SI20115A - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity - Google Patents

Abstract

Novel compounds, compositions and methods effective for the prevention and treatment of mast-cell mediated inflammatory disorders are described. The compounds, compositions and methods are effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other types of immunomediated inflammatory disorders, such as rheumatoid arthritis, conjunctivitis and inflammatory bowel disease, various dermatological conditions, as well as certain viral conditions. The compounds comprise potent and selective inhibitors of the mast cell protease tryptase. The compositions for treating these conditions include oral, inhalant, topical and parenteral preparations as well as devices comprising such preparations.

Description

COMPOUNDS AND COMPOSITIONS FOR TREATMENT OF DISEASES RELATED TO THE ACTIVITY OF SERINE PROSTHESAS, IN PARTICULAR TRIPTASE

FIELD OF THE INVENTION

This application is in part a continuation of the application with serial no. No. 08 / 833,674, filed April 7, 1997, which is, in part, a continuation of application no. No. 08 / 357,491, filed December 14, 1994, incorporated herein by reference, and relates to compounds and compositions for treating diseases related to the activity of serine proteases, in particular tryptase.

Area description:

Tryptase, the predominant protease that is secreted by human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream several hours after anaphylaxis (Schwartz et al. (1987) Eng /. Eng. J. Med. 316: 16221626), are increased in nasal and pulmonary lavage fluid (lavage) of atopic patients after a specific antigen challenge. (Castells et al. (1988) J. Allerg. Ciin. Immunol. 141: 563568) and are elevated in the pulmonary lavage of atopic asthmatics following an endobronchial allergen challenge. Smokers often have surprising levels of tryptase levels in the bronchoalveolar lavage, a finding that supports the hypothesis that the release of proteinases from activated mast cells may contribute to lung failure in smokers with pulmonary emphysema. (Celenteron et al. (1988) Chest 94: 119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that tryptase is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. Ciin. Invest. 88: 493499).

Asthma is recognized as an inflammatory disorder (Hood et al. (1984) In: Benjamin-Cummings, ed. Immunology 2nd ed.) And is often characterized by the progressive development of hypersensitivity of the trachea and bronchi to both immunospecific allergens and chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic conditions. The hyperresponsiveness of asthmatic bronchiolar tissue is probably the result of chronic inflammatory reactions that irritate and damage the epithelium surrounding the air wall

-2 Pathways and accelerate pathological swelling of underlying tissue. Bronchial biopsies in patients with mild asthma only show features of inflammation in the airway wall.

Allergic responses to inhaled allergens can trigger an inflammatory sequence. For example, allergens can activate mast cells and basophils present in epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release many ready-made or primary chemical mediators (eg, histamine) of the inflammatory response and produce many other secondary inflammatory mediators (eg, superoxide, lipid-derived mediators, etc.) in situ. In addition, several large molecules (eg proteoglycans, tryptase, chymase, etc.) are released by mast cell degranulation.

The release of these already prepared mediators from mast cells is probably considered an early bronchiolectric constriction in the asthmatic reaction to airborne allergens. The early phase of the asthmatic reaction is maximal about fifteen minutes after exposure to the allergen and is usually followed by improvement over the next one to two hours. Twenty-five to thirty-five percent of the patient population experiences a further decline in respiratory function, which is a maximum of six to twelve hours after exposure. This late phase of the asthmatic reaction is accompanied by a marked increase in the number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating bronchiol tissue. The infiltrated cells are attracted to this site by the release of the chemotactic agents obtained from mast cells and then activated during the late reaction phase. A late asthmatic response is probably a secondary inflammatory reaction, mediated in part by the secretory activity of granulocytes.

Tryptase has been implicated in the degradation of vasodilatory and bronchorelaxant 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. Whole Mol. Biol. 3: 27-32) and modulation of bronchial histamine responsiveness (Sekizawa et al. (1989) J. Ciin. Invest. 83: 175-179 ). These findings suggest that tryptase can increase bronchoconstriction in asthma by destroying bronchodilator peptides. Tryptase cleaves the fibrinogen α-chain and high molecular weight kininogen, suggesting that tryptase in heparin plays the role of a topical anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, indicating that tryptase is involved in tissue inflammation

-3ir »transformation and collapse of joints. Furthermore, administration of a tryptase inhibitor protects against the development of late-phase and hyper-responsive airway phases in allergen-induced sheep (Clark et al. (1995) Am. J. Respir. Crit. Charms Med. 152: 2076-2083) and inhibits the immediate skin response on intradermal allergen injection in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79 (6): 1966-1970). All of the findings described above clearly demonstrate the utility of tryptase inhibitors as therapeutic agents in the treatment of asthma and other respiratory tract-related diseases.

Disclosures of these and other documents, including patents and patent applications mentioned throughout this application, are hereby incorporated by reference.

SUMMARY OF THE INVENTION

This application relates to a compound of Formula I:

I in which:

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 comprises a fused heterobicyclic radical containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom being

1 optionally heteroatom, X and X are adjacent ring members of the aromatic ring and X is

-45 5 heteroatom moiety selected from -N =, -NR -, -O- and -S-, wherein R is hydrogen, (C 1-10) afkyl or hetero (C 2-6) alkyl;

C comprises a fused heteropolycyclic radical containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, each ring atom being optionally heteroatom, X ⁴ and X ⁵ being adjacent ring members of the aromatic ring, X ⁵ being 6 6 heteroatom a moiety selected from -N =, -NR-, -O- and -S-, wherein R is hydrogen, a group selected from (C 1-3) alkyl or hetero (C 2 - | 2) ^a * Rha, this group being optionally substituted with one to two substituents independently selected from (C1-8) alkanoyloxy, (C1-6) alkylamino, di (C1-6) alkylamino, three (C1-6) alkylammonio, (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxy, (C1-6) ^{a, which |} oxycarbonyl, (C 1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-14) aryl, halo, hetero (C 5 -aryl, hydroxy and sulphide, 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 hydrogen, (Ci_

8

g) alkyl, hetero (C2-i2) ^a lkil or together with R form a (C2-4) alkylene or hetero (C2-4) alkylene and R is hydrogen, (Cig) alkyl or hydroxy or together with R ⁷ form a (C2 -6) alkylene or (C 1-5) alkylidene, wherein 7 8 is any aliphatic or alicyclic moiety comprising R and / or R optionally substituted by one to three substituents selected from (C 1-6) alkylamino, di (C- (g) alkylamino, tri (C 1-6) alkylammonio, (C 1-6) alkyloxy, (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, amino, carboxy, carbamoyl, (C 1-6 alkylcarbamoyl, di (C 1-6). g) alkylcarbamoyl, halo and hydroxy;

R ¹ is amino (N- 4) azolidinyl, amino (Ni 4) azolyl, (N-4) azolidinyl, (Nf 4) azolyl, carbamoyl,

GGQQQO -ff) cyano, - (CH ₂ ) _X NHC (NR) R, - (CH ₂ ) _X NHC (NH) NR R, -C (NR) R, -C (NH) NHR,

-C (NH) NR ¹⁰ R ¹⁰ or - (CR ¹¹ R ¹¹ ) yNH 2 and bonded to any ring atom with an available 9 valence encompassed by B, wherein x is O or 1, y is O, 1, 2 or 3, each R is independently hydrogen or (C-) g) alkyl, each R ¹⁰ is independently (C -) g) 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 forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R ^{1 is} optionally substituted by one to two substituents independently selected from

-5 (C 1-6 alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy;

each R is independently (C1-6) alkyl, (C1-6alkyloxycarbonyl, (C1-6) alkanoyloxy, (C1-6) alkyloxy, carboxy, carbamoyl, (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) | .g) alkylsulfinyl, (C 1-10) alkylsulfonyl, (C 1-10) alkylthio, halo or hydroxy, and bonded to any ring atom with an available valence of B, wherein any aliphatic moiety 2 comprising R is optionally substituted by one to two substituents independently selected from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-8) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy;

each R is independently (C 1-6) alkyl, (C 1-6) alkyloxy, (C 1-6) alkylthio, cyano, halo, perhalo (C 1-6).

g) alkyl or hydroxy and bonded to any ring atom with an available valence of C; and

19 19 19 19 19 19 19 19

R is -R, -OR, -N (R) R, -SR, -S (O) R, -S (O) ₂ R, -S (O) ₂ OR, -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 ) _with 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 bonded to any ring carbon atom with available valence, covered by C, wherein:

z is 0.1 or 2,

15 θ 15 6

R is -R or -X - (R) N15> P ^ri where n15 is 1 or 2, X is a (Ci_io) ^{alkyl, alkylene} · cyclo (C3.io) alkyl, hetero (C ₂ .- | o) ^{a kylene} or heterocyclo (C3-10) alkylene and each R is independently hydrogen, (Cg_4) aryl, cyclo (C3-14) alkyl, polycyclo (Cg_4) aryl, heteropoxycyclo (C3-4) aryl, heterocyclo (C3-14) alkyl, hetero (C5 - | 4) aryl or as defined below,

R ¹³ is hydrogen, (Cj _g) alkyl or hetero (C ₂ .G) alkyl;

6 15

R is hydrogen, (C 1-8) alkyl or together with X and R forms (C 3-4) alkylene;

any aliphatic and alicyclic moiety comprising R is optionally substituted with one to five substituents independently selected from (C 1-6) alkyl, (C 1-8) alkylamino, di (C 1-6) alkylamino, (C 1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxy, (C1-6) alkyloxycarbonyl, (C1-6) alkylsulfinyl, (C1-6) alkylsulfonyl, (C1-6) alkylthio, amino, (C1-6) ) arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from cyano, guanidino, halo, halosubstituted (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} 16 as defined above and R is hydrogen, optionally mono-substituted (C1-6) alkyl (wherein the optional substituent is (C1-6) alkylamino, di (C1-6) alkylamino, tri (C1-6) alkylammonio , (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxycarbonyl, (C1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C3-8) alkyl, hetero (C 1-8) alkyl, hetero (C 5-8) aryl, heterocyclo (C 3-8) alkyl or phenyl;

3 with the proviso that n1 is not 0 when n2 is 0 or R is (C1-6) ^{alkyl or} (C1-6) alkyloxy, n3 is 0 or R is (C1-6) alkyl or (C1-8) alkyloxy, and R is hydrogen, (C- | .- | o) ^a lkil or (O- | _- | o) ^a Ikiloksi; and its Noxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

The present invention also provides pharmaceutical compositions of the compounds of the invention. These pharmaceutical compositions may take various forms, including oral dosage forms, inhalation forms, as well as injectable and infusion solutions. When used in inhalation or aerosol form, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier solution or a dry powder that can be converted to an aerosol form. Similarly, when used in oral administration, they are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used to treat immune-mediated skin inflammatory conditions, the compounds of the present invention are used in combination with a non-toxic, pharmaceutically acceptable topical

- 7 carriers. The compounds of the present invention may be used in combination with anti-inflammatory or other asthma therapies, such as β-adrenergic agonists, anti-inflammatory corticosteroids, anticholinergics, bronchodilators, such as methyl xanten and the like.

The compounds described herein are useful for the prevention and treatment of immune-mediated inflammatory disorders, and in particular those associated with the respiratory tract, including asthma, and in particular the hyperresponsive phase associated with chronic asthma and allergic rhinitis. Thus, the present invention also provides a method for treating immune-mediated inflammatory disorders, wherein a patient having an immune-mediated inflammatory disorder is administered a therapeutically effective dose (dose) or amount of a compound of the present invention. Further, the compounds described herein are useful for the treatment of syncytial viral infections.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 compares the specific lung resistance of the control (open squares) against 2- (5 aminomethyl-1 H -benzoimidazol-2-ylmethyl) - N - (3-phenylpropyl) -1 H -Abenzoimidazole-5carboxamide (Compound 4; closed squares ) over the time we measured in hours.

Figure 2 is a bar chart showing the airway hypersensitivity (measured as PC400) of antigen-elicited sheep treated with Compound 13 by administering an aerosol at three 1 mg doses to the control treated sheep.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless otherwise stated, the following terms used in the patent description and claims are defined for the purposes of this application and have the meanings given below:

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

-8Aliccyclic moiety means any saturated or unsaturated, monocyclic or polycyclic hydrocarbon moiety of a radical. For example, the alicyclic moiety refers to cycloalkyl as defined herein, as well as to the alicyclic moieties comprising cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylcarbamoyl and the like.

Aliphatic moiety means any straight or branched, saturated or unsaturated hydrocarbon moiety of a radical. For example, the aliphatic moiety refers to alkyl or heteroalkyl as defined herein, as well as to aliphatic moieties comprising alkyloxy, arylalkyl, heteroarylalkyl, alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl and the like.

Alkyl for the purposes of this application means a straight or branched, saturated or unsaturated aliphatic hydrocarbon radical having a specified number of carbon atoms, and any ketone, thioketone or iminoketone thereof (e.g., (C 1-3) 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, 1-propynyl, 2-propynyl, 3 -oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.)

Alkylene refers to a saturated or unsaturated hydrocarbon divalent radical having the indicated number of carbon atoms and any of its ketone, thioketone, iminoketone and substituted derivatives (e.g., (C1_- | o) ^{a ,, <i, one} includes methylene (-CH2-), ethylene (-CH2CH2-), methylethylene, vinylene, ethinylene, trimethylene (-CH2CH2CH2-), 2-oxotrimethylene (-CH2C (O) CH2-), 2-thiatrimethylene (-CH2C (S) CH2-), 2-iminotrimethylene ( -CH2C (NH) CH2-), propylene ((CH2CH = CH- or -CH = CHCH2-), propanylylidene (= CHCH2CH2-), propenedylene (= CHCH = CH-), 1-aminotetramethylene, pentamethylene, etc.).

Alkylidene means radical = CRR, wherein each R is independently hydrogen or alkyl, as defined above, having the total number of carbon atoms shown (e.g., (C 1-10) alkylidene includes methylidene, ethylidene, propylidene, isopropylidene, etc.) .

Alkyloxy means the radical -OR, wherein R is alkyl, as defined above, having the indicated number of carbon atoms (e.g., (C 1-10) alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy , tert-butoxy, vinyloxy, allyloxy, 1-9 propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethinyloxy, 1-propynyloxy, 2-propynyloxy, etc.).

Alkylsulfinyl, alkylsulfonyl and alkylthio mean radicals -SOR, -S (O) 2R and -SR, respectively, wherein R is alkyl as defined above having the number of carbon atoms shown (e.g., (C1-6alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylphenyl, propylphenyl, butylsulfonyl, phenylphenyl, propylsulfonyl, tert-butylphenyl, vinylphenyl, 1propylphenyl, phenylphenylphenylphenyl, propylphenyl, propylphenyl, butyl etc.).

Ammonio means the radical -ΝΗθ ^1- .

Amidino means radical -C (NH) NH2Amino means radical -NH2.

The animal includes humans, non-human mammals (eg, dogs, cats, rabbits, livestock, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.).

Aryl means an aromatic monocyclic or fused polycyclic hydrocarbon radical containing a specified number of carbon atoms, each ring consisting of 6 ring members (e.g., (C5-14) aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.).

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

Aromatic moiety means any aromatic moiety of a radical. For example, the aromatic moiety refers to aryl and heteroaryl as defined herein, as well as to aromatic moieties comprising arylalkyl, heteroarylalkyl, polycycloaryl, heteropoxycyloaryl and the like.

-10Asolidinyl means a saturated or unsaturated 5-membered monocyclic radical containing the indicated number of nitrogen atoms. For example, (Nj.4) azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, trizolidinyl, tetrazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.

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

Carbamoyl means radical -C (O) NH2Carboxy means radical -C (O) OH.

Cyano means the radical -CN.

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

-11Removal protection refers to the removal of any protecting groups present after a selective reaction has taken place.

The disease specifically includes any unhealthy condition of the animal or part thereof and includes a disease condition that may be caused by, or that occurs in, medical or veterinary therapy when given to such animals, e.g. side effects of such therapy.

Condensed heterocyclic radical includes a fused heterobicyclic radical and means a heterocyclic radical containing two to three fused (united) rings having a shown number of ring members, with at least two ring members of one ring in common with the other ring (e.g., heterocyclic radical, containing from 8 to 18 ring atoms and its carbocyclic ketone and thioketone derivatives include 1 H -benzimidazol-2-yl, 1 H-naphtho [2,3-c (| imidazol-2-yl, 1 H-imidazo [4,5-flkinorm] -2-yl, 1Himidazo [4,5-b] pyridin-2-yl, 1 H -phenantro [9,10-c] imidazol-2-yl, 1 H-imidazo [4,5-g] quinoxalin-2yl , 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl, 2,6-dithioxo-2,3,6,9-tetrahydro-1H-purin-8-yl , 7/7-purin-8-yl, 1,6-dihydrocyclopentaimidazol-2-yl, 4-quinolin-2-yl, etc.).

Guanidino means radical -NHC (NH) NH2 ·

Halo means fluoro, chloro, bromo or iodo.

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

Heteroatomic moiety, unless otherwise indicated, means a moiety selected from -N =, -NR ¹⁷ -, -0-, -S-, -S (O) -, -S (O) 2-, -P ( O) (OR ¹⁷ ) -, wherein R ^{17 is} hydrogen or (C 1-6) alkyl.

Heteroalkyl means alkyl as defined above, except that one or more of the indicated carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero (C 2 - 2) ^{a, kil} includes methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 3methoxymethoxycarbonylmethoxy, 2- (N-ethyl- / N-methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).

-12Heteroalkylene means alkylene as defined above, except that one or more carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention, or any suitable combination thereof (e.g., -OS (O) 2-, - S (O) 2O-, -N (R) S (O) 2, -S (O) 2NR ¹⁷ -, -OP (O) (OR ¹⁷ ) O- and the like, wherein R ^{17 is} hydrogen or (C (, (e) alkyl), and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero (C2-10) a ^l kylene includes azaethylene (-CH2NH-), 2-azapropenylene (-CH2N = CH2-), 1- oxatrimethylene (-CH2CH2O-), 2-oxo-3-azapentamethylene, 3-aza-2-thiopentamethylene, 2-oxa-3oxopentamethylene, 3-aza-2-iminopentamethylene (-CH2CH2NHC (NH) CH2-), 2,4- aza-2-methyl3,3-dioxo-3-thiapentamethylene (-CH2NHS (O) 2N (CH3) CH2-), 3-hydroxy-2,4-oxa-3-oxo-3phosphapentamethylene (-CH2OP (O) (OH OCH2-), 3-aza-2-oxo-4-carboxyhexamethylene, 4-aza1-oxa-3-oxohexamethylene, 1-thia-3-oxo-4-azahexamethylene, 1-thia-1,1,3-trioxo -4azahexamethylene (-CH2CH2NHC (O) CH2S (O) 2-), 3-aza-4-oxoheptamethylene, 1,4,7 trioxaoctamethylene, 6-aza-1-oxa-2,5-dioxooctamethylene (-CH2CH2NHC (O) CH2CH2C (O) O-), 3-aza-4-oxodecamethylene, etc.).

Heteroaryl means an aromatic monocyclic or fused polycyclic divalent radical having the indicated number of ring atoms, each ring of the radical having from 5 to 6 ring members and one or more ring atoms being a heteroatom moiety selected from -N =, -NR ¹⁷ -, -O- or -S-, wherein R ^{17 is} hydrogen or (C 1-10) alkyl, and each ring contained therein comprises 5 to 6 ring members (e.g., hetero (C 5 - 4) aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).

Heterocycloalkyl means cycloalkyl as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., heterocyclo term (e.g., the term heterocyclo) C 1-4 alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

Heterocycloalkylene means cycloalkylene as defined above, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom moiety such as

-13defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo (C3-14) alkylene includes piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, etc. morpholin, etc. morpholin.

Heteropolycycloaryl means polycycloaryl as defined below, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom moiety as defined in the Detailed Description of the Invention and any of its carbocyclic ketone, thioketone or iminoketone derivative (e.g. -io) alkyl includes 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H- [1,8] naphthyridinyl, 2,4-dioxo-3,4 -dihydro-2Hquinazolinyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, etc.).

Hydroxy means the radical -OH.

Immune-mediated inflammatory disorder means those diseases that are associated with the release of mast cell mediators and that can be treated with a tryptase inhibitor (e.g., immediate-type sensitization diseases such as asthma, allergic rhinitis, urticaria and angioedema, eczema anaphylaxis, dermatitis, as atopic dermatitis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disorder, ocular and vernal conjunctivitis, rheumatoid arthritis, inflammatory skin conditions, and the like).

Hyperresponsiveness means a late phase of bronchoconstriction and hyperreactivity of the airways that are associated with chronic asthma. The hyperresponsiveness of asthmatic bronchiolar tissue probably results from chronic inflammatory reactions that irritate and damage the epithelium lining the airway wall and accelerate pathological swelling of underlying tissue.

A syncytial viral infection means an infection with a virus, such as a respiratory syncytial virus, that causes the formation of a cellulame protoplasmic mass, that is, syncytia, through infection.

Imino means radical = NH.

Isomers mean compounds of Formula I that have identical molecular formulas but differ in the nature or sequence of bonding of their atoms or in the arrangement of their

-14 atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereomers and stereoisomers that are not superimposition mirror images are called enantiomers or sometimes optical isomers. The carbon atom bonded to four non-identical substituents is called a chiral center. A compound with a single chiral center has two enantiome forms with opposite chirality and is called a racemic mixture. A compound having more than one chiral center has 2 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either a single diastereomer or a mixture of diastereomers, called a diastereomeric mixture. When one chiral center is present, the stereoisomer can be characterized by the absolute configuration of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under study are classified according to the Sequence Rule of Cahn, Ingold, and Prelog, and the absolute descriptor of R or S is indicated in parentheses, followed by the hyphen and the chemical name of the compound. Compounds of Formula I containing a chiral center may exist as single stereoisomers or mixtures of stereoisomers. For the purposes of this application, when referring to a compound of Formula I by name or formula and configuration not indicated, it should be understood that the reference applies to all possible configurations of the compound.

Optional or optional means that the event or circumstance described later may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, the term optionally substituted with one to three radicals means that said group may or may not be substituted to fall within the scope of the invention.

