (m, 2H).

EXAMPLE

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazole-5-carbamate 2-phenylethyl trifluoroacetate (Compound 27)

2- [5- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -1F-benzoimidazol-2-ylmethyl] -7-benzoimidazole-5-carboxylic acid (0.060 g, 0.133 mmol) in phenethanol (0.160 mL) , 1.34 mmol) was combined with diphenylphosphoryl azide (0.034 mL, 0.158 mmol) and triethylamine (0.22 mL, 0.158 mmol) under nitrogen at room temperature. The mixture was stirred for 1 hour at 120 ° C, cooled to room temperature, and combined with ethanol (0.5 mL) and hydrazine (0.020 mL, 0.637 mmol). The mixture was stirred for 45 minutes at 95 ° C, cooled to room temperature and diluted with 3N hydrochloric acid (0.5 mL). The mixture was stirred at 55 ° C for 20 minutes and then filtered. The filtered solids were washed with 3N hydrochloric acid and combined with the filtrate, washed with ethyl acetate (15 mL) and lyophilized. The residue, purified by preparative reverse phase HPLC, was the desired product (0.008 g, 11% yield); 1 H-NMR (300 MHz, CD ₃ OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 7.63 (d, 1H, J = 9.3 Hz), 7.38-7.44 (m, 2H), 7.19-7.32 (m, 5H), 4.36 (t, 2H, J = 6 , 8 Hz), 4.23 (s, 2H), 1.98 (t, 2H, J = 6.8 Hz).

EXAMPLE

2- (5-Guanidino-1/7-benzoimidazol-2-ylmethyl) -N- (2-naphthalen-1-yl-ethyl) -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 28) (a) A mixture of 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) was stirred at room temperature for 15 minutes, followed by the addition of diethyl ether (1 L) and the resulting precipitate. The precipitate was filtered off, washed with additional ether and dried in vacuo to give 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) heated at 60 ° C. and stirred for 1.5 hours, allowed to cool to room temperature, and then added with excess diethyl ether to precipitate a precipitate. The precipitate was filtered off, washed with additional ether and dried in vacuo to give 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 of N- (4-amino-3-nitrophenyl) guanidine hydrochloride (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL), and methanol (100 mL) hydrogenated at atmospheric pressure, filtered, and concentrated in vacuo to give N - (3,4-diaminophenyl) guanidine hydrochloride (10.3 g, 98% yield) as a dark solid; 1 H-NMR (300 MHz, DMSO):

9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).

(d) A mixture of N- (3,4-diaminophenyl) guanidine hydrochloride (9.9 g, 49 mmol), ethoxycarbonimidoyl acetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL), heated in an oil bath at 110 ° C for 1.5 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol (15 mL), and then ethyl acetate (10 mL) was added to the solution to give a precipitate in suspension. The suspension was filtered and additional ethyl ether was added to the suspension to give a second precipitate. The precipitate was filtered off, washed with additional ethyl ether and dried in vacuo to give

5-guanidino-1H-benzoimidazol-2-yl acetate hydrochloride (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 (quartet), 1.2 (t).

(e) A mixture of 4-nitro-3-methoxybenzoic acid (5.0 g,

25.4 mmol) and aqueous methylamine (40%, 15 mL) in a sealed tube was heated in an oil bath at 100 ° C for 12 hours, allowed to cool to room temperature and then poured into a stirred mixture of 1 M aqueous hydrochloric acid and water. , yields an orange precipitate. The precipitate was filtered off, washed with water and recrystallized from hot ethanol to give 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 (quartet), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).

(f) A mixture of 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxybenzenetriazole hydrate (9.9 g, 73.0) mmol), dimethylformamide (100 mL) and N-methylmorpholine (18.3 mL) were stirred at room temperature for 15 minutes, and then 2-naphthylene-1-ethyl ethylamine (13.8 g,

66.3 mmol). The mixture was stirred for another 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 aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by recrystallization from hot ethanol to give 3-methylamino-N- (2-naphthalen-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 (quartet), 8.1 (d), 7.9 (d), 7 8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (quartet), 3.3 (t), 3.0 (d) .

(g) A mixture of 3-methylamino- N - (2-naphth-1-ylethyl) -4-nitrobenzamide (21.3 g, 61 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL) and methanol (100 mL), hydrogenated under one atmosphere, filtered and concentrated in vacuo to give 4-amino-3-methylamino-N - (2-naphth-1-ylethyl) -4-benzamide (18.4 g, 95% yield) as a colorless amorphous substance; 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 (quartet), 3.2 (t), 2.7 (s).

(h) A mixture of 5-guanidino-1H-benzoimidazol-2-yl-ethyl acetate hydrochloride (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N- (2-naphth-1-yl-ethyl) ) -4-benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 mL), heated in an oil bath at 185 ° C and stirred under nitrogen for 3.5 hours, cooled to room temperature and poured into stirred acetonitrile (150 mL) , yields a precipitate. The precipitate, washed with additional acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo, gave an off-white solid. The material purified by reverse phase preparative HPLC is 2- (5-guanidino-1/7-benzoimidazol-2-ylmethyl) -N- (2-naphthalen-1-ylethyl) -3-methyl-3H-benzoimidazole-5-carboxamide as a white solid. (0.5 g, 57% yield); LRMS (ESI): C 30 H 28 N 8 O. Calculated: 516.6; Found (MH ⁺ ): 517.2.

EXAMPLE

2- (4- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4- oxobutyl) ethyl benzoate (Compound 29) (a) A solution of 2-cyanoethyl propionate (100 g, 0.29 mol) in ethanol (65 mL) was cooled to 0 ° C and then saturated with hydrogen chloride vapor. The mixture was allowed to warm to room temperature, stirred for 24 hours, cooled to 0 ° C again, and saturated with hydrogen chloride vapor. The mixture was allowed to warm to room temperature and stirred for another 24 hours. Addition of ethyl ether: hexane (1: 1) to the mixture gives a precipitate. The precipitate, filtered off and dried in vacuo, is 2- (N -ethoxyamidine) ethyl propionate hydrochloride (119.6 g, 73% yield) as a white solid; ¹ H-NMR (300 MHz, DMSO):

12.5 (pi. S, 2H), 4.50 (quartet, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H).

(b) A mixture of 3,4-diaminopyridine (51.7 g, 0.46 mol), 2- (Netroxyamidine) ethyl propionate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 ml), heated at 85 ° C and stirred for 18 hours and then heated at 120 ° C and stirred for an additional hour. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was neutralized with an excess of 5 M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dried (MgSO ₄ ), filtered and concentrated in vacuo to give 1H-imidazo [4,5c] pyridine-2-ethyl carboxylate (60.4 g, 58%). yield); ¹ H-NMR (300 MHz, CDCl 3): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (quartet, 2H), 3, 90 (quartet, 1H), 1.75 (d, 3H), 1.25 (tr, 3H).

(c) A mixture of 1/7-imidazo [4,5-c] pyridine-2-ethyl carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 mL) and platinum oxide (2.5 g) Hydrogenated in a Parr apparatus at 344.7 kPa for 24 hours, filtered and concentrated in vacuo. The oily residue was dissolved in a minimum amount of ethanol and treated with dry hydrogen chloride in dioxane solution (4 M, 120 mL, 475 mmol). excess ethyl ether was added to this solution to give a precipitate. The precipitate was filtered off, dried in vacuo to give 1,4,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridine-2-ethyl carboxylate dihydrochloride (30.7 g, 66% yield); ¹ H-NMR (300 MHz, DMSO-d 6): 10.00 (pi, 2H), 4.35 (quartet, 1H), 4.20 (pi, 2H), 4.10 (m , 2H), 3.35 (m, 2H), 2.90 (pi, 2H), 1.55 (d, 3H), 1.15 (tr, 3H).

(d) A mixture of 1,4,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridine-2-ethyl carboxylate dihydrochloride (60.2 g, 0.20 mol), acetonitrile ( 500 mL) and diisopropylethylamine (100 mL, 0.60 mol) cooled to 0 ° C and stirred until benzyl chloroformate (58 mL, 0.40 mol) was added slowly. The mixture was allowed to warm slowly to room temperature, stirred for 16 hours, and concentrated in vacuo. The residue was dissolved in ethyl ether (500 mL) and the solution was washed with 0.1 M aqueous hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a colorless oil. The residue was dissolved in ethanol (320 mL), the resulting solution was cooled to 0 ° C, and then a solution of sodium ethoxide in ethanol (2.6 M, 85 mL, 0.22 mol) was added slowly. The mixture was stirred for one hour at 0 ° C and then a solution of hydrogen chloride in dioxane (4 M, 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 and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-benzyl-2-ethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-2,5-dicarboxylate. as a yellow amorphous material (52 g, 72% yield): ¹ H-NMR (300 MHz, DMSO-d ₆ ): 11.75 (ppm, 1H), 7.30 (s, 5H), δ 10 (s, 2H), 4.40 (pi, 2H), 4.05 (m, 2H), 3.75 (quartet, 1H), 3.65 (pi, 2H), 1, 40 (d, 3Η), 1.15 (tr, 3H).

(e) A mixture of 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), tert-butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g, 8.2 mmol), heated at 50 ° C under a dry nitrogen atmosphere for 12 hours, yielding a white suspension. The suspension was partitioned between ethyl ether (250 mL) and water, the organic layer was separated and washed successively with water, followed by 0.1 M aqueous hydrochloric acid, saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to colorless oils. The oil redistilled at a column of 0.5 mm Hg (51 ° C) is tert-butyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); ¹ H-NMR (300 MHz, CDCl 3): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H).

(f) A mixture of ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 mL) and 4-chloro-tert-butyl butyrate (4.08 g, 22.8 mmol), heated at 70 ° C and stirred for 12 h. The mixture was partitioned between ethyl ether (100 mL) and water, the organic layer was separated and washed with water (3 times), then with saturated aqueous sodium chloride, dried over anhydrous magnesium succinate, filtered and concentrated in vacuo to a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane with (10: 1) hexane: ethyl acetate to give 2- (3-irefbutoxycarbonylpropoxy) ethyl benzoate (3.6 g, 62% yield); ¹ H-NMR (300 MHz, CDCl 3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (quartet, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).

(g) 2- (3-tert-Butoxycarbonylpropoxy) ethyl benzoate (3.60 g, 11.7 mmol) was treated with excess trifluoroacetic acid at room temperature for more than one hour. The solution was concentrated in vacuo and the oily residue was purified by silica gel flash chromatography using (10: 1) hexane: ethyl acetate with pure ethyl ether to give 4- (2-ethoxycarbonylphenoxy) butanoic acid as a colorless crystalline solid (2.81 g, 95% yield). ); ¹ H-NMR (300 MHz, CDCl ₃ ): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (quartet, 2H), 4, 15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H).

(h) A mixture of 2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-ethylcarboxylate (1.7 g, 4.8 mmol), N- (3,4-diaminophenyl) guanidine hydrochloride (0.8 g, 4.0 mmol) and dimethylformamide (2 mL) heated in an oil bath at 185 ° C and stirred under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature and poured into stirring acetonitrile (150 mL) to give a precipitate. The precipitate, washed with additional acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo, gave an off-white solid. The material purified by reverse phase preparative HPLC is 2 [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-benzyl carboxylate white solid (1.0 g, 55% yield); LRMS (ESI): C ₂₄ H ₂₆ N ₈ O ₂ . Calculated: 458.5; Found (MH ⁺ ): 459.2.

(i) A mixture of 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -ethyl] -1,4,6,7-tetrahydro-imidazo [4,5-c] pyridine-5-benzylcarboxylate (1, 0 g, 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 mL) and methanol (50 mL), hydrogenated at atmospheric pressure, filtered and concentrated in vacuo to give N- {2- [ 1,4,6,7-Tetrahydroimidazo [4,5-c] pyridyl-2-yl) ethyl] -1-benzoimidazol-5-yl} guanidine (0.69 g, 97% yield); LRMS (ESI): C ₁₆ H ₂₀ N ₈ . Calculated: 324.4; Found (MH ⁺ ): 325.2.

(j) A mixture of 4- (2-ethoxycarbonylphenoxy) butanoic acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenzotriazole hydrate (87 mg, 0.64 mmol), N -methylmorphorpholine (0.16 mL, 0.92 mmol) and dimethylformamide (2.5 mL) were stirred at room temperature for 10 minutes, and then 7- [2- (1,4,6,7-tetrahydroimidazo [4.5]) was added. -c] pyridin-2-yl) ethyl] -1,7-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 HPLC. The pure fractions pooled and lysed are 2- (4- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -1,4,6,75 tetrahydroimidazo [4 , 5-c] pyridin-5-yl} -4-oxobutyl) ethyl benzoate; LRMS (Biolon): C 29 H 34 N 8 O 4. Calculated: 558.6; Found (MH ⁺ ): 559.3.

EXAMPLE

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -31 ° methyl-3 H -benzoimidazole-5-carboxamide (Compound 30) (a) A solution of tert -butyl 2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0 ° C and stirred until diisopropylethylamine (33.8 mL, 193.9 mmol) was first added and followed by the dropwise addition of mesyl chloride (13.7 mL, 177.8 mmol). The mixture was allowed to warm to 23 ° C, stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3 M, 3 χ 25 mL) and saturated aqueous sodium bicarbonate (2 χ 25 mL). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo to give tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield); MS (PB-PCI): C ₈ H ₇ NO ₄ S, m / e. Calculated: 239.08; Found (MH ⁺ ): 240.

(b) Lithium bromide (136 g, 1.56 mol) was dissolved in tetrahydrofuran (600 mL) at 0 ° C. The mixture was allowed to warm to 23 ° C for 18 hours and then 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 to afford fref-butyl 2-bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI): C ₇ H ₁₄ BrNO ₂ , m / e. Calculated: 224.10; Found (MH ⁺ ): 225.

(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 until fref. butyl 2-bromoethylcarbamate (20 g, 89.3 mmol).

The mixture was stirred for 24 h and then poured into ethyl ether: hexane (1: 1, 400 mL) and washed with water (5 x 50 mL). The aqueous layer was extracted with ethyl ether: hexane (1: 1, 3 x 40 mL) and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give tert-butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.22 g, 97%). % yield) as a yellow oil; MS (PB-PCI): C ₁₄ H ₂₁ NO ₄ , m / e. Calculated: 267.32; Found (MH ⁺ ): 268.

