CZ345499A3 - Compounds and preparations for treating diseases connected with serine protease activity , particularly tryptase - Google Patents

Abstract

Compounds, compositions and methods are described prevention and treatment of venous cell inflammation. Preferred embodiments of the invention are compounds of formula I, wherein the dotted lines represent each other independently any binding; each R 2 is independently of one another (C 1 's). 6) alkyl, (C 1-6) alkyloxy, halogen or hydroxy; Each R3 is independently of one another (C 1-6 alkyl, (C 1-6 alkyloxy) halogen or hydroxy; X 3 is -C (O) - or -CR 7 R 8; X 8 is -CH (R 1) nine -C (R *) n1, wherein R 1 is amino (Ni 4) azolidinyl, amino (N1,4) azolyl, (N ^ Jazolidinyl, (Ni.4) azolyl, - NHC (NH) NR 9 R 9, -C (NR 9) R 9, - C (NH) NHR 10, - C (NH) NR 'R10 or - (CR1IRI1) VNH2, or X8 -N = or - NH (R ') "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 of one another second, hydrogen or (C 1-6) alkyl and each R 10 is independently one on the other (C 1-6) alkyl; and X 9 is -CH (R 4) or -C (R 4) =, wherein R 4 is -R 12, -OR 12, -N (R 13) R 12, -SR 12, -S (O) R 12, -S (O) 21 R 12, S (O) 2 OR 12, -S (O) 2 N (R 13) R 12, -N (R 13) S (O) 2 R 12. -C (O) R12, - 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 -N = or -N (R 4) -, wherein R 4 is -C (O) R 12, -C (O) OR 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 defined in the invention. R 5 is hydrogen or (C 1-4) alkyl, R 6 is hydrogen or (C 1-4) alkyl, wherein alkyl is optionally substituted with one to two substituents selected independently of one another from (C 1-4) alkyloxy, hydroxy and sulfo, R 7 is hydrogen or methyl and R 8 is hydrogen, methyl or hydroxy. The compounds, compositions and methods are effective for preventing and treating inflammations associated with the respiratory tract, such as asthma and allergic rhinitis, but also other types of immunologically induced inflammations such as rheumatoid arthritis, conjunctivitis and intestinal inflammations, various skin diseases, but also some viral diseases disease. The compounds are potent protease inhibitors viable cells - tryptase. means for treating these diseases include oral, inhalation, ointment and parenteral preparations, as well as apparatus containing these preparations.

Description

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

Technical field

This application is a continuation of Serial Number 08/833674, filed Apr. 7, 1997, which is a continuation of Serial No. 08/357491, filed Dec. 14, 1994, which is incorporated by reference, and relates to compounds and compositions for treating diseases associated with serine protease activity. especially tryptases.

BACKGROUND OF THE INVENTION

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

Asthma is an inflammatory disease (Hood et al., (1984) in: Benjamin-Cummings, Immunology, Second Edition), which is characterized by an increased response of trachea and bronchi to immunospecific allergens and generally to chemical or physical stimuli. Both acute and chronic disease include a number of biochemical mediators. The increased response of asthmatic bronchial tissue is the result of chronic inflammation that irritates and destroys the epithelium lining the bronchial pathways and changes it pathologically. Signs of inflammation in patients with mild asthma are shown by biopsy of the bronchial pathways.

The inflammatory process may trigger allergic responses to the inhaled allergen. For example, the allergens may activate the living cells and basophils that are present in the epithelium and the underlying layer of smooth muscle tissue by binding IgEs that are located on the surface of these 4 4 44444 ' s.

4 4 «4 4 ·····« «* * 44 cells. Activated living cells release a number of precursors or primary chemical mediators of inflammation (eg, histamine) and generate a number of other secondary inflammatory mediators at the site of the inflammation (eg, hyperoxide, lipid-derived mediators). In addition, some large molecules (eg, proteoglycans, tryptase, chymasa, etc.) are released by the degradation of the living cells.

Mediator precursors contained in living cells are likely to play a role in early bronchial spasm in asthma caused by aerial allergens. The peak of the early phase of the asthmatic reaction occurs approximately 15 minutes after exposure to the allergen, and is generally followed by a return to baseline within 1 to 2 hours. 25 to 35% of the patient population experience a subsequent deterioration in respiratory function that lasts 6 to 12 hours after exposure. This late reaction phase is accompanied by an increased amount of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) that infiltrate bronchial tissue. Infiltrating inflammatory cells are chemotactically attracted by substances released from living cells that have been activated during the late reaction phase. The late asthmatic response is probably a secondary inflammatory response based on the secretively active granulocyte region.

Tryptase is involved in the degradation of vasodilatory and bronchorelaxant neuropeptides (Caughey et al., (1988) J. Pharmacol. Exp. Ther. 244: 133-137; Franconi et al., (1988) J. Pharmacol. Exp. Ther. 248: 947 Tam et al. (1990) Am. J. Respir. Cell Mol. Biol. 3: 27-32) and modulates bronchial sensitivity to histamine (Sekizawa et al., (1989) J. Clin. Invest. 83 : 175-179. These findings suggest that tryptase may increase bronchoconstriction in asthma through the destruction of peptides with bronchodilator effect. Tryptase cleaves the α-chains of fibrinogen and high molecular weight kininogen, suggesting that tryptase, together with heparin, plays the role of a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, suggesting that tryptase is involved in tissue inflammation and remodeling, which are part of the destructive changes in rheumatoid arthritis. The administration of tryptase inhibitors prevents the development of a late respiratory hypersensitivity phase in allergic sheep and inhibits the immediate skin response after intradermal injection of allergen into the allergic sheep. All the above findings clearly point to the applicability of tryptase inhibitors as therapeutic agents in the treatment of asthma and other diseases associated with inflammation of the respiratory tract.

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

• * β I I · v v v.. V v

SUMMARY OF THE INVENTION

Summary of the Invention

The application relates to compounds of formula I:

where:

n 1 is 0 or 1;

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

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

A together with B forms a fused heterobicyclic group containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each atom cyclically optionally heteroatom, X ¹ and X ² are adjacent aromatic ring members and X ³ is a heteroatom group selected from -N =, -NR ⁵ -, -O- and -S-, wherein R ⁵ is hydrogen, (C _1-6 ) alkyl or hetero (C 2-6) alkyl;

C is a fused heteropolycyclic group containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, wherein any ring atom may be a heteroatom, X ⁴ and X ⁵ are adjacent aromatic ring members, X ⁵ is a heteroatom group selected from -N =, -NR ⁶ -, -O- and -S-, where R ⁶ is hydrogen, a group selected from (C sjalkylů or hetero (C ₂ -i2) alkyl, which group is optionally substituted with one to two substituents independently selected one on the other of (C _1-6 ) alkanoyloxy, (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, tri (C _1-6 ) alkylammonio, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C 1-6) ₆ ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C _1-6 ) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C 6-14) aryl, halogen, hetero (C 5-14) aryl, hydroxy and sulfo, or as defined below and any carbocyclic keto, thioketo and iminoketo derivative thereof;

X ³ is -O-, -S-, -S (O) -, -S (O) 2, -C (O) -, -NR ⁷ - or -CR ⁷ R ⁸ -, wherein R ⁷ is hydrogen, (Ci-6) alkyl, hetero (C2-i2) alkyl or together with R ⁶ form a (C2 ^) alkylene or hetero _(C2 ^) alkylene and ^R8 is hydrogen, (Ci.6) alkyl or hydroxy, or together with R ⁷ forms (C 2-6) alkyl or (C 1-6) alkylidene, wherein any aliphatic or alicyclic group R ⁷ and / or R ⁸ are optionally

9

9

9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 999999 substituted with one to three substituents selected from (C 1-6) alkylamino, di (C _1-6 ) alkylamino, tri (C 1-6) alkylammonio, (C _1-6 ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C 1-6) ₆ ) alkanoyloxy, amino, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, halogen and hydroxy;

R ¹ is amino (NM) azolidinyl, amino (NM) azolyl, (NM) azolidinyl, (NM) azolyl, carbamoyl, cyano, - (CH2) X NHC ^{(NR9) R9,} - (CH2) _x NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , -C (NH) NR ¹⁰ R ^10, or - (CR ¹¹ R ¹¹ ) y NH 2, and is bonded to any atom of cycle B with available valency, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R ⁹ is independently of one another hydrogen or (C 1-6) alkyl, each R ¹⁰ is independently of one another (C 1-6) alkyl and each R ¹¹ independently of one another is hydrogen, (C 1-3) alkyl, or together with another R ¹¹ and the carbon atom to which they are both attached to form cyclopropyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one to one two substituents selected independently of one another from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C _1-6 ) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy;

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

each R ³ is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxy, (C 1-6 alkylthio, cyano, halogen, perhalo (C 1-6) alkyl or hydroxy, and is bonded to any atom of the C 5-6 cycle by available valency;

R ⁴ is -R ¹² , -OR ¹² , -N (R ¹³ ) R ¹² , -SR ¹² , -S (O) R ¹² , -S (O) 2 R ¹² , -S (O) 2 OR ¹² , -S (O) 2N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) R ¹² , -OC (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) OR ¹² , - (CH ₂ ) _z N ( R ¹³ ) C (O) N (R ¹³ ) R ¹² , -OP (O) (OR ¹³ ) OR ¹² or -C (O) N (R ¹⁴ ) CH- (COOH) R ¹² , and is bound to any C-ring atom with available valency, where:

z is 0, 1 or 2,

R ¹² is -R ¹⁵ or -X ⁶ - (R ¹⁵ ) n ¹⁵ , wherein n 15 is 1 or 2, X ⁶ is (C 1-10) alkylene, cyclo (C 3-10) alkylene, hetero (C 2-10) alkylene or heterocyclo ( C 3-10 alkylene and each R ¹⁵ is independently of one another hydrogen, (C 6-14), cyclo (C 3-14) alkyl, polycyclo (C 6-14) aryl, heteropolycyclo (C 6-14) aryl, heterocyclo (C 3-14) alkyl , hetero (C 5-14) aryl or as defined below,