N-oxide derivatives means derivatives of a compound of Formula I wherein the nitrogen is in an oxidized state (e.g., O-N) and which has the desired pharmacological activity. The / V-oxide derivatives of compounds of Formula I can be prepared by methods known to one of ordinary skill in the art.

Disease pathology means the original nature, causes and development of the disease, as well as the structural and functional changes that result from the disease processes.

Pharmaceutically acceptable means that what is useful in the preparation of the pharmaceutical composition is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that what is acceptable for veterinary use is also acceptable for human pharmaceutical use.

Pharmaceutically acceptable salts means salts of compounds of Formula I that are pharmaceutically acceptable as defined above and which have the desired pharmacological activity. Such salts include salts obtained by the addition of acids formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid 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, maleic acid, maleic acid, citric acid , benzoic acid, o- (4hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-sulfonobenzenesulfonate, sulfonic acid acid, camphrasulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3phenylpropionic acid , trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid saliva, muconic acid and the like.

Pharmaceutically acceptable salts also include salts obtained by the addition of bases which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, 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 containing a specified number of carbon atoms, with at least one, but not all, of the fused rings being

-16 comprise a radical aromatic, and each ring contained therein comprises five to six ring members, and any of its carbocyclic ketone and thioketone derivatives (e.g., polycyclo (C9_10) aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl , 1,2-dihydronaphthyl, 2,4-dioxo1,2,3,4-tetrahydronaphthyl, etc.).

Prodrug derivatives means derivatives of compounds of Formula I that are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Suitable prodrug derivatives include those compounds of Formula I in which one or more nitrogen and / or oxygen atoms are available with free valence, substituted by an easily cleavable group in in vivo processes. For example, derivatives of prodrugs of compounds of Formula I may contain one or 18 more N-substituted amino groups (e.g., -NH 2 (R)), N-substituted nitrogen atoms, 18 incorporated into an aliphatic, alicyclic or aromatic structure (e.g. ., -N (R) -), N18 18 substituted imino or amidino groups (e.g., -C (NR) H, -C (NR) NH2 or

1818 -C (NH) NHR), / V-substituted guanidino groups (e.g., -NHC (NR) NHR,

18 18 1Q

-NHC (NH) NHR or -NHC (NR) NH ₂ ) and the like in which R (i) is -C (O) R or

1Q -tq

-CH (R) OC (O) R, wherein R is (C 1-10) alkyl, (C 1-10) * xyloxy, carbamoyl, (C 1-10) alkylcarbamoyl, di (C 1-10) alkylcarbamoyl, c (s-2- (C 1-10) alkanoyloxyphenylvinyl, 3 (C 1-10) alkanoyloxybutyryl, (C 3-10) cycloalkyl, hetero (C 3-10) cycloalkyl, (C 1-10) aryl, or

7 21 7 hetero (C 5-10) aryl and R is hydrogen or (C 1-10) alkyl; (ϋ) -X -R, where X is

22 is (C 1-10) alkylene and R is carboxy; or (iii) -C (O) OCH (R) OC (O) R, wherein R is hydrogen, (C 1-10) alkyl or (C 3-10) cycloalkyl and R is (C 1-10) alkyl or (C3_10) c »chloalkyl. In addition, prodrugs of the compounds of Formula I may contain one or more / V-hydroxylated imino or amidino groups (e.g., -C (NOR ²⁴ ) H, -C (NOR ²⁴ ) NH ₂ or -C (NH) NHOR ²⁴ ) or N24 24 hydroxylated guanidino groups (e.g., -NHC (NOR) NH2, -NHC (NH) NHOR) in which

25 26 25 25

R is hydrogen, methyl, -C (O) R or -CH (R) OC (O) R, wherein R is (C 1-10 alkyl or (C 3-10) cycloalkyl and R is hydrogen or (C 1-10) alkyl; substituted hydroxy groups (e.g.,

27 1Q 20 1Q 1Q 20

-OR), wherein R is -C (O) R or -CH (R) 0C (O) R, wherein R and R are as defined above: and / or carboxylic acid ester derivatives (e.g., -C (O) OR), at 28 where R is (C 1-10) ^{a, kil} or (C 3-1 o) ^c > ^{k, alkyl} ·

A protecting group has the meaning usually associated with it in synthetic argan chemistry, e.g., a group that selectively blocks one reactive site in a multifunctional compound such that

The -17chemical reaction can be carried out selectively at another unprotected reactive site, and can be easily removed when the selective reaction is complete.

Protected derivatives means derivatives of compounds of Formula I in which the reactive site or reactive sites are blocked by protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I. Suitable protecting groups for reactive nitrogen atoms include tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protecting groups (e.g., see TW Greene, Protective Groups and Organic Synthesis, John Wiley & Sons, Inc. 1981). A particularly suitably protected derivative of Formula I is exemplified by compound 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1W-benzoimidazol-2ylmethyl] -4,5,6,7-tetrahydro -1H-benzoimidazole-5-carboxylic acid.

Therapeutically effective amount means an amount that, when given to an animal, is effective in treating the disease.

Treatment refers to any administration of a compound of the present invention and includes:

(1) prevention of disease occurrence in an animal that may be predisposed to the disease but has not yet experienced or demonstrated pathology or disease. symptoms of the disease, (2) inhibiting the disease, that is, inhibiting the development of its pathology and / or symptoms, or (3) improving the disease, that is, eliminating its pathology and / or symptoms.

Suite means the radical -S (O) OH.

Uriedo means the radical -NHC (O) NH 2 Compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with the IUPAC nomenclature rules. For example, a compound of Formula I in which:

-18A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 5- (2-naphth-13 ylethylcarbamoyl) -1H-benzoimidazol-2-yl and X is -CH2- called 2- (5 -guanidino-1H-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethyl) -1H-benzoimidazole-5-carboxamide;

A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 6- (2-naphth-13 ylethylcarbamoyl) -1-methyl-1H-benzoimidazol-2-yl and X is -CH 2 - called 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;

A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 6- [2- (23 carboxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1H-benzoimidazol-2-yl and X is - CH2- is called 2- {2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-sulfopropyl) -3H-benzoimidazol-5-ylcarbonylamino] ethyl} benzoic acid; and

A together with B comprises 5-guanidino-1H-benzoimidazol-2-yl, C comprises 6- (2- (23 methoxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1H-benzoimidazol-2-yl and X is -CH2- is called 3- {2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -6- [2- (2methoxyphenyl) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid.

Certain compounds of Formula I exist in tautomeric equilibrium. For example, compounds of Formula I in which C comprises 4,5,6,7-tetrahydro-3H-imidase [4,5-c] pyridin-2-yl exist in equilibrium between tautomers of the following formulas:

-19and therefore, while the compounds of the present invention may be named, illustrated or otherwise described as one possible tautomer in this application, it should be understood that this means that all possible tautomers are covered by such names, illustrations and descriptions. Thus, it is thought that the name ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1 N-tetrahydro-imidazo. S-cypyridin5-yl} -4-Oxobutyl) benzoate includes its tautomers ethyl 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydro-imidase [4,5 -c] pyridin-5-yl} -4-oxobutyl) benzoate, ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3,4,6 , 7-tetrahydroimidazo [4,5c] pyridin-5-yl} -4-oxobutyl) benzoate and ethyl 2- (4- {2- [1- (5-guanidino-3H-benzoimidazol-2yl) ethyl] -3, 4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) benzoate.

Preferred designs:

While the broadest definition of this invention is explained in the Summary of the Invention, certain aspects of the invention are preferred. A preferred aspect of the invention is a compound of Formula I, wherein A together with B comprises a fused heterobicyclic radical, wherein A contains 5 ring members and B contains 6 ring members and X ⁴ and X ⁵ are adjacent oxazol-2-yl, 1 H -imidazol-2-yl or thiazol-2-yl ring.

A preferred aspect of the invention are compounds of Formula II:

in which:

the dashed lines independently represent optional bonds;

-202 each R is independently (C 1-6 alkyl, (C 1-6) alkyloxy, halo or hydroxy;

each R is independently (C 1-10) alkyl, (C 1-3 alkyloxy, halo or hydroxy;

X ³ is -C (O) - or -CR ⁷ R ⁸ -;

11 1 X is -CH (R) _n - | - or -C (R) _n i =, wherein R is amino (N- | -4) azolidinyl, amino (Ni_4) azolyl, (N- | _ ₄ ) a20lidinyl, (N ^ jazolyl, -NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹ ° -C (NH) NR ¹⁰ R ¹⁰ or - (CR ¹¹ R ¹¹ ) yNH2, or X ⁸ is -N = or -NH (R ¹ ) n- | -, 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 -C 5) alkyl ^and each R ¹⁰ is independently (C 1-10) 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 ,

- (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} as defined in the Summary of the Invention.

A preferred aspect of the invention are compounds of Formula I in which:

6

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

X ⁸ is -CH (R ⁴ ) - or -C (R ¹ ) _n i =, wherein R ^{1 is} aminomethyl, 1-aminocyclopropyl, 29 9 aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH ₂ ) _X NHC (NR) R,

- (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 ⁸ is -N (R ¹ ) _nr , where R ¹ is -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹ ° or -C (NH) NR ¹ ° R ¹⁰ , at 9 10 which is each R is independently hydrogen or methyl and each R is methyl, whichever is the one

-21aliphatic or alicyclic moiety comprising R ¹ optionally substituted with one to two substituents independently selected from methylsulfonyl and carboxy;

X ⁹ is -C (R ⁴ ) =, where 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 15 6 15 6 is -R or -X - (R) N15> P ^R wherein X is (Cf. ·)) alkyl or hetero (C2-io), ^{a 'to' len} * ^{n each} 15

R is independently hydrogen, (C 1-4) aryl, cyclo (C 3-4) alkyl, polycyclo (C 1-4) aryU heteropoxycyclo (C 1-4) aryl, heterocyclo (C 3-4) alkyl or hetero (C 5-4) aryl;

any aliphatic and alicyclic moiety comprising R ⁴ is optionally substituted with one to five substituents independently selected from (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from (C 1-4) alkyl, (C 1-4) alkyloxy, (C-). 4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C3-8) alkyloxy, halo, hetero (C-). 8) alkyl, hetero (C- | _8) ^al kilkarbonila, hetero (C5-6) aryl and trifluoromethyl; and their / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

A preferred aspect of the invention are compounds of Formula I in which:

A together with B comprises 4,5,6,7-tetrahydro-1 H-imidase [4,5-c] pyridin-2-yl, wherein n 2 is 0 and 1 9 9

R is -C (NR) R, or A together with B comprises 1 B-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1 H 1 2 benzoimidazol-2-yl, wherein R is aminomethyl or guanidino and each R is independently halo or hydroxy;

C comprises 4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl or 1 H-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 ·,. 15

4) alkylene or hetero (C2-4) alkylene and R is (C6-10) ^aryl · (C 1 -io) arylOxy, polycyclo (C 8-10) aryl · hetero (C 5-10) ^ar > 1, hetero (C 5) .- | o) ^ar >' ^ox · ^a '> heteropolicyclo (C6-i4) aryl; and

-2215 any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from (C 1-4) alkyl, (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, carboxy, carbamoyl, halo, hydroxy and tetrazol-1-yl; and their Noxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

A preferred aspect of the invention are compounds of Formula I in which n1 is 0 and each R is independently halo or hydroxy, in particular:

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

2- (2- {2- [1- (5,6-Difluoro-1A7-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid;

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

propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate; and isobutyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3-7-benzoimidazol-5ylcarbonylamino} ethoxy] benzoate.

A preferred aspect of the invention are compounds of Formula I in which R ^{1 is} guanidino or aminomethyl, in particular:

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

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

-232- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;

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

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

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide;

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

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

3H-benzoimidazole-5-carboxamide;

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

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

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3 H -benzoimidazole-5 carboxamide; and

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

-24 A preferred aspect of the present invention are compounds of Formula I in which C comprises 4,5,6,7-tetrahydro 1 H-imidase [4,5-c] pyridin-2-yl and R ¹ is -C (NH) R ⁹ , especially:

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

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

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

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

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

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

ethyl 2- (2- (2- (1- (5- [1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate;

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

-25ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl } -1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate; and

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

Pharmacology and utility:

The compounds of this invention are serine protease inhibitors, and as such, are useful in the treatment of diseases associated with increased activity of serine proteases. In particular, the compounds of this invention are tryptase inhibitors and are useful in treating diseases associated with increased tryptase activity. In vivo protocols for screening potential inhibitors for their ability to inhibit tryptase are known in the art. See, e.g., Sturzebecher et al. (1992) Biol. Chem. Hoppe-Sey / er 373: 1025-1030. Typically, these assays measure enzyme-induced hydrolysis of peptide-based chromogenic substances. Details of the illustrative method for measuring the inhibitory activity of tryptase are described below.

In addition, the activity of the compounds of the present invention can be evaluated in vivo in one of many 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; Wamer et al. (1990) Am. Rev. Respir. Dis. 141: 253-257. An ideal animal model would replicate the main clinical and physiological characteristics of human asthma, which include: airway hyperresponsiveness to chemical mediators and physical stimuli; read in airway obstruction with medicines useful in human asthma (β-adrenergics, methylxanthines, corticosteroids and the like); airway inflammation by infiltration of activated leukocytes; and chronic inflammatory degenerative changes such as swelling of the basement membrane, smooth muscle hypertrophy, and epithelial damage. The species of animals used as animal models include mice, rats, guinea pigs, rabbits, dogs and sheep. All animals have some limitations and the right choice of animal model depends on the question that needs to be answered.

-26The initial asthmatic response can be evaluated in guinea pigs and dogs, and in particular with crossbreeds between species of fables and Greyhound, which develop non-specific airway hypersensitivity to many non-allergenic substances, such as methacholine and citric acid. Certain selected sheep show a dual response after an antigen challenge with Ascaris proteins. In animals that respond twice to an initial asthmatic response (IAR), a late asthmatic response (LAR) is followed at 6-8 hours after exposure. Hypersensitivity to the cholinergic agonist carbachol is increased at 24 hours after the antigen challenge in those animals showing LAR.

The allergic sheep model (see below) was used to evaluate the potential anti-asthmatic effects of the compounds of the present invention. Administration of compositions comprising the compounds of the present invention to allergic sheep, both in oral or inhalation or aerosol formulations, before or after exposure to specific allergens, demonstrates that such compositions significantly reduce or eliminate the late asthmatic response and, consequently, hyperresponsiveness.

The compounds of the present invention are also useful for the treatment of other immune-mediated inflammatory disorders in which tryptase activity contributes to a pathological condition. Such diseases include mast cell-related inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, peptic ulcers and various skin conditions. Further, the compounds of the present invention can be used to treat syncytial virus infections.

The efficacy of the compounds of the present invention for the treatment of the vast majority of immune-mediated inflammatory diseases can be evaluated by either in vitro or in vivo methods. Such anti-inflammatory efficacy of the compounds of the present invention can be clearly demonstrated by tests well known in the art, for example, the PAW technique of reverse passive Arthus reaction (RPAR) (see, e.g., Gangly et al. (1992) U.S. Pat. No. 5,126,352). Tests for determining the therapeutic value of compounds in the treatment of various skin conditions, such as hyperproliferative skin disease, are well known in the art, for example, the arachidonic Acid Mouse Ear Test (see same patent). The compounds of the present invention can be evaluated for their antitumor activity according to the methods described by Chiu et al. (1984) in Archives Intemationales de Pharmacodynamie etde Therapie 270: 128-140.

-27The efficacy of the compounds of the present invention in blocking cell fusion caused by syncytial virus infection can be evaluated by methods generally explained in Tidwell et al., J. Med. Chem. 26: 294-298 (1983).

Ingredients and administration:

According to the present invention, a therapeutically effective amount of a compound of the invention is administered to a patient suffering from an immune-mediated inflammatory disorder. In one embodiment, the compositions of the present invention are useful for preventing or ameliorating asthma. When using the compositions of the present invention for the treatment of asthma, the compositions can be administered prophylactically before or after exposure to an allergen or other precipitating factor. The compounds of the present invention are particularly useful in improving the late phase of tissue destruction that can be observed in both seasonal and year-round rhinitis. Another aspect of the present invention is directed to the prevention and treatment of immune-mediated inflammatory disorders associated with mast cells, such as urticaria and angioedema, eczema dermatitis (atopic dermatitis) and anaphylaxis, as well as hyperproliferative skin disease, peptic ulcers and the like. In a further embodiment, the compounds of the present invention are used to treat syncytial virus infections, in particular respiratory syncytial virus infections.

Compounds containing the compounds may be administered for therapeutic and / or prophylactic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from the disease as described above in an amount sufficient to cure or at least partially contain the disease symptoms and their complications. An amount sufficient to achieve this is defined as a therapeutically effective amount or dose. The amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient's medical condition, and response to medication and judgment of the treating physician.

In prophylactic applications, compositions containing the compounds of the invention are administered to a patient prone to a particular disease or otherwise at risk of a particular disease, in an amount sufficient to prevent or improve the onset of symptoms. Such an amount is defined to be a prophylactically effective amount or dose. These compounds may be administered orally or by inhalation.

-28With this use, the exact amounts again depend on the patient's medical condition, weight and the like.

Once the patient's condition has improved once, if necessary, a maintenance dose is given. Subsequent dosing (dosing) or frequency of administration, or both, can be reduced as a function of symptoms to the level at which we maintain an improved state. Treatment can be stopped when symptoms are reduced to the desired level. However, patients may require intermittent treatment on a long-term basis, after any recurrence of disease symptoms.

In general, an effective dose (dose) of the compounds of the present invention will be in the range of 0.05 to 1000 milligrams (mg) per recipient per day, preferably in the range of 0.1 to 100 mg per day. The desired dosage is preferably administered at one, two, three four or more sub-doses given at specified intervals throughout the day. These sub-doses can be administered as unit dosage forms, for example, containing 0.01 to 1000 mg, preferably 0.01 to 100 mg of active ingredient per unit dosage form.

The composition to be used in these therapies can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, enteric coated tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusion solutions. Inhalation preparations, such as aerosols, are also included. Preferred formulations are those directed to oral, intranasal, topical and parenteral applications, but it will be appreciated that the preferred formulation will depend on the particular therapeutic application that is available. Oral and aerosol applications are particularly preferred. Methods for formulating and preparing therapeutic compositions comprising the compounds of the invention are known in the art and are described in, for example, the REMINGTON'S PHARMACEUTICAL SCIENCES and THE MERCK INDEX 11 Ed., (Merck & Co. 1989).

While it is possible to administer the active ingredient of the present invention only, it is preferable to administer it as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dose, together with a pharmacologically acceptable carrier. The pharmaceutical compositions will thus contain the compounds

-29 of the present invention in concentrations sufficient to give a suitable dose. For example, where the appropriate dose is 0.05 mg per day and where one dose per day is used, the concentrations of the compound of the invention in the pharmaceutical composition would be 0.05 mg per dose. For inhalable or aerosol compositions, the concentration of the compounds of the present invention in the composition will generally depend on the amount of dose. Typical concentrations of the compounds of the present invention in inhalable or aerosol compositions would be from about 0.01 to about 30 mg / ml. The formulation may include other clinically useful compounds, such as β-adrenergics (e.g., albuterol, terbutaline, formoterol, phenoterol and prenalin) and corticosteroids (e.g., beclometasoma, triamcinolone, flunisolid and dexamethasone).

Chemistry:

In general, the compounds of the present invention are synthesized using standard techniques and reagents that are known to and practiced by those skilled in the art. It will be appreciated that the bonds between the various functional groups generally comprise carbon bound to amide or carbamate nitrogen, carbamate oxygen or carbonyl carbon. Those skilled in the art will recognize that the methods and reagents for forming these bonds are well known and known

1U easily accessible. See, e.g., March, ADVANCED ORGANIC CHEMISTRY, 4 Ed. (Wiley

1992), Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH 1989); in Furniss, th et al., VOGEUS ΤΕΧΤΒΟΟΚ OF PRACTICAL ORGANIC CHEMISTRY 5 ed. (Longman 1989), each of which is incorporated herein by reference.

5

Compounds of Formula I in which X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring can be prepared by the methods described in the following reaction scheme:

-30 Scheme 1

in which L is a prominent group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring having 6 f the atom is optionally a heteroatom, R is -OH, -NHR or -SH, X is -O-, -NR - or -S-, and n2, n3, 12351234 6 n4, A, B, X, X, X, X, R, R, R, R and R are as defined in the Summary of the Invention.

5

Compounds of Formula I in which X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-ii or thiazol-2-yl ring (Formula l (a)) can be prepared by reacting a compound of Formula I , or a protected derivative thereof, with a compound of Formula 2, or a protected derivative thereof, and then, if necessary, deprotected. The reaction between the compounds of Formulas 1 and 2 can be carried out without diluting the reactants, but is preferably carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H -pyrimidinone (DMPU) or polyphosphorus acid at 160 to 200 ° C, preferably 180-190 ° C, and takes 1 to 5 hours to complete (e.g., see Examples 4 (d), 6 (h), 8 (k), 9 (d) and 10 (d), below). Removal of protection can be performed on any

-31 A method that removes the protecting group and gives the desired product in reasonable yield (e.g., see Example 2 (g), below).

2

In a similar manner, compounds of Formula I can be prepared in which X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl ring according to the methods described in the following reaction scheme:

Scheme 2

l (b)

ΟΛ R fi fi in which L is a prominent group, R is -OH, -NHR or -SH, X is -0-, -NR - or -S- and n2, n3, n4, B, C, X ¹ , X ³ , X ⁴ , 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).