(d) tert-Butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 ° C and stirred until a mixture of trifluoroacetic acid: dichloromethane (1: 1, 40 mL) was added. The mixture was allowed to warm to 23 ° C, stirred for 2 hours and concentrated in vacuo. The residue was returned to dichloromethane (100 mL) and the solution was washed with saturated sodium bicarbonate (3 x 20 mL) and aqueous sodium hydroxide (10%, 3 x 20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 2 - (2-methoxyphenoxy) ethylamine (13 g, 88% yield) as a light yellow solid; MS (PB-PCI): C ₉ H 31 NO ₂ , m / e. Calculated: 167.21; Found (MH ⁺ ): 168.

(e) A heterogeneous mixture of 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 mL, 391 mmol) was refluxed for one hour. The excess thionyl chloride was distilled off and the residue concentrated in vacuo to give 3-methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a light yellow solid: MS (PB-PCI): C ₈ H ₆ CINO ₄ , m / e. Calculated: 215.59; Found (MH ⁺ ): 216.

(f) A mixture of 2- (2-methoxyphenoxy) ethylamine (10g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) cooled to 0 ° C, followed by a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to 23 ° C for two hours, quenched with aqueous hydrochloric acid (3 M, 20 mL), washed with water (3 x 20 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give / V- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (14 g, 74% yield) as an off-white solid; MS (PB-PCI):? _{7? 2? 6} , m / e. Calculated: 346.34; Found (MH ⁺ ): 347.

(g) A mixture of N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol) in aqueous methylamine (40%, 10 mL) in a sealed tube. heated at 11 ° C for 4 h, then cooled and poured into water (25 mL). The diluted solution was treated with 3 M aqueous hydrochloric acid to give an orange solid. This solid was filtered off, and was N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI): C 17 H 19 N 3 O 5, m / e. Calculated: 345.35; Found (MH ⁺ ): 346.

(h) Mixture of N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol) suspended in palladium on carbon (10%, 0.5 g) ) in methanol (100 mL) and tetrahydrofuran (50 mL), stirred under nitrogen at normal pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to give 4-amino-N- [2- (2-methoxyphenoxy) ethyl] -3-methylaminobenzamide (3.37 g, 100% yield); MS (PB-PCI) H ₇ Cl ₂ IN ₃ O ₃ m / e. Calculated: 315.37; Found (MH ⁺ ): 316.

(i) A mixture of 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), palladium on carbon (10%, 1.0 g) and methanol (50 mL) hydrogenated in a Parr apparatus 344 , At 7 kPa for 3 hours, filtered through celite and concentrated in vacuo to give 3,4-diaminophenol (4.02 g, 91% yield) as a dark colored solid; MS (PB-PCI): C ₆ H ₈ N ₂ O, m / e. Calculated: 124.16; Rasta (MH ⁺ ); 125.

G) A mixture of 3,4-diaminophenol (3.661 g, 29.5 mmol), 2 - (/ vethoxamidine) ethyl propionate (7.423 g, 38.4 mmol) and ethanol (30 mL) was refluxed for 6 hours. and concentrated in vacuo. The residue, dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (3 x 20 mL) and brine (1 x 20 mL), dried (MgSO ₄ ) and concentrated in vacuo, gave 2- (5-hydroxy-1H benzoimidazol-2-yl) ethyl propionate (6.3 g, 91% yield) as a dark colored solid. This material was purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI): C ₁₂ H ₁₄ N ₂ O ₃ , m / e. Calculated: 234.28; Found (MH ⁺ ): 235.

(k) Mixture containing 2- (5-hydroxy-1β-benzoimidazol-2-yl) ethyl propionate (148 mg, 0.63 mmol), 4-amino-N- [2- (2-methoxyphenoxy) ethyl] -356 methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidone (0.5 mL), stirred at room temperature until homogeneous under nitrogen vacuum degassed and concentrated by heating at 170 ° C for 2 hours. The residue was cooled to room temperature and washed with excess ethyl ether. The resulting amorphous material was taken up in 50% aqueous acetonitrile and purified by reverse phase preparative HPLC (2-50% CH ₃ CN / H ₂ O) to give 2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl). ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (40 mg, 13% yield) as a light pink solid; MS (Biolon): C 27 H 27 N 5 O 4, m / e. Calculated: 485.59; Found (MH ⁺ ): 486.

Synthesized as in Example 8, the following compounds of the invention were obtained:

2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) methyl benzoate (Compound 31); MS (Biolon): C 28 H 26 N 5 O 4 F, m / e. Calculated: 515.54; Found: 516 (MH ⁺ );

2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 32); MS (Biolon): C 27 H 24 N 5 O 4 F, m / e. Calculated: 501.52; Found: 502.1 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 33); MS (Biolon): C 29 H 29 N 5 O 5, m / e. Calculated: 527.58; Found: 528.1 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 34); MS (Biolon): C 27 H 25 N 5 O 5, m / e. Calculated: 499.53; Found: 500.1 (MH ⁺ );

N-ethyl-2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 35); MS (Biolon): C 2 OH 21 N 5 O 2, m / e. Calculated: 363.42; Found: 364.1 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 36); MS (Biolon) C 21 H 23 N 5 O 3, m / e. 393.45; Found: 394.1 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate (Compound 37); MS (Biol) ₃ ιΗ33Ν Ο ₅ Ο _5, m / e. Calculated: 555.64; Found: 555.7 (MH ⁺ );

3- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzimidazol-1-yl} propane-1-sulfonic acid (Compound 38); MS (LGMS): C 30 H 35 N 3 O 6 S, m / e. Calculated: 635.72; Found: 635.4 (MH ⁺ );

N- [2- (2-Ethoxyphenoxy) ethyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 39) ); MS (Biolon): C 28 H 29 N 5 O 4, m / e. Calculated: 499.58; Found: 500.4 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxyphenoxy) ethyl] 3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 40); MS (Biolon): C 29 H 31 N 5 O 4, m / e. Calculated: 513.61; Found: 514.5 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-propoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 41) ; MS (Biol) C29H3iN _{4l 5} O m / e. Calculated: 513.61; Found: 514.2 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 N-benzoimidazol-5-ylcarbonylamino} ethoxy) propyl benzoate (Compound 42): MS (ESI) ): C ₃ H ₃₁ N ₅ 0 ₅ , m / e. Calculated: 541.61; Found: 542.2 (MH ⁺ );

2- (2- (2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) isobutyl benzoate (Compound 43); MS (Biol) θ3ΐΗ 3Ν5θ5 _3, m / e. Calculated: 555.64; found: 556.3 (MH ^+);

4- {2- [1- (5-Hydroxy-1 N-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylaminoethyl butyrate (Compound 44): MS (Biolon): C24H27N5O4, m. / e. Calculated: 449.51; Found: 449.9 (MH ⁺ );

4- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] butanoic acid (Compound 45); MS (Biolon): C 22 H 23 N 5 O 4, m / e. Calculated: 421.46; Found: 422.1 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1,7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) isopropyl benzoate (Compound 46); MS (ESI): C 30 H 31 N 5 O 5, m / e. Calculated: 541.61; Found: 542.2 (MH ⁺ );

N- {2- [2- (1-ethylpropoxy) phenoxy] ethyl} -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 47); MS (Biolon):

C 31 H 35 N ₅ O _4> m / e. Calculated: 541.65; Found: 542.5 (MH ⁺ );

2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3β-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 48); MS (Biolon): C 29 H 28 N 5 O 4 F, m / e. Calculated: 529.57; Found: 529.5 (MH ⁺ );

2- (2- {2- [1 '(5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) -2-methoxyethyl benzoate (Compound 49) ; MS (Biolon): C 30 H 31 N 5 O 6, m / e. Withheld: Withheld: 557.61; Found: 558.2 (MH ⁺ );

N - (3-methoxypropyl) -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 50); MS (Biolon): C 22 H 25 N 5 O 3, m / e. Calculated: 407.47; Found: 408.0 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] 3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 51) ); MS (Biolon): C 29 H ₂₉ N ₅ O ₄ , m / e. Calculated: 499.57; Found: 499.8 (MH ⁺ );

N - [2- (2-Ethoxymethylphenoxy) ethyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] 3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 52) ); MS (Biolon): C 29 H 31 N 5 O 4, m / e. Calculated: 513.60; Found: 514.1 (MH ⁺ );

2- (2- {2- [1- (6-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 53) ); MS (ESI): mass calcd. Calculated: 545.57; Found: 546.3 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) cyclohexanethyl carboxylate (Compound 54); MS (Biolon): C 29 H 35 N 5 O 5, m / e. Calculated: 533.63; Found: 534 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-propoxymethylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 55) ; MS (Biolon): C ₃₀ H ₃₃ N ₅ O ₄ , m / e. Calculated: 527.62; Found: 527.6 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3,7'-benzoimidazole-5-carboxamide (Compound 56); MS (Biolon): C 30 H 33 N 5 O 4, m / e. Calculated: 527.62; Found: 527.9 (MH ⁺ );

2- [1- (5-Hydroxy-1,7-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-3 H -benzoimidazole -5-carboxamide, (compound 57); MS (Biolon): C ₃₀ H ₃₃ N ₅ O ₅ m / e. Calculated: 543.62; Found: 543.4 (MH ⁺ );

2- (1- (1H-Benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 58); MS ( Biol): C 28 H ₂₉ N ₅ O _3l m / e Calcd: 483.57 Found: 484 (MH ⁺ );

N- [2- (2-Ethoxymethyl-phenoxy) -ethyl] -2- [1- (1H-benzoimidazol-2-yl) -ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 59); MS (Biolon): C ₂₉ H ₃₁ N ₅ O ₃ , m / e. Calculated: 497.6; Found: 498.3 (MH ⁺ );

2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-N- (2- (2-propoxymethylphenoxy) ethyl] 3 H -benzoimidazole-5-carboxamide (Compound 60): MS (Biolon) : C ₃₀ H ₃₃ N ₅ O ₃₎ m / e calcd: 511.62; Found: 511.5 (MH ⁺ );

2- [1- (1H-Benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 61): MS (Biolon): C ₃ H ₃₃ N _{50 3} , m / e. Calculated: 511.62; Found: 511.6 (MH ⁺ );

2- [1- (1H-Benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} 3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 62) ; MS (Biol) C ₃ oH ₃₃ N ₅ 0 _4, m / e. Calculated: 527.62; Found: 5277 (MH ⁺ );

2- (1- (5-Hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-morpholin-4-ylphenoxy) ethyl] -3 N -benzoimidazole-5-carboxyl. amide (Compound 63) MS (Biolon): C ₃₀ H ₃₂ N ₆ O _4l m / e Calcd: 540.73; Found: 541.8 (MH ⁺ );

N - (2-Phenylsulfonylethyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 64); MS (Biolon): C ₂₆ H ₂₅ N ₅ O ₄ S, m / e. Calculated: 503.59; Found: 504.2 (MH ⁺ );

2- (2- {2- [1- (6-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy] benzoic acid (Compound 65) MS (ESI): C ₂₇ H ₂₄ N ₅ O ₅ F, m / e Calcd: 517.52 Found: 518.2 (MH ⁺ );

2-Hydroxy-5- {2- [1- (5-hydroxy-1,7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethyl benzoate (Compound 66); MS (Biolon): C ₂₇ H ₂₅ N ₅ O ₅ , m / e. Calculated: 499.52; Found: 500.2 (MH ⁺ );

2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-morpholin-4-ylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide ( Compound 67); MS (Biolon):

CaoHaiNsOaF, m / e. Calculated: 542.62; Found: 543.4 (MH ⁺ );

N - (2-Phenylsulfonylethyl) -2- [1- (5-fluoro-1 H -benzoimidazol-2-yl) ethyl] 3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 68); MS (Biolon): C 26 H 24 N 5 O 3 FS, m / e. Calculated: 505.58; Found: 506.5 (MH ⁺ );

2 - (- 2- (2- (1- (4,6-Difluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (69 MS (Biolon): C 29 H 27 N 5 O 5 F 2, m / e Calcd: 563.52; Found: 563.4 (MH ⁺ );

2- (2- {2- [1- (4,6-Difluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3/9-benzoimidazol-5-ylcarbonylamino) ethoxy) benzoic acid (Compound 70); MS (Biolon): C 27 H 23 N 5 O 5 F 2, m / e. Calculated: 536.51; Found: 563 (MH ⁺ );

2 - (- 2- (2- (1- (4,6-Difluoro-5-imidazol-1-yl-1A) -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 71) MS (Biolon): C 32 H 29 N 7 O 4 F 2, m / e Calcd: 613.62; Found: 614.3 (MH ⁺ );

2- [1- (5-guanidino-1β, 7-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2- [2- (3-methyl [1,2,4] oxadiazol-5-yl) ) phenoxy] ethyl} -3 N-benzoimidazole-5-carboxamide (Compound 72) MS (Biolon): C 30 H 30 N 10 O 3, m / e calcd: 578.63, Found: 579.4 (MH ⁺ ), and

2- [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} -3 H -benzoimidazole-5-carboxamide (Compound 73) MS (Biolon): C 32 H 29 N 9 O 3, m / e calcd: 587.64; Found: 588.2 (MH ⁺ ).

EXAMPLE

2- (2- (2- (1- (5- (1-mininoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl) ethyl) -3 -methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 74) (a) A solution of 3,4-diaminopyridine (51.7 g, 0.46 mol) in acetic acid (400 mL) was heated to 85 ° C, followed by addition of methyl 1-iminodiethyl malonate (125 g, 0.60 mol) in three equal portions over a period of 6 hours, heated at 85 ° C for 12 hours and at 120 ° C for 1 hour, cooled and concentrated under reduced pressure. The residue was cooled to 0 ° C and neutralized with 5N ammonium hydroxide The aqueous layer was extracted several times with ethyl acetate and the combined extracts were washed successively with sodium bicarbonate and sodium chloride, dried (Na 2 SO 4), filtered and concentrated under reduced pressure (2). / 7-Imidazo [4,5-c] pyridin-2-yl) ethyl propionate (60.4 g, 58% yield) as an amber-like solid. 1 H-NMR (300 MHz, CDCl ₃ ), δ, md : 9.00 (s, 1H), 8.35 (d, 1H, J = 9.4 Hz), 7.50 (d, 1H, J = 9.4 Hz), 4.25 (m, 3H) , 1.78 (d, 3H, J = 7.8 Hz), 1.30 (t, 3H, J = 4.7 Hz).