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

• fl flf fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl Fl Fl Fl Fl Fl · * ·

R ¹⁴ is hydrogen, (C 1-6) alkyl or together with X ⁶ and R ¹⁵ form (C ³⁴ ) alkylene;

any aliphatic and alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C _1-6 ) alkyl, (C _1-6 ) alkylamino, di (C _1-6 ) alkylamino, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C _1-6 ) alkysulfonyl, (C _1-6 ) alkysulfonyl, (C 1-6) alkythio, amino, (C 1-6 iaryarylsulfonyl, carbamoyl) , carboxy, cyano, guanidino, halogen, hydroxy, mercapto and uriedo, and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from cyano, guanidino, halogen, halogenated (C 1-8) alkyl, -R ¹⁶ , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , -S (O) 2 R ¹⁶ , -S (O) 2 N (R ¹³ ) R ¹⁶ -, -C (O) R ¹⁶ , -C (O) OR ¹⁶ and -C (O) N (R ¹³ ) R ¹⁶ , wherein R ¹³ is as defined above and R ¹⁶ is hydrogen, optionally mono-substituted (C 1-8) alkyl (wherein the optional substitutent is (C _1-6 ) alkylamino , di (C _1-6 ) alkylamino, tri (C _1-6 ) alkylammonio, (C _1-6 ) alkylcarbamoy l, di (Ci. ₆₎ alkylcarbamoyl, (C ₆₎ alkyloxycarbonyl, (C ₆₎ alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo _{(C3. 6)} alkyl, hetero (C _"8) alkyl, hetero (C5-6) aryl, heterocyclo (C ₃ -6) alkyl or phenyl;

except that n 1 is not 0 when n 2 is 0 or R ² is (C 1-6) alkyl or (C 1-6) alkyloxy, n 3 is 0 or R ³ is (C 1-6) alkyl or (C 1-6 alkyloxy) and R ⁴ is hydrogen , (C 1-10) alkyl or (C 1-10) alkyloxy, and its N -oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

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

* 0 β

0 0 0 · 0 0

The compounds described herein are useful for the prevention and treatment of immunologically induced inflammations primarily affecting the respiratory tract, including asthma, especially the hyperreactive phase accompanying chronic asthma and allergic rhinitis. The present invention further provides a method for treating immunologically induced inflammation by administering to a patient having immunologically induced inflammation a therapeutically effective dose or amount of a compound of the present invention. Further disclosed are compounds useful for the treatment of syncytial viral infection.

Brief description of the pictures

Figure 1 compares specific pulmonary resistance after administration of control substance (open squares) and 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -177-benzoimidazole-5-carboxamide (compound 4, solid squares) over time (measured in hours)

Figure 2 shows, as a bar graph, airway hyperreactivity (measured as PC400) in sheep stimulated with antigen following Compound 4 aerosol administration in 3 doses of 1 mg compared to placebo.

Detailed description of the invention

Definition

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

"Akanoyl" refers to the group -C (O) R having the total number of carbon atoms (eg, (C 1-6) alkanoyl includes formyl, acetyl, propanoyl, bytanoyl, isobutanoyl, crotonyl, isocrotonyl, etc.), wherein R is alkyl, as defined below.

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

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

φ φ φ φ • φ

ΦΦΦ φφφφ "Alkyl" denotes, for the purposes of this application, linear or branched, saturated or unsaturated aliphatic hydrocarbon group having the indicated number of carbon atoms and any of its keto- or thioketo- iminoketone derivative thereof (e.g. (C _") alkyl includes methyl, ethyl, propyl, isopropyl, butyl, n-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 divalent hydrocarbon group having the indicated number of carbon atoms thereof, and any carbocyclic ketone, thioketo-, iminoketone or substituted derivative thereof (e.g. _(Ci-I0) alkylene includes methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), methylethylene, vinylene, ethinylene, trimethylene (-CH ₂ CH ₂ CH ₂ -), 2-oxotrimethylene (-CH ₂ C (O) CH ₂ -), 2-thiatrimethylene (-CH ₂ C (S) ) CH ₂ -), 2-iminotrimethylene (-CH ₂ C (NH) CH ₂ -), propenylene (-CH ₂ CH = CH- or -CH = CHCH ₂ -), propanylylidene (= CHCH ₂ CH ₂ -), propendiylene (= CHCH = CH-), 1-aminotetramethylene, pentamethylene, etc.).

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

"Alkyloxy" refers to the group -OR, wherein R is an alkyl (as defined above) with a specified number of carbon atoms (eg, (C 1-6) alkyloxy includes methoxy, ethoxy, propoxy, isopropoxy, isopropenyloxy, butoxy, n-butoxy, isobutoxy tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethinyloxy, 1-propynyloxy, 2-propynyloxy, etc.).

"Alkylsulfinyl", "alkylsulfonyl" and "alkylthio" refer respectively to -S (O) R, -S (O) ₂ R, and -SR, wherein R is alkyl (as defined above) with the number of carbon atoms indicated (e.g. (C 1-6) alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propenylsulfonyl, isopropenylsulfonyl, 2-butenylsulfonyl, 1-butenylsulfonyl, 1-butenylsulfonyl, -methylallylsulfonyl, ethynylsulfonyl, 1-propynylsulfonyl, 2-propylsulfonyl, etc.).

"Amonio" refers to the group -ΝΗ 3Λ "Amidino" refers to the group -C (NH) NH ₂ .

"Amino" refers to the group -NH ₂ .

"Animal" includes humans and other mammals (eg dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, game, etc.) and non-mammals (eg birds, etc.).

»» · «« «Φ φ φ φ φ φ φ φ φ φ · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ containing the indicated number of carbon atoms, each ring of which is composed of six ring members (eg (C 6-14) aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.).

"Arylsulfonyl" refers to the group -S (O) ₂ R, wherein R is aryl (as defined above) indicating the number of carbon atoms (eg, (C 6-10) arylsulfonyl includes phenylsulfonyl, naphth-1-ylsulfonyl, etc.).

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

"Azolidinyl" refers to a saturated or unsaturated 5-membered monocyclic group containing the indicated number of nitrogen atoms. For example, (Ni-4) azolidinyl includes pyrazolidinyl, pyrrolidinyl, imidazolidinyl, triazolidinyl, tetraazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl.

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

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

"Carboxy" refers to the group -C (O) OH.

"Cyano" refers to the group -CN.

"Cycloalkyl" refers to a saturated or unsaturated, monocyclic or fused polycyclic hydrocarbon group containing a designated number of carbon atoms, each ring of which includes 3 to 8 ring members, and any carbocyclic keto, thioketo or iminoketo derivative thereof (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 group containing a designated number of carbon atoms, each ring of which includes 3 to 8 ring members, and any carbocyclic keto, thioketo or iminoketo derivative thereof (eg ( C 3-10 cycloalkylene includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene,

1,4-cyclohexylene, 3-cyclohexen-1,2-ylene, 2,5-cyclohexadien-1,4-ylene, 1,4-bicyclo [2.2.2] octylene, 5-oxo-1,3-cyclohexylene, 2,5-dioxo-1,4-cyclohexylene, 5-thioxo-1,4-cyclohexylene, etc.).

"Deprotection" means the removal of any protecting group or groups present after the selective reaction has been carried out.

"Disease" includes, in particular, any non-physiological condition of individual organs that may be caused by iatrogenic medical or veterinary treatment, ie the "side effects" of such treatment, or the individual.

"Fused heteropolycyclic group" includes a "fused heterobicyclic group" and refers to a heterocyclic group containing two to three fused rings having the indicated number of ring members, at least two ring members of one ring being part of the other ring (eg, a heteropolycyclic group containing from 8 to 18 ring atoms and their carbocyclic keto- and thioketo derivatives include 17 H -benzimidazol-2-yl, 1 H -benzo [2,3-d] imidazol-2-yl, 1 H -imidazo [4,5- y] quinolin-2-yl, 1H-imidazo [4,5-a] pyridin-2-yl, 177-phenanthro- [9,10-d] imidazol-2-yl, 1H-imidazo [4,5] g] quinoxalin-2-yl, 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl, 777-purin-8-yl, 1,6-dihydrocyclopentaimidazole-2- yl,

4-quinolin-2-yl, etc.).

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

"Halogen" refers to -F, -Cl, -Br, or -I.

"Heteroatom" refers to an atom selected from N, O, S and P.

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

"Heteroalkyl" refers to an alkyl (as defined above) in which one or more carbon atoms are replaced by a heteroatom moiety (defined above) and any of its keto- thioketo- or iminoketone derivative thereof (e.g. hetero (C ₂ .I ₂₎ alkyl includes methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 2- (N -ethyl-N-methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).

"Heteroalkylene" refers to an alkylene (as defined above) in which one or more carbon atoms are replaced by a hetero group (as defined above) or any suitable combination thereof (eg, -0S (O) ₂ -, -S (O) ₂ -, -N (R) S (O) ₂ -, -S (O) ₂ NR ¹⁷ -, -OP (O) (OR ¹⁷ ) O- and the like, wherein R ¹⁷ is hydrogen or (C 1-6) alkyl), and any its keto-, thioketo- or iminoketone derivative thereof (e.g. a hetero _(C2 _io) alkylene includes azaethylen (-CH ₂ NH-), 2-azapropylen (N = _{-CH2 CH2} -), 1-oxatrimethylen (-CH _2- CH ₂ O-), 2-oxo-3-azapentamethylene, 3-aza-2-thiopentamethylene, 2-oxa-3-oxopentamethylene, 3-aza-2-iminopentamethylene (-CH ₂ CH ₂ NH-C (NH) CH ₂ -), 2,4-aza-2-methyl-3,3-dioxo-3-thiapentamethylene (-CH ₂ NHS (O) ₂ N (CH ₃ ) CH ₂ -), 3-hydroxy-2,4 -oxa-3-oxo-3-phosphapentamethylene (-CH ₂ OP (O) (OH) OCH ₂ -), 3-aza-2-oxo-4-carboxyhexanethylene, 4-aza-1-oxa-3-oxohexamethylene, 1-thia-3-oxo-4-azahexamethylene

99 9 9 9

999 999

9

-thia-1,1,3-trioxo-4-azahexamethylene (-CH 2 CH 2 NHC (O) CH 2 S (O) 2-), 3-aza-4-oxoheptamethylene, 1,4,7-trioxaoctamethylene, 6-aza-1- oxa-2,5-dioxooctamethylene (-CH ₂ CH ₂ NH-C (O) CH ₂ CH ₂ C (O) O-), 3-aza-4-oxodecamethylene, etc.).