The isolation and purification of the compounds and derivatives described herein may be carried out, if desired, by any suitable separation or purification process, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography or

-32-thick chromatography, high-pressure liquid chromatography (HPLC), or a combination of these methods. Specific explanations of suitable separation and isolation procedures can be given by reference to the examples below. However, other appropriate separation or isolation procedures may of course be used. Nuclear magnetic resonance (NMR) spectra were recorded on a General Electric QE Plus (300 MHz) spectrometer. Infrared spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR) spectrophotometer. Analytical HPLC was performed on an ultrafast microprotein analyzer, Michrom BioResources, Inc. equipped with a PLRP column, 1 mm x 150 mm. Preparative HPLC was performed on a Gilson LC (liquid chromatograph) using a VYDAC 1x25 cm C-g reverse phase (RP) column or Vaters Prep LC2000 system using a Vydac 5x25 cm C-ig RP column. Mass spectra (MS) were obtained on a Finnigan SSQ 710 apparatus with ESI source, direct injection or HPLC MS (ultrafast microprotein analyzer, Cig column, 2 mm X 150 mm). Unless otherwise noted, all reagents and equipment were either prepared according to published procedures or purchased from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (St. Louis, MO) and ICN Chemical Co. (Irvine, CA). The techniques used to perform the syntheses described below will be recognized by those skilled in the art as routine (see, e.g., March, Larock or Furniss, supra).

Additional procedures for the preparation of compounds of Formula I:

The compounds of Formula I can be prepared as pharmaceutically acceptable salts obtained by the addition of acids by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively the pharmaceutically acceptable salts of the compounds of Formula I obtained by the addition of bases can be prepared by reacting the free acid forms of the compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of Formula I are listed in the definition section of this publication. Alternatively, salt forms of compounds of Formula I may be prepared using salts of starting materials or intermediates.

-33 Forms of free acids or free bases of compounds of Formula I can be prepared from the corresponding salt form obtained by the addition of a base or a salt obtained by the addition of acid. For example, compounds of Formula I in the form of a salt obtained by the addition of acid can be converted to a corresponding free base by treatment with a primed base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of Formula I in the form of salts obtained by the addition of a base can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).

The V-oxides of the compounds of Formula I can be prepared by methods known to one of ordinary skill in the art. For example, / V-oxides can be prepared by treating the non-oxidized form of a compound of Formula I with an oxidant (e.g., trifluoroperoxyacetic acid, permaleic acid, perbenzoic acid, peracetic acid, mefa-chloroperoxybenzoic acid, etc.) in a suitable inert organ (e.g. ., a halogenated hydrocarbon such as methylene chloride) at about 0 ° C. Alternatively, the V-oxides of the compounds of Formula I can be prepared from the Noxide of a suitable starting material.

Compounds of Formula I in non-oxidized form can be prepared from the V-oxides of compounds of Formula I by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, etc. tribromide). an organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 ° C.

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

Protected derivatives of compounds of Formula I can be made by methods known to one of ordinary skill in the art. A detailed description of suitable techniques for forming protecting groups and removing them can be found in T.W. Greene, Protective Groups in Organic Synthesis by John Wiley & Sons, Inc. 1981.

-34 Compounds of Formula I can be prepared as their individual stereoisomers by reacting the racemic mixture of the compound with an optically active resolvent to form a pair of diastereoisomeric compounds, separating the diastereomers and obtaining the optically pure enantiomer. While resolution of enantiomers can be performed using covalent diastereomeric derivatives of compounds of Formula I, dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. Diastereomers have characteristic physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by exploiting these differences. The diastereomers can be separated by chromatography or, preferably, by separation or separation techniques. resolutions based on differences in solubility. The optically pure enantiomer is then again obtained together with the resolvent in any practical manner that does not result in racemization. A more detailed description of suitable techniques for resolving stereoisomeric compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Vilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).

In summary, one aspect of the present invention is a process for the preparation of a compound of Formula I, this process comprising:

(a) reacting a compound of Formula 1:

or a protected derivative thereof, with a compound of Formula 2:

K) n3

-35 or a protected derivative thereof, wherein L is a protuberant group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 ring atoms, each ring containing from 5 29 6 to 7 ring atoms and each ring atom is optionally heteroatom, R is -OH, -NHR or 12 3 1 2 3 4 β

-SH and n1, n2, n3, A, B, X, λ, X, R, R, R, R and R are as defined in the Summary of the Invention, and then, If protection is required to obtain a compound of Formula I in 4 5 wherein X and X are adjacent members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2-yl rings; or (b) reacting a compound of Formula 3;

or a protected derivative thereof, with a compound of formula 4:

5 or a protected derivative thereof, wherein L is a leaving group, R is -OH, -NHR or

-SH and n1, n2, n3, B, C, X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in the Summary of the Invention and then if removal is required protection to give a compound of Formula I in 1 2 wherein X and X are adjacent members of oxazol-2-yl, 1 H-imidazol-2-yl or thiazol-2-yl of the ring;

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

(d) optionally further converting a salt form of a compound of Formula I into a form other than a salt;

-36 (e) optionally further converting a non-oxidized form of a compound of Formula I into a pharmaceutically acceptable / V-oxide;

(f) optionally further converting the / V-oxide form of the compound of Formula I into its non-oxidized form;

(g) optionally further converting a non-derivatized compound of Formula I into a pharmaceutically acceptable prodrug derivative; and (h) optionally further converting the prodrug derivative of the compound of Formula I into its non-derivatized form.

Examples:

The following examples are given for purposes of explanation only and should in no case be construed as limiting the scope of the present invention. It will be apparent to those skilled in the art that certain variations and modifications may be made within the scope of the invention.

EXAMPLE 1 2-Naphth-2-ylethylamine

A solution comprising 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 ml) was combined with dipheniphosphoryl azide (0.74 ml, 3.42 mmol) and 1,8diazabicyclo [5.4.0] undec- in a nitrogen atmosphere. 7-ene (0.47 ml, 3.14 mmol). The mixture was heated at 65 ° C for 3 hours and then partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3 N hydrochloric acid and then saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was dissolved in THF (5 ml) and the solution was combined with triphenylphosphine (1 g, 3.81 mmol), stirred for 2 hours at room temperature, diluted with water (0.100 ml), stirred for 3 hours, diluted with concentrated hydrochloric acid (0.33 ml ) to give a precipitate, treated with ethanol (5 ml) to dissolve the precipitate and treated with diethyl ether added slowly to give a white precipitate. The white precipitate was isolated by filtration, washed with diethyl

-37 ether and dried in vacuo to give 2-naphth-2-ylethylamine hydrochloride (0.447 g, 75% yield);

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

Following the procedure as in Example 1, the following amine intermediates were prepared:

2-naphth-1-ylethylamine, yield = 56%, ¹ H-NMR (300MHz, DMSO-d ₆ ): 8.26 (brs, 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, J = 7.4 Hz) ;

3- cyclohexylpropylamine, yield = 40%, ¹ H-NMR (300MHz, CDCl 3): 2.68 (t, 2H, J = 7.2 Hz), 2.17 (br s, 2H), 1.64-1.71 (m, 5H), 1.46 ( m, 2H), 1.18 (m, 6H), 0.87 (m, 2H);

3-phenyl-2-propenilamin, yield = 53% ¹ H-NMR (300MHz, DMSO-dg): 8.39 (br s, 3H), 7.267.41 (m, 5H), 6.72 (d, 1 H, J = 16.2 Hz), 6.29 (dt, 1H, J = 16.2, 6.6 Hz), 3.56 (d, 2H, J = 6.6 Hz);

3-phenyl-2-propinilamin, yield = 62% ¹ H-NMR (300MHz, DMSO-dg): 8.67 (br s, 2H), 7.387.42 (m, 5H), 3.91 (m, 2H); and

3,3-difenilpropilamin, yield = 50% ¹ H-NMR (300MHz, DMSO-dg) 8.10 (br s, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1 H, J = 7.9 Hz), 2.62 (m, 2H), 2.33 (m, 2H).

EXAMPLE 2

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (4-phenylbutyl) -1H-benzoimidazole-5carboxamide trifluoroacetate (Compound 1) (a) Ethyl cyanoacetate (8 ml, 75 mmol) in anhydrous benzene (100 ml) was combined with anhydrous ethanol (6 ml, 105 mmol) under nitrogen atmosphere. The mixture was cooled to 10 [deg.] C. (ice / acetone) and dried over 20 minutes with dry gas hydrogen chloride. We're a mixture

-38 Slowly warm to room temperature, stopper and stir for about 18 hours. The mixture was diluted with diethyl ether (400 ml) and allowed to stand for 5 hours at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to give ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; ¹ H-NMR (300MHz, CDCl 3): 7.84 (d, 1 H, J = 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J = 5.7) Hz), 2.73 (t, 2H, J = 6.5 Hz), 1.89 (m, 4H).

(b) A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-3-iminopropionate and glacial (15 ml) was stirred for 30 minutes at 110 ° C under a nitrogen atmosphere. The mixture was poured over crushed ice (50 ml) and stirred for 30 minutes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 ml) was added to give a gray precipitate. The precipitate was isolated by filtration, 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 HNMR (300MHz, DMSO-d ₆ ): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7.57 (d, 1 H, J = 8.4 Hz) , 4.11 (q, 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) was stirred at -10 ° C (ice-acetone mixture) in nitrogen atmosphere, while diethyl 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 stored at -20 ° C for about 18 hours to give a crystalline solid. The solid was isolated by filtration and washed to give 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (24.6 g, 67% yield) as a gray-white crystalline solid; ¹ H-NMR (300MHz, DMSO-d 6): 7.877.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H).

(d) A mixture of 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (8 g, 24.4 mmol) prepared as in Example 1 and 10% palladium on carbon (300 mg) was combined with anhydrous ethanol ( 200 ml), anhydrous THF (100 ml) and ice (30 ml) under a continuous stream of nitrogen. The mixture was then stirred vigorously for 15 hours at room temperature under a hydrogen atmosphere, filtered and concentrated to a volume of about 30 ml by rotary evaporation. The mixture was diluted with water (100 ml) and ammonium hydroxide was added to give an orange precipitate. We're precipitation

-39 was filtered and washed several times with water to give 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 (broad s, 4H), 4.47 (s, 2H).

(e) Finely ground mixture of 2- (3,4-diaminobenzyl) isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated for 1 hour at 185 ° C under a nitrogen atmosphere. The mixture was suspended in a 1: 1 mixture of methylene chloride and ethanol (20 ml) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with a 1: 1 methylene chloride / ethanol mixture (3 x 20 mL) and dried to give 2- [5- (1,3-dioxo-1,3 dihydroisoindol-2-ylmethyl) - 1 H -benzoimidazol-2-ylmethyl] -1 H -benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); ¹ H-NMR (300MHz, DMSO-d ₆ ): 12.45 (broad s, 1H), 8.07 (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-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.05 g, 0.111 mmol) was dissolved in anhydrous dimethylformamide (0.5 ml) and the solution was combined with 1-hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (0.063 g, 0.121 mmol) and N-0.01 mmol (0.13 mmol), N-8 mmol ) at room temperature in an atmosphere of dry N2. After 2 minutes, 4-phenylbutylamine (0.02 ml, 0.127 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel containing 20% ethanol solution in ethyl acetate (7 ml), 0.2 N HCl (3.5 ml) and saturated aqueous NaCl (3.5 ml). The aqueous phase was extracted once with a 20% solution of ethanol in ethyl acetate (7 ml) and the combined organic phases were washed with a solution containing 0.2 N HCl (3.5 ml) in saturated aqueous NaCl (3.5 ml), followed by final washing with saturated aqueous sodium bicarbonate solution (7 ml). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness on a rotavapor to give 2- [5 (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazole- 2-ylmethyl] - N - (3-phenylpropyl) -1 Hbenzoimidazole-5-carboxamide as a crude material (0.14 g).

(g) 2- (5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] - N - (3-phenylpropyl) -1 H -benzoimidazole- 5-carboxamide (0.14 g, crude material) was dissolved in

-40hydrous ethanol (0.5 ml) and the solution combined with anhydrous hydrazine (0.15 ml, 0.48 mmol). The mixture was heated at reflux in an N ₂ atmosphere for 1 hour and then concentrated on a -4 rotavapor. The residue was placed in a vacuum (2x10 bar) for 2 hours to remove excess hydrazine. The residue was diluted with 3 M HCl (0.5 ml) and the mixture was heated at 50 ° C for 20 minutes. The reaction mixture was cooled to room temperature and stirred for an additional 20 minutes to give a solid precipitate. The precipitate was isolated by filtration and washed with water (4 x 1.5 ml). The filtrates were combined and washed with a 20% solution of ethanol in ethyl acetate (2x7 ml). The combined aqueous phases were lyophilized to give the crude product as the hydrochloride salt. The crude material was purified by preparative reverse phase HPLC to give 2- (5- (1,3 dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -N- (3- Phenylpropyl) -1H-benzoimidazole-5-carboxamide (0.04 g, 0.07 mmol) as a white solid; ¹ H-NMR (300 MHz, CD ₃ OD): 8.14 (s, 1H), 7.84-7.89 (m, 2H), 7.77 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.1 Hz), 7.56 (d, 1H, J = 8.1 Hz), 7.12-7.27 (m, 5H), 4.29 (s, 2H) , 3.43 (t, 2H, J = 7.2 Hz), 2.66 (t, 2H, J = 7.2 Hz), 1.69 (m, 4H).

Following the procedure as in Example 2, the following compounds of the invention were prepared:

2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) - N-naphth-1-ylmethyl-1 H -benzoimidazole-5carboxamide (Compound 2), ¹ H-NMR (300MHz, 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) - / \ / - benzyl-1/7-benzoimidazole-5-carboxamide (Compound 3) ¹ H-NMR (300MHz, CD3OD) 8.18 ( s, 1H), 7.91 (d, 1H, J = 7.9 Hz), 7.82 (S, 1H), 7.76 (d, 1H, J = 7.9 Hz), 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-1H-benzoimidazol-2-ylmethyl) - / V- (3-phenylpropyl) -1 H-benzoimidazol-5karboksamid (Compound 4) ¹ H-NMR (300MHz, CD3OD): 8.14 (s, 1H), 7.87 (d, 1H, J = 8.6 Hz), 7.8 (s, 1H), 7.76 (d, 1H, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 7.54 (d. 1H, J = 8.6 Hz), 7.24 (m, 4H), 7.16 (m, 1H), 4.28 (s, 2H), 3.46 (t, 2H, J = 7.9 Hz), 2.95 (t, 2H, J = 7.9 Hz), 1.62 (quintet, 2H, 7.9 Hz);

-412- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2-phenylethyl) -1H-benzoimidazol-5karboksamid (Compound 5) ¹ H-NMR (300MHz, DMSO-d6): 12.8 ( 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-1H-benzoimidazol-2-ylmethyl) - / V- (3-aminomethyl) benzyl-1H-benzoimidazol-5karboksamid (Compound 6) ¹ H-NMR (300MHz, DMSO-dg): 9.31 ( t, 1H, J = 5.7 Hz), 8.58 (br s, 3H), 8.41 (br s, 3H), 8.28 (s, 1H), 7.97 (m, 2H), 7.79 (d, 1H, J = 9.3 Hz). ), 7.75 (d, 1H, J = 9.3 Hz), 7.59 (d, 1H, J = 9.3 Hz), 7.43 (s, 1H), 7.35 (s, 3H), 5.07 (s, 2H), 4.50 (m , 2H), 4.18 (m, 2H), 3.97 (m, 2H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2-aminoethyl) -1-methyl-1H-benzoimidazol-5karboksamid (Compound 7) ¹ H-NMR (300MHz, DMSO- d6): 8.86 (br, 1H), 8.50 (br s, 3H), 8.24 (s, 1H), 8.08 (br s, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J = 8.7 Hz), 7.55 (d, 1 H, J = 9.2 Hz), 5.02 (brs, 2H), 4.16 (m, 2H), 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H) );

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2-aminoethyl) -1H-benzoimidazol-5karboksamid (Compound 8) ¹ H-NMR (300MHz, DMSO-dg): 8.97 ( t, 1H, J = 4.3 Hz), 8.58 (br s, 3H), 8.31 (s, 1H), 8.16 (brs, 3H), 7.97 (m, 2H), 7.79 (d, 1H, J = 10 Hz) , 7.73 (d, 1H, J = 10 Hz), 7.59 (d, 1H, J = 10 Hz), 5.09 (s, 1H), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m. 2H);

2- (5-Aminomephyl-1H-benzoimidazol-2-ylmethyl) - N - (4-aminobutyl) -1H-benzoimidazole-5carboxamide (Compound 9), ¹ H-NMR (300MHz, DMSO-d ₆ ): 8.77 (t, 1H, J = 5.7 Hz), 8.61 (br s, 3H), 8.24 (s, 1H), 7.90-8.02 (m, 5H), 7.78 (d, 1H, J = 9.3 Hz), 7.74 ( d, 1H, J = 9.3 Hz), 7.60 (d, 1H, J = 9.3 Hz), 5.09 (s, 1H), 4.18 (m, 2H), 3.28 (m, 2H), 2.78 (m, 2H). 1.12 (m, 4H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (3-aminopropyl) -1H-benzoimidazol-5karboksamid (Compound 10) ¹ H-NMR (300MHz, DMSO-de): 8.9 (t , 1H, J = 5.0 Hz), 8.53 (br s, 3H), 8.23 (s, 1H), 7.97 (br s, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J = 8.6 Hz). , 7.78 (d, 1H,

-42J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 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) - / \ / - cyclohexylmethyl-1H-benzoimidazol-5karboksamid (Compound 11) ¹ H-NMR (300MHz, CD3OD)?: 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), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).

EXAMPLE 3

2- (5-Aminomethyl-1/7-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole5-carboxamide (Compound 12) (a) A mixture comprising 3- nitro-4-chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine and water (10 ml) were heated in a sealed tube at 100 ° C for 11 hours, concentrated to 1 ml and then diluted with concentrated hydrochloric acid to give yellow precipitate. The precipitate was isolated by filtration, washed with water and then 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, 1 H, J = 2.1 Hz), 8.52 (q, 1 H, J = 8.6 Hz), 7.94 (dd, 1 H, 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 mi) was added to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09 g, 10.7 mmol) and 10% Pd / C (30 mg) under a constant stream of N ₂ . The mixture was stirred under a hydrogen atmosphere for 16 hours, filtered through a 0.22 [mu] m filter disk, type GV, and concentrated on a rotary evaporator. The residue was dried in vacuo to give 3-amino-4methylaminobenzoic acid (1.1 g, 61% yield).

(c) Ethyl 3-ethoxy-3-iminopropionate prepared as in Example 2 (a) was allowed to react with 3-amino-4-methylaminobenzoic acid under conditions similar to those described in Example 2 ( b) to give 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5carboxylic acid (71% yield); ¹ H-NMR (300MHz, DMSO-dg); 7.18 (dd, 1H, J = 8.1 Hz),

-437.11 (d, 1H, J = 1.2 Hz), 6.33 (d, 1H, J = 8.1 Hz), 5.28 (br s, 1H), 4.67 (br s, 1H), 3.34 (br s, 2H), 2.72 (s, 3H).

(d) 2- (3,4-Diaminobenzyl) isoindole-1,3-dione prepared as in Example 2 (d) was allowed to react with 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid under conditions similar to those described in Example 2 (e) to give 2- (5- (1,3-dioxo-1,3 dihydroisiondol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] - 1-methyl-1H-benzoimidazol-5karboksilno acid (48% yield); ¹ H-NMR (300MHz, DMSO-d6) 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H , J = 10.0 Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (S, 3H).

(e) 2- (5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methylH-benzoimidazole-5-carboxylic acid (0.05 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 the mono-BOC protected derivative of 1,3-diaminopropane were dissolved at 0 ° C in methylene chloride (1 ml) and DMF (the minimum amount was sufficient to form a solution) The solution was adjusted to pH ~ 8 with N-methylmorpholine and the mixture was allowed to warm slowly to room temperature and then stirred for 20 hours. was transferred to a funnel separator, diluted with methylene chloride, washed with 0.1 N HCl solution and then saturated NaHCC solution> 3, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (10% methanol / ethyl acetate) to give 2- [6- (1,3-dioxo-1,3 dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1-methyl- N - (3-aminopropyl) -1H-benzoimidazole was obtained -5-carboxamide (0.02 g, 28% profit); ¹ H-NMR (300MHz, CDCl 3): 7.757.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (brs, 1H), 7.27 (d, 1H, J = 8.6 Hz), 7.15 (d , 1H, J = 9.3 Hz), 5.10 (brt, 1H), 4.90 (brs, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J = 7.2 Hz), 3.24 (q, 2H, J = 7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H).

(f) 2- (6- (1,3-Dioxo-1,3-dihydroisoin dol-2-ylmethyl) -1,7-benzoimidazol-2-ylmethyl] -1-methyl-N / (3-aminopropyl) -1H-benzoimidazole-5-carboxamide was deprotected under conditions similar to those described in Example 2 (g) to give 2- (5-aminomethyl-1 Hbenzoimidazol-2-ylmethyl) - N - (3-aminopropyl) ) -1-methyl-1H-benzoimidazole-5-carboxamide (20% yield); ¹ H-NMR (300MHz, DMSO-d _6): 8.85 (t, 1H, J = 5.7 Hz), 8:55 (br s, 3H), 8.20 (s,

-441Η), 8.01 (brs, 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).