(b) A solution of 2- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl propionate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 mL) was hydrogenated for 2 days at 344.7 kPa. , in the presence of platinum (IV) oxide (5 g). The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0 ° C, treated with 4 M HCl / dioxane, slurried in ether, filtered and dried. Solutions containing a precipitate (15-20 g each) in hydrogenated trifluoroacetic acid (50 ml each) were pressurized for 24 hours at 344.7 kPa in the presence of platinum (IV) oxide (5 g each). The mixtures were filtered off and concentrated under reduced pressure. The residue was azeotropically dried with toluene / ethanol ~ 1: 1, 4 M HCl / dioxane, slurried in ether, filtered and dried in vacuo to give 2- (4,5,6,7-tetrahydroimidazo [4,5c] pyridin-2-yl). ethyl propionate dihydrochloride (61.80 g, 75% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ), δ, md: 10.00 (pi s, 2H), 4.35 (quartet, 1H, J = 7.1 Hz), 4.25 (pi s, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (pi, 2H), 1.60 (d, 3H, J = 7.1 Hz). , 1.20 (t, 3H, J = 6.9 Hz).

(c) 2- (4,5,6,7-Tetrahydroimidazo [4,5-c] pyridin-2-yl) ethyl propionate dihydrochloride (60.2 g, 0.20 mol) in acetonitrile (400 mL) cooled with nitrogen at 0 ° C, treated with N, N-diisopropylethylamine (35 mL, 0.20 mol), then cooled to 550 ° C (ice / acetone) and then treated with benzyl chloroformate in portions for 30 minutes ( 58 mL, 0.41 mol) and N.Ndiisopropylethylamine (70 mL, 0.40 mol). The mixture was cooled to ~ 5 ° C for 1 hour, allowed to warm to 20 ° C, and concentrated under reduced pressure after 16 hours. The residue was suspended in ether and the suspension was washed successively 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 550 ° C under a nitrogen atmosphere, followed by dropwise addition of sodium ethoxide (21 wt%, 85 mL, 0.22 mol) over 1 hour while maintaining the reaction temperature below 0 ° C. The mixture was cooled to 55 ° C for 1 h, boiled to neutral pH with 50 mL of 4 M hydrochloric acid, and 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) to give 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (52 g, 72% yield) as a light yellow solid. in the form of an oil; ¹ H-NMR (300 MHz, DMSO-d 6), δ, md: 11.72 (s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 ( pi. s, 2H), 4.02 (quartet, 2H, J = 9.3 Hz), 3.77 (quartet, 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 of 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 in vacuo, heated at 185 ° C for 4 hours under nitrogen, cooled and combined with equivalent benzene. Addition of ether to the mixture gives a precipitate. The precipitate was filtered off, dried quickly in vacuo and then purified by precipitation from hot ethanol / water. The precipitate was filtered off and dried, yielding 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-3 H -benzoimidazole. -5-carboxylic acid (4.73 g, 58% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ), δ, md: 12.70 (s, 1H), 11.8 (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 (quartet, 1H, J = 5.2 Hz), 4.32 (pi. s, 2H), 3.78 (s, 3H), 3.65 (pi. s, 2H), 2.52 (pi. s, 2H), 1.73 (d, 3H, J = 5.2 Hz).

(e) A mixture of 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3- methyl 3 H - benzoimidazole-5-carboxylic acid (0.75 g, 1.6 mmol), DMF-do (6.5 mL), methyl 2- (2-aminoethoxy) benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) cooled in a nitrogen atmosphere to -40 ° C, treated with EDC (0.32 g, 1.6 mmol) and N, N-diisopropylethylamine (0.29 mL, 1.6 mmol) and after 15 minutes with additional N, N-diisopropylethylamine (0.29 mL) was allowed to warm to 20 ° C and stirred for 16 h. The mixture was then cooled to 40 ° C, treated with additional EDC (0.080 g) and N, N-diisopropylethylamine (0.50 ml), stirred for 15 minutes at -40 ° C and 2 hours at 20 ° C, distilled using a brief distillation. The residue was partitioned between chloroform and sodium bicarbonate, and the organic layer was washed with sodium chloride, 05 M potassium sulfate, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue, purified by silica gel chromatography (CHCl3 / MeOH / AcOH: 95/5/1), contains 2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1Z7-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-benzyl carboxylate (0.69 g, 66% yield) as a vitreous brown foam; ¹ H-NMR (300 MHz, DMSO-d 6), δ, md: 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 (quartet, 1H, J) = 8.8 Hz), 4.30 (s, 2H), 4.20 (t, 1H, 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) 2- (1- {6- [2- (2-Methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5- c] A solution of pyridine-5-benzyl carboxylate (0.69 g, 1.1 mmol) in THF (2 mL) and water (2 mL) was cooled to 0 ° C under 2 N lithium hydroxide (1, 1 mL, 2.2 mmol), allowed to warm to 20 ° C and stirred for 8 hours. The mixture was then cooled to 0 ° C, treated with additional 2N lithium hydroxide (1.1 mL), allowed to warm to 20 ° C, stirred for 6 hours, cooled to 0 ° C, boiled in 1M hydrochloric acid and concentrated. under reduced pressure. The residue was carefully washed with cold sodium chloride and water and then dried in vacuo to give 5όβηζί ^ 3ίΚ3 ^ οηιΊ-2- {2- {3-Γηθ {ίΙ-2- [1- (4,5,6,74θΐΓ3ΐ ^ Γθ-). 1/7-benzo [4,5-d] [1,2,4] ethyl] -3H-benzoimidazol-5-ylcarbonylamino} -ethoxy) -benzoic acid (0.56 g, 83% yield) as a vitreous precipitate; ¹ H-NMR (300 MHz, DMSO-d 6), δ, md: 11.87 (pi s, 1H), 9.74 (s, 1H), 8.45 (s, 1H), 7.84 ( d, 1H, J = 9.7 Hz), 7.56 (d, 1H, J = 9.7 Hz), 7.42 (d, 1H J = 7.7 Hz), 7.32 (s) , 5H), 7.23 (t, 1H, J = 7.7 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.90 (t, 1H, J = 7.7 Hz), 5.08 (s, 2H), 4.63 (quartet, 1H, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 2.55 ( s, 2H), 1.71 (d, 3H, J = 7.7 Hz).

(g) 5-Benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1 Himidazo [4,5-c] pyridin-2-yl) ethyl] A solution of -3W-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.561 g, 0 90 mmol) in glacial acetic acid (2 mL) was heated under nitrogen in a water bath to 10 ° C then treated with hydrogen bromide in acetic acid (2 mL of 30 mL). and left to warm to 20 ° C for one hour, concentrated in a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the resulting solution was added dropwise to a stirred ether to give a brown precipitate. The precipitate was filtered off and dried to give 2- (2- (3-methyl-2 - [(4 _I, 5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -37 / -benzoimidazol-5ilkarbonilamino} -ethoxy) -benzoic acid hydrobromide (0.651 g); ¹ H-NMR (300 MHz, DMSO-d ₆₎ δ, ppm: 9.31 (br. s, 2H), 8.63 (m, 1H) 8.24 (s, 1H), 7.79 (d, 1H, J = 7.9 Hz), 7.63 (m, 2H), 7.47 (t, 1H, J = 7, 9Hz), 7.21 (d, 1H, J = 7.9Hz), 7.00 (t, 1H, J = 7.9Hz), 5.21 (quartet, 1H, J = 6.3Hz) ), 4.29 (s, 2H), 4.21 (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).

(h) 2- (2- {3-Methyl-2 - [(4,5,6,7-tetrahydro-1 H -imidazol-4,5-c] pyridin-2-yl) ethyl] -3 H -benzoimidazol-5-ylcarbonylamino} Ethoxy) benzoic acid hydrobromide (0.30 g, 0.46 mmol) in DMF (1.5 mL) was cooled with nitrogen to 0 ° C, treated with ethyl acetimidate (0.12 g, 0.92 mmol) and N Of Ndiisopropyl-ethylamine (0.25 mL, 1.4 mmol), cooled to 0 ° C for 30 minutes and then allowed to warm to 20 ° C, stirred for 20 hours. The mixture was then cooled again to 0 ° C, treated with additional ethyl acetimidate (0.06 g) and N, N-diisopropyl-ethylamine (0.16 ml), allowed to warm to 20 ° C and stirred for 2 hours. The mixture was cooled to 0 ° C, treated with additional ethyl acetate imidate (0.03 g), allowed to warm to 20 ° C and stirred for 2 hours, and the resulting mixture was added dropwise to the stirred ether * to give a precipitate. The precipitate was separated by solvent decantation and dried in vacuo. The residue was precipitated from ethanol / ether and purified by reverse phase preparative HPLC: 2 50% MeCN / H ₂ O (20 mL HCl) over 50 min. The lyophilized fractions give 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl). ethyl] -3α-benzoimidazol-5-ylcarbonylamino} ethoxy) -benzoic acid (0.145 g, 52% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ), δ, md: 9.77 (s, 2H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s) , 1H), 7.89 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz) ), 7.60 (d, 1H, 3 = 7.7 Hz), 7.49 (t, 1H, J = 7.7 Hz), 7.21 (d, 1H, 3 = 7.7 Hz), 6.99 (t, 1H, J = 7.7Hz), 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): C 29 H 31 N 7 O 4, m / e. Calculated: 529.61; Found: 530.3 (MH ⁺ ).

EXAMPLE

2- (2- {2- [1- (4,6,7-Trifluoro-1/7-imidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazole-5-carbonylamino] ethoxy} ethyl benzoate ( Compound 75) (a) A solution of 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) in ammonia / dioxane (Aldrich, 0.5 M, 7.5 mmol) stirred at room temperature for 3 hours The mixture is diluted with an equal volume of water to dissolve the white precipitate to give yellow crystals The crystals, separated and dried, yield 2,3,5-trifluoro-6-nitroaniline (307 mg, 51% yield) as yellow needles. mp 66 ° C; ¹ H-NMR (CDCl ₃ ), δ: 6.4 (m, 1H), 6.0 (s, 2H).

(b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol, hydrogenated overnight at atmospheric pressure, filtered under nitrogen, gives 1.2 -diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a purple solid; MS (M ⁺ ):

162.7, +41 +82 (+ ACN, + 2ACN). Calculated 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), 2-ethoxycarbonimidoethyl propionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml), heated under reflux until no further reaction was observed by thin layer chromatography, 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 2- (4,6,7trifluoro-1 H -benzoimidazole) ethyl propionate (1.37 g, 42% yield). in the form of a yellowish-brown crystalline substance; ¹ H-NMR (CDCl ₃ ), δ: 10.35 (s, 1 / 2H), 7.05 (s, 1 / 2H), 6.7 (m, 1H), 4.25 (dd, 2H) , 4.15 (dd, 1H), 1.73 (d, 3H), 1.31 (t, 3H); M ⁺ : 272.9; Calculated for C12H11F3N2O2: 272.23.

(d) 2- (4,6,7-Trifluoro-1 H -benzoimidazole) ethyl propionate (988 mg, 3.63 mmol) combined with 2- [2- (4-amino-3-methylaminobenzoylamino) ethoxy] benzoate (1) , 3 g, 3.63 mmol) and placed in vacuo for 4 hours and then combined with

DMPU (4 mL). The mixture was stirred until it became a solution, then held overnight under a deep vacuum to remove the residual gas, then heated at 195 ° C under 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 (step gradient 100% hexane to 100% ethyl acetate) and then crystallized from MeOH / THF / water to give 2- (2- {2 - ([1- (4,6,7-trifluoro) -1,7-Benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazole-5-carbonylamino} ethoxy) ethyl benzene (1.0 g, 49% yield) as a white crystalline solid; (CDCl ₃ ), δ: 6.84-8.07 (m, 8H), 4.93 (dd, 1H), 4.34 (dd, 2H), 4.27 (m, 2H), 3.95 (m, 2H), 3.9 (s, 3H), 1.93 (d, 3H), 1.78 (s, 2H), 1.38 (t, 3H), LCMS M ⁺ : 566.2; Biolon M ⁺ : 565.7 Calc'd: C29H26F3N5O4: 565.55.

Synthesized according to the procedure of Example 10, the following compounds of the invention were obtained:

2- (2- (2 - ((1- (5,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 76); MS (Biolon) m / e for C29H27N5O4F2 Calc'd: 547.56 Found: 548.1 (MH ⁺ );

2- (2- (2 - ((1- (4,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (77 MS (LCMS) m / e calcd for C 29 H 27 N ₅ O ₄ F 2: 547.56 Found: 548.3 (MH ⁺ );

2- (2- (2 - ((1- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (78 MS (LCMS) m / e calcd for C 29 H 26 N 5 O 4 F 3: 565.55; Found: 566.2 (MH ⁺ );

2- (2- {2 - ([1- (4,6,7-trifluoro-1 H -benzoimidazol-2-ylmethyl] -3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 79); MS (LCMS), m / e calcd for C ₂₈ H ₂₈ N ₅ O ₄ F ₃ : 551.52; Found: 551.2 (MH ⁺ ).

EXAMPLE

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

Mixture of 2- (2- (2 - ((1- (4.6 _L 7-trifluoro-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) ethyl benzoate (118 mg, 0.21 mmol), methanol (4 mL) and 2 N sodium hydroxide (2.1 mL), stirred at room temperature for 4 hours, neutralized with 2 N hydrochloric acid (2.1 mL) and partitioned between ethyl acetate and Saturated ammonium chloride The aqueous layer was separated and extracted with ethyl acetate (3 times) The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to a white solid The residue was dissolved in warm ethanol (10 mL) and 4M hydrogen chloride / dioxane solution. diluted with ethyl ether to give a precipitate, which was separated and dried to give 2- (2- (2 - ((1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3 / - / - benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid as a white solid, MS (LCMS) m / e for C ₂₇ H ₂ N ₅ O ₄ F ₃ : Calc'd: 537.50; Found: 538.4 (MH ⁺ ).

Synthesized according to the procedure of Example 11, the following compounds of the invention were obtained:

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) m / e calcd for C 11 H 11 N 5 ClF 3 O: 519.51; Found: 520.2 (MH +);

2- (2- {2 - ([1- (4,6-Difluoro-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 82) MS (LCMS) m / e: C 27 H 23 N 5 O 4 F 2 Calc'd: 519.51 Found: 520.2 (MH ⁺ ) and

2- (2- {2 - ([1- (4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl] -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 83); MS (Biolon), m C27H22N5O4F3 Calc'd: 537.5 Found: 537.7 (MH ⁺ ).