"Heteroaryl" refers to an aromatic monocyclic or fused polylic cyclic divalent group containing a designated number of ring atoms, each ring containing 5 to 6 ring members and one or more ring atoms being a hetero group selected from -N =, -NR ¹⁷ -, -O - or -S-, wherein R ¹⁷ is hydrogen or (Ci_6) alkyl (e.g. hetero (C ₅ .i ₄₎ aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo [b] thienyl, isobenzofuranyl , purinyl, isoquinolinyl, pterdinyl, perimidinyl, imidazolyl, pyridinyl, pyratolyl, pyrazinyl, quinolinyl, etc.) "Heterocycloalkyl" refers to a cycloalkyl (as defined above) in which one or more of the ring carbon atoms is replaced by a hetero group (as defined above) and any of its a keto, thioketo or iminoketo derivative (eg, the term heterocyclo (C 5-14) alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

"Heterocycloalkylene" refers to a cycloalkylene (as defined above) in which one or more ring carbon atoms are replaced by a hetero group (as defined above) and any keto, thioketo or iminoketo derivative thereof (eg, the term heterocyclo (C 3-14) alkylene includes piperidinylene , pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).

"Heteropolycycloaryl" refers to a polycycloaryl (defined below) in which one or more ring carbon atoms are replaced with a hetero group (as defined above) and any keto, thioketo or iminoketo derivative thereof (eg, heteropolycyclo (C 8-10) aryl includes

3,4-dihydro-2 H -quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2 H- [1,8] naphthyridinyl,

2,4-dioxo-3,4-dihydro-277-quinazolinyl, 3-oxo-2,3-dihydrobenzo [1,4] oxazinyl, etc.).

"Hydroxyl" refers to the group -OH.

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

Hypersensitivity response 'includes bronchoconstriction and airway hyperactivity characteristic of late-stage chronic asthma. Asthmatic hypersensitivity

ΒΒ · Β

Β Β Β Β

Β «Β Β

Β · Β ΒΒΒ

Ch Β • Β bronchial tissue is probably the result of a chronic inflammatory reaction that irritates and destroys the epithelium lining the respiratory tract and causes pathological weakening of the tissues under the lining.

Syncytial viral infection means a virus infection, eg, by respiratory syncytial virus, which leads to the formation of cellular protoplasmic mass, i.e. syncytia due to infection.

Imino refers to the group = NH.

Isomers are compounds of formula I having the same general formula, but are different in the nature or order of bonds between their atoms or the arrangement of atoms in space. Isomers which differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called diastereomers, and stereoisomers that do not have compatible mirror images are called enantiomers or optical isomers. A carbon atom that carries four different substituents is called a chiral center. A compound with one chiral center has two enantiomeric forms of opposite chirality and is called a "racemic mixture". A compound having more than one chiral center has 2 ⁿ¹ enantiomeric pairs, n being the number of chiral centers. Compounds with more than one chiral center can exist either as individual diastereoisomers or as a mixture of diastereoisomers, which is called a "diastereoisomeric mixture". When a single chiral center is present, the stereoisomer may be characterized by the absolute configuration of the chiral center. The absolute configuration indicates the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center are categorized according to the sequence rules of Cahn, Ingold, and Prelog, and on this basis the corresponding descriptor R or S is assigned, which is written in parentheses before the compound name, separated by a hyphen from the name. Compounds of formula I that contain a chiral center may exist as individual stereoisomers or as a mixture of stereoisomers. For the present invention, when a compound of formula I is defined by a name or formula and the configuration is not determined, it is meant that this name or formula denotes all possible configurations of the compound.

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

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

'Pathology' of a disease means the development of disease changes that includes the causal cause and sequence of disease changes, including structural and functional changes that result from disease processes.

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

Pharmaceutically acceptable salts are salts of the compounds of formula I which are pharmaceutically acceptable (described above) and which have the desired pharmacological activity. Such salts include acid salts formed with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like, or an organic acid such as acetic, propanoic, hexanoic, heptanoic, cyclopentane propanoic, glycolic, pyruvic, milky, malonic, amber, cider, maleic, fumaric, tartar, lemon, benzoic, o- (4-hydroxybenzoyl) benzoic, cinnamon, almond, methanesulfonic, ethanesulfonic, 1,2-ethanedisulfonic, 2-hydroxyethanesulfonic, p-benzenesulfonic , 2-naphthalenesulfonic, 77-toluenesulfonic, camphorsulfonic, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic, glucoheptane, 4,4'-methylenebis (3-hydroxy-2-en-1-car- boxyl), 3-phenylpropane, trimethylacetic, Z-butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphtho, salicylic, stearic, muconic and the like.

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

Polycycloaryl means a fused polycyclic group containing the indicated number of carbon atoms, wherein at least one carbon of the fused rings of the group, but not all, is aromatic and each ring present has 5 to 6 ring members. Also included is any carbocyclic keto- or thioketo-derivative thereof (eg, polycyclo (C 9-10) aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphityl, 2,4-dioxo-1). , 2,3,4-tetrahydronaphthyl, etc.).

·· ·· • 0 0 0

999 999

9 • 0 ·

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

For example, prodrug derivatives of compounds of Formula I may contain one or more N-substituted amino groups (eg, -NH ₂ (R ¹⁸ )), N-substituted nitrogen atoms that are part of an aliphatic, alicyclic, or aromatic structure (eg, -N (R ^18)). -), V-substituted imino or amidino groups (e.g. -C (NR ¹⁸ ) H, -C (NR ¹⁸ ) NH 2 or -C (NH) NHR ¹⁸ ), N-substituted guanidino groups (e.g. -NHC ( NR ¹⁸ ) NHR ¹⁸ , -NHC (NH) NHR ¹⁸ or -NHC (NR ¹⁸ ) NH 2), and the like, wherein R ¹⁸ is (i) -C (O) R ¹⁹ or -CH (R ²⁰ ) OC ( O) R ¹⁹ wherein R ¹⁹ is (C 1-10) alkyl, (C 1-10) alkyloxy, carbamoyl, (C 1-10) alkylcarbamoyl, di (C 1-10) alkylcarbamoyl, cis-2- (C 1-10) alkanoyloxyphenylvinyl, 3 - (C 1-10) alkanoyloxybutanoyl, (C 3-10) cycloalkyl, hetero (C 3-10) cycloalkyl, (C 6-10) aryl or hetero (C 5-10) aryl and R ²⁰ is hydrogen or (C 10) alkyl; (ii) -X ⁷ -R ²¹ , wherein X ⁷ is (C 1-10) alkylene and R ²¹ is carboxy; or (iii) -C (O) OCH (R ²² ) OC (O) R ²³ wherein R ²² is hydrogen, (C 1-10) alkyl or (C 3-10) cycloalkyl and R ²³ is (C 1-10) alkyl or ( C 3-10 cycloalkyl. Further, the drug derivatives of the compounds of formula I may contain one or more N-hydroxylated imino or amidino groups (e.g. -C (NOR ²⁴ ) H, -C (NOR ²⁴ ) NH 2, or -C (NH) NHOR ²⁴ ) or N - hydroxylated guanidino groups (e.g. -NHC (NOR ²⁴ ) NH 2, -NHC (NH) NHOR ²⁴ ), wherein R ²⁴ is hydrogen, methyl, -C (O) R ²⁵ or -CH (R ²⁶ ) OC (O) R ²⁵ , wherein R ²⁵ is (C 1-10) alkyl or (C 3-10) cycloalkyl and R ²⁶ is hydrogen or (C 1-6 alkyl; N 6 -substituted hydroxy groups (eg, -OR ²⁷ ) wherein R ²⁷ is -C ( O) R ¹⁹ or -CH (R ²⁰ ) OC (O) R ¹⁹ , wherein R ¹⁹ and R ²⁰ are as defined above, and / or carboxylic acid esters (eg -C (O) OR ²⁸ ), wherein R ²⁸ is (C 1-10) alkyl or (C 1-10) cycloalkyl.

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

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

"Therapeutically effective amount" means that amount which, when administered to an animal, is capable of effectively treating the disease.

"Treatment" or "treatment" means administration of a compound of the invention and includes:

(1) prevention of disease in an animal predisposed to disease but not yet showing symptoms of the disease; (2) stopping further progression of the disease, both its biological and clinical manifestations; biological or clinical manifestations.

Sulfo refers to the group -S (O) OH.

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

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

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

A together with B is 5-guanidino-1H-benzoimidazol-2-yl, C is 6- (2-naphth-1-ylethylcarbamoyl) -1-methyl-177-benzoimidazol-2-yl, and X ³ is -CH 2 - is named 2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl-77- (2-naphth-1-ylethyl-3 H -benzoimidazole-5-carboxamide;

A together with B is 5-guanidino-1 H -benzoimidazol-2-yl, C is 6- [2- (2-carboxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl) -1 H -benzoimidazol-2-yl and X ³ is -CH 2 - is named 2- {2- [2- (5-guanidino-177-benzoimidazol-2-ylmethyl) -3- (3-sulfopropyl) -3 H -benzoimidazol-5-ylcarbonylamino] ethyl [ benzoic acid; and

A together with B is 5-guanidino-1 H -benzoimidazol-2-yl, C is 6- [2- (2-methoxyphenyl) ethylcarbamoyl] -1- (3-sulfopropyl-1H-benzoimidazol-2-yl) and X is -CH 2 - is named 3- {2- (5-guanidino-17 H -benzoimidazol-2-ylmethyl) -6- [2- (2-methoxyphenyl) ethylcarbamoyl] benzoimidazol-1-yl} propan-1 - sulfonic acid.