Following the procedure as in Example 3, the following compounds of the invention were prepared:

3- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N / - (2-naphth-1-ylethyl l) -1 / 7-benzoimidazol-5karboksamid (Compound 13) ¹ H-NMR (300MHz, 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) -1H-benzoimidazole-5carboxamide (Compound 14), ¹ H-NMR (300MHz, CD 3 OD): 8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J = 9.3 Hz), 7.56 (d, 1H, J = 9.3 Hz), 7.23-7.39 (m, 8H), 7.13 -7.19 (m, 2H), 4.30 (S, 2H), 4.07 (t, 1 H, J = 7.2 Hz), 3.40 (t, 2H, J = 7.2 Hz), 2.44 (q, 2H, J = 7.2 Hz) );

2- (5-aminomethyl-1/7-benzoimidazol-2-ylmethyl) - / \ / - (2-naphth-2-yl-ethyl) -1H-benzoimidazol-5karboksamid (Compound 15) ¹ H-NMR (300MHz, CD3OD ): 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- (1 H-benzoimidazol-2-ylmethyl) -N- [2- (1H-indol-3-yl) ethyl] -1 H-benzoimidazole-5-carboxamide (Compound 16) ¹ H-NMR (300MHz , CD3OD): 8.09 (s, 1H), 7.81-7.84 (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-benzoimidazol5-carboxamide (Compound 17) ¹ H-NMR (300MHz, CD3OD): 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);

-452- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (2,3,4,5,6-pentahydroxyhexyl) -1Hbenzoimidazol-5-carboxamide (Compound 18) ¹ H-NMR (300MHz , CD3OD / D2O (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) - / \ / - (2-phenoxyethyl) -1 / 7-benzoimidazol-5karboksamid (Compound 19) ¹ H-NMR (300MHz, CD3OD) 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) - / V- (3-phenylprop-2-ynyl) -1-benzoimidazol-5karboksamid (Compound 20) ¹ H-NMR (300MHz, 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 Hz), 7.71 (d, 1H, J = 9.3 Hz) , 7.55 (d, 1H, J = 9.3 Hz), 7.38-7.43 (m, 2H), 7.28-7.32 (m, 3H), 4.40 (s, 2H), 4.27 (s, 2H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) - / V- (E-3-phenylallyl) -1 H-benzoimidazol-5karboksamid (Compound 21) ¹ H-NMR (300MHz, CD3OD): 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) - / V- (3-cyclohexylpropyl) -1H-benzoimidazol-5karboksamid (Compound 22) ¹ H-NMR (300MHz, CD3OD): 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-1H-benzoimidazol-2-ylmethyl) - / V-oct-1-yl-1 H-benzoimidazol-5karboksamid (Compound 23) ¹ H-NMR (300MHz, CD3OD): 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, 11 H), 0.88 ( m, 2H);

-462- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-methyl-N- (2-phenylethyl) -1H-benzoimidazole-5carboxamide (Compound 24), ¹ H-NMR (300MHz, CD ₃ OD); 7.76 (s), 7.69 (d), 7.63 (d), 7.447.55 (m), 7.20-7.28 (m), 7.09-7.14 (m), 6.97 (d), 6.85 (brs), 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) - / V- (1-methyl-3-phenylpropyl) -1 H-benzoimidazol-5karboksamid (Compound 25) ¹ H-NMR (300MHz, 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), 1.171.93 (m, 2H), 1.18 (d, 3H, J = 7.2 Hz).

PEIMER4

C- {2- [5- (4-Phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazol-5-yl} methylamine (Compound 26) (a) 4-Phenyl-1-butanol (1 ml , 6.49 mmol) in THF (3 ml) was combined under dry nitrogen atmosphere with sodium hydride (0.26 g, 6.5 mmol) in 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 for 10 hours at room temperature. The mixture was partitioned between diethyl ether and 3 N hydrochloric acid. The aqueous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography (mixture of hexane and diethyl ether, 9: 1) to give 4- (4-phenylbutoxy) -1,2-dinitrobenzene (1.16 g, 72% yield); ¹ H-NMR (300MHz, CDCl 3): 7.84 (d, 1 H, 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) Ethyl 3-ethoxy-3-iminopropionate prepared as in Example 2 (a) was allowed to react with 2- (3,4-diaminobenzyl) isoindole-1,3-dione under conditions similar to those described in Example 2 (b) to give ethyl 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazole-2yl acetate (71% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J = 9.43 Hz), 4.82 (s, 2H). 4.07 (q, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J = 7.2 Hz).

-47 (c) 4- (4-Phenylbutoxy) -1,2-dinitrobenzene was reduced under conditions similar to those described in Example 3 (b) to give 4- (4-phenylbutoxy) benzene-1,2- diamine (86% crude yield).

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

(e) 2- {2- [5- (4-Phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -3 / 7-benzoimidazol-5ylmethyl} isoindole-1,3-dione was deprotected under conditions similar to those observed; described in Example 2 (g) to give C- {2- [5- (4-Phenylbutoxy) -1H-benzoimidazol-2-ylmethyl] -1Hbenzoimidazol-5-yl} methylamine (0.05 g, 55% yield ); ¹ H-NMR (300MHz, CD 3 OD): 7.83 (d, 1 H, 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, 1 H, 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 5

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

2- (5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-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 (0.022 ml, 0.158 mmol) at room temperature under a nitrogen atmosphere. 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 3 N hydrochloric acid (0.5 ml), and the mixture was stirred for 20 minutes at 55 ° C. C and jo

-48 then filtered. The filtered solids were washed with 3 N hydrochloric acid and the combined filtrates were washed with ethyl acetate (15 ml) and lyophilized. The residue was purified by preparative reverse phase HPLC to give the desired product (0.008 g, 11% yield); ¹ H-NMR (300MHz, 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) , 7.387.44 (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 6

2- (5-Guanidino-1 H -benzoimidazol-2-ylmethyl) - N - (2-naphthalen-1-ylethyl) -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 28) (a) Solution. comprising 2-nitro-1,4-phenylenediamine (21.0 g, 137 mmol) in ethanol (350 ml) and 4.0 M hydrogen chloride in dioxane (30.8 ml, 123 mmol) were stirred at room temperature for 15 minutes and then diethyl ether ( 1 I) that we were given a precipitate. The precipitate was collected by filtration, washed with additional diethyl ether and dried in vacuo to give 2-nitro-1,4-phenylenediamine hydrochloride (23.3 g, 100% yield).

(b) A mixture comprising 2-nitro-1,4-phenylenediamine hydrochloride (15.0 g, 79.1 mmol), cyanamide (25.0 g, 595 mmol) and water (5 ml) was heated at 60 ° C and stirred for 1.5 hours, allowed to cool to room temperature and then slowly added excess diethyl ether to obtain a precipitate. The precipitate was collected by filtration, washed with additional diethyl ether and dried in vacuo to give the hydrochloride of N- (4-amino-3-nitrophenyl) guanidine (18.0 g, 98% yield); ¹ H-NMR (300MHz, DMSO-d ₆ ): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7.1 (d).

(c) A mixture comprising hydrochloride / N- (4-amino-3-nitrophenyl) guanidine (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 ml) and methanol (100 ml) hydrogenated at 1.013 bar, filtered and concentrated in vacuo to give the hydrochloride N (3,4-diaminophenyl) guanidine (10.3 g, 98% yield) as a dark solid; ¹ H-NMR (300MHz, DMSO-d6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).

-49 (d) A mixture comprising hydrochloride / N- (3,4-diaminophenyl) guanidine (9.9 g, 49 mmol), ethoxycarbonimidoylacetic acid ethyl ester hydrochloride (12.4 g, 59 mmol) and acetic acid (20 ml) was heated to oil bath at 110 ° C and stirred for 1.5 hours, 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 excess ethyl ether was added to the filtrate to give a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried in vacuo to give the hydrochloride of ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate (14.1 g, 94% yield) as a gray-white solid; ¹ H-NMR (300MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s),

4.2 (q), 1.2 (t).

(e) A mixture comprising 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 slurry of 1M aqueous hydrochloric acid and ice to give an orange precipitate. The precipitate was collected by filtration, washed with water and recrystallized from hot ethanol to give 3-methylamino-4-nitrobenzoic acid as a living red crystalline solid (3.6 g, 73% yield); ¹ HNMR (300MHz, DMSO-d ₆ ); 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).

(f) Mixture comprising 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxybenztriazole hydrate (9.9 g, 73.0 mmol), dimethylformamide (100 ml) and N-methylmorpholine (18.3 ml) was stirred at room temperature for 15 minutes and then 2-naphthylene-1-ylethylamine (13.8 g, 66.3 mmol) was added. The mixture was stirred for an additional 30 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, 0.1 M aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by recrystallization from hot ethanol to give 3-methylamine-W- (2-naphthalen-1-yl-ethyl) -4nitrobenzamide as a living red crystalline solid (21.3 g, 92% yield); ¹ H-NMR (300MHz, DMSO-dg): 8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d), 7.8 (d), 7.6-7.3 (m), 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 (d).

-50 (g) Mixture comprising 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) were hydrogenated at 1,013 bar of hydrogen, 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 discolored amorphous solid; ¹ H-NMR (300MHz, DMSO-d ₆ ); 8.3 (d), 8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 (m), 7.1 (d), 6.9 (s), 6.5 (d), 5.0 (s), 3.5 (q ), 3.2 (t), 2.7 (s).

(h) A mixture comprising the hydrochloride of ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N- (2-naphth-1-ylethyl) -4- benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 ml) were heated in an oil bath at 185 ° C and stirred under a nitrogen atmosphere

3.5 hours, cooled to room temperature and poured into stirred acetonitrile (150 ml) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 ml), collected by filtration and dried in vacuo to give a gray-white solid. The solid was purified by preparative reverse phase HPLC to give 2- (5-guanidino-1 H -benzoimidazol-2ylmethyl) -N- (2-naphth-1-ylethyl) -3-methyl-3H- benzoimidazole-5-carboxamide as a white solid (0.5 g, 57%); LRMS (ESI): Calculated for C30H28N8O: 516.6; Found (MH ⁺ ): 517.2.

EXAMPLE 7

Ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridin-5-yl} - 4-Oxobutyl) benzoate (Compound 29) (a) A solution comprising ethyl 2-cyanopropionate (100 g, 0.29 mol) in ethanol (65 ml) was cooled to 0 ° C and then saturated with dry gas hydrogen chloride. The mixture was allowed to warm to room temperature, stirred for 24 hours, cooled to 0 ° C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred for a further 24 hours. Ethyl ether: hexane (1: 1) was added to the mixture to give a precipitate. The precipitate was isolated by filtration and dried in vacuo to give the ethyl hydrochloride ethyl 2- ((V-ethoxyamidino) propionate (119.6 g, 73% yield) as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H).

-51 (b) A mixture comprising 3,4-diaminopyridine (51.7 g, 0.46 mol), ethyl 2- (Netoxyamidino) propionate hydrochloride (125 g, 0.69 mol) and glacial (200 ml) was heated at 85 ° C and stirred 18 hours and then warmed to 120 ° C and stirred for an additional hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized by the addition of excess 5M aqueous ammonium hydroxide and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated in vacuo to give ethyl 1H-imidase [4,5-c] pyridine-2-carboxylate (60.4 g , 58% yield); ¹ H NMR (300MHz, CDCl ₃ ): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3.90 (q, 1H), 1.75 (d. 3H), 1.25 (tr, 3H).

(c) A mixture comprising ethyl 1H-imidase [4,5-c] pyridine-2-carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 ml) and platinum oxide (2.5 g) was hydrogenated in a Parr hydrogenation apparatus at 3.44 bar of hydrogen for 24 hours, filtered and concentrated in vacuo. The oily residue was dissolved in a minimal amount of ethanol and dry hydrogen chloride in dioxane solution (4 M, 120 ml, 475 mmol) was added to the solution. An excess of ethyl ether was added to the solution to give a precipitate. The precipitate was collected by filtration and dried in vacuo to give ethyl 1,4,6,7-tetrahydro-1/4-imidazo [4,5-c] pyridine-2-carboxylate dihydrochloride (30.7 g, 66% yield) ); ¹ H NMR (300MHz, DMSO-d ₆ ): 10.00 (br s, 2H), 4.35 (q, 1H), 4.20 (br s, 2H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (brs, 2H), 1.55 (d, 3H), 1.15 (tr, 3H).

(d) A mixture comprising the dihydrochloride ethyl 1,4,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2carboxylate (60.2 g, 0.20 mol), acetonitrile (500 ml) and diisopropylethylamine (100 ml , 0.60 mol) was cooled to 0 ° C and stirred while benzylchloroformate (58 ml, 0.40 mol) was added slowly. The mixture was slowly warmed to room temperature, stirred for an additional 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 aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a colorless solution. The residue was dissolved in ethanol (320 ml) and the solution cooled to 0 ° C, then sodium ethoxide in ethanol solution (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, 50 ml) was added. The mixture was concentrated in

-52 vacuum and the residue was dissolved in ethyl acetate (250 ml) and saturated aqueous sodium hydrogen carbonate. 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-tetrahydroimidase [4,5-c] pyridine -2,5 Dicarboxylate as yellow amorphous material (52 g, 72% yield); ¹ H NMR (300MHz, DMSOdg): 11.75 (br s, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (br s, 2H), 4:05 (m, 2H), 3.75 (q, 1H) ,

3.65 (br s, 2H), 1.40 (d, 3H), 1.15 (tr, 3H).

(e) A mixture comprising 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) was heated at 50 °. C under a dry nitrogen atmosphere for 12 hours to give a white suspension. The suspension was partitioned between ethyl ether (250 ml) and the water and the organic layer separated and washed successively with water, then 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 a colorless oil. The oil was distilled at -4 o

6.66 x 10 bar (51 C) to give ferrobutyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); ¹ H NMR (300MHz, CDCl ₃ ): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H), (f) Mixture comprising ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g, 18.9 mmol), dimethylformamide (25 ml) and tert-butyl 4-chlorobutyrate (4.08 g, 22.8 mmol) were heated at 70 ° C and stirred for 12 hours. The mixture was partitioned between ethyl ether (100 ml) and the water and organic layer separated and washed with additional water (3x) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane to a mixture of hexane: ethyl acetate (10: 1) to give ethyl 2- (3-tert-butoxycarbonylpropoxy) benzoate (3.6 g, 62% yield) as a colorless oil; ¹ H NMR (300MHz, CDCl 3): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H) , 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).

(g) Ethyl 2- (3-tert-butoxycarbonylpropoxy) benzoate (3.60 g, 11.7 mmol) was treated with excess trifluoroacetic acid at room temperature for one hour. We are the solution

-53 concentrated in vacuo and the oily residue purified by silica gel flash chromatography using a mixture of hexane: ethyl acetate (10: 1) to pure ethyl ether to give 4- (2ethoxycarbonylphenoxy) butyric acid as a colorless crystalline solid (2.81 g, 95%, 2.81 g, 95%) profit); ¹ H NMR (300MHz, CDCl ₃ ): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H) ), 2.20 (m, 2H), 1.40 (mp, 3H).

(h) Mixture comprising benzyl 2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo [4,5c] pyridine-5-carboxylate (1.7 g, 4.8 mmol), hydrochloride / N- (3,4-diaminophenyl) guanidine (0.8 g, 4.0 mmol) and dimethylformamide (2 ml) were 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 stirred acetonitrile (150 ml) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150 ml), collected by filtration and dried in vacuo to give a gray-white solid. The solid was purified by preparative reverse phase HPLC to give benzyl 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidase [4,5 -c] pyridine-5carboxylate as a white solid (1.0 g, 55% yield); LRMS (ESI); Calculated for θ24 ^Η 26Ν8θ2 · 458.5; Found (MH ⁺ ); 459.2.

(i) A mixture comprising benzyl 2- [1- (5-guanidino-1W-benzoimidazol-2-yl) ethyl] -1,4,6,7tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (1.0 g , 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 ml) and methanol (50 ml) were hydrogenated at 1,013 bar, filtered and concentrated in vacuo to give Λ / - {2- [1 - (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2yl) ethyl] -1H-benzoimidazol-5-yl} -guanidine (0.69 g, 97% yield); LRMS (ESI); Calculated for C-I6H20N8 ·· 324.4; Found (MH ⁺ ): 325.2.

(j) Mixture comprising 4- (2-ethoxycarbonylphenoxy) butyric acid (155 mg, 0.61 mmol), PyBOP (360 mg, 0.69 mmol), hydroxybenztriazole hydrate (87 mg, 0.64 mmol), Nmethylmorpholine (0.16 ml, 0.92 mmol) and dimethylformamide (2.5 ml) was stirred at room temperature for 10 minutes and then N- {2- [1- (4,5,6,7-tetrahydroimidase [4,5-c] pyridin-2yl) ethyl] -3 N - Benzimidazol-5-yl} guanidine (203 mg, 0.63 mmol). The mixture was stirred for 3 hours at room temperature and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product was purified by preparative reverse phase HPLC. The combined pure fractions were then lyophilized to give ethyl 2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-54yl) ethyl] -1,4,6,7-tetrahydroimidase [4 , 5-c] pyridin-5-yl} -4-oxobutyl) benzoate; LRMS (Bioion): Calculated for 02 ^ 34 ^ 04: 558.6; Found: 559.3.

EXAMPLE 8

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 30) (a) A solution of tert-butyl 2-hydroxyethylcarbamate (25 ml, 161.6 mmol) in dichloromethane (60 ml) was cooled to 0 ° C and stirred, while diisopropylethylamine (33.8 ml, 193.9 mmol) was added first and then mesyl chloride (13.7) was added dropwise. 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 (3M, 3 x 25 ml) and saturated aqueous sodium hydrogen carbonate (2 x 25 ml). . The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17NO5S m / e calcd. 239.08; found 240 (MH ⁺ ).

(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 and tert-butyl-2methylsulfonyloxyethylcarbamate (37.39 g, 156 mmol) was added dropwise. The mixture was stirred at 23 ° C for 18 hours and concentrated in vacuo. The residue was dissolved in hexane and the organic layer was washed with water and brine, dried (Na ₂ SO4) and concentrated in vacuo to give ferrobutyl 2bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI) C7H- | 4BrNO ₂ m / e calcd. 224.10; found 225 (MH &lt; ⁺ &gt;).

(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 while tert -butyl 2bromoethylcarbamate (20 g, 89.3) was added. mmol). The mixture was stirred for 24 hours 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 a mixture of ethyl ether.hexane (1: 1, 3 x 40 ml) and the combined organic layers were dried (Na ₂ SO4) and concentrated in vacuo to give tert-butyl 2- (2-methoxyphenoxy) ethylcarbamate ( 23.22

-55g, 97% yield) as a yellow oil; MS (PB-PCI) C14H21NO4 m / e calcd. 267.32; found 268 (MH &lt; ⁺ &gt;).

(d) Tert-Butyl 2- (2-methoxyphenoxy) ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 ° C and stirred while trifluoroacetic acid: dichloromethane (1: 1, 40 ml) was added dropwise. The mixture was allowed to warm to 23 ° C, stirred for 2 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (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- (2methoxyphenoxy) ethylamine (13 g, 88% yield), a pale yellow solid, was obtained; MS (PB-PCI) C9H13NO2 m / e calcd. 167.21; found.168 (MH ⁺ ).

(e) A heterogeneous mixture containing 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 ml, 391 mmol) was refluxed for one hour. Excess thionyl chloride was removed by distillation and the residue was concentrated in vacuo to give 3methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a pale yellow solid; MS (PBPCI) C ₈ H ₆ CINO ₄ m / e calc. 215.59; found 216 (MH &lt; ⁺ &gt;).

(f) A mixture comprising 2- (2-methoxyphenoxy) ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 ml, 81.6 mmol) and dichloromethane (80 ml) was cooled to 0 ° C and a solution of 3- was added dropwise. 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 gave N - [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4nitrobenzamide (14 g, 74% yield), a fuzzy white solid; MS (PB-PCI) C17H- [qN2O6] m / e calcd. 346.34; found 347 (MH &lt; ⁺ &gt;).

(g) Mixture comprising N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 ml) and DMSO (2 ml) in a sealed tube, it was heated at 110 ° C for 4 hours, cooled and then poured into water (25 ml). The diluted mixture was treated with 3 M aqueous hydrochloric acid to give an orange solid. The solid was isolated

-56s filtration to give N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI) C17H19N3O5 m / e calcd. 345.35; found 346 (MH &lt; ⁺ &gt;).

(h) Mixture comprising N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), suspended palladium on carbon (10%, 0.5 g) in methanol (100 ml ) and tetrahydrofuran (50 ml) were stirred under a hydrogen atmosphere at ambient pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to give 4-amino- N- [2- (2methoxyphenoxy) ethyl] -3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PB-PCI) C-17H21N3O3 m / e calcd. 315.37; found 316 (MH &lt; ⁺ &gt;).

(i) A mixture comprising 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), palladium on carbon (10%, 1.0 g) and methanol (50 ml) was hydrogenated in a Parr apparatus at 3.44 bar for 3 hours, filtered through celite and concentrated in vacuo to give 3,4-diaminophenol (4.02 g, 91% yield) as a dark solid; MS (PB-PCI) C6H8N2O m / e calcd. 124.16; found 125 (MH &lt; ⁺ &gt;).

(j) A mixture comprising 3,4-diaminophenol (3.661 g, 29.5 ml), ethyl 2 - (/ Vetoxyamidino) propionate (7.423 g, 38.4 mmol) and ethanol (30 ml) was refluxed for 6 hours and concentrated in vacuo. . The residue was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3 x 20 ml) and brine (1 x 20 ml), dried (MgSO4) and concentrated in vacuo to give ethyl 2- ( 5-hydroxyH-benzoimidazol-2-yl) propionate (6.3 g, 91% yield) as a dark solid. The solid was further purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI) C12H14N2O3 m / e calcd. 234.28; found 235 (MH &lt; ⁺ &gt;).

(k) Mixture comprising ethyl 2- (5-hydroxy-1H-benzoimidazol-2-yl) propionate (148 mg, 0.63 mmol), 4-amino- N - [2- (2-methoxyphenoxy) ethyl] - 3-Methylaminobenzamide (200 mg, 0.63 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (0.5 ml) were stirred at room temperature until homogeneous, degassed in vacuum and concentrated by heating at 170 ° C for 2 hours under N2 flow. The residue was cooled to room temperature and washed with excess diethyl ether. The resulting amorphous material was dissolved in 50% aqueous acetonitrile and purified by preparative reverse phase HPLC (2-50% CH3CN / H2O) to give 2- [1- (5-hydroxy-1H-57benzoimidazol-2-yl) ethyl] - N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (40 mg, 13% yield) as a light pink solid; MS (Biolon) C27H27N5O4 m / e calcd. 485.59; found 486.5 (MH &lt; ⁺ &gt;).