EXAMPLE

2- (2- {2 - ([1- (1-Isobutyryl-5-methoxycarbonyloxy-7 H -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl Benzoate (Compound 84)

Mixture of 2- (2- {2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazole-5-carbonylamino} ethoxy) ethyl benzoate ( 0.50 g, 0.95 mmol), dimethylformamide (5 mL), cesium carbonate (0.93 g, 2.85 mmol) and isobutanoic anhydride (0.17 mL, 1.05 mmol) were stirred for 2 hours, followed by it was diluted with dichloromethane (50 mL) and passed through a celite filter. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5. mL). The solution was combined with diisopropylethylamine (0.47 mL, 2.7 mmol) and methylene chloroformate (0.1 mL, 1.3 mmol), and the resulting mixture was stirred for 1 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography eluting with ethanol and dichloromethane to give 2- (2- {2 - ([1- (1-isobutyryl-5-methoxycarbonyloxy-7 H- benzoimidazol-2-yl) ethyl)] -methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (0.20 g, 32% yield) as a colorless amorphous material, MS (Biolon), m / e C35H37N5O8: Calculated: 655.72; Found: : 656.1 (MH ⁺ ).

Synthesized according to the procedure of Example 12, the following prodrugs of the invention were obtained:

2- (1- {6- [2- (2-Ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-hydroxybenzoimidazol-1-methyl carboxylate (Compound 85); MS (ESI)

C31H31N5O7, m / e. Calculated: 585.62; Found: 586.2 (MH ⁺ );

2- (1- {6- [2- (2-Ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1 H -benzoimidazol-2-yl} ethyl) -5-methoxycarbonyloxybenzoimidazol-1-ethyl carboxylate (Compound 86); MS (ESI): C 33 H 33 N 5 O 7, m / e. Calculated: 643.66; Found: 644.2 (MH ⁺ );

2- (2- {2- [1- (5-Hydroxy-1-isobutyryl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,710-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate ( Compound 87); MS (ESI):

C33H35N5O6, m / e. Calculated: 597.68; Found: 598.2 (MH ⁺ );

2- (2- {2- [1- (1-Benzoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (88 Compound): MS (ESI): C 36 H 33 N 5 O 6, m / e. Calculated: 631.69; Found: 632.3 (MH ⁺ );

2- (2- {2- [1- (1-Dimethylcarbamoyl-5-hydroxy-1?, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy} ethyl benzoate (Compound 89): MS (ESI): C 32 H 34 N 6 O 6, m / e. Calculated: 598.66; Found: 599.3 (MH ⁺ );

2- (2- {2- [1- (1-Acetoxymethyl-5-hydroxy-1?, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate ( Compound 90), MS (Biolon): C 32 H 33 N 5 O 7, m / e. Calculated: 599.65; Found: 600.7 (MH ⁺ );

2- [2- (2- {1- [1- (2,2-Dimethylpropionyloxymethyl) -5-hydroxy-1H-benzoimidazol-2-yl] ethyl} -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy ] -ethyl benzoate (Compound 91); MS (ESI): C 35 H 39 N 5 O 7, m / e. Calculated: 641.74; Found: 642.3 (MH ⁺ );

2- (2- {2- [1- (1-Isobutyl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -325-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 92) ; MS (Biolon): C 35 H 37 N 5 O 8, m / e. Calculated: 655.72; Found: 656.1 (MH ⁺ );

5-Ethoxycarbonyloxy-2- (1- {6- [2- (2-ethoxycarbonyl-phenoxy) -ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} -ethyl) -benzoimidazole-1-ethyl-carboxylate (Compound 93): MS ( ESI): C 35 H 37 N 5 O 9, m / e. Calculated: 671.72; Found: 672.4 (MH ⁺ );

2- (1- {6- [2- (2-Ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-isopropoxycarbonyloxybenzoimidazole-1-isopropyl carboxylate (Compound 94); MS (ESI): C 37 H 41 N 5 O 9, m / e. Calculated: 699.79; Found: 700.4 (MH ⁺ ); and

2- (2- {2- [1- (1-Acetyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 95) ); MS (ESI): C 31 H 31 N 5 O 6, m / e. Calculated: 569.62; Found: 570.1 (MH ⁺ ).

When synthesized as described in this application or by methods known to those skilled in the art, the following additional compounds of the invention were obtained:

C- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3,7-benzoimidazol-5-yl] methylamine (Compound 96);

C- [2- (1H-naphtho [2,3-d] imidazol-2-ylmethyl) -1,7-benzoimidazol-5-yl] methylamine (Compound 97): MS (Biolon): C20H17N5, m / e. Calculated: 327.4; Found: 328.1 (MH ⁺ );

C- [2- (5-Methyl-1β-benzoimidazol-2-ylmethyl) -1,7-benzoimidazol-5-yl] methylamine (Compound 98); MS (Biolon): C ₁₇ H ₁₇ N ₅ , m / e. Calculated: 291.4; Found:

292.3 (MH ⁺ );

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

3- [2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -1 H -benzoimidazole-5-ylcarbonylamino] propionic acid (Compound 100); 1 H-NMR (300 MHz, CD ₃ OD): 1.92 (m, 2H, J = 7.2Hz), 2.38 (t, 2H, J = 7.2, Hz), 3.47 (t , 2H, J = 7.2 Hz), 4.30 (s, 2H), 7.54 (d, 1H, J = 10.0 Hz), 7.69 (d, 1H, J = 8.6 Hz) ), 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-naphth-1-ylethyl) -1,7-benzoimidazole-5-carboxamide (Compound 101); ¹ H-NMR (300 MHz, CD ₃ OD): 3.42 (t, 2H, J = 7.5 Hz), 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) -3,7-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-yl-propionic acid (Compound 104); ¹ H-NMR (300 MHz, CD ₃ OD): 3.36 (dd, 1H, J = 14.6, 8.1 Hz), 3.53 (dd, 1H, J = 14.6, 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, 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 substituted);

(R) -2- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-yl-propionic acid (Compound 105); ¹ H-NMR (300MHz,

CD ₃ OD): 3.35 (dd, 1H, J = 14.5, 8.1 Hz), 3.51 (dd, 1H, J = 14.4, 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 substituted);

2- (1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-yl-ethyl) -1H-benzoimidazole-520-carboxamide (Compound 106); ¹ H-NMR (300 MHz, CD ₃ OD): 3.42 (t, 2H, J = 7.4 Hz), 3.76 (t, 2H, J = 7.4 Hz), 3.97 (s , 3H), 7.38-7.60 (m, 5H), 7.65 (d, 1H, J = 8.7Hz), 7.72-7.79 (m, 4H), 7.85 ( dd, 1H, J = 8.6, 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 (Biolon): C 22 H 27 N 7 O 1, m / e.

Calculated: 405.4; Found: 406.5 (MH ⁺ );

2- [1- (5-Aminomethyl-1H-benzoimidazol-2-yl) -ethyl] -3-methyl- N - (2-naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 108); MS (Biol) ₃₀ C ₃ N ₆ iH Oh, m / e. Calculated: 502.6; Found: 503.3 (MH ⁺ );

2- (1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-ethyl-ethyl) -3,7-benzoimidazole-5-carboxamide (Compound 109); MS (Biolon): C 24 H 34 N 5 O 2 m / e.

Calculated: 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 (Biolon): C ₃₀ H 26 N ₆ O ₂ , m / e. Calculated: 502.6; Found: 503.6 (MH ⁺ );

2- (5-Carbamoyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-yl-ethyl) -1H-benzoimidazole-5-carboxamide (Compound 111);

2- (5-Aminomethyl-4,5,6,7-tetrahydro-1 H -benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (112 compound); 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, 9.3 Hz), 2.76 (m, 2H), 2.90 (dd, 1H, J = 15.7, 7.5 Hz), 3.05 (d, 2H, J = 6 , 9Hz), 3.41 (t, 2H, J = 7.4Hz), 3.75 (t, 2H, J = 7.4Hz), 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, 1.2 Hz), 7.99 (d, 1H, J = 0.9 Hz), 8.26 (d, 1H, J = 8.4 Hz);

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, 2Hz), 4.01 (s, 3H), 4.29 (s, 2H), 7.12-7.17 (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 = 1H);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-phenoxyethyl) -3,7-benzoimidazole-5-carboxamide (Compound 114); ¹ H-NMR (300 MHz, CD ₃ OD): 3.80 (t, 2H, J = 5.0 Hz), 3.99 (s, 3H), 4.17 (t, 2H, J = 5, 0Hz), 4.27 (s, 2H), 6.88 (t, 1H, J = 7.5Hz), 6.92 (d, 2H, J = 7.5Hz), 7.22 (t, 2H) , J = 7.5 Hz), 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 [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphthyl) 1-yl-3H-benzoimidazole-5-carboxamide (Compound 115); ¹ 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 [4,5-c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1) -ethyl) -3H-benzoimidazole-5-carboxamide (Compound 116); 1 H-NMR (300 MHz, CD ₃ OD): 2.45 (2.43, s, 3H), 3.03 (m, 2H), 3.41 (t, 2H, J = 7.4 Hz). , 3.74 (t, 2H, J = 7.4 Hz), 3.97 (m, 2H), 4.18 (4.18, s, 3H), 4.66 (4.80, s, 2H) ),

7.38- 7.54 (m, 4H), 7.72-7.92 (m, 4H), 8.04 (s, 1H), 8.26 (d, 1H, J = 7.8 Hz);

2- (5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3α-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), 7.39-7.52 (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, 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, 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 [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-phenoxyethyl) -3H Benzoimidazole-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 = 5.6 Hz). , 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 = 7.3 Hz), 6.93 (d, 2H, J = 8.6 Hz), 7.23 (dd, 2H, J = 8.6, 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 [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-benzo [1, 3] dioxol-4-ylethyl) -3 H -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), 6.656.74 (m , 3H), 7.64 (d, 1H, J = 7.8 Hz), 7.76-7.79 (m, 1H), 8.06 (m, 1H);

2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-17 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (benzoimidazol-1-yl ethyl) ) -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), 3.95-4.01 (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, 2.2 Hz), 7.93 (s, 1H), 7.98 (dd, J = 6.5, 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-1 H -imidazo [4, 5-c] pyridin-2-ylmethyl] -3-methyl-3β-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, 1H, J = 8.5, 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, 1H, J = 8.4, 1.2 Hz), 7.87 ( d, 1H, J = 1.2 Hz);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2 -chlorophenoxy) ethyl] -3W-benzoimidazole-5-carboxamide (Compound 123); MS (Biolon): C 26 H 28 N 7 O 2 Cl, m / e calcd: 506.0; Found: 506.3 (MH ⁺ );

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (3-chlorophenoxy) ) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 124) MS (Biolon): C26H28N7O2Cl, m / e Calcd: 506.0 Found: 506.7 (MH ⁺ );

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphth-1 ethyl) -3,7-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 , 90-4.05 (m, 7H), 4.76 (4.76, s, 2H), 6.64 (6.66, s, partially substituted), 7.457.95 (m, 9H), 8, 02 (m, partially substituted), 8.17 (d, 1H, J = 8.1 Hz), 8.96 (s, partially substituted);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-hydroxy- 2-naphth-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, 1H, J = 13.6, 8.3 Hz), 3.91-3.99 (m, 6H), 4.70 (4.80, s, 2H), 5.78 (dd, 1H, J = 8.3, 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 = 8.4Hz);

2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2-hydroxynaphthyl) -1-yl) ethyl] -3,7-benzoimidazole-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). ), 7.11 (d, 1H, J = 8.7 Hz), 7.21 (t, 1H, J = 7.5 Hz), 7.38 (dt, 1H, J = 1.2, 7, 6Hz), 7.50-7.61 (m, 2H), 7.69-7.75 (m, 2H), 7.93 (s, 1H), 8.07 (d, 1H, J = 8 , 4 Hz);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (4-hydroxynaphthalene) -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, 2H), 6.72 (d, 1H, J = 7.8 Hz), 7.17 (d, 1H, J = 7.5 Hz), 7.37 (t, 1H, J = 7.5 Hz), 7.46 (dt, 1H, J = 0.9, 6.9 Hz), 7.62 (d, 1H, J = 8.5 Hz), 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] -3 N-benzoimidazole-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-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N-naphth-2-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, 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-pyrid-4-ylpropyl) ) -3,7-Benzoimidazole-5-carboxamide (Compound 131); 1 H-NMR (300 MHz, CD ₃ OD): 2.11 (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, 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 (Biolon): C ₃₂ H ₃₂ N ₈ O ₃ , m / e. Calculated: 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, 8.5 Hz), 4.61 (dd, 1H, J = 14.9, 3.2 Hz), 7.36-7.52 (m , 4H), 7.66-7.85 (m, 4H), 8.14 (s, 1H), 8.25 (d, 1H, J = 7.8 Hz);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (4-methoxyphenoxy) ethyl] -3,7-benzoimidazole-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) -3,7-benzoimidazole-5-carboxamide (134 compound); MS (Biolon): C 32 H 30 N 7 O 4, m / e. Calculated: 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, 3.5 Hz), 7.34-7 , 51 (m, 5H), 7.617.65 (m, 2H), 7.72-7.86 (m, 4H), 8.05 (d, 1H, J = 1.2Hz), 8.25 (d , 1H, J = 8.1 Hz);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo (4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (1 , 2,3,4-Tetrahydronaphth-1-yl) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 135), ¹ H-NMR (300 MHz, CD ₃ OD): 1.69-2.11 (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), 7.15-7, 18 (m, 1H), 7.67 (d, 1H, J = 8.7 Hz), 7.827.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1β-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2- (3-methoxyphenoxy) ) ethyl] -3,7-benzoimidazole-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), 6.46-6.54 (m, 3H), 7.12 (t, 1H, J = 8, 0 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.83 (m, 1H), 8.12 (m, 1H, J = 1.2 Hz);

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

2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphthylethyl) -3,7-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, 2H, J = 7.1 Hz), 7.32 (dd, 1H, J = 8.6, 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), 8.11 (s , 1H), 8.28 (d, 1H, J = 8.1 Hz);

2- (5-Guanidino-1/7-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3,7-benzoimidazole-5-carboxamide (Compound 139 '); MS (Biolon): C ₂₉ H ₃₂ N ₈ O ₅ , m / e. Calculated: 572.62; Found: 573.3 (MH ⁺ ); ¹ H-NMR (300 MHz, CD ₃ OD): 3.58-3.69 (m, 2H), 3.80 (m, 5H), 4.07 (m, 1H), 4.17 (t, 2H, J = 5.3 Hz), 4.47 (dd, 1H, J = 15.0, 8.4 Hz), 4.64 dd, 1H, J = 15.0, 3.0 Hz), 6 , 66-7.00 (m, 4H), 7.38 (dd, 1H, J = 8.6, 1.7 Hz), 7.66 (d, 1H, 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, 1.5 Hz), δ , 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) -3,7-benzoimidazole- 5-Carboxamide (Compound 140); MS (Biolon): C 33 H 34 N 8 O 3, m / e. Calculated: 590.7; Found: 591.3 (MH ⁺ );