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

9 ·

therefore, the compounds of the invention may be termed, illustrated or otherwise described herein as one possible tautomer, but it should be understood that all possible tautomers of such name, drawing and description are included. This means that the name ethyl-2- (4- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] ] pyridin-5-yl} -4-oxobutyl) benzoate also includes tautomers thereof, i.e. ethyl 2- (4- {2- [1- (5-guanidino-3/7-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) benzoate, ethyl 2- (4- {2- [1- (5-guanidino-177- benzoimidazol-2-yl) ethyl] -3,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) benzoate and ethyl 2- (4- {2- [1] - (5-guanidino-377-benzoimidazol-2-yl) ethyl] -3,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl} -4-oxobutyl) benzoate.

Preferred embodiments

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

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

(R ³⁾ n3

N (Π)

where:

the dotted lines represent, independently of each other, any bonds; each R ² is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxy, halogen or hydroxy; each R ³ is independently of one another (C 1-6) alkyl, (C _1-6 ) alkyloxy, halogen or hydroxy; X ³ is-C (O) -or-CR ⁷ R ⁸ ;

X ⁸ is -CH (R 1) n ^{1 -} or -QR ¹ , R ¹ wherein R ¹ is amino (Ni-4) azolidinyl, amino (Ni 4) azolyl, (N _M ) azolidinyl, (N _M ) azolyl, -NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , -C (NH) NR ¹⁰ R ^10, or - (CR ¹¹ R ¹¹ ) _y NH ₂ , or X ^{8 is} -N = or -N (R ¹ ) 4 -, wherein R ¹ is -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ or -C (NH) NR ¹⁰ R ¹⁰ , each R ⁹ is independently of one another hydrogen or (C 1-6) alkyl and each R ¹⁰ is independently of one another (C 1-6) alkyl; and

X ⁹ is -CH (R ⁴ ) - or -C (R ⁶ ), 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) 2 OR ¹² , -S (O) 2 N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ^12,

-C (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) R ¹² , -OC (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) OR ^12, - (CH _{2) n4} -N (R ¹³⁾ C (O) N (R ¹³⁾ -R ^12, -OP (O) (oR ¹³⁾ oR ¹² or -C (O) N ^(R14) CH (COOH ) R ¹² , or is X ⁹ -N = or N (R ⁴ ) -, wherein R ⁴ is -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² -OC (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , wherein R ¹² , R ¹³ and R ¹⁴ are as defined in the Summary of the Invention.

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

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

X ⁸ is -CH (R ⁴ ) - or -C (R ') _n i =, wherein R ¹ is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl , tetrazolyl,

- (CH ₂ ) _X NHC (NR ⁹ ) R ⁹ , - (CH ₂ ) _x NHC (NH) NR ⁹ R ⁹ and -C (NR ⁹ ) R ⁹ , each R ⁹ independently of one another hydrogen or methyl, or ^X8 is -N (R ¹⁾ Ni, where R ¹ is -C ^{(NR9) R9,} -C (NH) ^NHR10 or -C (NH) NR ¹⁰ R ¹⁰ wherein each R ⁹ is independently a on the other, hydrogen or methyl and each R ¹⁰ is methyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one to two substituents selected independently of one another from methylsulfonyl and carboxy;

X ⁹ is -C (R ⁴ ) -, wherein R ⁴ is -R ¹² , -OR ¹² , -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , wherein R ¹³ and R ¹⁴ are each independently hydrogen or (C 1-6) alkyl; R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ ni5, wherein X ⁶ is (Cj.iojalkylen or hetero (C2.io) alkylene and each R ¹⁵ is independently from each other hydrogen, (C6_i ₄₎ aryl, cyclo (C ₃ .i ₄₎ alkyl, polycyclo (C6-i ₄₎ aryl, heteropolycycle (C6-i ₄₎ aryl, heterocyclo (C ₃ _i ₄₎ alkyl or hetero (C5.i ₄₎ aryl;

00

0 0 0

0 0 0

0 0 0 0 0 0 0

00, any aliphatic and alicyclic R ⁴ is optionally substituted with one to five substituents selected independently of one another are (C _M) alkyloxy, (CI-4) alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another, from (C _M) alkyl, (CM) alkoxy, (CI-4) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C _3.6) alkyloxy, halogen, hetero (C _1-8 ) alkyl, hetero (C _1-8 ) alkylcarbonyl, hetero (C _5-6 ) aryl and trifluoromethyl; and their V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

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

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

-C (NR ⁹ ) R ⁹ , or A is taken together with B 1 / T -benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1 H -benzoimidazol-2-yl, wherein R is aminomethyl or guanidino and each R is independently of one another halogen or hydroxy;

C is 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 1-4) alkylene or hetero (C 2-4) alkylene and R ¹⁵ is (C 6 -) io) aryl, _(C6-iO) aryloxy, polycyclo (C ₆ _io) aryl, hetero (C5-io) aryl, a hetero / Cs-iojaryloxy heteropolycycle or (C6-i4) aryl; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C 1-4) alkyl, (C 1-4) alkyloxy, (C 1-4) alkyloxycarbonyl, carboxy, carbamoyl, halogen, hydroxy and tetrazol-1-yl; and their V-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

A preferred embodiment of the invention are compounds of formula I wherein n1 is 0 and each R is independently of one another halogen or hydroxy, in particular:

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

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

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

propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; a φ Φ · · φ φ φ φ φ

Isobutyl-2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazole-5 - ylcarbonylamino} ethoxy) benzoate.

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

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -377-benzoimidazole-5-carboxamide, ethyl 2- (4- { 2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5- c] pyridin-5-yl} -4-oxobutyl) benzoate;

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ylethyl) -377-benzoimidazole-5-carboxamide;

2- (5-guanidino-l / 7-benzimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) ^propyl-N - (2-naphth-1-ylethyl) -3 // - benzoimidazol-5- carboxamide;

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

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-1-ylethyl) -377-benzoimidazole-5-carboxamide;

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

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

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

5-Chloro-2- [2- ({2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid acid;

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl ethyl) -3H-benzoimidazole-5-carboxamide; and

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

A preferred embodiment of the present invention are compounds of formula I wherein C is 4,5,6,7-tetrahydro-177-imidazo [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-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid;

44 44 44

4 4 4 4 4 5

4 4 4 4 4

4 449 444

4 4 4 ··· 49 · 44 *

4

4 4

944 44

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-N - (2-naphth-1) (ethyl) -37 H -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) -1-ylethyl) -3H-benzoimidazole-5-carboxamide;

2- (5-Iminomethyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -377-benzoimidazole-5-carboxamide;

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

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-77- [2- (2- hydroxynaphth-1-yl) ethyl] -377-benzoimidazole-5-carboxamide;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-N- [2- ( 4-hydroxynaphth-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-naphth-1-ylethyl) -377-benzoimidazole-5-carboxamide;

ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-377-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate;

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

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

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-N - [ 2- (2-Tetrazolylphenoxy) ethyl] -37Y-benzoimidazole-5-carboxamide.

Pharmacology and use

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

• · ·

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

The initial allergic response can be determined in guinea pigs and dogs, especially in greyhound-basen hybrids, who exhibit a non-specifically increased airway response to a number of non-allergenic substances such as methacholine and citric acid. Some sheep strains show a double response after antigenic stimulation with Ascaris proteins. In animals with dual response, the initial asthmatic response (IAR) is followed by the late asthmatic response (LAR) 6 to 8 hours after exposure. Hypersensitivity to the cholinergic agonist carbachol, increases in animals showing LAR 24 hours after antigen stimulation.

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

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

The efficacy of the compounds of the present invention in treating the vast majority of immunologically induced inflammations can be determined by in vitro or in vivo methods. The anti-inflammatory activity of the compounds of the present invention can be demonstrated by assays well known

..........

in this field, e.g., Reversed Passive Arthus Reaction (RPAR) -PAW (see, eg, Gangly et al., (1992) U.S. Patent No. 5,126,352). Assays for determining a therapeutic amount of a compound for the treatment of various skin diseases, such as proliferative skin changes, are well feasible, eg, arachidonic acid assay in the ear of the mouse. The anti-ulcer activity of the compounds of this invention can be determined using the methods described (Chiu et al., Archives Internationales de Pharmacodynamie et de Therapie 270: 128-140).

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

Means and administration

According to the invention, a therapeutically or pharmaceutically effective amount of a compound of the invention is administered to a patient suffering from immunologically induced inflammation. In one embodiment, the compounds of the present invention are useful for preventing or alleviating asthma. When using the compositions of the present invention in the treatment of asthma, the compounds may be administered prophylactically, ie before or after the animal is exposed to an allergen or threatening condition. In particular, the compounds of the present invention are useful for alleviating tissue damage that occurs in the late phase of seasonal and chronic rhinitis. Another embodiment of the present invention is directed to the prevention and treatment of other immunologically induced inflammation associated with living cells such as utrika, angioedema, eczematous dermatitis (atopic dermatitis) and anaphylaxis, as well as proliferative skin changes, peptic ulcer and others. In another embodiment, the compounds of the present invention are used to treat syncytial viral infections, particularly respiratory-tract infections with syncytial virus.

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

In prophylactic applications, the compositions containing the compounds of this invention are administered to a patient at risk or at risk of the disease in an amount sufficient to prevent or ameliorate the initial φ • φ φ φφφ φ · Φ φ φ φ φ φ φ φ φ φ φ φ

................

signs. Such an amount is defined as a "prophylactically effective amount or dose." These may be administered orally or by inhalation. In this use, the exact amount again depends on the patient's health, weight, etc.

If an improvement in patient discomfort is achieved and if necessary, the maintenance dose should be changed. Thus, the dosages or frequency of administration may be reduced, depending on the symptoms, up to a level at which the improved condition is maintained. Treatment may be discontinued after the severity of symptoms has dropped to an acceptable level. However, in the event of a relapse, the need to temporarily resume administration may occur.