Following the procedure as in Example 8, the following compounds of the invention were prepared:

Methyl 2- (2- {2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoate (Compound 31 ), MS (Biolon) C28H26N5O4F m / e calcd. 515.54; found 516 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 32), MS (Biolon) C27H24N5O4F m / e calcd. 501.52; found 502.1 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 33), MS (Biolon ) C29H29N5O5 m / e calcd. 527.58; found 528.1 (MH ⁺ );

2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 34), MS (Biolon) C27H25N5O5 m / e calcd. 499.53; found 500.1 (MH &lt; ⁺ &gt;);

N-ethyl-2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (Compound 35), MS (Biolon) C20H21N5O2 m / e calc. . 363.42; found 364.1 (MH &lt; ⁺ &gt;);

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - (2-methoxyethyl) -3-methyl-3A7-benzoimidazole-5carboxamide (Compound 36), MS (Biolon) C21H23N5O3 m / e calc. 393.45; found 394.1 (MH &lt; ⁺ &gt;);

-58-Butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoate (Compound 37). MS (Biolon) C31H33N5O5 m / e calcd. 555.64;

found 555.7 (MH &lt; ⁺ &gt;);

3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2methoxyphenoxy) ethylcarbamoyl] benzimidazol-1-yl} propane-1-sulfonic acid (Compound 38 ), MS (LCMS) C 30 H _{3 5} N ₈ O ₆ S m / e calcd. 635.72; found 635.4 (MH &lt; ⁺ &gt;);

N- [2- (2-Ethoxyphenoxy) ethyl] -2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 39) , MS (Biolon) C28H29N5O4 m / e calcd. 499.58; found 500.4 (MH &lt; ⁺ &gt;);

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-isopropoxyphenoxy) ethyl] -3-phenyl-3H-benzoimidazole-5-carboxamide (Compound 40). MS (Biolon) C29H31N5O4 m / e calcd. 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 (Biolon) C29H31N5O4 m / e calcd. 513.61; found 514.2 (MH ⁺ );

Propyl 2- (2- {2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 42), MS (ESI) C30H31N5O5 m / e calcd. 541.61; found 542.2 (MH &lt; ⁺ &gt;);

isobutyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 43). MS (Biolon) C31H33N5O5 m / e calcd. 555.64; found 556.3 (MH &lt; ⁺ &gt;);

ethyl 4- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} butyrate (Compound 44), MS (Biolon) C24H27N5O4 m / is calcd. 449.51; found 449.9 (MH ⁺ );

-594- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} butyric acid (Compound 45), MS (Biolon) C22H23N5O4 m / e calcd. 421.46; found 422.1 (MH &lt; ⁺ &gt;);

isopropyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 46) , MS (ESI) C30H31N5O5 m / e calcd. 541.61; found 542.2 (MH &lt; ⁺ &gt;);

N- {2- [2- (1-ethylpropoxy) phenoxy] ethyl} -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5- carboxamide (Compound 47), MS (Biolon) C31H35N5O4 m / e calcd. 541.65; found 542.5 (MH &lt; ⁺ &gt;);

ethyl 2- (2- {2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H + benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 48), MS ( Biolone) C29H28N5O4F m / e calcd. 529.57; found 529.5 (MH ⁺ );

2-Methoxyethyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 49) , MS (Biolon) C30H31N5O6 m / e calcd. 557.61; found 558.2 (MH &lt; ⁺ &gt;);

N- (3-methoxypropyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole5-carboxamide (Compound 50), MS (Biolon) C22H25N5O3 m / is calcd. 407.47; found 408.0 (MH &lt; ⁺ &gt;);

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 51), MS (Biolon) C28H29N5O4 m / e calcd. 499.57; found 499.8 (MH &lt; ⁺ &gt;);

N - [2- (2-ethoxymethylphenoxy) ethyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 52), MS (Biolon) C29H31N5O4 m / e calcd. 513.60; found 514.1 (MH &lt; ⁺ &gt;);

-60ethyl 2- (2- {2- [1- (6-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 53 ), MS (ESI) C29H28N5O5F m / e calcd. 545.57; found 546.3 (MH &lt; ⁺ &gt;);

ethyl 2- (2- {2- [1- (5-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3B-benzoimidazole-5ylcarbonylamino} ethoxy) cyclohexanecarboxylate (Compound 54), MS ( Biolone) C29H35N5O5 m / e calcd. 533.63; found 534 (MH &lt; ⁺ &gt;);

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxymethylphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 55), MS ( Biolone) C30H33N5O4 m / e calcd. 527.62; found 527.6 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl3H-benzoimidazole-5-carboxamide (Compound 56) , MS (Biolon) C30H33N5O4 m / e calcd. 527.62; found 527.9 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] - N - {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3methyl-3 H -benzoimidazol-5 -carboxamide (Compound 57), MS (Biolon) C30H33N5O5 m / e calcd. 543.62; found 543.4 (MH &lt; ⁺ &gt;);

2- (1- (1B-benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3Bbenzoimidazole-5-carboxamide (Compound 58), MS (Biolon ) 028 ^Η 29 ^Ν 5θ3 m / θ calc 483.57; found 484 (MH ⁺ );

N- [2- (2-Ethoxymethylphenoxy) ethyl] -2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3B-benzoimidazole5-carboxamide (Compound 59), MS (Biolon) C29H31N5O3 m / e calcd. 497.6; found 498.3 (MH &lt; ⁺ &gt;);

2- (1- (1 B-benzoimidazol-2-yl) ethyl] -3-phenyl-N- [2 '(2-propoxymethylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 60), MS (Biolon) C30H33N5O3 m / e calc 511.62; found 511.5 (MH ⁺ );

-612- [1- (1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3Hbenzoimidazole-5-carboxamide (Compound 61), MS (Biolon ) C30H33N5O3 m / e calcd. 511.62; found 511.6 (MH ⁺ );

2- (1- (1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-3Hbenzoimidazole-5-carboxamide (Compound 62) , MS (Biolon) C30H33N5O4 m / e calc 527.62; found 527.7 (MH ⁺ );

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide ( Compound 63), MS (Biolon) C30H32N6O4 m / e calcd. 540.73; found 541.8 (MH &lt; ⁺ &gt;);

N- (2-Phenylsulfonylethyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole5-carboxamide (Compound 64), MS (Biolon) C26H25N5O4S m / e calcd. 503.59; found 504.2 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (6-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 65). MS (ESI) C27H24N5O5F m / e calcd. 517.52; found 518.2 (MH ⁺ );

ethyl 2-hydroxy-5- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} benzoate (Compound 66), MS (Biolon) C27H25N5O5 calcd. 499.52; found

500.2 (MH &lt; ⁺ &gt;);

2- [1- (5-Fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-morpholin-4-ylphenoxy) ethyl] -3W-benzoimidazole-5-carboxamide (Compound 67), MS (Biolon) C30H31N6O3F m / e calcd. 542.62; found 543.4 (MH &lt; ⁺ &gt;);

N- (2-Phenylsulfonylethyl) -2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (Compound 68), MS (Biolon ) C26H24N5O3FS m / e calcd. 505.58; found 506.5 (MH ⁺ );

-62ethyl 2- (2- {2- [1- (4,6-difluoro-5-hydroxy-1 H + benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate ( Compound 69), MS (ESI) C29H27N5O5F2 m / e calcd. 563.52; found 563.4 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (4,6-Difluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 70 ), MS (Biolon) C27H23N5O5F2 m / e calcd. 536.51; found 563 (MH &lt; ⁺ &gt;);

ethyl 2- (2- {2- [1- (4,6-difluoro-5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H + benzoimidazol-5- ylcarbonylamino} ethoxy) benzoate (Compound 71), MS (Biolon) C32H29N7O4F2 m / e calcd. 613.62; found 614.3 (MH &lt; ⁺ &gt;);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - {2- [2- (3-methyl- [1,2,4] oxadiazol-5yl) ) phenoxy] ethyl} -3 H -benzoimidazole-5-carboxamide (Compound 72), MS (Biolon) C30H30N10O3 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] Oxadiazol5-yl) phenoxy] ethyl} -3H-benzoimidazole-5-carboxamide (Compound 73), MS (Biolon) C32H29N9O3 m / e calc. 587.64; found 588.2 (MH &lt; ⁺ &gt;).

EXAMPLE 9

2- [2- (2- {1- [5- (1-aminoethyl) -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 74) (a) A solution containing 3,4-diaminopyridine (51.7 g, 0.46 mol) in acetic acid (400 ml) was heated at 85 ° C. and then diethyl methyl-1-iminomalonate (125 g, 0.60 mol) was added in 3 equivalent portions over 6 hours. The mixture was heated at 85 ° C for 12 hours and at 120 ° C for another hour, cooled and concentrated under reduced pressure. The residue was cooled to 0 ° C and neutralized with 5 N ammonium hydroxide. The aqueous layer was extracted with several portions of ethyl acetate and the combined extracts were sequentially washed with sodium bicarbonate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to give

-63 Ethyl 2- (1H-imidazo [4,5-c] pyridin-2-yl) propionate (60.4 g, 58%) was obtained as a tan solid. ¹ H-NMR (300 MHz, CDCl 3) δ ppm: 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 comprising ethyl 2- (1H-imidase [4,5-c] pyridin-2-yl) propionate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 ml) was hydrogenated at 3.44 bar in the presence of platinum (IV) oxide (5 g) for 2 days. The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0 ° C, treated with 4 M HCl / dioxane, suspended in ether, isolated by filtration and dried. Solutions containing the residue (15-20 g each) in fresh trifluoroacetic acid (50 ml each) were hydrogenated at 3.44 bar in the presence of platinum (IV) oxide (5 g each) for 24 hours. The mixtures were filtered and concentrated under reduced pressure. The residue was azeotropically dried with toluene / ethanol ~ 1: 1 mixture, with 4 M HCl in dioxane, suspended in ether, isolated by filtration and dried in vacuo to give ethyl 2- (4,5,6,7tetrahydroimidase dihydrochloride [4 , 5-c] pyridin-2-yl) propionate (61.80 g, 75% yield); ¹ H-NMR (300 MHz, DMSO-d6) d ppm: 10.00 (br s, 2H), 4.35 (q, 1 H, J = 7.1 Hz), 4.25 (br s, 2H), 4.15 (m, 2H) , 3.35 (m, 2H), 2.90 (br s, 2H), 1.60 (d, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 6.9 Hz).

(c) A solution comprising the dihydrochloride of ethyl 2- (4,5,6,7-tetrahydroimidase [4,5-c] pyridin2-yl) propionate (60.2 g, 0.20 mol) in acetonitrile (400 ml) was cooled to 0 ° C under nitrogen atmosphere, treated with N, N-diisopropylethylamine (35 ml, 0.20 mol), further cooled to ~ -5 ° C (ice / acetone mixture) and then treated with benzyl chloroformate (58 ml, 0.41 mol) and N, Ndiisopropylethylamine (70 ml, 0.40 mol) in alternating portions over 30 minutes. The mixture was cooled to -5 ° C for 1 hour and allowed to warm to 20 ° C and concentrated under reduced pressure after 16 hours. The residue was suspended in ether and the suspension was sequentially washed with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 ml) and the solution was cooled to -5 ° C under a nitrogen atmosphere and then sodium ethoxide (21% by weight, 85 ml, 0.22 mol) was added dropwise over 1 hour while maintaining the reaction temperature below 16 ° C. The mixture was cooled to -5 ° C for 1 hour, adjusted 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

-64Natrium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate mixture) to give benzyl 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidase [4,5-c] pyridine-5-carboxylate (52 g , 72%) as pale yellow oil; ¹ H-NMR (300 MHz, DMSO-cfe) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H), 4.02 (q, 2H) , J = 9.3 Hz), 3.77 (q, 1H, J = 8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H, J = 8.3 Hz), 1.13 (t, 3H , J = 9.3 Hz).

(d) A mixture comprising benzyl 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5c] pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino-3 - (/ V-methylamino) benzoic acid (2.70 g, 0.016 mol) and DMPU (20 ml) were briefly degassed in vacuo, heated at 185 ° C under a nitrogen atmosphere for 4 hours, cooled and combined with an equivalent volume of benzene. Then ether was added to the mixture to give a precipitate. The precipitate was isolated by filtration, dried rapidly in vacuo and further purified by conversion from a mixture of hot ethanol and water. The precipitate was again isolated by filtration and dried to give 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3 -methyl-3H-benzoimidazole-5-carboxylic acid (4.73 g, 58%); ¹ H-NMR (300 MHz, DMSO-cfe) d ppm: 12.70 (brs, 1H), 11.80 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H, J = 8.3 Hz), 7.64 ( d, 1H, J = 8.3 Hz), 7.31 (S, 5H), 5.09 (s, 2H), 4.66 (q, 1H, J = 5.2 Hz), 4.32 (br S, 2H), 3.78 (s, 3H) , 3.65 (br s, 2H), 2.52 (br s, 2H), 1.73 (d, 3H, J = 5.2 Hz).

(e) A mixture comprising 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5c] pyridin-2-yl) ethyl] -3-methyl-3H-benzoimidazole -5-carboxylic acid (0.75 g, 1.6 mmol), DMF (6.5 ml), methyl 2- (2-aminoethoxy) benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) were cooled under nitrogen to -40 ° C, treated with EDC (0.32 g, 1.6 mmol) and N, Ndiisopropylethylamine (0.29 ml, 1.6 mmol) and 15 minutes later with additional N, Ndiisopropylethylamine (0.29 ml), allowed to warm to 20 ° C and stirred for 16 hours . The mixture was then cooled to -40 ° C, treated with additional EDC (0.080 g) and N, N-diisopropylethylamine (0.050 ml), stirred for 15 minutes at -40 ° C and 2 hours at 20 ° C and concentrated by distillation using a short column. The residue was partitioned between chloroform and sodium bicarbonate, and the organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ΟΗΟΙβ / ΜβΟΗ / ΑοΟΗ: 95/5/1) to give benzyl 2- (1- {6- [2-65 (2-methoxycarbonyl-enoxy) ethylcarbamoyl] -1-methyl-1 H-benzoimidazoi-2-yl} ethyl) -1,4,6,7tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (0.69 g, 66%) as a glassy brown foam; ¹ H NMR (300 MHz, DMSO-d ₆ ) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J = 5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1 H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1 H, J = 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1 H, J = 9.9 Hz), 6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J = 8.8 Hz), 4.30 (br s, 2H),

4.20 (t, 2H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J = 8.8) Hz).

(f) A solution comprising benzyl 2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] 1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7-tetrahydroimidase [4,5-c] pyridine-5-carboxylate (0.69 g, 1.1 mmol) in THF (2 ml) and water (2 ml) were cooled to 0 ° C under a nitrogen atmosphere, treated with 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 2 N lithium hydroxide (1.1 ml), allowed to warm to 20 ° C, stirred for 6 hours, cooled to 0 ° C, adjusted to pH 7 with 1 M 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 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1 / - N-imidazo [4,5-c] pyridin-2-yl) ethyl] 3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.56 g, 83%) as a glassy residue; ¹ H-NMR (300 MHz, DMSO-d 6) δ ppm; 11.87 (br 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 (q, 1H, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 3.84 (s, 3H), 3.64 (m, 4H), 2.55 ( s, 2H), 1.71 (d, 3H, J = 7.7 Hz).

(g) A solution comprising 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ) ethyl] -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.561 g, 0.90 mmol) in ice (2 ml) was heated under a nitrogen atmosphere in a water bath to 10 ° C, treated with hydrogen bromide in acetic acid ( 2 ml of 30% solution) and allowed to warm to 20 ° C and concentrated one hour later with a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the solution was added dropwise to the stirred ether to give a pale brown precipitate. The precipitate was isolated by filtration and dried to give 2- (2- {3-methyl-2- [4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2 hydrobromide -yl) ethyl] -3H-66benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.651 g); ¹ H-NMR (300 MHz, DMSO-d ₆ ) d 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 = 7.9 Hz), 7.21 (d, 1 H, J = 7.9 Hz), 7.00 (t, 1H, J = 7.9 Hz).

5.21 (q, 1H, J = 6.3 Hz), 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) A solution comprising hydrobromide 2- (2- {3-methyl-2- [4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] - 3H-Benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.30 g, 0.46 mmol) in DMF (1.5 ml) was cooled under nitrogen to 0 ° C, treated with ethyl acetimidate (0.12 g, 0.92 mmol) and Λ /. N-diisopropylethylamine (0.25 ml, 1.4 mmol) was cooled at 0 ° C for 30 minutes and then allowed to warm to 20 ° C and stirred for 20 hours. The mixture was then cooled to 0 ° C, treated with additional ethyl acetimidate (0.06 g) and N, N-diisopropylethylamine (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 acetimidate (0.03 g), allowed to warm to 20 ° C and stirred for 2 hours. The mixture was then added dropwise to the stirred ether to give a precipitate. The precipitate was isolated by decanting the solvent and dried in vacuo. The residue was precipitated from ethanol / ether and purified by preparative RP-HPCL: 2 50% MeCN / HgO (20 mM HCl) for 50 minutes. The fractions were lyophilized to give 2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H- imidazo [4,5-c] pyridine) -2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ilkarbonilamino) ethoxy] benzoic acid (0.145 g, 52%); ¹ H-NMR (300 MHz, DMSO-dg) d ppm: 9.77 (s, 1H ), 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), 7.60 ( d, 1 H, J = 7.7 Hz), 7.49 (t, 1 H, J = 7.7 Hz), 7.21 (d, 1 H, J = 7.7 Hz), 6.99 (t, 1H, J = 7.7 Hz), 5.37 (m, 1H), 4.71 (2s, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.82 (s, 1H), 3.66 (m, 2H), 2.83 (m, 2H), 2.49 ( s, 1H), 2.40 (d, 3H, J = 3.5 Hz), 1.85 (d, 3H, J = 5.1 Hz) MS (ESI) C28H31N7O4 m / e calc 529.61, found 530.3 (MH ⁺ ).

EXAMPLE 10

Ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazole-5carbonylamino} ethoxy) benzoate (Compound 75)

-67 (a) A solution comprising 2,3,4,6-tetrafluororonitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5 M, 7.5 mmol) was stirred at room temperature for 3 hours to give a fine white precipitation. The mixture was diluted with an equal volume of water to dissolve the white precipitate to give yellow crystals. The crystals were isolated, collected and dried to give 2,3,5-trifluoro-6-nitroaniline (307 mg, 51%) as yellow needles; melting point 66 ° C; ¹ H NMR (CDCl ₃ ) δ 6.4 (1 H, m), δ 6.0 (2H, s).

(b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol was hydrogenated overnight at a pressure of 1,013 bar, filtered under a nitrogen atmosphere and concentrated to give 1,2-diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a violet crystalline solid; MS M ⁺ 162.7, +41, +82 (+ ACN, + 2ACN). (calculated for ΟρΠΥβΥ 162.11).

(c) A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), ethyl 2ethoxycarbonimidoylpropionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml) was heated at reflux until TLC showed , to prevent the reaction from proceeding, filtered from NH4Cl and concentrated. The residue was purified by chromatography on silica gel (hexane: methylene chloride: ethyl acetate, 5: 5: 1) to give ethyl 2- (4,6,7-trifluoro-1 Hbenzoimidazol-2-yl) propionate (1.37 g. 42%) as a yellow-brown crystalline solid; NMR (CDCl3): δ 10.35 (s, 1/2 H), δ 7.05 (s, 1/2 H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 1 H) , δ 1.73 (d, 3H), δ 1.31 (t, 3H); M ⁺ 272.9 (calcd. For C ₁₂ Hi 1F3N2O2: 272.23).

(d) Ethyl 2- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) propionate (988 mg, 3.63 mmol) and ethyl 2- [2- (4-amino-3-methylaminobenzoylamino) ethoxy] benzoate (1.3 g, 3.63 mmol) was combined and vacuumed for 4 hours and then further combined with DMPU (4 ml). The mixture was stirred to form a solution which was evacuated overnight in high vacuum to remove residual gases, heated to 195 ° C under a stream of nitrogen for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (gradient gradient from 100% hexane to 100% ethyl acetate) and further purified by crystallization from a mixture of MeOH / THF / water to give ethyl 2- (2- {2- [1-68 (4 , 6,7-Trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carbonylamino} ethoxy) benzoate (1.0 g, 49%) as a white crystalline solid:

NMR (CDCI ₃ ): δ 6.84-8.07 (m, 8H), δ 4.93 (dd, 1H), δ 4.34 (dd, 2H), δ 4.27 (m, 2H), δ 3.95 (m, 2H), δ 3.9 (s, 3H), δ 1.93 (d, 3H), δ 1.78 (s, 2H), δ 1.38 (t, 3H); LCMS M ⁺ 566.2 Bioion M ⁺ 565.7 (calcd for C29H26F3N5O4: 565.55).

Following the procedure of Example 10, the following compounds of the invention were prepared:

ethyl 2- (2- {2- [1- (5,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 76), MS (Bioion) C29H27N5O4F2 m / e calcd. 547.56; found 548.1 (MH &lt; ⁺ &gt;);

ethyl 2- (2- {2- [1- (4,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 77), MS (LCMS) C29H27F2N5O4 m / e calcd. 547.56; found 548.3 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 78 ), MS (LCMS) 029 ^Η 26 ^ρ 3 ^Ν 5θ4 m / e calc. 565.55; found 566.2 (MH &lt; ⁺ &gt;); and ethyl 2- {2- [3-methyl-2- (4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl) -3H-benzoimidazol-5ylcarbonylamino] ethoxy} benzoate (Compound 79), MS (Bioion) C28H24F3N5O4 m / e calcd. 551.52; found 551.52 (MH &lt; ⁺ &gt;).

EXAMPLE

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

Mixture comprising ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carbonylamino} ethoxy) benzoate (118 mg, 0.21 mmol), methanol (4 ml) and 2 N sodium hydroxide (2.1 ml) were stirred at room temperature for 4 hours, neutralized with 2N

-69 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 X). 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 a 4 M solution of hydrogen chloride and dioxane. The solution was diluted with ethyl ether to give a precipitate. The precipitate was isolated and dried to give 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzoimidazol-2-yl) ethyl] -3methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid as a white solid; MS (LCMS) C27H22F3N5O4 m / e calcd. 537.50; found 538.4 (MH &lt; ⁺ &gt;).

Following the procedure as in Example 11, the following compounds of the invention were prepared:

2- (2- {2- [1- (5,6-Difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 81), MS (LCMS) C27H23N5O4F2 m / e calcd. 519.51; found 520.2 (MH ⁺ );

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

2- (2- {2- [1- (4,5,6-Trifluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carbonylamino} ethoxy) benzoic acid (Compound 83). MS (Biolon) C27H22F3N5O4 m / e calcd. 537.5; found 537.7 (MH &lt; ⁺ &gt;).