2- (5-Guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) - [7 - [2- (2-methoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 141) ; MS (Biolon): C ₂₉ H ₃₀ N ₈ O 6, m / e. Calculated: 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 = 5.4Hz), 4.38 (t, 1H, J = 12.0Hz), 4.57 (dd, 1H, J = 12.0, 3.5Hz), 6.85 -7.00 (m, 4H), 7.30 (dd, 1H, J = 8.7, 2.2 Hz), 7.60 (d, 1H, J = 2.2 Hz), 7.64 (d) , 1H, J = 8.4 Hz), 7.74 (d, 1H, J = 8.7 Hz), 7.80 (dd, 1H, J = 8.4.1.5 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] -3H-benzoimidazole- 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, 8, 7Hz), 4.62-4.66 (m 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H, J = 8.7, 1.2 x 25Hz) , 7.68 (d, 1H, J = 8.4 Hz), 7.77-7.80 (m, 2H), 7.84 (dd, 1H, J = 8.4, 1.4 Hz), 8.21 (d, 1H, J = 1.4 Hz);

2- {2- [2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] ethoxy} methyl benzoate (Compound 143); MS (Biolon): C ₂₈ H ₂₈ N ₈ O ₄ , m / e. Calculated: 54.56; Found: 541.4 (MH ⁺ );

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

3 - {- 2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] ethoxy} methyl benzoate (Compound 145); MS (Biol) ϋ 8Η _{2 28 3} Ν Ο _4, m / e. Calculated: 540.5; Found: 541.4 (MH ⁺ );

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - [2- (2,6-.

dimethoxy) phenoxyethyl] -3,7-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, 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, 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 (147 compound); ¹ H-NMR (300 MHz, CD ₃ OD): 3.57-3.69 (m, 2H), 3.80 (m, 5H), 4.05 (m, 1H), 4.17 (t , 2H, J = 5.4Hz), 4.45 (dd, 1H, J = 15.0, 8.7Hz), 4.58-4.65 (m, 3H), 6.85-7, 00 (m, 4H), 7.50 (dd, 1H, J = 8.7, 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, 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] -3,7-benzoimidazol-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, 8.7 Hz), 4.64 (dd, 1H, J = 15.0) ,

3.0 Hz), 4.69 (4.73, s, 2H), 6.86-7.01 (m, 4H), 7.51 (dd, 1H, J = 8.1, 1.5 Hz) ), 7.69 (d, 1H, J = 8.6 Hz), 7.76-7.79 (m, 2H), 7.84 (dd, 1H, J = 8.6, 1.3 Hz) , 7.96 (8.12, s, 1H), 8.21 (d, 1H, J = 1.3 Hz);

2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (2-hydroxy-2-quinol-4-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 149); ¹ H-NMR (300 MHz,

CD3OD): 3.60 (dd, 1H, J = 13.8, 7.5 Hz), 3.97-4.06 (m, 4H), 5.99 (dd, 1H, J = 7.5, 3.6 Hz), 7.35 (dd, 1H, J = 8.7, 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, 1.5 Hz), 7.99 (m, 1H), 8.11-8.18 (m, 2H), 8.26 (d, 1H, J = 8.4Hz), 8.33 (d, 1H, J = 5.7Hz), 8.88 (d, 1H, J = 8.7 Hz), 8.15 (d, 1H, J = 5.7 Hz);

2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-methyl-2,4-dioxoquinazolin-1-yl) ethyl] -3,7-benzoimidazol-5-one. carboxamide (compound 150); MS (Biolon): C ₂₉ H ₂₈ N ₁₀ O ₃ , m / e. Calculated: 564.6; Found: 565.5 (MH ⁺ );

2- {2- [2- (5-Guanidino-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino] -ethoxy} methyl-benzoate (Compound 151); MS (Biol) ₂ Ο ₃ Ο 8Η26Ν _5, m / e. Calculated: 554.5; Found: 554.8 (MH ⁺ );

2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl- N - (2-naphthylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 152) ); ¹ H-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, 1.8 Hz), 7.40-7 , 54 (m, 4H), 7.61 (d, 1H, 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] -3/7 Benzoimidazole-5-carboxamide (Compound 153);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2-hydroxyethyl) -N- (2-naphth-2-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 154); ¹ H-NMR (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, 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-1 H -benzoimidazol-2-ylcarbonyl) -3-methyl- N - (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 155);

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

2- (5-Imidazol-1-yl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 157);

2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 158); MS (Biol) C _{3 3} oN iH _s Oh, m / e. Calculated: 530.6; Found: 531.1 (MH ⁺ );

2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N - (2-naphth-1-yl) -3,7-benzoimidazol-5 -carboxamide (compound 159); MS (Biolon): C 33 H 29 N 7 O 1, m / e. Excluded; 539.6; Found: 540.1 (MH ⁺ );

2- {1- [5- (2-Amino-imidazol-1-yl) -1H-benzoimidazol-2-yl] -ethyl} -3-methyl-N- (2-naphth-5-yl-ethyl) -3H-benzoimidazol-5-one. -carboxamide (compound 160); MS (Biolon):

C33H30NaO1, m / e. Calculated: 554.7; Found: 555.2 (MH ⁺ );

1- (5-guanidino-1/7-benzoimidazol-2-yl) -3-hydroxy-1-methyl-N- (2-naphth-1-yl-ethyl) 3,4-dihydro-1 / 7-2- oxa-4a, 9-diazafluorene-6-carboxamide (Compound 161);

2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (4-hydroxybutyl) -N- (2-naphth-110-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 162) ); MS (Biolon):

C34H36N8O2, m / e. Calculated: 588.7; Found: 589.3 (MH ⁺ );

3- [2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-yl-ethylcarbamoyl) -benzoimidazol-1-yl] -propane-1-sulfonic acid (Compound 163) ): MS (Biolon): C 33 H 34 N 8 O 4 S, m / e. Calculated: 638.7; Found: 639.2 (MH ⁺ );

3- [2- [1- (5-Imidazol-1-yl-17H-benzoimidazol-2-yl) -ethyl] -6- (2-naphthylethyl-ethylcarbamoyl) -benzoimidazol-1-yl] -propane-1-sulfonic acid ( Compound 164): MS (Biolon): C 35 H 33 N 7 O 4 S, m / e. Calculated: 647.8; Found: 648.2 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -2-methylpropyl] -3-methyl-N- (2-naphth-1-yl-ethyl) -3 / 7- benzoimidazole-5-carboxamide (compound 165); MS (Biolon):

C33H34N8O1, m / e. Calculated: 558.7; Found: 559.6 (MH ⁺ );

2- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-N- (2-naphth-1-yl) -3,7-benzoimidazole-5 -carboxamide (compound 166); MS (Biolon): C 29 H 26 N 6 O 1, m / e. Calculated: 474.6; Found: 475.2 (MH ⁺ );

2- {5- [1- (N-Methylimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-225-ylmethyl} -3-methyl-N- (2-naphth-1-ethyl) -3,7-benzoimidazole-5-carboxamide (Compound 167); MS (Biolon): C 31 H 33 N 7 O, m / e. Calculated: 519.71; Found: 520.9 (MH), imino (2- {1- [1-methyl-6- (2-naphth-1-yl-ethylcarbamoyl) -1,7-benzoimidazol-2-yl] ethyl} 1,4,6 , 7-tetrahydroimidazo [4,5-c] pyridin-5-yl) acetic acid (Compound 168); MS (Biolon): C 31 H 31 N 7 O 3, m / e. Calculated: 549.6; Found: 550.2 (MH ⁺ );

2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 169); MS (Biolon); C31H33N7O1, m / e. Calculated: 519.6; Found; 520.3 (MH ⁺ );

2- {1- [5 - (N-methylamidino) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-N - ( 2-naphth-1-ylethyl) -3W-benzoimidazole-5-carboxamide (Compound 170); MS (Biolon); C31H34N8O1, m / e. Calculated: 534.7; Found: 535.1 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1β, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) -5-methoxybenzoic acid (Compound 171); MS (Biolon): C 29 H 30 N 8 O 5, m / e. Calculated: 570.6; Found: 571.2 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 172) ; MS (Biolon): C 29 H 30 N 8 O 5, m / e. Calculated: 570.6; Found: 571.3 (MH ⁺ );

2- (2- {2- [1- (5-Guanidino-1/7-benzoimidazol-2-yl) -1-hydroxyethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) -6-methoxybenzoic acid (Compound 173); MS (Biolon): C 29 H 30 N 8 O 6, m / e. Calculated: 586.6; Found: 587.2 (MH ⁺ );

2- [2- (2- {1- [5 - (N-acetylguanidino) -1 N-benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] ethyl benzoate (174 compound); MS (Biolon); C31H32N8O5, m / e. Calculated: 596.6; Found: 597.2 (MH ⁺ );

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

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

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

2- [2- (2- {1- [5 - (N-acetylguanidino) -1,7-benzoimidazol-2-yl] ethyl} -3-methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 178) ); MS (Biolon): C 30 H 30 N 8 O 5, m / e. Calculated: 582.6; Found: 583.3 (MH ⁺ );

2- [2- (2- {1- [5- (1-Aminocyclopropyl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 179) ); MS (Biolon): C 30 H 30 N 6 O 4, m / e. 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 (Biolon): C 26 H 29 N 7 O 1, m / e Calcd: 455.6; Found: 456.2 (MH ⁺ );

2- (1H-Benzoimidazol-2-ylethyl) -3-methyl- N - (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 181); MS (Biolon): C 26 H 25 N 5 O 2, m / e. Calculated: 439.5; Found: 440.2 (MH ⁺ );

2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl) -3-methyl) -3 H - benzoimidazol-5-ylcarbonylamino) ethoxy] ethyl benzoate (Compound 182);

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 183);

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

N-ethyl-2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 185); MS (Biolon): C 23 H 23 N 7 O 1, m / e. Calculated: 413.5; Found: 414.1 (MH ⁺ );

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 186); MS (Biolon): C 24 H 25 N 7 O 2, m / e. Calculated: 443.5; Found: 444.2 (MH ⁺ );

- (2- (1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) -4-methylpentanoic acid (Compound 187) MS (Biolon): C 27 H 29 N 7 O 3, m / e Calcd: 499.6, Found: 500.3 (MH ⁺ );

2- (2- (2- (1- (5-imidazol-1-yl-1 H, 7-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 188); MS (Biolon): C 30 H 27 N 7 O 4, m / e calcd: 549.6, Found: 550.2 (MH ⁺ );

2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 N -imidazo [4,5-c] pyridin-2-yl] ethyl) 3-methyl- 3 - [(benzoimidazol-5-ylcarbonylamino) -4-methylpentanoic acid (Compound 189);

2- {1- [5 - (N, N-dimethylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl -3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 190); MS (Biolon): C 39 H 34 N 8 O 4, m / e. Calculated: 558.6; Found: 559.3 (MH ⁺ );

2- [2- (2- {1- [5- (2-Carboxy-1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl) ] ethyl} -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 191); MS (Biolon): C 29 H 31 N 7 O 6, m / e. Calculated: 573.6; Found: 530.3 (MH ⁺ ), with loss of CO ₂ ;

2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) 3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 192); MS (Biol) ₃₁ C 2 H ₃ N7O5 m / e. Calculated: 593.6; Found: 594.2 (MH ⁺ );

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -N- (2-methoxyethyl) -3,7-benzoimidazol-5 -carboxamide (compound 193); MS (Biolon): C 26 H 29 N 7 O 3, m / e. 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) -3,7-benzoimidazol-5-ylcarbonylamino) ethoxybenzoic acid (Compound 194);

3- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 185); MS (Biolon): C 28 H 28 N 8 O 4, m / e. 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 (Biolon): C 30 H 32 N 8 O 5, m / e. Calculated: 584.6; Found: 585.3 (MH ⁺ );

2- (2- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 197) ; MS (Biolon): C 30 H 32 N 8 O 7 S, m / e. Calculated: 648.7; Found: 649.6 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (compound 198); MS (Biolon): C 32 H 31 N 7 O 7 S, m / e. Calculated: 657.7; Found: 658.4 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-3-methyl-3,7-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy ) benzoic acid (compound 199); MS (Biolon): C 31 H 29 N 7 O 4, m / e. Calculated: 563.6; Found: 564.2 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid ( Compound 200);

MS (Biolon): C 32 H 31 N 7 O 5, m / e. Calculated: 593.6; Found: 594.3 (MH ⁺ );

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

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 202); MS (Biolon): C 30 H 32 N 8 O 4, m / e. Calculated: 568.6; Found: 569.5 (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-Tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] ethyl benzoate (Compound 203); MS (Biolon): C 28 H 36 N 8 O 4, m / e. Calculated: 549.0; Found: 548.2 (MH ⁺ );

4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethyl butyrate (Compound 204); MS (Biolon): C 25 H 30 N 8 O 3, m / e. 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] -3,7-benzoimidazol-5 -carboxamide (compound 205); MS (Biolon): C 28 H 28 N 12 O 2, m / e. Calculated: 564.56; Found: 565.3 (MH ⁺ );

2- [2- (2- {1- [5- (1-iminoethylamino) -1,7-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 206) ; MS (Biolon): C ₃₁ H ₃₃ N ₇ O ₄ , m / e. Calculated: 567.6; Found: 568.4 (MH ⁺ );

4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 207); MS (Biolon): C 30 H 32 N 8 O 4, m / e. Calculated: 568.6; Found: 569.4 (MH ⁺ );

5- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 208); MS (Biolon): C 29 H 28 N 8 O 6, m / e. Calculated: 584.6; Found: 585.3 (MH ⁺ );

4- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 209); MS (Biolon): C ₂₈ H ₂₈ N ₈ O ₄ , m / e. Calculated: 540.6; Found: 541.2 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 210);

MS (Biolon): C ₃₀ H ₃₂ N ₈ O ₅ , m / e. Calculated: 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 (211 compound); MS (Biolon): C ₃₀ H ₂₉ N ₇ O ₂ , m / e. Calculated: 535.6; Found: 536.3 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 212); MS (Biolon): C ₂₇ H ₂₆ N ₈ O ₄ , m / e. Calculated: 526.6; Found: 527.2 (MH ⁺ );

2- [1- (5-Imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-phenoxyethyl) -3,7-benzoimidazole-5-carboxamide (Compound 213) ); MS (Biolon): C ₂₉ H ₂₇ N ₇ O ₂ , m / e. Calculated: 505.6; Found: 506.2 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,7-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 214); MS (Biolon): C ₂₉ H ₂₅ N ₇ O ₄ , m / e. Calculated: 535.6; Found: 536.4 (MH ⁺ );

2- (2- {2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino} ethoxy) -4-methylethylbenzoate (Compound 215) ); MS (Biol) ₃₄ Ν 03ΐΗ ₈ 04 m / e. Calculated: 582.7; Found: 583.5 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-benzoimidazol-5-ylcarbonylamino} -ethoxy) -4-methyl-benzoic acid (Compound 216); MS (Biolon): C ₂₉ H ₃₀ N ₈ O ₄ , m / e. 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-Tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 217); MS (ESI): C ₂₆ H ₃₂ N ₈ O ₄ , m / e. Calculated: 520.58; Found: 521.3 (MH ⁺ );

2- (2- {2- [5- (N-Methylamidino) -1,7-benzoimidazol-2-ylmethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 218); MS (Biol) C3oH iN _{7 3} 0 _4, m / e. Calculated: 553.6; Found: 554.3 (MH ⁺ );

2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} -3- (3-sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] 86 benzoic acid (Compound 219): MS (Biolon): C30H35N7O7, m / e. Calculated: 637.7; Found: 638.3 (MH ⁺ );

2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl) 3-methyl -3 H -benzoimidazol-5-ylcarbonylamino) -4-ethylmethyl valerate (Compound 220):

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

2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 222): MS (Biolon ): C27H27N5O3, m / e.