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

The composition used in these therapies may be in a variety of forms. Included are, for example, solid, liquid and solid dosage forms, such as tablets, granules, pills, powders, liquid solutions or suspensions, liposomes, injectable or infusible solutions. Also included are inhalable preparations such as aerosols. Preparations for oral, intranasal, ointment and parenteral applications are preferred, taking into account the treatment needs. Especially preferred are aerosol or oral preparations. Methods for preparing and preparing therapeutic compositions containing the compounds of this invention are well known in the art and are described, for example, in Remington's Pharmaceutical Sciences and The Merck Index 11th Edition, (Merck & Co. 1989).

Although it is possible to administer the active ingredient of the present invention alone, it is preferred that it is part of a pharmaceutical formulation. The compositions of the invention comprise at least one compound described herein in a therapeutically or pharmacologically effective dose together with a pharmacologically acceptable carrier. The dosage form should contain the compounds of the invention in concentrations to provide the required dosage. For example, if the required dose is 0.05 mg per day, then the concentration of the compound of the invention in the pharmaceutical composition should be 0.05 mg per dose, with a single dose per day being used. In the case of inhaled or aerosol formulations, the concentrations of the compounds of this invention will generally be dose-dependent. Typical concentrations of the compounds of this invention in inhalation and aerosol formulations should be from 0.01 to 30 mg / ml. The composition may also contain other clinically useful compounds such as β-adrenergics (eg albuterol, terbutaline, formoterol, phenoterol and prenalin) and corticosteroids (eg beclomethasome, triamcinolone, flunisolide and dexamethasone) .

Chemistry

In general, the compounds of the present invention were prepared using standard techniques and reagents known and used by those skilled in the art. It should be noted that bonds between different functional groups generally include carbon bonded to the amide or carbamate nitrogen, carbamate oxygen or carbonyl carbon. One skilled in the art will recognize that the methods and reagents forming these bonds are well known and readily available (see, eg, March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Larock, Comprehensive Organic Transformations (VCH 1989); and Fumiss et al. , VogeVs Textbookof Practical Organic Chemistry, 5th Edition (Longman 1989), incorporated herein by reference).

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

Wherein L is a leaving group, D together with the vinylene group to which it is fused forms a monocyclic or fused bicyclic divalent group containing 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring containing 5 to 7 ring atoms;

atom rings optionally a heteroatom, ^R29 is -OH, -NHR ⁶ or -SH, X ⁸ is -0-, -NR ⁶ - or -S- and n2, n3, n4, A, Β, X ^1, X ^2, X ³ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁶ are described in the Summary of the Invention.

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

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

Wherein L is a leaving group, R ³⁰ is -OH, -NHR ⁵ or -SH, X ⁸ is -O-, -NR ⁶ - or

-S- and 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 described in the Summary of the Invention (see e.g. 2 (e) and 7 (h), below).

Flfl fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll fll

The isolation and purification of the compounds and intermediates described herein may be carried out, if necessary, by any suitable separation or purification technique, eg, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, high pressure liquid chromatography (HPLC) or a combination of these techniques. Typical examples of suitable separation and isolation techniques can be given by the examples below. Of course, another equivalent separation or isolation procedure may be used. Nuclear magnetic resonance (NMR) spectra were measured on a General Electric QE Plus (300 MHz) spectrometer. Infrared spectra (IR) were measured on a PerkinElmer 1600 Fourier Transform IR (FTIR) instrument. Analytical HPLC was performed on an Ultrafast Microprotein Analyzer, Michrom BioResources, Inc. with PLRP column, 1 mm x 150 mm. Preparative HPLC was performed on a Gilson LC using a Vydac 1 x 25 cm _{Cl 8} reverse phase (RP) or a Waters Prep LC2000 system using a Vydac 5 x 25 cm Cl ₈ RP. Mass spectra (MS) were recorded on a Finnigan SSQ 710 with the ESI source with direct input or by HPLC MS (Ultrafast Microprotein Analyzer, column Cl ₈ column 2mm X 150 mm). Unless otherwise noted, all reagents and devices were either prepared according to published procedures or obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, WI); (St. Louis, MO) and ICN Chemical Co. (Irvine, Calif.). The techniques used to perform the syntheses described below are routine to one of ordinary skill in the art (see, eg, March, Larock, or Fumiss, supra).

Additional processes for the preparation of compounds of formula I

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

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

9 99 * · 999999

9 9 9 9 9

................

the salt form with a base can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid and the like).

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

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

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

Protected derivatives of compounds of formula I may be prepared by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the introduction and removal of protecting groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & 1981.

Compounds of formula I may be prepared as their individual stereoisomers by reacting a racemic compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers and releasing the optically pure diastereoisomers. Although cleavage into the single enantiomers can be accomplished using covalent diastereoisomeric derivatives of the compounds of Formula I, dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. Diastereomers have different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be readily separated by utilizing these unequal properties. Diastereomers can be separated by chromatography or more preferably by separation / resolution techniques based on different solubilities. The optically pure enantiomers are subsequently obtained together with the resolving agent by any method that does not result in cracemization. A more detailed description of techniques applicable to the resolution of stereoisomers of the compounds from their racemic mixture can be found in U.S. Pat

Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).

In general, an aspect of the invention is a process for preparing a compound of formula I, wherein the process comprises:

a) reaction of compound 1:

or a protected derivative thereof with compound 2:

or a protected derivative thereof in which L is a leaving group, D together with a vinylene group to which it is fused forms a monocyclic or fused bicyclic divalent group containing from 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring atom is optionally heteroatom, R ²⁹ is -OH, -NHR ⁶ or -SH and n 1, n 2, n 3, A, Β, X ¹ , X ² , X ³ , R ¹ , R ² , R ³ , R ⁴ and R ⁶ are described in the Summary of the Invention. If necessary to obtain a compound of Formula I wherein X ⁴ and X ⁵ are adjacent members of the oxazol-2-yl, 177-imidazol-2-yl or thiazol-2-yl ring, deprotection is followed; or

b) reaction of compound 3:

or a protected derivative thereof with compound 4:

ΒΒ ΒΒ ··

Β Β · Β Β Β

Β ΒΒΒΒ

ΒΒΒ Β ΒΒΒ ΒΒΒ

Β Β Β

ΒΒ ΒΒ ΒΒ • Β

or a protected derivative thereof, wherein L is a leaving group, R ³⁰ is -OH, -NHR ⁵ or -SH and n 1, n 2, n 3, B, C, X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in the Summary of the Invention. If necessary to obtain a compound of formula I wherein X ¹ and X ² are adjacent members of the oxazol-2-yl, 177-imidazol-2-yl or thiazol-2-yl ring, deprotection is followed;

c) optionally, subsequently converting the compound of formula I to a pharmaceutically acceptable salt;

d) optionally converting the compound of formula I from the salt form to the free form;

e) optionally subsequently converting the compound of formula I from the non-oxidized form to a pharmaceutically acceptable V-oxide;

f) optionally converting the N-oxidized form of the compound of formula I to its non-oxidized form;

g) optionally converting the non-derivatized compound of formula I into a pharmaceutical prodrug derivative; and

h) optionally, the prodrug derivative of the compound of formula I is subsequently converted to its non-derivatized form.

DETAILED DESCRIPTION OF THE INVENTION

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

Example 1

2- (Nait-2-yl) ethylamine

A solution containing 2- (naphth-2-yl) ethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) was mixed with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) α1 under nitrogen. 8-diazabicyclo [5.4.0] undec-7-ene (0.47 mL, 3.14 mmol). The mixture was heated at 65 ° C for 3 hours and then partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3 N hydrochloric acid.

and then saturated sodium bicarbonate solution, dried (MgSO4), filtered and concentrated on a rotary evaporator. The residue was dissolved in THF (5 mL) and the solution was mixed 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 (0.15 mL). 33 mL) to form a precipitate. Addition of ethanol (5 mL) dissolved the precipitate and slowly added diethyl ether to precipitate a white precipitate. The precipitate was then filtered off, washed with diethyl ether and dried in vacuo. There was thus obtained 2- (naphth-2-yl) ethylamine hydrochloride (0.447 g, 75% yield);

¹ H-NMR (300 MHz, DMSO-d 6): 8.18 (br s, 3H), 7.82-7.88 (m, 3H), 7.74 (s, 1H), 7.38-7 48 (m, 3H); 3.07 (m, 4H).

The following amine intermediates were prepared as in Example 1:

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

3-cyclohexylpropylamine, yield = 40%, 1 H-NMR (300 MHz, 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-propenylamine, yield = 53%, ¹ H-NMR (300 MHz, DMSO-d 6): 8.39 (br s, 3H), 7.26-7.41 (m, 5H), 6 72 (d, 1H, J = 16.2 Hz), 6.29 (dt, 1H, J = 16.2 and 6.6 Hz), 3.56 (d, 2H, J = 6.6 Hz) ;

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

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

Example 2

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (4-phenylbutyl) -177-benzoimidazole-5-carboxamide (Compound 1) (a) Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was treated with anhydrous ethanol (6 mL, 105 mmol) under a nitrogen atmosphere. The mixture was cooled to 10 ° C (ice / acetone) and bubbled with dry hydrogen chloride gas for 20 minutes. The mixture was slowly warmed to room temperature, sealed and stirred for about 18 hours. The mixture was diluted with diethyl ether (400 mL) and left at room temperature for 5 hours. The resulting solid was collected by filtration, washed several times with anhydrous diethyl ether and dried under vacuum. This gave ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as colorless.