EXAMPLE 12

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

Mixture comprising ethyl 2- (2- {2- [1- (1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3Wbenzoimidazole-5-carbonylamino} ethoxy) benzoate (0.50 g , 0.95 mmol), dimethylformamide (5 ml), cesium carbonate (0.93 g, 2.85 mmol) and isobutyric anhydride (0.17 ml, 1.05 mmol) were stirred for 2 hours, then diluted with dichloromethane (50 ml) and passed through a pad of celite.

-70 was removed in vacuo and the residue dissolved in dichloromethane (5 ml). The solution was combined with diisopropylethylamine (0.47 ml, 2.7 mmol) and methyl chloroformate (0.1 ml, 1.3 mmol) and the mixture stirred for 1 hour. The solvents were removed in vacuo and the residue purified by silica gel chromatography using ethanol and dichloromethane as eluent to give ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazole-2- yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (0.20 g, 32% yield) as a colorless amorphous solid; MS (Biolon) 0351437 ^ 03 m / e calcd. 655.72; found 656.1 (MH &lt; ⁺ &gt;).

Following the procedure as in Example 12, the following derivatives of the prodrugs of the invention were prepared:

methyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) 5-hydroxybenzoimidazole-1-carboxylate (Compound 85), MS (ESI ) C31H31N5O7 m / e calcd. 585.62; found 586.2 (MH &lt; ⁺ &gt;);

ethyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1/4-benzoimidazol-2-yl} ethyl) -5methoxycarbonyloxybenzoimidazole-1-carboxylate (Compound 86), MS (ESI ) C33H33N5O7 m / e calcd. 643.66; found 644.2 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (5-hydroxy-1-isobutyryl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/4-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 87), MS (ESI) C33H35N5O6 m / e calcd. 597.68; found 598.2 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (1-benzoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 88) , MS (ESI) C35H33N5O6 m / e calcd. 631.69; found 632.3 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (1-dimethylcarbamoyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 89) , MS (ESI) C32H34N5O5 m / e calcd. 598.66; found 599.3 (MH &lt; ⁺ &gt;);

-71ethyl 2- (2- {2- [1- (1-acetoxymethyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 90 ), MS (Biolon) C32H33N5O7 m / e calcd. 599.65; found 600.7 (MH &lt; ⁺ &gt;);

ethyl 2- [2- (2- {1- [1- (2,2-dimethylpropionyloxymethyl) -5-hydroxy-1H-benzoimidazol-2-yl] ethyl} -3methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy ] benzoate (Compound 91), MS (ESI) ^C 35 ^H 39 ^N 5 ° 7 m / e calc. 641.74; found 642.3 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 92) , MS (Biolon) C35H37N5O8 m / e calcd. 655.72; found 656.1 (MH &lt; ⁺ &gt;);

ethyl 5-ethoxycarbonyloxy-2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) benzoimidazole-1-carboxylate (Compound 93), MS (ESI ) C35H37N5O9 m / e calcd. 671.72; found 672.4 (MH &lt; ⁺ &gt;);

isopropyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2yl} ethyl) -5-isopropoxycarbonyloxy-benzoimidazole-1-carboxylate (Compound 94). MS (ESI) C37H41N5O9 m / e calcd. 699.79; found 700.4 (MH &lt; ⁺ &gt;); and ethyl 2- (2- {2- [1- (1-acetyl-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 95 ), MS (ESI) C31H31N5O5 m / e calcd. 569.62; found 570.1 (MH &lt; ⁺ &gt;).

The following additional compounds of the invention have been prepared by the method described in this application or by methods known to one of ordinary skill in the art:

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

C- [2- (1B-naphtho [2,3-c] imidazol-2-ylmethyl) -1H-benzoimidazol-5-yl] methylamine (Compound 97), MS (Biolon) C20H17N5 m / e calc. 327.4; found 328.1 (MH &lt; ⁺ &gt;);

-72C- [2- (5-methyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-yl] methylamine (Compound 98), MS (Biolon) C17H17N5 m / e calc. 291.4; found 292.3 (MH &lt; ⁺ &gt;);

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

3- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5ylcarbonylamino} propionic acid (Compound 100), ¹ H-NMR (300 MHz, CD 3 OD): 1.92 (m, 2H, J = 7.2 Hz), 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, 1 H, 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-ylethI) -1H-benzoimidazole-5carboxamide (Compound 101), ¹ H-NMR (300 MHz , CD3OD): 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-5carboxamide (Compound 102), ¹ H-NMR (300 MHz, CD3OD): 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), 7.717.77 (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-A / - (2-naphth-1-ylethyl) -3 / - / - benzoimidazol-4karboksamid (Compound 103) ¹ H-NMR (300 MHz, CD3OD): 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-ylpropionic acid (Compound 104), ¹ H-NMR (300 MHz, CD3OD): 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).

-731.5 Hz), 7.60-7.66 (m, 2H), 7.73-7.80 (m, 3H), 7.96 (d, 1H, J = 0.9 Hz), 8.39 (d, J = 7.5 Hz, partially replaced);

(R) -2- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -1 H-benzoimidazol-5-ylcarbonylamino] -3-indol-3-ylpropionic acid (Compound 105) ¹ H-NMR ( 300 MHz, CD3OD): 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 replaced);

2- (1 H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1H-benzoimidazol-5-carboxamide (Compound 106) ¹ H-NMR (300 MHz, CD3OD): 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 = 8.7 Hz) , 7.72-7.79 (m, 4H), 7.85 (dd, 1 H, J = 8.6,1.5 Hz), 8.04 (d, 1 H, J = 1.2 Hz), 8.26 (d, 1 H, J = 8.4 Hz) ;

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (4-aminobutyl) -3H-benzoimidazole-4carboxamide (Compound 107), MS (Biolon) C22H27N7O1 m / e calc. 405.4; found 406.5 (MH ⁺ );

2- [1- (5-Aminomethyl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-naphth-1-ethyl) -3 / 7-benzoimidazole5-carboxamide (Compound 108) , MS (Biolon) C31H30N6O1 m / e calcd. 502.6; found 503.3 (MH &lt; ⁺ &gt;);

2- (1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5carboxamide (Compound 109), MS (Biolon ) C28H24NgO- | m / e calcd. 460.5; found 461.3 (MH &lt; ⁺ &gt;);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylcarbonyl) -3-methyl- N - (2-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 110), MS (Biolon) θ3θΗ26 ^ 6θ2 m / e calcd. 502.6; found 503.6 (MH &lt; ⁺ &gt;);

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

-742- (5-Aminomethyl-4,5,6,7-tetrahydro-1 B-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) 3B-benzoimidazol-5- carboxamide (Compound 112), ¹ H-NMR (300 MHz, CD 3 OD): 1.67 (m, 1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd, 1H, J = 15.3, 9.3 Hz) ), 2.76 (m, 2H), 2.90 (dd, 1H, J = 15.7, 7.5 Hz), 3.05 (d, 2H, J = 6.9 Hz), 3.41 (t, 2H, J = 7.4 Hz), 3.75 (t , 2H, J = 7.4 Hz), 3.90 (s, 3H), 7.35-7.53 (m, 5H), 7.61 (d, 1H, J = 8.4 Hz), 7.72-7.75 (m, 2H), 7.85 (dd, 1H, J = 8.1,1.2 Hz), 7.99 (d, 1H, J = 0.9 Hz), 8.26 (d, 1H, J = 8.4 Hz);

2- (5-Aminomethyl-1 B-benzoimidazo-2-ylmethyl) -3-methyl-N- (3-phenylpropyl) -3B-benzoimidazole-5carboxamide (Compound 113), ¹ H-NMR (300 MHz, CD 3 OD): 1.98 (m, 2H), 2.72 (t, 2H, J = 7.6 Hz), 3.46 (t, 2H, J = 7.2 Hz), 4.01 (s, 3H), 4.29 (s, 2H), 7.12-7.17 (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-1B-benzoimidazol-2-ylmethyl) -3-methyl - / \ / - (2-phenoxyethyl) -3B-benzoimidazol-5karboksamid (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 = 5.0 Hz), 4.27 (s, 2H), 6.88 (t, 1H, J = 7.5 Hz) , 6.92 (d, 2H, J = 7.5 Hz),

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-1B-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-napht- 1iletil) -3B-benzoimidazole-5-carboxamide (compound 115) ¹ H-NMR (300 MHz, CD3OD): 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-1 B-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl- N - (2-naphthyl) -ylethyl) -3B-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);

-752- (5-iminomethyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-napht- 1iletil) -3H-benzoimidazole-5-carboxamide (compound 117) ¹ H-NMR (300 MHz, CD3OD): 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-naphthylethyl) -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) - 3/7-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, 1 H, J = 7.8 Hz), 7.85 (d, 1 H, J = 7.8 Hz), 8.13 (s, 1 H);

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), 6.65-6.74 (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-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (benzoimidazole -1-ylethyl) -3H-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-1H-imidazo [4 , 5c] Pyridin-2-ylmethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 122), ¹ H-NMR (300

-76MHz, 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] -3H-benzoimidazole-5-carboxamide (Compound 123), MS (Biolon) C26 ^h 28 N7 O ₂ CI m / e calc 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] -3H-benzoimidazole-5-carboxamide (Compound 124), MS (Biolon) C26H28N7O2CI m / e calc 506.0; found 506.7 (MH ⁺ );

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2- naphth-1 ylethyl) -3H-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 replaced), 7.45-7.95 (m, 9H), 8.02 (m, partially replaced ), 8.17 (d, 1H, J = 8.1 Hz), 8.96 (s, partially replaced);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2hydroxy-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 = 8.4 Hz);

2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2hydroxynaphthyl) -1-yl) ethyl] -3H-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, 7.6 Hz), 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-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2 - (4hydroxynaphthal-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, 1 H, 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, 1 H, J = 8.4 Hz), 8.17 (d, 1H, J = 8.4). Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (2methoxyphenoxy) ethyl] -3-7-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-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N-naphthyl- 2ylmethyl-3/7-benzoimidazole-5-carboxamide (Compound 130)? H-NMR (300 MHz, CD3OD): 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 _I 7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (3- Pyrid-4ylpropyl) -3 / 7-benzoimidazole-5-carboxamide (Compound 131)? H-NMR (300 MHz, CD3OD): 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-1/7-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) -3-7benzoimidazole-5-carboxamide ( Compound 132), MS (Biolon) ¢ 32 ^ 2 ^ 03 m / e calcd. 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);

-782- (5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- ( 4methoxyphenoxy) ethyl] -3W-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, 1 H, J = 8.4 Hz), 7.84 (m, 1 H), 8.13 (d, 1 H, J = 1.2 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) 3H-benzoimidazole-5-carboxamide (Compound 134), MS (Biolon) C32H30N7O4 m / e calcd. 590.6; found 590.7 (MH &lt; ⁺ &gt;); 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), 7.61-7.65 (m, 2H), 7.72-7.86 (m, 4H). 8.05 (d, 1H, J = 1.2 Hz), 8.25 (d, 1H, J = 8.1 Hz);

2- [5- (1-yninoethyl) -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] -3H-benzoimidazole-5-carboxamide (Compound 135)? H-NMR (300 MHz, CD3OD): 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), 7.82-7.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo (4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2- (3methoxyphenoxy) ethyl] -3H-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, 1 H, J = 8.0 Hz), 7.66 (d, 1 H, J = 8.4 Hz), 7.83 (m, 1 H), 8.12 (m, 1 H, J = 1.2 Hz) ;

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

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-1-ylethyl) -3Hbenzoimidazol-5-carboxamide (Compound 138), ¹ H- NMR (300 MHz, CD3OD): 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

-79Ηζ), 7.32 (dd, 1Η, 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- (2methoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide ( Compound 139), MS (Biolon) C29H32N8O5 m / e calcd. 572.62; found 573.3 (MH &lt; ⁺ &gt;); ¹ H-NMR (300 MHz, CD 3 OD): 3.583.69 (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), 8.24 (d , 1H, J = 1.5 Hz);

2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ethyl) -3H-benzoimidazol-5 -carboxamide (Compound 140), MS (Biolon) C33H34N8O3 m / e calcd. 590.7; found 591.3 (MH &lt; ⁺ &gt;);

2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) - N - [2- (2methoxyphenoxy) ethyl] -3H-benzoimidazole-5- carboxamide (Compound 141), MS (Biolon) C29H30N8O6 m / e calcd. 586.6; found 587.5 (MH &lt; ⁺ &gt;); ¹ H-NMR (300 MHz, CD 3 OD): 3.33 (m, 1H), 3.81 (m, 5H), 3.98 (d, 2H, J = 4.5 Hz), 4.18 (t, 2H, J = 5.4 Hz), 4.38 (t, 1H, J = 12.0 Hz),

4.57 (dd, 1H, J = 12.0, 3.5 Hz), 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- (2methoxy) phenoxyethyl] -3H-benzoimidazol-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, 8.7 Hz), 4.62-4.66 (m, 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H, J = 8.7,1.2 Hz), 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);

-80methyl 2- {2- [2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-3H-benzoimidazol-5ylcarbonylamino] ethoxy} benzoate (Compound 143), MS (Biolon) 02δΗ28 ^Ν 8θ4 m / e calc. 540.56; found 541.4 (MH &lt; ⁺ &gt;);

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

methyl S - N - [beta] -S-guanidino-1H-benzoimidazol-4-ylmethyl-S-methyl-SH-benzoimidazole-Silcarbonylamino] ethoxy} benzoate (Compound 145), MS (Biolon) 02δΝ28 ^Ν 8θ4 m / e calc. 540.5; found 541.4 (MH &lt; ⁺ &gt;);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-A / - [2- (2,6-dimethoxy) phenoxyethyl] -3Hbenzoimidazol-5-carboxamide (Compound 146) ¹ H-NMR (300 MHz, CD3OD): 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- (2methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 147 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 = 5.4 Hz), 4.45 ( dd, 1H, J = 15.0, 8.7 Hz), 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- (2methoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide (Compound 148) , ¹ H-NMR (300 MHz, CD 3 OD): 3.58-3.70 (m, 2H), 3.81 (m, 5H), 4.06 (m, 1H), 4.19 (t, 2H, J = 5.4 Hz), 4.46 (dd , 1H, J = 15.0, 8.7 Hz), 4.64 (dd, 1H, J = 15.0, 3.0 Hz), 4.69 (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);

-812- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl- / V- (2-hydroxy-2-quinol-4-ylethyl) -3Hbenzoimidazol-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 = 8.4 Hz), 8.33 (d, 1H, J = 5.7 Hz) , 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-1yl) ethyl] -3 H -benzoimidazole- 5-carboxamide (Compound 150), MS (Biolon) C29H28N10O3 m / e calcd. 564.6; found 565.5 (MH &lt; ⁺ &gt;);

methyl 2- {2- [2- (5-guanidino-1/7-benzoimidazol-2-ylcarbonyl) -3-methyl-3W-benzoimidazol-5ylcarbonylamino] ethoxy} benzoate (Compound 151), MS (Biolon) C29H26N8O5 m / is calcd. 554.5; found 554.8 (MH &lt; ⁺ &gt;);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 152), ¹ H-NMR (300 MHz, CD3OD): 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] -3H-benzoimidazole -5-carboxamide (Compound 153);

2- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (2-hydroxyethyl) - / V- (2-naphth-2-ylethyl) -3Hbenzoimidazol-5-carboxamide (Compound 154), ¹ H- NMR (300 MHz, CD3OD): 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), 7.387.52 (m, 4H), 7.58 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.7 Hz), 7.71-7.76 (m, 3H), 7.86 (d , 1H, J = 8.6 Hz), 8.06 (s, 1H), 8.26 (d, 1H, J = 8.1 Hz);

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

-822- (5-guanidino-1H-benzoimidazol-2-ylcarbonyl) -3- (3-hydroxypropyl) - N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 156);

2- (5-imidazol-1-yl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole5-carboxamide (Compound 157);

2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-1 H (2-naphth-1-ethyl) -3H-benzoimidazole 5-carboxamide (Compound 158 ), MS (Biolon) C31H30N8O-1 nri / e calcd. 530.6; found 531.1 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide ( Compound 159), MS (Biolon) C33H29N7O1 m / e calcd. 539.6; found 540.1 (MH &lt; ⁺ &gt;);

2- {1- [5- (2-aminoimidazol-1-yl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazol-5 -carboxamide (Compound 160), MS (Biolon) C33H30N8O1 m / e calcd. 554.7; found 555.2 (MH &lt; ⁺ &gt;);

- (5-guanidino-1H-benzoimidazol-2-yl) -3-hydroxy-1-methyl- N - (2-naphth-1-ethyl) -3,4-dihydro-1 H2-oxa- 4a, 9-diazafluoren-6-carboxamide (Compound 161);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (4-hydroxybutyl) - N - (2-naphth-1-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 162), MS (Biolon) C34H35N8O2 m / e calcd. 588.7; found 589.3 (MH &lt; ⁺ &gt;);

3- [2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-ylethylcarbamoyl) benzoimidazol-1-yl] propane-1-sulfonic acid (Compound 163) , MS (Biolon) C33H34N8O4S m / e calcd. 638.7; found 639.2 (MH &lt; ⁺ &gt;);

-833- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6- (2-naphth-1-ylethylcarbamoyl) benzoimidazol-1-yl] propan-1 -sulfonic acid (Compound 164), MS (Bioion) C35H33N7O4S m / e calc 647.8; found 648.2 (MH ⁺ );

2- (1- (5-guanidino-1H-benzoimidazol-2-yl) -2-methylpropyl] -3-methyl-N- (2-naphth-1-ethyl) -3 Hbenzoimidazole-5-carboxamide (Compound 165), MS (Bioion) C33H34N8O1 m / e calc 558.7; found 559.6 (MH ⁺ );

2- [1- (1B-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ethyl) -3H-benzoimidazole -5carboxamide (Compound 166), MS (Bioion) C29H26N6O1 m / e calcd. 474.6; found 475.2 (MH &lt; ⁺ &gt;);

2- (5- (1- (N-Methylimino) ethyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl} -3-methyl- / V (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 167), MS (Bioion) C31H33N7O m / e calc 519.71; found 520.9 (MH ⁺ );

imino (2- (1- (1-methyl-6- (2-naphth-1-ylethylcarbamoyl) -1H-benzoimidazol-2-yl] ethyl} -1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-yl) acetic acid (Compound 168), MS (Bioion) C31H31N7O3 m / e calc 549.6; found 550.2 (MH ⁺ );

2- (1- (5- (1-iminoethyl) -4 ₎ 5,6,7-tetrahydro-1B-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-N- - (2-naphthyl-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 169), MS (Bioion) C31H33N7O1 m / e calc 519.6; found 520.3 (MH ⁺ );

2- (1- [5 - (N-methylamidino) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- / V - (2naphth-1-ylethyl) -3B-benzoimidazole-5-carboxamide (Compound 170), MS (Bioion) C31H34N8O1 m / e calc 534.7; found 535.1 (MH ⁺ );

2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) -5-methoxybenzoic acid (Compound 171), MS (Bioion) C29H30N8O5 m / e calc 570.6; found 571.2 (MH ⁺ );

-842- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) isophthalic acid (Compound 172), MS (Biolon ) C29H30N8O5 m / e calcd. 570.6; found 571.3 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) -1-hydroxyethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) -6-methoxybenzoic acid (Compound 173), MS (Biolon) ^ 29 ^ 30 ^ 806 ^m / ^e calcd. 586.6; found 587.2 (MH &lt; ⁺ &gt;);

ethyl 2- [2- (2- {1- [5- (N-acetylguanidino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3/7-benzoimidazol5-ylcarbonylamino) ethoxy] benzoate ( Compound 174), MS (Biolon) C31H32N8O5 m / e calcd. 596.6; found 597.2 (MH &lt; ⁺ &gt;);

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

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

2- {1- [5- (1-iminoethyl) -4 _l 5,6,7-tetrahydro-1 / - / - 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) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3/7-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 178), MS (Biolon) C30H30N8O5 m / e calcd. 582.6; found 583.3 (MH &lt; ⁺ &gt;);

2- [2- (2- {1- [5- (1-Aminocyclopropyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 179) , MS (Biolon) θ3οΗ3οΝθθ4 m / e calcd. 538.6; found 539.3 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (3-methylbutyl) -3H-benzoimidazole5-carboxamide (Compound 180). MS (Biolon) C26H29N7O1 m / e calcd. 455.6; found 456.2 (MH &lt; ⁺ &gt;);

-852- (1/7-Benzoimidazol-2-ylethyl) -3-methyl - N - (2-phenoxyethyl) -3 H - benzoimidazole-5-carboxamide (Compound 181), MS (Biolon) C26H25N5O2 m / e calc. 439.5; found 440.2 (MH &lt; ⁺ &gt;);

ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate (Compound 182);

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

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

N-ethyl-2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carboxamide (Compound 185), MS ( Biolon) 023 ^Η 23 ^Ν 7θ1 ' ^zra ^ · 413.5; found 414.1 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 186), MS (Biolon) C24H25N7O2 m / e calcd. 443.5; found 444.2 (MH &lt; ⁺ &gt;);

- (2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino) -4-methylpentanoic acid (Compound 187); MS (Biolon) C27H29N7O3 m / e calcd. 499.6; found 500.3 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid ( Compound 188), MS (Biolon) C30H27N7O4 m / e calcd. 549.6; found 550.2 (MH &lt; ⁺ &gt;);

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

-862- {1- [5- (A /, / V-dimetilamidino) -4 _I 5.6 _l of 7-tetrahydro-1H-imidazo [4,5-c] piriclin-2-yl] ethyl} -3- methyl3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 190), MS (Biolon) C39H34N8O4 m / e calcd. 558.6; found 559.3 (MH &lt; ⁺ &gt;);

2- [2- (2- {1- [5- (2-carboxy-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 (Compound 191), MS (Biolon) C29H31 ΝχΟθ m / e calcd. 573.6; found 530.3 (MH ⁺ ), loss of CO2;

2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (Compound 192), MS (Biolon) C32H31N7O5 m / e calcd. 593.6; found 594.2 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -N- (2-methoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 193), MS (Biolon) C26H29N7O3 m / e calcd. 487.6; found 488.2 (MH &lt; ⁺ &gt;);