Calculated: 469.5; Found: 469.5 (MH ⁺ );

2- (2-Ethoxycarbonylphenoxy) ethyl 2- [1- (6-guanidino-1H-benzoimidazol-2-yl) ethyl] 1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate ( Compound 223): MS (Biolon): C ₂₈ H 32 N ₈ O _5l m / e. Calculated: 560.62; Found: 561.3 (MH ⁺ );

4- (2- (1- (5-guanidino-1A-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-15-ylcarbonylamino} butanoic acid (Compound 224): MS (Biolon): C23H26N8O3, m / e Calculated: 462.52 Found: 462.8 (MH ⁺ );

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) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 225); MS (ESI): C 28 H 31 N 11 O 2, m / e calcd: 553.6; Found: 553.5 (MH ⁺ ). ;

2- (2- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl) -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isopropyl benzoate (Compound 226) MS (Biolon): C33H33N7O4, m / e Calcd: 591.3; Found: 591.4 (MH ⁺ );

2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N - [ 2- (3-Tetrazolylphenoxy) ethyl] -3 N-benzoimidazole-5-carboxamide (Compound 227): MS (Biolon): C 28 H 31 NHO 2, m / e calcd: 553.59; Found: 553.5 (MH ⁺ );

2- (1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl-N- [ 2- (4-Tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 228); MS (ESI): C ₂₈ H ₃₁ N ₆ O ₂ , m / e calcd: 553.59; Found: 553.5 (MH ^+). );

2- (2- {2- [1- (5-imidazol-1-yl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) cyclohexylethoxybenzoate (Compound 229); MS (ESI): C 36 H 37 N 7 O 4, m / e. Calculated: 631.3; Found: 631.5 (MH ⁺ );

2- [2- (2- {1- [5 - (N-methylamidino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3F / 5 benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (230 compound); MS (Biolon): C 28 H 27 N 7 O 4, m / e. Calculated: 525.6; Found: 525.5 (MH ⁺ );

2- [2- (2- {1- [5- (1-iminoethylamino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 231) ); MS (Biolon): C 29 H 29 N 7 O 4, m / e. 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): C 27 H 30 N 8 O 4, m / e. Calculated: 530.60; Found: 531.7 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,715 tetrahydroimidazo [4,5-c] pyridin-5-ylformyloxy} ethoxy) benzoic acid (compound 233 '); MS (Biolon): C 26 H 28 N 8 O 5, m / e. Calculated: 532.56; Found: 533.2 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) -2 -methoxyethyl benzoate (compound 234);

MS (Biolon): C 33 H 33 N 7 O 5, m / e. Calculated: 607.3; Found: 607.4 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 N / benzoimidazol-5-ylcarbonylamino} ethoxy) isobutyl benzoate (235 compound); MS (Biolon): C 34 H 35 N 7 O 4, m / e. Calculated: 605.3; Found: 605.4 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H25 benzoimidazol-5-ylcarbonylamino} ethoxy) -2- (2- methoxyethoxy) ethyl benzoate (Compound 236); MS (Biolon): C 35 H 37 N 7 O 6, m / e. Calculated: 651.3; Found: 651.3 (MH ⁺ );

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate ( Compound 237); MS (Biol) H35N ₇ 3 ₄ O _4, m / e. Calculated: 605.3; Found: 605.4 (MH ⁺ );

2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3H Benzoimidazole-5-carboxamide (Compound 238); MS (Biolon); C28H26N6O3, m / e. 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] -3 H -benzoimidazole-5-carboxamide (Compound 240);

2- (1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-isopropoxyphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 241); MS (Biolon): C29H31N5O3, m / e Calc'd: 497.2 Found: 497.6 (MH ⁺ );

2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-N- (2- (2-methylphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 242); MS (Biolon): 027 ^ 7 ^ 02, m / e Calc'd: 453.2 Found: 453.5 (MH ⁺ );

2- (1- (1 H -benzoimidazol-2-yl) ethyl] -3-methyl-N - [2- (2-ethoxyphenoxy) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 243); MS (Biolon): C 28 H 29 N 5 O 3, m / e Calcd: 483.2 Found: 483.5 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 244); MS (Biolon): C 28 H 30 N 8 O 3, m / e. Calculated: 526.6; Found: 526.8 (MH ⁺ );

2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 245) MS (Biolon): C 28 H 33 N 9 O 4, m / e calcd: 559.6; Found: 559.6 (MH ⁺ );

2- (2- (2- (1- (1A) -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) -2-methoxyethyl benzoate (Compound 246); Biol): C ₃₀ H ₃₁ N ₅ O ₄₎ m / e calcd: 541.6 Found: 541.5 (MH ⁺ );

2- (2- (2- (1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 247); MS (Biolon) : C 29 H ₃₀ N ₈ O ₄ , m / e calcd: 554.6; Found: 555.4 (MH ⁺ );

2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 248); MS (Biolon ): C 25 H 25 N 2 Cl 2, m / e Calcd: 540.6 Found: 541.3 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -S-methyl-5 H -benzoimidazole-5-carboxamide (Compound 249) ; MS (Biolon):

C28H29N9O3, m / e. Calculated: 539.6; Found: 540.5 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 250); MS (Biolon): C 28 H 28 N ₈ O ₃ Cl, m / e. 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): C 28 H ₂₇ N ₈ O ₄ Cl, m / e. Calculated: 575.0; Found: 575.2 (MH ⁺ );

5-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 252); MS (Biolon): Ο ₂₈ Η ₂₇ Ν ₈ Ο ₄ 0., M / e. Calculated: 575.0; Found; 575.2 (MH ⁺ );

6-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 253); MS (Biolon): C ₂₈ H ₂₇ NaO ₄ Cl, m / e. Calculated: 575.0; Found: 575.2 (MH ⁺ );

4,6-Dichloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 254) ; MS (Biolon): Ο 28 ₈ Η ₂ 6Ν ₈ Ο ₄ ΟΙ ₂ , m / e. Calculated: 609.5; Found: 609.1 (MH ⁺ );

2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carbonylamino} ethoxy) ethyl benzoate (Compound 255); MS (Biol) ₂ C 9 H ₂₉ N5O _4, m / e. Calculated: 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 (Biol) ₃₄ C ₄ H ₃ 0 ₀ ONI Si m / e. Calculated: 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-quinazoline-1] -yl-ethyl} -3H-benzoimidazole-5-carboxamide (Compound 257); MS (Biolon): C ₂₉ H ₂₈ N ₁₀ O ₃ , m / e. Calculated: 564.6; Found: 565.2 (MH ⁺ );

2- [1- (1H-Benzoimidazol-2-yl) ethyl] -N- [2- (2-cyanophenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 258); MS (Biol) ₂ C ₆ H _2l 7H24N m / e. Calculated: 454.5; Found: 465.1 (MH ⁺ );

5- (2- {2- [1- (1/7-Benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 259); MS (Biolon): C 26 H 25 N 5 O 6, m / e. Calculated: 527.5; Found: 528.4 (MH ⁺ );

2- (2- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) -2- (2-methoxyethoxy) ethyl benzoate (260 compound); MS (Biolon): C 32 H 35 N 5 O 6, m / e. Calculated: 585.7; Found: 585.4 (MH ⁺ );

2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyrid-5-ylcarbonylamino} ethoxy ) benzoic acid (compound 261); MS (Biolon): C 29 H 29 N 9 O 4, m / e. Calculated: 531.6; Found: 531.5 (MH ⁺ );

2- [1- (1/7-imidazo [4, _5-a] pyridin-2-yl) ethyl] - / V- [2- (2-methoxyphenoxy) ethyl] -3-metil3H-benzoimidazol-5-carboxamide (Compound 262); MS (Biolon): C 26 H ₂₆ N ₆ O ₃₎ m / e. Calculated: 470.54; Found: 471.4 (MH ⁺ );

2- [1- (5-Fluoro-1/7-benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 263) ); MS (Biolon): C 27 H 26 N 5 O 3 F, m / e. Calculated: 487.54; Found: 488.1 (MH ⁺ );

2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-tetrazol-1-yl-ethyl) -3W-benzoimidazole-5-carboxamide (Compound 264) ); MS (ESI): C 24 H 23 NHO, m / e. Calculated: 481.47; Found: 482.6 (MH ⁺ );

2- [1- (4-Hydroxy-1 H -benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 265) ); MS (Biol) C27H27N _{4l 5} O m / e. Calculated: 485.59; Found: 486.3 (MH ⁺ );

2- [1- (4-Aminobenzoxazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 266); MS (Biol) ₂ C ₅ H ₄ 7H27N, m / e. Calculated: 485.59; Found: 486.1 (MH ⁺ );

3- {2- [1- (1H-Benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] -benzoimidazol-1-yl} -propane-1-sulfonic acid (Compound 267), MS (Biolon) : C ₂₉ H ₃ iN ₅ O ₆ S, m / e. 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-1-sulfonic acid ( Compound 268); MS (Biolon): C 32 H 33 N 7 O 6 S, m / e. Calculated: 643.72; Found: 644.6 (MH ⁺ );

2- [2- (2- {1- [1- (2-methoxyethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3,7-benzoimidazole-5-carbonylamino) ethoxy] ethyl benzoate (269 compound); MS (Biolon): C 32 H 35 N 5 O 5, m / e. Calculated: 569.66; Found: 570.5 (MH ⁺ );

2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-benzyl carboxylate (Compound 270) ; MS (Biolon): C 29 H 30 N 3 O 6, m / e. Calculated: 586.6; Found: 587.2 (MH ⁺ );

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

1- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin5-yl} -4- (2-methoxyphenoxy) butane- 1-one (compound 272);

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

N - [3- (2-Ethoxyphenyl) propyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide (Compound 274). ); MS (Biolon): C 29 H 31 N 5 O 3, m / e. Calculated: 497.62; Found: 497.4 (MH ⁺ );

N- [3- (2-Butoxyphenyl) propyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 275); MS (Biolon): C 31 H 35 N 5 O 3, m / e. Calculated: 525.65; Found: 526.3 (MH ⁺ );

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [3- (2-propoxyphenyl) propyl] -3 H -benzpimidazole-5-carboxamide (Compound 276) ); MS (Biolon): C ₃₀ H 33 N ₅ O ₃ / _l m / e. Calculated: 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-3 N-benzoimidazole-5-carboxamide (Compound 277); MS (Biolon): C 29 H 27 N 7 O 4, m / e. Calculated: 538.1; Found: 537.58 (MH ⁺ );

2- (2- {2- [1- (4-Fluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (Compound 278); MS (ESI):

C29H28N5O5, m / e. Calculated: 545.57; Found: 545.6 (MH ⁺ );

2- (2- {2- [1- (4-Fluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 279); MS (Biolon): C ₂₇ H ₂₄ N ₅ O ₅ F, m / e. Calculated: 517.52; Found: 517.4 (MH ⁺ );

2- (2- {2- [1- (6-Fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (280 compound); MS (Biolon): C 29 H 28 N 5 O 5 F, m / e. Calculated: 545.57; Found: 545.9 (MH ⁺ );

2- (2- {2- [1- (6-Fluoro-4-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 280); MS (Biolon): C 27 H 24 N 5 O 5 F, m / e. Calculated: 517.52; Found: 517.6 (MH ⁺ );

2- (2- {2- [1- (4,5-Difluoro-7-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) ethyl benzoate (281 compound); MS (Biolon): C 29 H 27 N 5 O 5 F 2, m / e. Calculated: 563.56; Found: 563.9 (MH ⁺ ); and

2- (2- {2- [1- (4,5-Difluoro-7-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 282); MS (ESI): C 29 H 27 N 5 O 5 F 2, m / e. Calculated: 536.1; Found: 535.51 (MH ⁺ ).

EXAMPLE

In vitro studies of tryptase inhibition

Tryptase solution (60 g / ml) was prepared by dissolving tryptase purified from human lung or skin tissue samples or human stem cell line (HMC-1) or commercially available, e.g., ICN Biomedicals, Irvine, California; Athens Research & Technology, Athens, Georgia, et al., In a solvent mixture of 10 mM 2-N-morpholinoethanesulfonic acid, 2 mM CaCl ₂ , 20% glycerol and 50 g / ml heparin. Substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys-para-nitroanilide) obtained from Sigma. Compounds solutions were prepared by diluting ten times the stock solution (1 mg test compound / 200 μils dimethylsulfoxide (DMSO)) in assay buffer (containing: Tris-HCl (pH 8.2), mM; NaCl, 100 mM; 0.05% polyoxyethylene sorbitan monolauroate (Tween20®); and zinc chloride, 150 μΜ) followed by seven additional triplicate dilutions in 10% DMSO assay buffer.