Φ φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ krystal krystal krystal krystal 1 H-NMR (300 MHz, CDCl ₃ ): 7.84 (d, 1H,> 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, > 5.7 Hz), 2.73 (t, 2H, > 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 acetic acid (15 mL) was stirred at 110 ° C for 30 minutes under a nitrogen atmosphere. The mixture was poured onto crushed ice (50 mL) and stirred for 30 minutes to give a dark yellow oil. The mixture was stirred and the addition of diethyl ether (25 mL) gave a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether and dried in vacuo. There was thus obtained 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 12.77 (br s, 1H), 8.10 (s, 1H), 7.79 (d, 1H,> 8.4 Hz), 57 (d, 1H, > 8.4 Hz), 4.11 (q, 2H, > 7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, > 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) under nitrogen and diethyl azodicarboxylate (20.7 mL, 131 mmol) was added dropwise. The mixture was stirred at -10 ° C for 2 hours and then diluted with diethyl ether (900 mL) and stored at -20 ° C to ca. 18 hours. The precipitated crystalline material was filtered off and washed. There was thus obtained 2- (3,4-dinitrobenzyl) isoindole-1,3-dione (24.6 g, 67% yield) as an off-white crystalline solid; ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.87-7.94 (m, 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 in Example 2 and 10% Pd / C (300 mg) was mixed with anhydrous ethanol (200 mL), anhydrous THF (100 mL) and glacial acetic acid (30 mL) under a constant 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 ca. 30 ml on a rotary evaporator. The mixture was diluted with water (100 mL) and an orange precipitate was added by addition of aqueous ammonia. The precipitate was collected by filtration and washed several times with water. There was thus obtained 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 (br s, 4H), 4 47 (s, 2H).

(e) A mixture of finely divided 2- (3,4-diaminobenzyl) isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0) (93 g, 3.75 mmol) was heated at 185 ° C for 1 hour under a nitrogen atmosphere. The mixture was suspended in 20 mL of methylene chloride with ethanol (1: 1) and stirred vigorously for 1 hour. The solid was filtered, washed with methylene chloride and ethanol (1: 1, 3 x 20 mL) and dried. There was thus obtained 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1H-benzoimidazol-2-ylmethyl] -1H-benzoimidazole-5-carboxylic acid (0.98) g, 29% yield); ¹ H-NMR (300 MHz, DMSO99)

9 9 9 9 9 9 9 9

9 9 9 9 9 9

99 9 9 9 999999 d ₆ ): 12.45 (br s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H,> 7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H,> 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] -1 H -benzoimidazole-5-carboxylic acid (0.05 g, 0.111 mmol) was dissolved in anhydrous dimethylformamide (0.5 mL) and this solution was mixed with 1-hydroxybenzotriazole hydrate (0.017 g, 0.126 mmol), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (0.063 g, 0.121 mmol) and α-methylmorpholine (0.013 mL). (0.118 mmol) at room temperature under a dry nitrogen atmosphere. After 2 minutes, 4-phenylbutylamine (0.02 mL, 0.127 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel containing 20% ethanol / ethyl acetate (7 mL), 0.2 N HCl (3.5 mL) and saturated aqueous NaCl (3.5 mL). The aqueous phase was extracted once with 20% ethanol / ethyl acetate solution (7 mL). The combined organic phases were washed with a solution containing 0.2 N HCl (3.5 mL) in a saturated aqueous solution of NaCl (3.5 mL) and then washed with a saturated aqueous solution of sodium bicarbonate (7 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. Crude 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] - N - (3-phenylpropyl) -1 H- was thus obtained. 7-Benzoimidazole-5-carboxamide (0.14 g).

(g) 2- [5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] - N - (3-phenylpropyl) -1 H -benzoimidazole -5-carboxamide (0.14 g, crude) was dissolved in anhydrous ethanol (0.5 mL) and mixed with anhydrous hydrazine (0.15 mL, 0.48 mmol). The mixture was heated to reflux under nitrogen for 1 hour and then concentrated on a rotary evaporator. The excess hydrazine was removed from the residue by placing it under a vacuum of 20 Pa (0.15 Torr) for 2 hours. The residue was diluted with 3 M HCl (0.5 mL) and heated to 50 ° C for 20 minutes. The reaction mixture was cooled to room temperature and stirred for an additional 20 minutes. The resulting precipitate was collected by filtration and washed with water (4x 1.5 mL). The filtrates were combined and washed with 20% ethanol / ethyl acetate solution (2 x 7 mL). The combined aqueous phases were lyophilized to give the crude product as the hydrochloride. The crude product was purified by reverse phase preparative HPLC to give 2- (5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] -N- (3). -phenyl-propyl) -1 H -benzoimidazole-5-carboxamide (0.04 g, 0.07 mmol) as a white solid 1 H-NMR (300 MHz, CD ₃ OD): 8.14 (s 1 H, 7.84-7.89 (m, 2H), 7.77 (d, 1H,> 8.1 Hz), 7.71 (d, 1H,> 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,> 7.2 Hz), 2.66 (t, 2H,> 7.2 Hz), 1.69 (m, 4H).

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

· 9 99 · · · ·

9

9 * 9 999

9 9 9 •

2- (5-aminomethyl-1H-benzimidazol-2-ylmethyl) -N-naphth-1-ylmethyl-1H-benzoimidazole-5-carboxamide (Compound 2), 1 H-NMR (300 MHz, CD ₃₎ OD): 8.13 (m, 2H), 7.88 (m, 2H), 7.80 (m, 2H), 7.73 (d, 1H, J = 7.9 Hz), 7.67 ( d, 1H,> 7.9 Hz), 7.38-7.54 (m, 5H), 5.01 (s, 2H), 4.26 (s, 2H);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N-benzyl-1H-benzoimidazole-5-carboxamide (Compound 3), ¹ H-NMR (300 MHz, CD ₃ OD): 8 18 (s, 1H), 7.91 (d, IH, > 7.9 Hz), 7.82 (s, IH), 7.76 (d, IH, > 7.9), 7.72 ( d, 1H, > 7.9 Hz), 7.54 (d, 1H, > 7.9 Hz), 7.23-7.38 (m, 5H), 4.60 (s, 2H), 4, 28 (s. 2H);

2- (5-Aminomethyl-177-benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 4), 1 H-NMR (300 MHz, CD ₃ OD): 8.14 (s, 1H, 7.87 (d, 1H, > 8.6 Hz), 7.8 (s, 1H), 7.76 (d, 1H, > 8.6 Hz), 7, 71 (d, 1H, > 8.6 Hz), 7.54 (d, 1H, > 8.6 Hz), 7.24 (m, 4H), 7.16 (m, 1H), 4.28 ( s, 2H), 3.46 (t, 2H, > 7.9 Hz), 2.95 (t, 2H, > 7.9 Hz), 1.62 (kv, 2H, 7.9 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenylmethyl) -1H-benzoimidazole-5-carboxamide (Compound 5), ¹ H-NMR (300 MHz, DMSO-) d ₆ ): 8.12 (s, 1H), 7.83 (m, 2H), 7.78 (d, 1H,> 9.3 Hz), 7.71 (d, 1H,> 9.3 Hz) 7.55 (d, 1H,> 9.3 Hz), 7.29 (m, 4H), 7.22 (m, 1H), 4.29 (s, 2H), 3.65 (t, 2H,> 7.9 Hz), 2.95 (t, 2H,> 7.9 Hz);

2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) -N- (3-aminomethyl) benzyl-17-benzoimidazole-5-carboxamide (Compound 6), 1 H-NMR (300 MHz, DMSO-d 6) 9.31 (t, 1H,> 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, > 9.3 Hz), 7.75 (d, 1H, > 9.3 Hz), 7.59 (d, 1H, > 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) -N- (2-aminoethyl) -1-methyl-1H-benzoimidazole-5-carboxamide (Compound 7), ¹ H-NMR (300 MHz, DMSO-d6): 8.86 (br, 1H), 8.50 (br s, 3H), 8.24 (s, 1H), 8.08 (br s, 3H), 7.93 (m (2H), 7.77 (d, 1H, > 8.7 Hz), 7.55 (d, 1H, > 9.2 Hz), 5.02 (br, s, 2H), 4.16 (m) 2H, 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -2H- (2-aminoethyl) -1H-benzoimidazole-5-carboxamide (Compound 8), 1 H-NMR (300 MHz, DMSO-d ₆ ):? 97 (t, 1H, > 4.3 Hz), 8.58 (br s, 3H), 8.31 (s, 1H), 8.16 (br s, 3H), 7.97 (m, 2H) ), 7.79 (d, IH, > 10 Hz), 7.73 (d, IH, > 10 Hz), 7.59 (d, IH, > 10 Hz), 5.09 (s, IH), 4.19 (m, 2H); 3.54 (m, 2H); 2.99 (m, 2H);

2- (5-aminomethyl-1H-benzimidazol-2-ylmethyl) -N- (4-aminobutyl) -1H-benzoimidazole-5-carboxamide (Compound 9), 1 H-NMR (300 MHz, DMSO-d) ₆ ): 8.77 (t, 1H,> 5.7 Hz), 8.61 (br s, 3H), 8.24 (s, 1H), 7.90-8.02 (m, 5H), 7.78 (d, 1H,> 9.3 Hz), 7.74 (d, IH,> 9.3 Hz),

7.60 (d, 1H,> 9.3 Hz), 5.09 (s, 1H), 4.18, (m, 2H), 3.28 (m, 2H), 2.78 (m, 2H) 1.12 (m, 4H);

Fc fcfc fcfc fcfc fcfcfc

2- (5-aminomethyl-1H-benzimidazol-2-ylmethyl) -N- (3-aminopropyl) -1H-benzoimidazole-5-carboxamide (Compound 10), ¹ H-NMR (300 MHz, DMSO-) d ₆ ): 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, IH, > 8.6 Hz), 7.71 (d, IH, > 8, 6), 7.57 (d, 1H, J = 8.6 Hz), 5.03 (s, 2H), 4.40 (m, 2H), 3.34 (m, 2H), 2.81 (s) m, 2H), 1.81 (m, 2H); and

2- (5-aminomethyl-1 H -benzoimidazol-2-ylmethyl) - N -cyclohexylmethyl-1 H -benzoimidazole-5-carboxamide (Compound 11), 1 H-NMR (300 MHz, CD ₃ OD): δ, 15 (s, 1H), 7.88 (d, 1H, > 7.6 Hz), 7.84 (s, IH), 7.76 (d, IH, > 7.6 Hz), 7.72 ( d, 1H, > 7.6 Hz), 7.54 (d, 1H, > 7.6 Hz), 4.29 (s, 2H), 3.26 (d, 2H, > 7.2 Hz), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H).