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

3- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 195), MS (Biolon) 028Η28 ^Ν 8θ4 m / e calc. 540.6; found 541.3 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 196), MS (Biolon) C30H32N8O5 m / e calcd. 584.6; found 585.3 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3W-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 197 ), MS (Biolon) C30H32N8O7S m / e calcd. 648.7; found 649.6 (MH &lt; ⁺ &gt;);

-872- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (Compound 198), MS (Biolon) C32H31N7O7S m / e calcd. 657.7; found 658.4 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-imidazol-1-yl-3-methyl-3H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H + benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 199), MS (Biolon) C31H29N7O4 m / e calcd. 563.6; found 564.2 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-imidazol-1-yl-3H-benzoimidazol-2-yl) ethyl-3- (2-hydroxypropyl) -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 200), MS (Biolon) C32H31N7O5 m / e calcd. 593.6; found 594.3 (MH &lt; ⁺ &gt;);

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

Ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 202), MS (Biolon ) θ30 ^Η 32Νδθ4 m / e calc. 568.6; found 569.5 (MH &lt; ⁺ &gt;);

ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 203), MS (Biolon) 028? 36? 804 m / θ calc. 549.0; found 548.2 (MH &lt; ⁺ &gt;);

ethyl 4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} butyrate (Compound 204), MS (Biolon) C25H30N8O3 m / e calc. 490.57; found 491.3 (MH &lt; ⁺ &gt;);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-tetrazol-1-ylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 205), MS (Biolon) 02βΗ28 ^Ν ΐ2θ2 m / θ ' ^zra ^. 564.56; found 565.3 (MH &lt; ⁺ &gt;);

-882- [2- (2- {1- [5- (1-Iminoethylamino) -1W-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 206 ), MS (Biolon) C31H33N7O4 m / e calcd. 567.6; found 568.4 (MH &lt; ⁺ &gt;);

ethyl 4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 207), MS (Biolon ) C30H32N8O4 m / e calcd. 568.6; found 569.4 (MH &lt; ⁺ &gt;);

5- (2- {2- [1- (5-guanidino-1W-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) isophthalic acid (Compound 208), MS (Biolon) C29H28N8O6 m / e calcd. 584.6; found 585.3 (MH &lt; ⁺ &gt;);

4- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 209), MS (Biolon) 02δΗ28 ^Ν 8θ4 m / e calc. 540.6; found 541.2 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (Compound 210). MS (Biolon) C30H32N8O5 m / e calcd. 584.6; found 585.4 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3Wbenzoimidazole-5-carboxamide (Compound 211), MS (Biolon) C30H29N7O2 m / e calcd. 535.6; found 536.3 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 212), MS (Biolon) C27H26N8O4 m / e calcd. 526.6; found 527.2 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 213), MS (Biolon) C29H27N7O2 m / e calcd. 505.6; found 506.2 (MH &lt; ⁺ &gt;);

-892- (2- (2- (1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1B-benzoimidazole-5ylcarbonylamino} ethoxy) benzoic acid (Compound 214), MS (Biolon) C29H25N7O4 m / e calc 535.6; found 536.4 (MH ⁺ );

ethyl 2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) -4-methylbenzoate (Compound 215). MS (Biolon) C31H34N8O4 m / e calc 582.7; found 583.5 (MH ⁺ );

2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-benzoimidazole-5ylcarbonylamino} ethoxy) -4-methylbenzoic acid (Compound 216), MS (Biolon ) C29H30N8O4 m / e calc 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} - 1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 217), MS (ESI) C26H32N8O4 m / e calc 520.58; found 521.3 (MH ⁺ );

Ethyl 2- (2- (2- [5 - (N-methylamidino) -1H-benzoimidazol-2-ylmethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 218), MS (Biolon) C30H31N7O4 m / e calc 553.6; found 554.3 (MH ⁺ );

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

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

ethyl 2- (2- (2- (1- (5- (1- (N-hydroxyimino) ethyl) -4,5,6,7-tetrahydro-1 B-imidazo (4,5-c] pyridine) 2yl} ethyl) -3-methyl-3W-benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (Compound 221);

-902- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 222), MS (Biolon ) C27H27N5O3 m / e calcd. 469.5; found 469.5 (MH &lt; ⁺ &gt;);

2- (2-ethoxycarbonylphenoxy) ethyl 2- [1- (6-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7tetrahydroimidazo [4,5-c] pyridine-5-carboxylate ( Compound 223), MS (Biolon) C 2 ^H 32 ^N 8 ^O 5 m / e calcd. 560.62; found 561.3 (MH &lt; ⁺ &gt;);

4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylaminobutyric acid (Compound 224), MS (Biolon) C23H26N8O3 m / e calcd. 462.52; found 462.8 (MH &lt; ⁺ &gt;);

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1/7-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-A N - [2- (2-Tetrazolylphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 225), MS (ESI) N 28 N 31 N 1 - (02 m / e calc. 553.6; found 553.5 (MH ⁺ );

Isopropyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol5-ylcarbonylamino} ethoxy) benzoate (Compound 226) , MS (Biolon) C33H33N7O4 m / e calcd. 591.3; found 591.4 (MH &lt; ⁺ &gt;);

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- / V - [2- (3tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 227), MS (Biolon) C28H31N-j 10 O 2 m / e calcd. 553.59; found 553.5 (MH &lt; ⁺ &gt;);

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- N- [2- (4tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 228), MS (ESI) θ28 ^Η 31 ^Ν 11θ2 m / e calc. 553.59; found 553.5 (MH &lt; ⁺ &gt;);

cyclohexyl 2- (2- {2- [1- (5-imidazol-1-yl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxybenzoate (Compound 229). MS (ESI) C36H37N7O4 m / e calcd. 631.3; found 631.5 (MH &lt; ⁺ &gt;);

-912- [2- (2- {1- [5 - ((N-methylamidino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 230), MS (Biolon) 028 ^Η 27 ^Ν 7θ4 m / e calcd. 525.6; found 525.5 (MH ⁺ );

2- [2- (2- {1- [5- (1-Iminoethylamino) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazol-5ylcarbonylamino) ethoxy] benzoic acid (Compound 231) , MS (Biolon) C29H29N7O4 m / e calcd. 539.6; found 539.8 (MH &lt; ⁺ &gt;);

2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin5-ylcarbonyl} propoxy) benzoic acid (Compound 232), MS (Biolon) C27H3qNqO4 m / e calcd. 530.60; found 531.7 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1? 7-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin5-ylformyloxy} ethoxy) benzoic acid (Compound 233), MS (Biolon) 02θΗ28 ^Ν 8θ5 m / θ calc. 532.56; found 533.2 (MH &lt; ⁺ &gt;);

2-Methoxyethyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 234), MS (Biolon) C33H33N7O5 m / e calcd. 607.3; found 607.4 (MH &lt; ⁺ &gt;);

Isobutyl 2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 235), MS (Biolon) C34H35N7O4 m / e calcd. 605.3; found 605.4 (MH &lt; ⁺ &gt;);

2- (2-methoxyethoxy) ethyl 2- (2- {2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5- ylcarbonylamino} ethoxy) benzoate (Compound 236), MS (Biolon) C35H37N7O6 m / e calcd. 651.3; found 651.3 (MH &lt; ⁺ &gt;);

butyl 2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate ( Compound 237), MS (Biolon) C34H35N7O4 m / e calcd. 605.3; found 605.4 (MH &lt; ⁺ &gt;);

-922- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4yl) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 238), MS (Biolon) 02δΗ26 ^Ν 6θ3 ^m ^ ^e calcd. 494.2; found 494.5 (MH &lt; ⁺ &gt;);

2- (1- (1H-7-benzoimidazol-2-yl) ethyl] -3-methyl-N - [2- (2-fluorophenoxy) ethyl] -3H-benzoimidazole · 5carboxamide (Compound 239);

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

2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-isopropoxyphenoxy) ethyl] -3Hbenzoimidazole-5-carboxamide (Compound 241), MS (Biolon) C29H31N5O3 m / e calc 497.2; found 497.6 (MH ⁺ );

2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - (2- (2-methylphenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 242), MS (Biolon) C27H27N5O2 m / e calc 453.2; found 453.5 (MH ⁺ );

2- (1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2- (2-ethoxyphenoxy) ethyl] -3H-benzoimidazole-5carboxamide (Compound 243), MS (Biolon) 028Η29 ^Ν 5θ3 m / e calc 483.2; found 483.5 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 244), MS (Biolon) θ2δΗ30 ^Ν 8θ3 ^m ^ ^e calc- 526.6; found 526.8 (MH ⁺ );

ethyl 2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridin-5-ylcarbonylamino} ethoxy) ) benzoate (Compound 245), MS (Biolon) C28H33N9O4 m / e calc 559.6; found 559.6 (MH ⁺ );

-932-Methoxyethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 246), MS (Biolon) C30H31N5O4 m / e calcd. 541.6;

found 541.5 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 247), MS (Biolon ) C29H30N8O4 m / e calcd. 554.6; found 555.4 (MH &lt; ⁺ &gt;);

2- (2- (2- (1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 248), MS (Biolon ) 02βΗ28 ^Ν 8θ4 m / θ calc 540.6; found 541.3 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 249), MS (Biolon) 02δΒ29 ^Ν 9θ3 m / θ ' ^2ra ^ · 539.6; found 540.5 (MH &lt; ⁺ &gt;);

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl · 3H-benzoimidazole-5- carboxamide (Compound 250), MS (Biolon) 028Η28 ^Ν 9θ3θ ' ^m ^ ^e calcd · 574.0; found 574.2 (MH &lt; ⁺ &gt;);

4-Chloro-2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid ( Compound 251), MS (Biolon) C28H27N8O4CI m / e calcd. 575.0; found 575.2 (MH &lt; ⁺ &gt;);

5-Chloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 252). MS (Biolon) C28H27N8O4CI m / e calcd. 575.0; found 575.2 (MH &lt; ⁺ &gt;);

6-chloro-2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 253). MS (Biolon) C28H27N8O4CI m / e calcd. 575.0; found 575.2 (MH &lt; ⁺ &gt;);

-944,6-Dichloro-2- (2- {2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol5-ylcarbonylamino} ethoxy) benzoic acid (compound 254), MS (Biolon) C2sH26 ^N 8O4 ^Cl 2 m / e calcd. 609.5; found 609.1 (MH &lt; ⁺ &gt;);

Ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5carbonylamino} ethoxy) benzoic acid (Compound 255), MS (Biolon) C29H29N5O4 m / e calc. 511.6; found 512.2 (MH ⁺ );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2,4-dioxo-3- (2-trimethylsylanylethyl) -3,4-dihydro -2W-quinazolin-1-yl] ethyl} -3W-benzoimidazole-5-carboxamide (Compound 256), MS (Biolon) C34H40N10O3S1 m / e calcd. 664.8; found 665.4 (MH &lt; ⁺ &gt;);

2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl- N - {2- [2,4-dioxo-3,4-dihydro-2Hquinazoline-1- yl] ethyl} -3H-benzoimidazole-5-carboxamide (Compound 257), MS (Biolon) C29H28N10O3 m / e calcd. 564.6; found 565.2 (MH &lt; ⁺ &gt;);

2- [1- (1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-cyanophenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5carboxamide (Compound 258), MS (Biolon) C27H24N6O2 m / e calcd. 454.5; found 465.1 (MH &lt; ⁺ &gt;);

5- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) isophthalic acid (Compound 259), MS (Biolon) C28H25N5O6 m / e calcd. 527.5; found 528.4 (MH &lt; ⁺ &gt;);

2- (2-methoxyethoxy) ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 260). MS (Biolon) C32H35NgOg m / e calcd. 585.7; found 585.4 (MH &lt; ⁺ &gt;);

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyrid-5ylcarbonylamino} ethoxy) benzoic acid (Compound 261), MS (Biolon) C29H29N9O4 m / e calcd. 531.6; found 531.5 (MH &lt; ⁺ &gt;);

-952- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide ( Compound 262), MS (Biolon) C 26 ^H 26 ^N 6 ° 3 ^{m / e} calc. 470.54; found 471.4 (MH &lt; ⁺ &gt;);

2- [1- (5-Fluoro-1 H -benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 263), MS (Biolon) C27H26N5O3F m / e calcd. 487.54; found 488.1 (MH &lt; ⁺ &gt;);

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-tetrazol-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 264), MS (ESI) C24H23N11O m / e calcd. 481.47; found 482.6 (MH &lt; ⁺ &gt;);

2- [1- (4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 265), MS ( Biolone) C27H27N5O4 m / e calcd. 485.59; found 486.3 (MH &lt; ⁺ &gt;);

2- [1- (4-aminobenzoxazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3H-benzoimidazole5-carboxamide (Compound 266), MS (Biolon) C27H27N5O4 m / e calcd. 485.59; found 486.1 (MH &lt; ⁺ &gt;);

3- {2- [1- (1-7-benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid (Compound 267). MS (Biolon) C29H31N5O6S m / e calcd. 577.66; found 577.4 (MH ⁺ );

3- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -6- [2- (2methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfone acid (Compound 268), MS (Biolon) C32H33N7O5S m / e calcd. 643.72; found 644.6 (MH &lt; ⁺ &gt;);

Ethyl 2- [2- (2- {1- [1- (2-methoxyethyl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-3H-benzoimidazole-5carbonylamino) ethoxy] benzoate (Compound 269) , MS (Biolon) C32H35N5O5 m / e calcd. 569.66; found 570.5 (MH &lt; ⁺ &gt;);

-96benzyl 2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5c] pyridine-5-carboxylate (Compound 270 ), MS (Biolon) C29H30N8O6 m / e calcd. 586.6; found

587.2 (MH &lt; ⁺ &gt;);

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

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

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

N- [3- (2-Ethoxyphenyl) propyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 274) , MS (Biolon) C29H31N5O3 m / e calcd. 497.62; found 497.4;

N- [3- (2-Butoxyphenyl) propyl] -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3Hbenzoimidazole-5-carboxamide (Compound 275), MS (Biolon) C31H35N5O3 m / e calcd. 525.65; found 526.3;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [3- (2-propoxyphenyl) propyl] -3H-benzoimidazole-5-carboxamide (Compound 276), MS (Biolon) C30H33N5O3 m / e calcd. 511.62; found 512.3;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (3-methyl- [1,2,4] oxadiazol-5yl) phenoxy] ethyl } -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 277), MS (Biolon) C29H27N7O4 m / e calcd. 538.1; found 537.58;

Ethyl 2- (2- {2- [1- (4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 278 ), MS (ESI) C29H28N5O5F m / e calcd. 545.57; found 545.6;

-972- (2- {2- [1- (4-Fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 279), MS (Biolon) C27H24N5O5F m / e calcd. 517.52; found 517.4;

Ethyl 2- (2- {2- [1- (6-fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3/7-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate (Compound 280), MS (Biolon) C29H28N5O5F m / e calcd. 545.57; found 545.9;

2- (2- {2- [1- (6-Fluoro-4-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid (Compound 280). MS (Biolon) C27H24N5O5F m / e calcd. 517.52; Found 517.6;

ethyl 2- (2- {2- [1- (4,5-difluoro-7-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate ( Compound 281), MS (Biolon) C29H27N5O5F2 m / e calcd. 563.56; found 563.9; and

2- (2- {2- [1- (4,5-Difluoro-7-hydroxy-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid ( Compound 282), MS (ESI) C29H27N5O5F2 m / e calcd. 536.1; found 535.51.

-98PRIMER13

In vitro tryptase inhibition assay

Tryptase solution (60 g / ml) was prepared by dissolving tryptase, which was purified from preparations of human lung or skin tissue, respectively. human mast cells (HMC1) or obtained from commercial sources, e.g. ICN Biomedicals, Irvine, California, Athens Research & Technology, Athens, Georgia, etc., in a solvent mixture comprising: 10 mM 2-N-morpholinoethane sulfonic acid, 2 mM CaCIg, 20% glycerol and 50 g / ml heparin. A substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys - /> nitroanilide) was obtained from Sigma. Solutions of test compounds were prepared by diluting ten times the stock solution (1 mg of test compound in 200 μ 200 dimethyl sulfoxide (DMSO)) in assay buffer (comprising: Tris-HCl (pH 8.2), 50 mM; NaCl, 100 mM; 0.05% polyoxyethylene sorbitan monolaurate (Tween-20®); and zinc chloride, 150 μΜ) and then prepared seven additional triple dilutions in 10% DMSO in assay buffer.

Aliquots (50 μΙ) of each of the eight dilutions of the test compound solution were poured into separate wells in a U-bottom microtiter plate and 96 wells. Tryptase solution (25 μΙ) was added to each well and the solutions were stirred for 1 hour at room temperature. Substrate solution (25 μΙ) was added to initiate the enzymatic reaction and the microtiter plates were immediately transferred to a UV / MAX kinetic microplate reader (Molecular Devices). Hydrolysis of the chromogenic substrate was followed spectrophotometrically at 405 nanometers for five minutes. The initial velocity dimensions were calculated from progressive curves using a kinetic analysis program (BatchKi; Petr Kuzmic, University of Wisconsin, Madison, Wl). Actual inhibition constants (Kj) were calculated from enzyme progressive curves using standard mathematical models.

The following compounds of the invention were tested according to the tryptase inhibitory activity according to the method as described in this application or by methods known to one of ordinary skill in the art:

Compound 1, Kj = 0.09 μΜ; Compound 12, K, = 29 μΜ; Compound 26, Kj = 33 μΜ;

Compound 27, Kj = 0.6 μΜ; Compound 28, Kj = 0.00007 μΜ; Compound 29, Kj = 0.0008 μΜ;

Compound 30, Kj = 0.009 μΜ; Compound 37, Kj = 0.002 μΜ; Compound 42, Kj = 0.008 μΜ;

-99 Compound 43, Kj = 0.002 μΜ; Compound 74, Kj = 0.006 μΜ; Compound 75, K ·, = 0.03 μΜ;

Compound 80, Kj = 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, Kj = 0.008 μΜ; Compound 126, Kj = 0.008 μΜ; Compound 127, Kj = 0.006 μΜ; Compound 128, K; = 0.002 μΜ; Compound 169, Kj = 0.001 μΜ; Compound 132, Kj = 0.00002 μΜ; Compound 134, Kj = 0.00002 μΜ;

Compound 138, Kj = 0.0002 μΜ; Compound 152, Kj = 0.0005 μΜ; Compound 182, Kj = 0.004 μΜ; Compound 194, Kj = 0.009 μΜ; Compound 203, Kj = 0.008 μΜ; Compound 225, Kj = 0.008 μΜ; Compound 249, Kj = 0.0007 μΜ; Compound 250, Kj = 0.0004 μΜ; Compound 251, Kj = 0.0008 μΜ; and Compound 252, Kj = 0.0004 μΜ.

EXAMPLE A model of asthma on sheep

The allergic sheep model of asthma was used to evaluate in vivo the compounds of the invention as anti-asthmatics. 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 J. Appl. Physiol. 59: 1416-1422; Soler et al. (1989) J. Appl. Physiol. 67: 406413). Each sheep serves as its own control. The body weights of these animals were in the range of 20-50 pounds.

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

Twenty-four hours after the antigen challenge, both the control and the sheep experiment developed airway hyperresponsiveness. Airway hyperresponsiveness is expressed as PC400, a carbachol concentration that causes a 400% increase in SRL (specific lung resistance); therefore, the decrease in PC400 indicates hyperresponsiveness. Compound 13 was found to block the onset of hyperresponsiveness. As shown in Figure 2, this compound maintains the PC400 at a baseline value of 15 respiratory units. The number of respiratory units is for those animals in

The control group dropped to 7. Thus, treatment with Compound 13 resulted in a significant improvement in airway function in antigen-induced sheep.

Thus, the present invention provides compounds and compositions useful for the prevention and treatment of immune-mediated inflammatory disorders, especially those associated with the respiratory tract, including asthma and the hyperresponsive phase associated with chronic asthma in addition to allergic rhinitis. The present invention is also recognized as providing a method for treating immune-mediated inflammatory disorders that are susceptible to treatment with a compound of the present invention.

It should be understood that the foregoing description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art after reviewing the description above. The scope of the invention should therefore be determined not by reference to the foregoing description, but should instead be determined by reference to the appended claims, together with the full range of equivalents to which such claims are addressed.