Portions of the sample (50 μΙ) from the eighth dilution of each test compound were added to separate wells of a 96-well U-bottom microtiter plate. Tryptase solution (25 μΙ) was added to each well and the solutions were stirred at room temperature for 1 hour. A substrate solution (25 μΙ) was added to initiate the enzymatic reaction and the microtiter plate was immediately transferred to a UV / MAX kinetic microplate reader (molecular instrument). The hydrolysis of the chromogenic substrate was performed spectrophotometrically at 405 nanometers for 5 minutes. Initial velocity values were subtracted from progressive curves by kinetic analysis programs (BatchKr, Peter Kuzmic, University of Wisconsin, Madison, Wl). The putative inhibition constants (Κ;) were subtracted from the enzymatic reaction curves using standard mathematical models.

Using the methods described herein or by methods known to those of skill in the art, the following compounds of the invention have been tested for their tryptase inhibitory activity:

compound, Kj = 0.09 μΜ; Compound 12, Kj = 29 μΜ; Compound 26, K, = 33 μΜ; Compound 27, Kj = 0.6 μΜ; Compound 28, K, = 0.00007 μΜ; Compound 29, K = 0.0008 μΜ; Compound 30, K = 0.009 μΜ; Compound 37, Kj = 0.002 μΜ; Compound 42, Kj = 0.008 μΜ; Compound 43, Kj = 0.002 μΜ; Compound 74, K = 0.006 μΜ; Compound 75, K = 0.03 μΜ; Compound 80, K = 0.01 μΜ; Compound 81, Kj = 0.01 μΜ; Compound 84, Kj = 2.6 μΜ; Compound 102, Kj = 0.00007 μΜ; Compound 112, Kj = 0.00005 μΜ; Compound 115, Kj = 0.003 μΜ; Compound 116, Kj = 0.006 μΜ; Compound 117, K = 0.008 μΜ; Compound 126, K, = 0.008 μΜ; Compound 127, Kj = 0.006 μΜ; Compound 128, K, = 0.002 μΜ; Compound 169, K = 0.001 μΜ; Compound 132, Kj = 0.00002 μΜ; Compound 134, Kj = 0.00002 μΜ; Compound 138, K = 0.0002 μΜ; Compound 152, Kj = 0.0005 μΜ; Compound 182, K = 0.004 μΜ; Compound 194, Kj = 0.009 μΜ; Compound 203, K = 0.008 μΜ; Compound 225,

Kj - 0.008 μΜ; Compound 249, K, = 0.0007 μΜ; Compound 250, K, = 0.0004 μΜ; Compound 251, K, = 0.0008 μΜ; and compound 252, K = 0.0004 μΜ.

EXAMPLE Sheep Asthma Model

The allergic sheep asthma model was used to evaluate the compounds of the invention as anti-asthmatic compounds in vivo. These methods have been previously published (see, Abraham et al., (1983), Am. Rev. Respir. Dis., 128: 839-844; Allegra et al., (1983), J. Appl. Physiol., 55). : 726-730; Russi et al., (1985), J. Appl. Physiol., 59: 14161422; Soler et al., (1989), J. Appl. Physiol., 67: 406-413). Each sheep served only its own test. These animals weighed between 20 and 50 kilograms.

In these studies, 1 mg of Compound 13 was dissolved in 3 ml of distilled water and the whole solution was presented as an aerosol 0.5 hours before, 4 hours and 24 hours after antigen challenge (total dose = 1 mg; n = 3). The results of this experiment are summarized in Figure 1.

24 hours after antigen challenge in both cases for both control and drug testing, sheep developed increased airway reactivity. The increased airway reactivity is expressed as PC400, i. i.e., the concentration of carbachol which causes a 400% increase in SRL; therefore, a decrease in PC400 indicates increased reactivity. Compound 13 was found to block the resulting increased reactivity. As shown in Figure 2, this compound maintains PC400 at a baseline value of 15 inhalation units. In animals in the control group, the inspiratory units drop to 7. Thus, treatment with compound 13 results in a significant improvement in airway function in the antigen-treated sheep.

Thus, the present invention provides compounds and compositions useful for the protection or treatment of immune-mediated inflammatory disorders, and in particular those associated with the respiratory tract, including asthma, and the reactive phase associated with chronic asthma, an additive, and allergic rhinitis. The present invention also provides for the treatment of immuno-mediated inflammatory disorders which are treated with the compounds of the present invention.

It should be understood that the above description is illustrative and not limiting. Many embodiments for those skilled in the art may be apparent from the description above. Therefore, the scope of the invention is not to be construed as embracing the references given in the description, but must be defined within the scope of the disclosure, including all equivalents in the specification.

Claims (26)