Example 3

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl-1H-benzoimidazole-5-carboxamide (Compound 12) (a) Mixture containing 3-nitro-4 -chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine in water (10 mL) was heated to 100 ° C in a sealed vial for 11 hours, concentrated to 1 mL and then diluted with concentrated hydrochloric acid to give a yellow precipitates. The precipitate was collected by filtration, washed with water, diethyl ether and dried. There was thus obtained 3-nitro-4-methylaminobenzoic acid (2.1 g, 86% yield); ¹ H-NMR (300 MHz, CDCl ₃ ): 8.56 (d, 1H,> 2.1 Hz), 8.52 (q, 1H,> 8.6 Hz), 7.94 (dd, IH, 9.3 and 2.1 Hz), 7.00 (d, 1H, > 9.3 Hz), 2.97 (d, 3H, > 8.6 Hz).

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

3-Amino-4-methylaminobenzoic acid (1.1 g, 61% yield).

(c) Ethyl 3-ethoxy-3-iminopropanoate, prepared as in Example 2 (a), was reacted with 3-amino-4-methylaminobenzoic acid under similar conditions to Example 2 (b) to give 2-ethoxycarbonylmethyl -1-methyl-1 H -benzoimdazole-5-carboxylic acid (71% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.18 (dd, 1H,> 8.1 Hz), 7.11 (d, 1H,> 1.2 Hz), 6.33 (d, 1 H,> 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 reacted with 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid

99 99

9 · · 9

9

9,999,999

9 with acid under similar conditions to Example 2 (e) to give 2- [5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] -1- methyl-1H-benzoimidazole-5-carboxylic acid (48% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H,> 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-methyl-1H-benzoimidazole-5-carboxylic acid ( 0.05 g, 0.108 mmol), 1-hydroxybenztriazole (0.016 g, 0.118 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and propane-1,3-diamine are all the Boc-protected amino group (t-butyloxycarbonyl) was dissolved at 0 ° C in methylene chloride (1 mL) and DMF (minimum amount necessary to form a solution). The pH of the solution was adjusted to ca. ca. with N-methylmorpholine. 8 and the mixture was slowly warmed to room temperature and stirred for 20 hours. The mixture was transferred to a separatory funnel, dissolved in methylene chloride, washed with 0.1 N HCl and then saturated NaHCO 3, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (10% methanol / ethyl acetate) to give 2- [6- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] -1 -methyl- (3-aminopropyl) -1H-benzoimidazole-5-carboxamide (0.02 g, 28% yield); ¹ H-NMR (300 MHz, CDCl ₃ ): 7.75-7.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (br s, 1H), 7, 27 (d, 1H, > 8.6 Hz), 7.15 (d, 1H, > 9.3 Hz), 5.10 (br t, 1H), 4.90 (br s, 2H), 4, 57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, > 7.2 Hz), 3.24 (q, 2H, > 7.2 Hz), 1.72 ( m, 2H), 1.41 (s, 9H);

(f) 2- [6- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-ylmethyl] -1-methyl-N- (3-aminopropyl) -1 7-Benzoimidazole-5-carboxamide was deprotected under conditions similar to Example 2 (g) to give 2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) -N- (3-aminopropyl) -1-methyl- 1 H -benzoimidazole-5-carboxamide (20% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 8.85 (t, 1H,> 5.7 Hz), 8.55 (br s, 3H), 8.20 (s, 1H), 8, Δ (br s, 3H), 7.74 (m, 2H), 7.80 (d, 1H,> 6.6 Hz), 5.07 (s, 2H), 4.16 (m, 2H), 3.96 (s, 3H), 3.32 (m, 2H), 2.79 (m, 2H), 1.80 (m, 2H).

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

3- [2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1H-benzoimidazole-5-carboxamide (Compound 13), 1 H-NMR (300 MHz, CD ₃ OD): 8.25 (d, 1H,> 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, > 7.4 Hz), 3.41 (t, 2H, > 7.4 Hz);

• 99 99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 999 999

9 9 9 9 9

..... .......... ·

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (3,3-diphenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 14), ¹ H-NMR (300 MHz, CD ₃ OD): 8.11 (s, IH), 7.77-7.86 (m, 3H), 7.70 (d, IH,> 9.3), 7.56 (d, IH,> 9.3 Hz), 7.23-7.39 (tn, 8H), 7.13-7.19 (m, 2H), 4.30 (s, 2H), 4.07 (t, 1H,> 7.2 Hz), 3.40 (t, 2H, > 7.2 Hz), 2.44 (q, 2H, > 7.2 Hz);

2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) -1H- (2-naphth-2-ylethyl) -1H-benzoimidazole-5-carboxamide (Compound 15), ¹ H-NMR (300 MHz, CD ₃₎ OD): 8.10 (s, 1H), 7.67-7.86 (m, 8H), 7.55 (d, 1H,> 10.0 Hz), 7.38-7.44 (m, 3H), 4.28 (s, 2H), 3.72 (t, 2H, > 7.2 Hz), 3.10 (t, 2H, > 7.2 Hz);

2- (177-benzoimidazol-2-ylmethyl) -N- [2- (1H-indol-3-yl) ethyl] -1H-benzoimidazole-5-carboxamide (Compound 16), 1 H-NMR (300 MHz) CD ₃ OD): 8.09 (s, 1H), 7.81-7.84 (m, 2H), 7.74 (d, 1H,> 8.6 Hz), 7.67 (d, 1H) > 8.6 Hz), 7.52-7.58 (m, 2H), 7.30 (d, 1H,> 7.9 Hz), 7.01-7.08 (m, 2H), 6 94 (t, 1H, > 7.9 Hz), 4.26 (s, 2H), 3.68 (t, 2H, > 6.8 Hz), 3.06 (t, 2H, > 6.8 Hz);

2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) -N- [2- (5-methoxy) indol-3-yl] -1H-benzoimidazole-5-carboxamide (Compound 17), * H -NMR (300 MHz, CD ₃ OD): 8.10 (s, 1H), 7.81-7.85 (m, 2H), 7.76 (d, 1H,> 8.2 Hz), 7, 69 (d, 1H, > 8.2 Hz), 7.54 (d, 1H, > 8.2 Hz), 7.20 (d, 1H, > 8.2 Hz), 7.07 (m, 2H) 6.70 (dd, 1H,> 10.0 and 2.2 Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3.04 (t, 2H) ,> 7.2 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2,3,4,5,6-pentahydroxyhexyl) -1H-benzoimidazole-5-carboxamide (Compound 18), 1 H-NMR (300 MHz, CD ₃ OD / D ₂ O (1/1)): 8.15 (s, 1H), 7.86-7.90 (m, 2H), 7.83 (d, 1H) > 9.6 Hz), 7.77 (d, 1H, > 9.6 Hz), 7.61 (d, 1H, > 9.6 Hz), 4.32 (s, 2H), 4.01 (m, 1H), 3.62-3.86 (m, 6H), 3.47-3.55 (m, 1H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-phenyloxyethyl) -1H-benzoimidazole-5-carboxamide (Compound 19), ¹ H-NMR (300 MHz, CD ₃₎ OD): 8.16 (s, 1H), 7.88 (d, IH,> 9.3 Hz), 7.84 (s, IH), 7.76 (d, IH,> 9.3 Hz) 7.71 (d, 1H,> 9.3 Hz), 7.55 (d, IH,> 9.3 Hz), 7.23 (2H,> 7.9 Hz), 6.85-6, 96 (m, 3H), 4.27 (s, 2H), 4.16 (t, 2H, > 6.1 Hz), 3.78 (t, 2H, > 6.1 Hz);

2- (5-aminomethyl-1 H -benzoimidazol-2-ylmethyl) -N- (3-phenylprop-2-ynyl) -1 H -benzoimidazole-5-carboxamide (Compound 20), 1 H-NMR (300) MHz, CD ₃ OD): 8.18 (s, IH), 7.91 (d, IH,> 9.3 Hz), 7.84 (s, IH), 7.76 (d, IH,> 9 3), 7.71 (d, 1H,> 9.3 Hz), 7.55 (d, 1H,> 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-177-benzoimidazol-2-ylmethyl) -N- (E -3-phenylallyl) -1 H -benzoimidazole-5-carboxamide (Compound 21), 1 H-NMR (300 MHz, CD ₃₎ OD): 8.19 (s, 1H), 7.92 (d, IH,> 9.3 Hz), 7.86 (s, IH), 7.76 (d, IH,> 9.3 Hz) , 7.71 (d, IH,> 9.3 Hz), 7.55 (d, IH,> 9.3) • flfl • fl flfl •·· • flfl • flflfl flfl · · • fl flfl · · • Flflfl flflfl flfl flfl flfl flfl

Hz), 7.33-7.39 (m, 2H), 7.18-7.30 (m, 3H), 6.60 (d, 1H,> 15.8 Hz), 6.34 (dt, 1H,> 15.8 and 6.1 Hz), 4.27 (s, 2H), 4.17 (d, 2H,> 6.1 Hz);

2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) - N - (3-cyclohexylpropyl) -1,77-benzoimidazole-5-carboxamide (Compound 22), ¹ H-NMR (300 MHz, CD ₃ OD) 8.13 (s, 1H), 7.86 (d, 1H, > 9.3 Hz), 7.81 (s, 1H), 7.74 (d, 1H, > 9.3 Hz), 7 69 (d, 1H, > 9.3 Hz), 7.53 (d, 1H, > 9.3 Hz), 4.27 (s, 2H), 3.36 (t, 2H, > 7.2 Hz), 1.61-1.78 (m, 7H), 1.19-1.32 (m, 6H), 0.90 (m, 2H);