Claims (24)

REQUIREMENTS A compound of Formula I: (R ² ) «2 (R *) nl (R) n) in which: 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 comprises a fused heterobicyclic radical containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom being 1 2 1 optionally heteroatom, X and X are adjacent ring members of the aromatic ring and X is A 5 heteroatom moiety selected from -N =, -NR-, -O- and -S-, wherein R is hydrogen, (C 1-6) alkyl or hetero (C 2-6) alkyl; C comprises a fused heteropolycyclic radical containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, each ring atom being optionally 4 5 5 heteroatoms, X and X are adjacent ring members of the aromatic ring, X is 6 is a heteroatom moiety selected from -N =, -NR -, -O- and -S-, wherein R is hydrogen, a group selected from (C 1 -C 5) alkyl or hetero (C 2-12) ^a * ^k '* ^a · ^this group being optionally substituted with one to two substituents independently selected from (Cv6) ^{a kanoiloksi>} (Ci-6) alkylamino, di (-6) alkylamino, tri (C- | .G) alkilamonio (Cj.6) ^alk ' ^{lkarl:) a} moila, -102di (C1-6) alkylcarbamoyl, (C1-6) alkyloxy, (C1-6) acyloxycarbonyl, (C1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C1-6) aryl, halo, hetero ( C5.i4) aryl, hydroxy and sulfo, or as defined below; and any of its 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 hydrogen, θ (C1-6) alkyl, hetero (C2-12) ^alkyl or together with R forms (C2-4) alkylene or hetero (C2-4) alkylene and 8 7 R is hydrogen, (C 1-6) alkyl or hydroxy or together with R forms (C 2-6) alkylene or (C 1-10) alkylidene, at 7 8 wherein any aliphatic or alicyclic moiety comprising R and / or R is optionally substituted with one to three substituents selected from (C - (. G) alkylamino, di (C 1-6) alkyl ⁿ o, three (C 1-6 ) alkylammonio, (C1-8) alkyloxy, (C1-8) alkyloxycarbonyl, (C1-8) alkanoyloxy, amino, carboxy, carbamoyl, (C1-8) alkylcarbamoyl, di (C1-8) alkylcarbamoyl, halo and hydroxy; R ¹ is amino (N- | -4) azolidinyl, amino (Ni-4) azolyl, (N-4-4) azolidinyl, (N-4-4) azolyl, carbamoyl, GG GG GG 1Π cyano, - (CH ₂ ) _X NHC ( NR) R, - (CH ₂ ) _X NHC (NH) NR R -C (NR) R, -C (NH) NHR, -C (NH) NR ¹⁰ R ¹⁰ or - (CR ¹¹ R ¹¹ ) yNH 2 and bonded to any ring atom with an available g valence encompassed by B, wherein x is O or 1, y is O, 1,2 or 3, each R is independently hydrogen or (C 1-8) alkyl, each R ¹⁰ is independently (C 1-8) alkyl and each R ¹¹ is independently hydrogen, (C 1-3) alkyl or together with another R ¹¹ and carbon the atom to which they are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R ^{1 is} optionally substituted with one to two substituents independently selected from (C 1-10) alkyloxycarbonyl, (C 1-10) alkanoyloxy, carboxy, carbamoyl, ( C1-8) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-8) alkylsulfonyl and hydroxy; each R is independently (C1-8) alkyl, (C1-6) alkyloxycarbonyl, (C1-8) alkanoyloxy, (C1-6) alkyloxy, carboxy, carbamoyl, (C1-8) alkylcarbamoyl, di (C1-8) alkylcarbamoyl, (C1-6). g) alkylsulfinyl, (C1-g) alkylsulfonyl, (C1-6) alkylthio, halo or hydroxy and bonded to any ring atom with an available valence encompassed by B, wherein any aliphatic moiety 2 comprising R is optionally substituted by one to two substituents independently selected from (C1-8) alkyloxycarbonyl, (C1-8) alkanoyloxy, carboxy, carbamoyl, (C1-8) alkylcarbamoyl, di (C1-8) alkylcarbamoyl, (C-f6) ^{a, k} i ^{, s} ufonif and hydroxy ; -1033 each R is independently (C1-C6) alkyl, (C1-C10) alkyloxy, (C1-6alkylthio, cyano, halo, perhalo (C1-6) alkyl or hydroxy and bonded to any ring atom with available valence by comprises C; and 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 , - (CH ₂ ) _with 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 bonded to any ring carbon atom with available valence , covered by C, wherein: z is 0.1 or 2, 12 15 6 15 6 R is -R or -X - (R) _n -f5, where n15 is 1 or 2, X is (C 1-10) alkylene, 15 cyclo (C 3-10) alkylene, hetero (C ₂ -io) ^{a, which is} ' ^{en a} ' · heterocyclo (C3-10) ^a lkylene and each R is independently hydrogen, (C8-14) aryl, cyclo (C3-14) alkyl, polycyclo (Cg.i4) aryl, heteropolycyclo (C6-14) aryl , heterocyclo (C 3-4) alkyl, hetero (C 5-4) aryl or as defined below, R is hydrogen, (C- | .G) alkyl or hetero (C ₂ -6) alkyl; 14 6 15 R is hydrogen, (C 1-3) alkyl or together with X and R forms (C 3-4) alkylene; any aliphatic and alicyclic moiety comprising R optionally is substituted with one to five substituents independently selected from (C-i_6) ^{al! <yl alkyl,} (C-t_6) alkyl, ^a mine, di (Ci_g) ^a lkilamino, (C-6 ) ^alkilkarba MOIL, di (C- | -6) alkylcarbamoyl, (Ci_g) alkyloxy, (C- | _5) alkyloxycarbonyl, (C-g) alkylsulfinyl, (Ci.gjalkilsulfonila, (Ci-6) ^{alkyl |} ti °> amino , (C8-10) arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from cyano, guanidino, halo, halosubstituted ₈ ) alkyl, -R ^{15 16} , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , -S (O) ₂ R ¹⁶ , -104-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 as defined above and R is hydrogen, optionally mono-substituted (C 1-6) alkyl (wherein the optional substituent is (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C - (_) 5) alkylammonio, (C1-5) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-8) alkyloxycarbonyl, (C1-6alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C3-8) alkyl , hetero (C1-8) alkyl, hetero (C5-g) aryl, heterocyclo (C3-8) alkyl or phenyl; 2 3 with the proviso that n1 is not 0, when n2 is 0, or R is (C ₃ _g) alkyl, or (Ci) alkyloxy, n3 is 0, or R is (Ci_g) alkyl or (Cj.g) alkyloxy and R is hydrogen, (Οι.ΐο) ³ · Μ ^{a, and} (C 1-10) alkyloxy; and its non-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 1 wherein A contains 5 ring members and B contains 6 ring members The 1 5 members and X and X are adjacent members of the oxazol-2-yl, 1 H-imidazol-2-yl or thiazol-2-yl ring; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 2 which is a compound of Formula II: in which: the dashed lines independently represent optional bonds; each R is independently (C 1-6) alkyl, (C 1-8) alkyloxy, halo or hydroxy; -1053 each R is independently a (C- | _ _8> alkyl, (Cj.g) alkyloxy, halo or hydroxy; X ³ is -C (O) - or -CR ⁷ R ⁸ -; 8 11 1 X is -CH (R) _n - (- or -C (R) _n i =, wherein R is amino (N- | 4) azolidinyl, amino (N- | 4) azolyl, (N-1-4) ) azolidinyl, (Ni ^ azolyl, -NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ -C (NH) NHR ¹⁰ , -C (NH) NR ¹³ R ¹³ or - (CR ¹¹ R ¹¹ ) yNH 2, or X ⁸ is -N = or -NH (R ¹ ) _n - | -, wherein R ¹ is qqm mm o -C (NR) R, -C (NH) NHR, or -C (NH) NR R, wherein each R is independently hydrogen or (C 1-6) alkyl and each R ¹⁰ is independently (C ·) g) 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 , - (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 A compound according to claim 3 wherein: 5 6 R is hydrogen or (C 1-4) alkyl, R is hydrogen or (C 1-4) alkyl, where alkyl is optionally substituted with one to two substituents independently selected from (C 1-4) alkyloxy, hydroxy and 7 8 sulfo , R is hydrogen or methyl and R is hydrogen, methyl or hydroxy; 8 1 1 X is -C (R) ni =, P ^r > wherein R is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2 amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH2) XNHC (NR ⁹ ) R ⁹ , - (CH 2) _X NHC (NH) NR ⁹ R ⁹ 9 9 9 8 1 and -C (NR) R, wherein each R is independently hydrogen or methyl, or X is -N (R) _π - | -, wherein R ¹ is -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹ ° or -C (NH) NR ¹ ° R ¹⁰ , wherein each R ^{9 is} independently hydrogen or methyl and each R ¹⁰ is methyl, wherein any aliphatic or alicyclic moiety comprising R ^{1 is} optionally substituted with one to two substituents independently selected from methylsulfonyl and carboxy; -106X ⁹ is -C (R ⁴ ) =, wherein R ⁴ is -R ¹² , -OR ¹² , -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , wherein R ¹³ and R ^{14 are} independently hydrogen or (C 1-10) alkyl; R ¹² 15 615 6 is -R or -X - (R) _n i5, where X is (C 1 -ioblic or hetero (C 2 -10) ^a ' ^k ' * ^en ' ^{n every} 15 R is independently hydrogen, (C 8-14) aryl, cyclo (C 3-4) alkyl, polycyclo (C 3-4) aryl, heteropoxycyclo (C 3-4) aryl, heterocyclo (C 3-4) alkyl or hetero (C 5-4) ) aryl; any aliphatic and alicyclic moiety comprising R optionally is substituted with one to five substituents independently selected from (C- | _4) alkyloxy, (C- | -4) ^a lkiloksikarbonila, amino, carbamoyl, carboxy and hydroxy; and any aromatic moiety comprising R optionally is substituted with one to three substituents independently selected from {d_4) alkyl, (C- | .4) ^a lkiioksi, (C- | _ 4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo ( C 3-8 alkyloxy, halo, hetero (C 1-8) alkyl, hydroxy, hetero (C 1-8) alkylcarbonyl, hetero (C 3-8) aryl and trifluoromethyl; and its Λ / oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 4 wherein: A together with B comprises 4,5,6,7-tetrahydro-1 B-imidase [4,5-c] pyridin-2-yl, wherein n 2 is 0, R ¹ 9 9 5 is -C (NR) R and R is hydrogen, or A together with B comprises 1 B-benzoimidazol-2-yl or 4,5,6,71 2 tetrahydro-1 H-benzoimidazol-2-yl, wherein R is aminomethyl or guanidino and each R is independently halo or hydroxy; C comprises 4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl or 1 B-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 15 (C 1-4) alkylene or hetero (C 2-4) ^a alkylene and R is (C6-10-) ^aryl > (Ce_10) ^a ryloxy, polycyclo (Cg_10) ^a h1, hetero (C5-10) ^aryl, > hetero ( ^C5-10 ) ^aryloxy, and ^al > heterocyclo (Cg-10) aryl; and any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from (C 1-4) alkyl, (C 1-4) ^a, chloxy, (C 1-4) alkyloxycarbonyl, carboxy, carbamoyl, halo, hydroxy and tetrazol-1-yl; and its / V-oxide -107 derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 5 wherein A together with B comprises 1-7-benzoimidazol-2-yl and 2 is each independently halo or hydroxy; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 6 wherein n 1 is 0; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 7, selected from: 2- (2- {2- [1- (4,6,7-Trifluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5,6-Difluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3W-benzoimidazol-5ylcarbonylamino} ethoxy) benzoic acid; butyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonylamino} ethoxy) benzoate; propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5ylcarbonylamino} ethoxy) benzoate; and isobutyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 5 wherein R ^{1 is} guanidino or aminomethyl and and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. -10810. The compound of claim 9, which is selected from: 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3-7-benzoimidazole-5carboxamide; ethyl 2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5 c] pyridin-5-ylcarbonylamino} propoxy) benzoate; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ethyl) -3W-benzoimidazole-5-carboxamide; 2- (5-guanidino-1/7-benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl- N - (2-naphth-1-ylethyl) 3H-benzoimidazole-5-carboxamide; 2- (5-guanidino-1/7-benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide; 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl 3/7-benzoimidazole-5-carboxamide; 4-Chloro-2- [2 - ({2- [1- (5-guanidino-1/7-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonyl} amino) ethoxy] benzoic acid ; 5-Chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5ylcarbonyl} amino) ethoxy] benzoic acid; -1092- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5carboxamide; and 2- (5-Aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ethyl) 3H-benzoimidazole-5-carboxamide ; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 5 wherein A together with B comprises 4,5,6,7-tetrahydro-1 H 1 9 imidase [4,5-c] pyridin-2-yl and R is -C (NH) R; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 11, which is selected from: 2- (2- (2- (1- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3-methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1A7-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2-napht- 1ylethyl) -3H-benzoimidazole-5-carboxamide; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl- N - (2-naphthyl- ylethyl) -3H-benzoimidazole-5-carboxamide; 2- (5-iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl- N - (2-naphthylethyl) -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 - (2hydroxy-2 -naphthal-1-ylethyl) -3H-benzoimidazole-5-carboxamide; 2- (5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2hydroxynaphthyl) -1-yl) ethyl] -3H-benzoimidazole-5-carboxamide; -1102- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (4hydroxynaphthal-1-yl) ethyl] -3H-benzoimidazole-5-carboxamide; 2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- / V - (2-naphthyl-ylethyl) -3H-benzoimidazole-5-carboxamide; ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl3 / 7-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate; 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 3- (2methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} - 1,4,6,7tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate; and 2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl- / V - [2- (2tetrazolylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 12, which is 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1Himidazo [4,5-c] pyridin-2 -yl] ethyl} -3-methyl-3H-benzoimidazole-5ylcarbonylamino) ethoxy] benzoic acid; and its / V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 14, further comprising a β-adrenergic agonist compound. -11116. The pharmaceutical composition of claim 14, wherein said βadrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, formoterol, phenoterol and prenalin. The pharmaceutical composition according to claim 14, wherein said composition comprises a pharmaceutically acceptable topical carrier. The pharmaceutical composition according to claim 14, wherein said composition comprises a pharmaceutically acceptable oral carrier. The pharmaceutical composition according to claim 14, wherein said composition comprises a pharmaceutically acceptable aerosol carrier. 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 aerosolized form suitable for inhalation. A compound of claim 1 for the treatment of an immune-mediated inflammatory disorder in a mammal by administering a therapeutically effective amount of said compound to said mammal. The compound of claim 1 for the treatment of rheumatoid arthritis in a mammal by administering a therapeutically effective amount of said compound to said mammal. The compound of claim 1 for the treatment of conjunctivitis in a mammal by administering a therapeutically effective amount of said compound to said mammal. The compound of claim 1 for the treatment of syncytial virus infections in a mammal by administering a therapeutically effective amount of said compound to said mammal. -11225. The compound of claim 1 for the treatment of an immune-mediated inflammatory disorder of the mammalian respiratory tract by administering a therapeutically effective amount of the unknown compound to said mammal. 26. A process for the preparation of a compound of Formula I; in which: 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 comprises a fused heterobicyclic radical containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom being 1 12 optionally heteroatom, X is a heteroatom moiety selected from -N =, -O- and -S- and X and X are adjacent ring members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2- or a ring wherein 5 is 5 a ring member 1 B-imidazol-2-yl ring is optionally-NR -, wherein R is hydrogen, (C 1-6) alkyl or hetero (C 2-6) alkyl; or C comprises a fused heteropolycyclic radical containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, each ring atom being optionally 5 4 5 heteroatom, X is a heteroatom moiety selected from -N =, -O- and -S- and X and X are adjacent ring members of oxazol-2-yl, 1H-imidazol-2-yl or thiazol-2- il of the ring, wherein the ring member is 6 6 1 H-imidazol-2-yl is optionally -NR-, wherein R is hydrogen, the group selected from -113 (C .G) alkyl or hetero (C ₂ -i2) ^{a hernia>} which group is optionally substituted with one to two substituents independently selected from (C- | .G) alkanoyloxy, (C-i_6) alkylamino, di (C1-6) alkylamino, trKC1-6alkylammonio, (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, (C1-6) alkyloxy, (C1-6) alkyloxycarbonyl, (C1-6) g) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C8-14) aryl, halo, hetero (C5-14) aryl, hydroxy and sulfo, or as defined below and any of its carbocyclic ketone, thioketone and iminoketone derivatives; X ^{2 3 * * *} is -O-, -S-, -S (O) -, -S (O) ₂ -, -C (O) -, -NR ⁷ - or -CR ⁷ R ⁸ -, at wherein R ^{7 is} hydrogen, (Cv 6 8 g) alkyl, hetero (C ₂ -i2) ^{alkyl or} together with R form a (C ₂ -4) alkylene or hetero (C ₂ -4) alkylene and R is hydrogen, (C _E) alkyl or hydroxy, or together with R ⁷ form a (C ₂ -6) alkyl or (C- | .G) alkylidene, whereby 7 8 is any aliphatic or alicyclic moiety comprising R and / or R is optionally substituted with one to three substituents selected from (C .G ) alkylamino, di (C1-6) alkylamino, tri (C1-5) alkylammonio, {C1-6) alkyloxy, (C1-6) alkyloxycarbonyl, (C1-6) alkanoyloxy, amino, carboxy, carbamoyl, ( C-), g) alkylcarbamoyl, di (C1-8) alkylcarbamoyl, halo and hydroxy; R ¹ is amino (N- | -4) azolidinyl, amino (Ni_4) azolyl, (N- | _4) azolidinyl, (N- | _4) azolyl, carbamoyl, qqoqqq and cyano, - (CH ₂ ) _X NHC (NR) R - (CH ₂ ) _X NHC (NH) NR R, -C (NR) R -C (NH) NHR, -C (NH) NR ¹⁰ R ¹⁰ or - (CR ¹¹ R ¹¹ ) yNH 2 and bonded to any ring atom with an available g valence encompassed by B, wherein x is O or 1, y is O, 1, 2 or 3, each R is independently hydrogen or (Cvg) alkyl, each R ¹⁰ is independently (C 1-8) alkyl, and each R ¹¹ is independently hydrogen, (C 1-3) alkyl, or together with another R ¹¹ and a carbon atom to which both are attached. cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R ^{1 is} optionally substituted with one to two substituents independently selected from (C 1-10) alkyloxycarbonyl, (C 1-10) alkanoyloxy, carboxy, carbamoyl, (C 1 -g) alkylcarbamoyl, di (C 1-10) alkylcarbamoyl, (C 1-10) alkylsulfonyl and hydroxy; each R is independently (C 1-10) alkyl, (C 1-6) ^{a |} chloxycarbonyl, (C1-8) alkanoyloxy, (C1-8) alkyloxy, carboxy, carbamoyl, (C1-6) alkylcarbamoyl, di (C1-8) alkylcarbamoyl, (C1-8) alkylsulfinyl, (C-). g) alkylsulfonyl, (C1-10) ^a alkylthio, halo or hydroxy and bonded to any ring atom with an available valence covered by B, wherein any aliphatic moiety comprising R is optionally substituted by one to two substituents independently -114 selected from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy; each R is independently (C 1-6 alkyl, (C 1-8) alkyloxy, (C 1, g) alkylthio, cyano, halo, perhalo (C 1-6) ^a, · or hydroxy, and bonded to any ring atom with available valence covered by C; and 4 19 19 1 * i 19 19 19 19 19 R is -R, -OR, -N (R) R, -SR, -S (O) R, -S (O) ₂ R -S (O) ₂ OR, -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 ) _with 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 bonded to any ring carbon atom with available valence , covered by C, wherein: z is 0.1 or 2, R ¹² is -R ¹⁵ or -X ⁶ - (R ¹⁵ ) _{n i 5} , where _n ¹⁵ is 1 or 2, X ⁶ is (C 1-10) alkylkifen, 15 cyclo (C 3-10) alkylene, hetero (C ₂ . -) o) ^a alkylene or heterocyclo (C3_i o) ^a H <il © n ^and each R is independently hydrogen, (Cg_14) aryl, cyclo (C3_- | 4) alkyl, polycyclo (Cg_i4) aryi, heteropolicyclo (Cg .- | 4) aryl, heterocyclo (C3- | 4) alkyl, hetero (C5- | 4) aryl or as defined below, R is hydrogen, (C, .6) alkyl or hetero (C ₂ .G) alkyl; 14 6 15 R is hydrogen, (C1-8) alkyl or together with X and R forms (C3-4) alkylene; any aliphatic and alicyclic moiety comprising R is optionally substituted with one to five substituents independently selected from (C1-6) alkyl, (C1-8) alkylamino, di (C1-8) alkylamino, (C1-8) alkylcarbamoyl, di (C- | _6) alkitkarb ^a MOIL ^a (Cj _g) alkyloxy, (Cf _6) ^a lkiloksikarbonila, (Cj _g) alkyl-sulfinyl, (C- | _g) alkylsulfonyl, (C- | _g) alkylthio , amino, (C1-8) arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and -11515 any aromatic moiety comprising R is optionally substituted with one to three substituents independently selected from cyano, guanidino, halo, halosubstituted (C 1-6 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} 16 as is defined above and R is hydrogen, optionally mono-substituted (C1-6) alkyl (wherein the optional substituent is (C1-6) alkylamino, di (C1-8) alkylamino, tri (C1-6) 5) alkylammonio, (C 1-6 alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkyloxycarbonyl, (C 1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C 3-6) alkyl, hetero (C 1-6) alkyl, hetero (C 5-5) aryl, heterocyclo (C 3-6) alkyl or phenyl; 2 3 with the proviso that n1 is not 0 when n2 is 0 or R is (C1-6) alkyl or (C1-8) alkyloxy, n3 is 0 or R is (C1-8) alkyl or (C1-6alkyloxy and R is hydrogen, (C 1-10) alkyl or (C 1-10) alkyl ° xy; and its Noxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts; this process comprises: (a) reacting a compound of Formula 1: or a protected derivative thereof with a compound of Formula 2: -116or its protected derivative, wherein L is a prominent group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 ring atoms, each ring containing from 5 to 7 29 6 ring atoms and each ring atom is optionally heteroatom, R is -OH, -NHR or -SH, θ wherein R is hydrogen or a group selected from (C 1-10) alkyl or hetero (C 2-12) ^alkyl > ^this group is optionally substituted with one to two substituents independently selected from (C1-6alkanoyloxy, (C1-6) alkylamino, di (C1-6) alkylamino, tri (C1-6) alkylammonio, (C1-6). 6) alkylcarbamoyl, di (C 1-6) ^a, kyl ^k arbamoyl, (C 1-6) alkyloxy, (C 1-6 alkyloxycarbonyl, (C 1-6). 6) alkyloxysulfonyl, amino, carboxy, carbamoyl, (Οθ.- | parila, halo, hetero (C5-- | parila, 1231234 6 hydroxy and sulfo, and n1, n2, n3, A, B, X, X, X, R, R, R, R and R are as defined above and then deprotecting if necessary, or (b) reacting a compound of Formula 3: or a protected derivative thereof with a compound of Formula 4: 30 5 or a protected derivative thereof, wherein L is a leaving group, R is -OH, -NHR or 3451234 5 -SH and n1, n2, n3, B, C, X, X, X, R, R, R, R and R are as defined above, and then deprotecting if necessary; (c) optionally further converting the compound of Formula I into a pharmaceutically acceptable salt; -117 (d) optionally further converting a salt form of a compound of Formula I to a form other than a salt; (e) optionally further converting the non-oxidized form of the compound of Formula I into a pharmaceutically acceptable / V-oxide; (f) optionally further converting the ΛΖ-oxide form of the compound of Formula I into its non-oxidized form; (g) optionally further converting a non-derivatized compound of Formula I into a prodrug pharmaceutical derivative; and (h) optionally further converting the prodrug derivative of the compound of formula I into its non-derivatized form. 1/2