DEFINITION OF INVENTION 1. A compound of formula I: R 'where: n1 is 0 or 1; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; A together with B forms a fused heterobicyclic radical containing from 8 to 12 ring atoms, each ring having from 5 to 7 ring members, each ring atom being optionally a heteroatom, X ¹ and X ² being adjacent ring members of the aromatic ring and X ¹ is a heteroatom residue selected from -N =, NR ⁵ -, -O- and -S- wherein R ⁵ is hydrogen, (C 6 -C 6) alkyl or hetero (C ₂ -C 6) alkyl; C forms a fused heteropolycyclic radical having from 8 to 18 ring members, each ring having from 5 to 7 ring members, each atom being optionally a heteroatom, X ⁴ and X ⁵ being adjacent members of the aromatic ring, X ⁵ being the residue of a heteroatom selected of -N =, -NR ⁶ -, -O-, and -S-, wherein R ⁶ is hydrogen, a group selected from (Ci- ₈₎ alkyl or hetero (C _{2nd 12)} alkyl, are optionally substituted with one or two substituents independently selected from (Ci. ₆₎ alkanoyloxy, (Ci. ₆₎ alkylamino, di (Ci- ₆₎ alkylamino, tri (Ci. ₆₎ alkylammonium (Ci ^) alkylcarbamoyl, di (Ci- ₆₎ alkylcarbamoyl (Ci. ₆₎ alkyloxy, (C ^ alkyloxycarbonyl, (C? alkiloksisulfonilo, amino, carboxy, carbamoyl, (C ₆ i ₄₎ aryl, halogen, hetero (C5-i ₄₎ aryl, hydroxy and sulfo group, or and any of their carbocyclic ketone, thioketone and iminoketone derivatives; X ³ is -O-, -S-, -S (O) -, -S (O) 2 -, -C (O) -, -NR ⁷ - or -CR ⁷ R ⁸ - wherein R ⁷ is hydrogen (Cvejalkilas, hetero (C2.i ₂₎ alkyl, or together with R ⁶ form a (C _2-4) alkylene or hetero (C 2-4) alkylene and R ⁸ is hydrogen, (Oi.6) alkyl or hydroxy, or together with R ⁷ forms a (C 2-6) alkylene or a (C 1-6 alkylidene) in which any aliphatic or alicyclic residue containing R ⁷ and / or R ^{8 is} optionally substituted with one to three substituents selected from (C 1-4 alkylamino) diC 1-4 alkylamino, tri (Ci-6) alkylammonium (Ci-6) alkyloxy, (C ^ alkyloxycarbonyl, (Ci-C 6) alkanoyloxy, amino, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl, halo and hydroxy groups; R ¹ is amino (Ni 4) azolidinyl, amino (Ni 4) azolyl, (Ni 4) azolidinyl, (Ni 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 ¹¹ R ¹¹ ) yNH 2 and attached to any with a free valence of the ring atom including B when x is 0 or 1, y is 0, 1, 2 or 3 and each R ^{9 is} independently hydrogen or (C 1-6) alkyl, each R ¹⁰ is independently (C _1-6) ) alkyl and each R ^{11 is} independently hydrogen, (C 1-3) alkyl, or together with another R ¹¹ and the carbon atom to which they are both attached form a cyclopropyl wherein any aliphatic or alicyclic residue containing R ¹ is is optionally changed from one / < up to two substituents independently selected from (Ci_6) alkyloxycarbonyl, (Ci. ₆₎ alkanoyloxy, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci-6) alkylcarbamoyl (Cvejalkilsulfonilo and hydroxyl groups; each R ^{2 is} independently (C 1-6) alkyl, (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, (C 1-6) alkyloxy, carboxyl, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) ) alkylcarbamoyl, (C 1-6) alkylsulfinyl, (C 1-6) alkylsulfonyl, (C 1-6) alkylthio, halogen or hydroxyl and attached to any ring atom by free valence, including B when any aliphatic residue having R ² is optionally substituted with one to two substituents independently selected from (Ci-6) alkyloxycarbonyl, (C ^ alkanoyloxy, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci.6) alkylcarbamoyl, (Ci- ₆₎ alkylsulphonyl and hydroxyl groups; each R ^{3 is} independently (C 1-6) alkyl, (C 1-6) alkyloxy, (Cv6) alkylthio, cyano, halo, perhalogen (C _1-6 ) alkyl or hydroxyl and attached to any ring atom by free valence, including C; 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) z} 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 and attached to any ring carbon atom free valence, including C, wherein: z is 0, 1 or 2, R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ _n i5 where n15 is 1 or 2, X ⁶ is (Ci.io) alkylene, cyclo (C ₃ .io) alkylene, hetero (C ₂ s ₀₎ alkylene or heterocyclo (C ₃ -io) alkylene and kiekvienasR ¹⁵ are independently hydrogen, (C ₆ .u) aryl, cyclo (C ₃ .i ₄₎ alkyl, polycycloalkanes (C ₆ -i4) aryl heteropolycycle (C ₆ i ₄ ) aryl, heterocyclo (C ₃ -C 14) alkyl, hetero (C ₅ -C 14) aryl or as defined below, R ¹³ is hydrogen, (Ci. ₆₎ alkyl or hetero (C ₂ -6) alkyl; R ¹⁴ is hydrogen, (Cl-6) alkyl, or together with X ⁶ and R ¹⁵ form a (C _{3rd 4)} alkylene; any aliphatic or alicyclic moiety comprising ^R4 optionally is substituted by one to five substituents independently selected from (Ci. ₆₎ alkyl, (Ci. ₆₎ alkylamino, di (Ci- ₆₎ alkylamino (Ci. ₆₎ alkylcarbamoyl di (Ci. ₆₎ alkylcarbamoyl (Ci.6) alkyloxy, (Ci-6) alkyloxycarbonyl, (Ci. ₆₎ alkylsulfinyl, (Ci-6) alkylsulfonyl, (Ci.6) alkylthio, amino, (C ₆ - io) arylsulfonium, carbamoyl, carboxyl, cyano, guanidine, halogen, hydroxyl, mercapto and ureido groups; and any aromatic residue containing R ^{15 is} optionally substituted with one to three substituents independently selected from cyano, guanidine, halogen, halo-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 substituted with mono-substituted (C 1-8) alkyl (wherein the substituents are (C 1-6) alkylamine, di (C . ₆₎ alkylamino, tri _(Ci6) alkylammonium (Ci6) alkylcarbamoyl, diiCveĮalkilkarbamoilas (Cvejalkiloksikarbonilas (Cbejalkiloksisulfonilas, amino, carboxy, carbamoyl, hydroxy or sulfo-group), cyclo (C ₃ -6) alkyl, hetero (Ci. ₈₎ alkyl, hetero _{(C5. 6)} aryl, heterocyclo (C ₃ -6) alkyl or phenyl; with the proviso that n1 is not 0, when n2 is 0 or R ² is (Ci-6) alkyl or (Ci_6) alkyloxy, n3 is 0 or R ³ is (Ci-6) alkyl or (Ci- ₆₎ alkyloxy and R ⁴ is hydrogen, (C 1-10) alkyl or (C 1-10) alkyloxy; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1 wherein A has 5 ring members and B has 6 ring members and X ¹ and X ⁵ are oxazol-2-yl, 1/7-imidazol-2-yl or thiazol-2-yl. related members of the ilo ring; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 3. A compound according to claim 2, which is a compound of formula II: where: dashed line represents independently selected connections; each R ^{2 is} independently (C). ₆₎ alkyl, (Ci. ₆₎ alkyloxy, halo or hydroxy; each R ^{3 is} independently (C 1-6) alkyl, (C 1-6) alkyloxy, halo or hydroxyl; X ³ is -C (O) - or -CR ⁷ R ⁸ -; X ⁸ is -CH (R ¹ ) ni or -C (R ¹ ) ni = when R ¹ is amino-N, N-azolidinyl, amino (Ni-4) azolyl, (N-azolidinyl, (Ni-4) azolyl, -NHC). (NH) NR ⁹ R ^9, -C (= NR ⁹⁾ R ^9, -C (NH) NHR ^10, -C (NH) NR R ^{1O W} or - (CR ¹¹ R ¹¹⁾ yNH _2, or X ⁸ is N - or -NH (R ¹ ) _n 1100 where R 'is -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ or -C (NH) NR ¹⁰ R ¹⁰ wherein each R ^{9 is} independently hydrogen or (C 1 -C 6) alkyl and each R ^{10 is} independently (C 1 -C 6) alkyl; X ⁹ is -CH (R ⁴ ) - or -C (R ⁴ ) = when 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 O 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 (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 ) - when 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 . 4. A compound according to claim 3 wherein: R ⁵ is hydrogen or (C 1-4) alkyl, R ⁶ is hydrogen or (C 1-4) alkyl when alkyl is optionally substituted with one to two substituents independently selected from (C _1-4 ) alkyloxy, hydroxy and sulfo. , R ⁷ is hydrogen or methyl and R ³ is hydrogen, methyl or hydroxyl; X ³ is -C (R ¹ ) ni = when R ¹ is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, (CH 2) _x NHC (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 hydrogen or methyl, or X ³ is -N (R ¹ ) n 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 hydrogen or methyl and each R ¹⁰ is methyl in which any aliphatic or the alicyclic residue containing R ¹ is optionally substituted with one to two substituents independently selected from methylsulfonyl and carboxyl; X ⁹ is -C (R ⁴ ) = when 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 hydrogen or (C 1-6) alkyl; R ¹² is -R ¹⁵ or -X ⁶ - (R ¹⁵ ) ni 5. when X ⁶ is (C 1-10) alkylene or hetero (C 2-10) alkylene and each R ¹⁵ is independently hydrogen, (C 6 -C ₁₄ ) aryl, cyclo (C 3 -C ₁₄ ) alkyl, polycyclic (C 6 -C ₁₄₎ ) aryl, heteropolycycle (C6-i ₄₎ aryl, heterocyclo (C3-i4) alkyl or hetero (C5-u) aryl; 101 any aliphatic and alicyclic residue containing R ^{4 is} optionally substituted with one to five substituents independently selected from (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, amino, carbamoyl, carboxyl and hydroxyl; and any aromatic moiety of R ¹⁵ is optionally substituted with one to three substituents independently selected from (Ci.4) alkyl, _{(C1. 4)} alkyloxy, (Ci. ₄₎ alkyloxycarbonyl, carbamoyl, carboxy, cyano , cyclo (C 3-6) alkyloxy, halo, hetero (Ci.e) alkyl, hydroxy, hetero (Ci-8) alkylcarbonyl, hetero (C ₅ .6) aryl and trifluoromethyl; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 5. A compound according to claim 4 wherein: A together with B comprises 4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-yl, wherein n2 is 0, R ¹ is -C (NR ⁹⁾ R ⁹ and R ^{5 is} hydrogen, or A together with B forms 1A 7-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1/7-benzoimidazol-2-yl wherein R ¹ is aminomethyl or guanidine and each R ^{2 is} independently halogen or hydroxyl; C forms 4 _{l of} 5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-yl or 1/7-benzoimidazol-2-yl wherein R ⁴ is -C (O) X ^{6 *. *} -R ¹⁵ , -C (O) OX ⁶ -R ¹⁵ or -C (O) NHX ⁶ R ¹⁵ wherein X ⁶ is (C 1-4 alkylene or hetero (C 2-4) alkylene and R ¹⁵ is (C 6 -C 10) ) aryl, (Ce-io) aryloxy, polycycloalkanes (C6-io) aryl, hetero (C5-io) aryl-heterofCs uOariloksi heteropolycycle or (C ₆ -i4) aryl, and any aromatic moiety comprising ^R15 optionally substituted with one to three substituents independently selected from (C _1-4 ) alkyl, (C _1-4 ) alkyloxy, (C _1-4 ) alkyloxycarbonyl, carboxyl, carbamoyl, halo, hydroxy and tetrazol-1-yl, and its N-oxide derivatives , prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 6. A compound according to claim 5 wherein: A together with B forms 1/7-benzoimidazol-2-yl and each R ^{2 is} independently halogen or hydroxyl; and its / V-oxide derivatives, prodrug derivatives, blocked 102 derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 7. A compound according to claim 6 wherein n1 is 0; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 8. The compound of claim 7, wherein it is selected from: 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5,6-Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5-Hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5-ylcarbonylamino} ethoxy) butyl benzoate; 2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonylamino} ethoxy) propyl benzoate; and 2- (2- {2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) isobutyl benzoate; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 9. A compound according to claim 5, characterized in that it ^R1 represents guanidino or aminomethyl, and / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 10. A compound according to claim 9, which is selected from: 103 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide; 2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino} propoxy ) ethyl benzoate; 2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide; 2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl- N - (2-naphthylethyl) -3W-benzoimidazole-5-carboxamide; 2- (5-guanidino-1H-benzoimidazole-2-yl) -3- (2-hydroxy) ethyl-N- (2-naphthylethyl) -3H-benzoimidazole-5-carboxamide; 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] 3-methyl-3 H -benzoimidazole-5-carboxamide; 2- [1- (5-Guanidino-1?, 7-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3,7-benzoimidazole-5-carboxamide ; » 4-chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid; ' 5-chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3,7-benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid; 2- (5-Aminomethyl-1/7-benzoimidazo-2-ylmethyl) -3-methyl- N - (2-naphth-1-ethyl-3) -benzoimidazole-5-carboxamide; and 2- (5-Aminomethyl-4,5,6,7-tetrahydro-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3 W -benzoimidazole-5-carboxamide; and its α-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 11. A compound according to claim 5 wherein A together with B forms 4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-yl and R ¹ is -C (NH) R ⁹ ; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 104 12. A compound according to 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-3,7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; 2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] 3-methyl-N- (2-naphthyl) -1-ylethyl) -3H-benzoimidazole-5-carboxamide; 2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl- N - (2-naphthyl) 1-ylethyl) -3,7-benzoimidazole-5-carboxamide; 2- (5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl-ethyl) - 3W-benzoimidazole-5-carboxamide; 2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-hydroxy-2- naphth-1-ylethyl) -3 N-benzoimidazole-5-carboxamide; 2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2-hydroxynaphthyl) -1-yl) ethyl] -3H-benzoimidazole-5-carboxamide; 2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (4-hydroxynaphthalene) -1-yl) ethyl] -3,7-benzoimidazole-5-carboxamide; 2- (1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl- - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide; 2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl) -3-methyl-3W) benzoimidazol-5-ylcarbonylamino) ethoxy] ethyl 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) -3 N-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} -1,4 , 6,7-Tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] ethyl benzoate; 2- {1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} 3-methyl- - [2- (2-Tetrazolyl-phenoxy) -ethyl] -3H-benzoimidazole-5-carboxamide and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 105 13. A compound according to claim 12 which is 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} 3 - methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 14. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 15. A pharmaceutical composition according to claim 14, further comprising a β-adrenergic agonist mixture. 16. The pharmaceutical composition of claim 14, wherein said mixture of β-adrenergic agonist is selected from the group consisting of albuterol, terbutaline, formoterol, phenoterol and prenaline. 17. The pharmaceutical composition of claim 14, wherein said composition comprises a pharmaceutically acceptable topical carrier. 18. The pharmaceutical composition of claim 14, wherein said composition comprises a pharmaceutically acceptable oral carrier. 19. The pharmaceutical composition of claim 14, wherein said composition comprises a pharmaceutically acceptable aerosol carrier. 20. An aerosol device comprising a compound of claim 1 in a pharmaceutically acceptable carrier solution or dry powder, and a means for converting said solution or dry powder into an aerosol formulation suitable for inhalation. 106 A compound according to claim 1 for the treatment of immunomodulatory inflammatory disorders in a mammal. A compound according to claim 1 for the treatment of rheumatoid arthritis in a mammal. A compound according to claim 1 for the treatment of conjunctivitis in a mammal. A compound according to claim 1 for the treatment of syncytial viral infection in a mammal. A compound according to claim 1 for the treatment of an immune-mediated inflammatory disorder of the respiratory tract of a mammal. 26. Compound of Formula I: where: n1 is 0 or 1; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; A forms together with B a fused heterobicyclic radical having from 8 to 12 ring atoms, each ring having from 5 to 7 ring members and each ring atom being optionally a heteroatom, X ¹ being a heteroatom residue selected from -N =, -O - and -S-, and X ¹ and X ² are adjacent ring members of the oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl selected from -NR ⁵ -. wherein R ⁵ is hydrogen, (C _1-6 ) alkyl or hetero (C 2-6) alkyl; or C forms a fused heteropolycyclic radical having from 8 to 18 ring members, each ring having from 5 to 7 ring members and each ring having 107 atom optionally is a heteroatom, X ⁵ is a heteroatom moiety selected from N =, -O-, and -S and X ⁴ and X ⁵ is oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring-linked ring members wherein the 1H-imidazol-2-yl ring member is optionally NR ⁶ - when R ⁶ is hydrogen, a group selected from (C 1 -C 6) alkyl or hetero (C ₂ -I ₂ ) alkyl when the group is is optionally substituted with one or two substituents independently selected from (C 1-6) alkanoyloxy, (C _1-6 ) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylammonium, (C 1-6) alkylcarbamoyl, di ( Ci-6) alkylcarbamoyl, (Ci. ₆₎ alkyloxy, (Ci-6) alkyloxycarbonyl, (Ci-6) alkiloksisulfonilo, amino, carboxy, carbamoyl, (C _6. i4) aryl, halogen, hetero (C5-i4) aryl , hydroxyl and sulfo groups, or as defined below, and any carbocyclic ketone, thioketone and iminoketone 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 s 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 hydroxyl or together with R ⁷ forms (C 2-6) alkylene or (C 1-6) alkylidene, wherein any aliphatic or alicyclic residue containing R ⁷ and / or R ^{8 is} optionally substituted with one to three substituents selected from (C -6) alkylamino, di (Ci-6) alkylamino, tri (Ci-6) alkiIamoriio (Ci- ₆₎ alkyloxy, (Ci-6) alkyloxycarbonyl, (Ci- ₆₎ alkanoyloxy, amino, carboxy, carbamoyl, (C - ₆₎ alkylcarbamoyl, di (Ci- ₆₎ alkylcarbamoyl, halo and hydroxy; R ¹ is amino (Ni.4) azolidinyl, amino (N1.4) azolyl, (N ^ jazolidinilas (N ^ jazolilas, carbamoyl, cyano, - (CH2) XNHC (NR ⁹⁾ R ^9, (CH2) xNHC (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 ) yNH 2 and attached to any ring free valence of the atom, including B wherein x is 0 or 1, y is 0, 1, 2 or 3 and each R ^{9 is} independently hydrogen or ((C 1-4 alkyl), each R ¹⁰ is independently (C 1-4) alkyl and each R ^{11 is} independently hydrogen, (C 1-3) alkyl, or together with another R ¹¹ and the carbon atom to which they are both attached form a cyclopropyl wherein any aliphatic or alicyclic residue containing R ¹ is substituted with one to two substituents independently selected from (Ci. ₆₎ alkyloxycarbonyl, (C ,. ₆₎ alkanoyloxy, carboxy, carbamoyl, 108 (C-6) alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl (Ci-6) alkylsulfonyl, and hydroxyl groups; each R ² is independently (Cv ^ alkyl, (Ci. ₆₎ alkyloxycarbonyl, (Ci-C 6) alkanoyloxy, (Ci. ₆₎ alkyloxy, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl, (C 1-6 alkylsulfinyl, (C _1-6 ) alkylsulfonyl, (C 1-4 alkylthio, halo or hydroxyl) and attached to any ring atom by free valence, including B, wherein any aliphatic residue containing R ² is optionally substituted with one to two substituents, independently selected from (CV6) alkyloxycarbonyl, (Cvejalkanoiloksi, carboxy, carbamoyl, (Ci. ₆₎ alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl, (Ci- ₆₎ alkylsulphonyl, and hydroxyl groups; each R ³ is independently (Ci. ₆₎ alkyl, (Ci. ₆₎ alkyloxy, (Ci. ₆₎ alkylthio, cyano, halo, perhalo (Cl-6) alkyl or hydroxy and bonded to any annular atom free valence , comprising C; 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 O 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 ) ₂ 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 and attached to any ring atom by free valence , comprising C, wherein; z is 0,1 or 2, R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ _n i5 where n15 is 1 or 2, X ⁶ is (Cviojalkilenas, cyclo (C ₃ .io) alkylene, hetero (C ₂ .i ₀₎ alkylene or heterocyclo (C _{3rd 10)} alkylene and kiekvienasR ¹⁵ are independently hydrogen, (C ₆ s ₄₎ aryl, cyclo (C ₃ s ₄₎ alkyl, polycycloalkanes (C6-i ₄₎ aryl, heteropolycycle (C ₆ .i ₄ ) aryl, heterocyclo (C ₃ .i ₄₎ alkyl, hetero (C ₅ .i ₄₎ aryl or as defined below, R ¹³ is hydrogen, (Ci- ₆₎ alkyl or hetero (C _{2nd 6)} alkyl; R ¹⁴ is hydrogen, (Cl-6) alkyl, or together with X ⁶ and R ¹⁵ form a (C _{3rd 4)} alkylene; any aliphatic or alicyclic residue containing R ^{4 is} optionally substituted with one to five substituents independently selected from 109 (Ci. ₆₎ alkyl, (Ci. ₆₎ alkylamino, di (Ci. ₆₎ alkylamino (Ci. ₆₎ alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl (C₁-ejalkiloksi (Ci-6) alkyloxycarbonyl, (Ci-ejalkilsulfinilo (Ci-6) alkylsulfonyl, (Ci. ₆₎ alkylthio, amino, (C ₆ .io) arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, and ureido groups; and any which aromatic residue containing R ^{15 is} optionally substituted with one to three substituents independently selected from cyano, guanidine, halogen, halo-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 substituted with mono-substituted (C _1-6 ) alkyl (wherein the substituents are (C _1-6 ) alkylamino, di (C _1-6) ) alkylamino, tri (C ,. ₆₎ alkylammonium (Ci. ₆₎ alkylcarbamoyl, di (Ci. ₆₎ alkylcarbamoyl, (Ci. ₆₎ alkyloxycarbonyl, (Cvejalkiloksisulfonila S, amino, carboxy, carbamoyl, hydroxy or sulfo-group), cyclo (C ₃ -6) Ato, hetero (Ci-e) alkyl, hetero (C ₅ -6) aryl, heterocyclo (C ₃ -6) alkyl or phenyl; with the proviso that n1 is not 0, when n2 is 0 or R ² is (C ^ ejalkilas or (Oj-6) alkyloxy, n3 is 0 or R ³ is (Ci.6) alkyl or (Ci- ₆₎ alkyloxy and R ⁴ is hydrogen, (thio) alkyl or (Coyloxy) and its N-oxide derivatives, prodrug derivatives, blocked derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof, which process comprises: (a) For a compound of formula 1: or a blocked derivative thereof with a compound of formula 2: 110 di (C _1-6 ) alkylamino, difC 1-4 alkylcarbarnoyl, or a blocked derivative thereof, wherein L is a leaving group, D together with the vinylene residue to which it is fused include a monocyclic or fused bicyclic divalent radical containing from 5 to 15 ring atoms, wherein each ring has from 5 to 7 ring atoms and each ring atom is a heteroatom, R ²⁹ is -OH, -NHR ⁶ or -SH when R ⁶ is hydrogen or a group selected from (C 1-6) alkyl or hetero ( C ₂ s ₂₎ alkyl which group is optionally substituted with one to two substituents independently selected from (C ^ alkanoyloxy, (Ci-6) alkylamino, tri (Ci-6) alkylammonium (Ci. ₆₎ alkylcarbamoyl ( Ci-6) alkyloxy (Ci-6) alkyloxycarbonyl, (Ci. ₆₎ alkiloksisulfonilo, amino, carboxy, carbamoyl, (C ₆ s ₄₎ aryl, halo, hetero (C ₅ -i4) aryl, hydroxy and sulfo- 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 as defined above, followed, if necessary, de or (b) reacting a compound of formula 3 or a blocked derivative thereof with a compound of formula 4: Or a protected derivative thereof, where 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, followed, if necessary, deblocking; (c) optionally thereafter converting a compound of formula I into a pharmaceutically acceptable salt; (d) then optionally converting the compound of formula I into a non-salt form; (e) optionally thereafter converting the unoxidized form of the compound of formula I into a pharmaceutically acceptable N-oxide; (F) then optionally converting the N-oxide form of the compound of formula I into its non-oxidized form; (g) optionally subsequently converting the non-derivatized form of the compound of formula I into a pharmaceutical prodrug derivative thereof; and (h) then optionally converting the compound of formula I into a non-derivatized form of the pharmaceutical prodrug derivative.