3- [2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) -N-oct-1-yl-177-benzimidazole-5-carboxamide (Compound 23), 1 H-NMR (300 MHz, CD ₃₎ OD): 8.13 (s, 1H), 7.86 (d, 1H, &gt; 9.7 Hz), 7.82 (s, 1H), 7.74 (d, 1H, > 9.7 Hz) 7.69 (d, 1H, > 9.7), 7.49 (d, 1H, > 9.7 Hz), 4.27 (s, 2H), 3.39 (t, 2H, > 7, 2 Hz), 1.64 (m, 2H), 1.26-1.43 (m, 11H), 0.88 (m, 2H);

2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) - N -methyl-N- (2-phenyl ethyl) -177-benzoimidazole-5-carboxamide (Compound 24), 1 H-NMR (300 MHz, CD ₃ OD): 7.76 (s), 7.69 (d), 7.63 (d), 7.44-7.55 (m), 7.20-7.28 (m), 7, 09-7.14 (m), 6.97 (d), 6.85 (br s), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s) 1.08, 3.08 (s), 2.87 (t), 2.76 (t); and

2- (5-aminomethyl-177-benzoimidazol-2-ylmethyl) -N- (1-methyl-3-phenylpropyl) ^-1 H -benzoimidazole-5-carboxamide (Compound 25), ¹ H-NMR (300 MHz, CD ₃₎ OD): 8.05 (s, 1H), 7.79 (d, 1H,> 9.3 Hz), 7.75 (s, 1H), 7.68 (d, 1H,> 9.3 Hz) 7.63 (d, 1H,> 9.3 Hz), 7.46 (d, 1H,> 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,> 7.9 Hz), 1.17-1.93 (m, 2H), 1 18 (d, 3H, > 7.2 Hz).

Example 4

C- {2- [5- (4-Phenylbutoxy) -1 H -benzoimidazol-2-ylmethyl] -1 H -benzoimidazol-5-yl} methylamine (Compound 26) (a) 4-Phenyl-1-butanol (1 mL, 6.49 mmol) in THF (3 mL) was mixed with a 60% dispersion of sodium hydride in mineral oil (0.26 g, 6.5 mmol) under dry nitrogen. The mixture was stirred vigorously for 5 minutes. 3,4-Dinitrochlorobenzene (1.3 g, 6.42 mmol) was then added and the mixture was stirred at room temperature for 10 hours. The mixture was partitioned between diethyl ether and 3 N hydrochloric acid. The aqueous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO 4), filtered and concentrated on a rotary evaporator. The residue was purified by flash chromatography (9: 1 hexane / diethyl ether) to give

4- (4-phenyl-butoxy) -1,2-dinitrobenzene (1.16 g, 72% yield); 1 H-NMR (300 MHz, CDCl ₃ ): 7.84 (d, 1H,> 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, > 5.7 Hz), 2.73 (t, 2H, > 6.5 Hz), 1.89 (m, 4H).

• ·

9 9 9 9 9 9 · 99999 999 (b) Ethyl 3-ethoxy-3-iminopropanoate, prepared as in Example 2 (a), was reacted with 2- (3,4-diaminobenzyl) isoindole-1,3- dione under similar conditions to Example 2 (b) to give ethyl 5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -1 H -benzoimidazol-2-yl acetate (71% yield); ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J = 9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H,> 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H,> 7, 2 Hz).

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

(d) A mixture of 5- (4-phenylbutoxy) benzene-1,2-diamine (0.06 g, 0.234 mmol) and ethyl 5- (1,3-dioxo-1,3-dlHydroisoindol-2-ylmethyl) - 17 H -benzoimidazol-2-yl acetate (0.1 g, 0.234 mmol) was heated at 185 ° C for 1 hour under a nitrogen atmosphere. The mixture was suspended in diethyl ether and stirred vigorously for 1 hour. The solid was filtered off, washed with diethyl ether and dried. There was thus obtained 2- {2- (5- (4-phenylbutoxy) -177-benzoimidazol-2-ylmethyl] -377-benzoimidazol-5-ylmethyl} isoindole-1,3-dione (0.1g, 0.18 mmol). ).

(e) 2- {2- (5- (4-phenylbutoxy) -177-benzoimidazol-2-ylmethyl] -377-benzoimidazol-5-ylmethyl} isoindole-1,3-dione was deprotected under conditions similar to Example 2 (g) to give C- {2- [5- (4-phenylbutoxy) -1,77-benzoimidazol-2-ylmethyl] -1 H -benzoimidazol-5-yl} methylamine (0.05 g, 55% yield); 1 H-NMR (300 MHz, CD ₃ OD): 7.83 (d, 1H, J = 8.6 Hz), 7.76 (s, 1H), 7.69 (d, 1H,> 10.0) Hz), 7.48 (d, 1H, > 8.6 Hz), 6.99-7.16 (m, 5H), 6.92 (d, 1H, > 10.0 Hz), 6.80 ( t, 1H, > 7.2 Hz), 4.44 (s, 2H), 3.93 (t, 2H, J = 6.5 Hz), 2.56 (t, 2H, > 7.2 Hz) 1.72 (m, 2H).

Example 5

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

2- [5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) -1,77-benzoimidazol-2-ylmethyl] -1 H -benzoimidazole-5-carboxylic acid (0.060 g, 0.133 mmol) in phenylethanol (0.160 mL, 1.34 mmol) was mixed with diphenylphosphoryl azide (0.034 mL, 0.158 mmol) and triethylamine (0.022 mL, 0.158 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred at 120 ° C for 1 h, cooled to room temperature and ethanol (0.5 mL) and hydrazine (0.020 mL, 0.637 mmol) were added. The mixture was stirred at 95 ° C for 45 min, cooled to room temperature and diluted with 3 N hydrochloric acid (0.5 mL). The mixture was stirred at 55 ° C for 20 minutes and then filtered. The filtered solid was washed with 3 N hydrochloric acid and the combined filtrates were washed with ethyl acetate (15 mL) and lyophilized. The residue was purified by preparative reverse phase HPLC to give the desired product (0.008 g, 11% yield); ¹ H-NMR (300 MHz, CD ₃ OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 7.63 (d, 1H,> 9.3 Hz), 7.38-7.44 (m, 2H), 7.19-7.32 (m, 5H), 4.36 (t, 2H, J = 6, 8 Hz), 4.23 (s, 2H), 1.98 (t, 2H, J = 6.8 Hz).

Example 6

2- (5-Guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -3-methyl-3 H -benzoimidazole-5-carboxyamide (Compound 28) (a) Solution containing 2-nitro-1,4-phenylenediamine (21.0 g, 137 mmol) in ethanol (350 mL) and 4.0 M hydrogen chloride in dioxane (30.8 mL, 123 mmol) was stirred at room temperature for 15 minutes and then diethyl ether (11) was added. The resulting precipitate was filtered off, washed with diethyl ether and dried in vacuo. There was thus obtained 2-nitro-1,4-phenylenediamine hydrochloride (23.3 g, 100% yield).

(b) A mixture containing 2-nitro-1,4-phenylenediamine hydrochloride (15.0 g, 79.1 mmol), cyanamide (25.0 g, 595 mmol) and water (5 mL) was stirred at 60 ° C for 1 hour. , Allowed to cool to room temperature, and then excess diethyl ether was added slowly. The resulting precipitate was filtered off, then washed with diethyl ether and dried in vacuo. There was thus obtained N- (4-amino-3-nitrophenyl) guanidine hydrochloride (18.0 g, 98% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d), 7 1 (d).

(c) A mixture containing N- (4-amino-3-nitrophenyl) guanidine hydrochloride (12.0 g, 51.8 mmol), 10% Pd / C (1.0 g), tetrahydrofuran (100 mL) and methanol ( 100 ml) was hydrogenated at 101 kPa (atm), filtered and concentrated in vacuo. There was thus obtained N- (3,4-diaminophenyl) guanidine hydrochloride (10.3 g, 98% yield) as a dark solid; ¹ H-NMR (300 MHz, DMSO-d ₆ ): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4 , 7 (s).

(d) A mixture of N- (3,4-diaminophenyl) guanidine hydrochloride (9.9 g, 49 mmol), ethyl ethoxycarbimidoylacetate hydrochloride (12.4 g, 59 mmol) and acetic acid (20 mL) was stirred and heated. in an oil bath at 110 ° C for 1.5 hours, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) and the addition of ethyl acetate (10 mL) gave a precipitate suspension. The suspension was filtered and an additional precipitate was added by addition of excess ethyl ether. The precipitate was filtered off, then washed with diethyl ether and dried in vacuo. Ethyl 5-guanidino-1 H -benzoimidazol-2-ylacetate hydrochloride (14.1 g, 94% yield) was obtained as an off-white solid; ¹ H-NMR (300 MHz, DMSO-d ₆ ): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4 2 (q), 1.2 (t).

(e) A mixture containing 4-nitro-3-methoxybenzoic acid (5.0 g, 25.4 mmol) and an aqueous solution of methylamine (40%, 15 mL) was heated in a sealed vial in an oil bath at 100 ° C for 12 hours, allowed to cool to room temperature and then poured into a stirred slurry of 1 M aqueous hydrochloric acid and ice to form an orange precipitate. The precipitate was filtered off, washed with water and recrystallized from hot ethanol. There was thus obtained 3-methylamino-4-nitrobenzoic acid as a bright red crystalline solid (3.6 g, 73% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3 , 0 (d).

(f) A mixture containing 3-methylamino-4-nitrobenzoic acid (13.0 g, 66.3 mmol), PyBOP (38.0 g, 73.0 mmol), hydroxybenztriazole hydrate (9.9 g, 73.0 mmol) Dimethylformamide (100 ml) and N-methylmorpholine (18.3 ml) were stirred at room temperature for 15 minutes and then 2-naphth-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 hydrochloric acid, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by crystallization from hot ethanol. Thus, to obtain ^{3-methylamino-N} - (2-naphth-l-yl-ethyl) -4-nitrobenzamide as a bright red crystalline solid (21.3 g, 92% yield off obstructions); 1 H-NMR (300 MHz, DMSO-d 6):?

8.8 (t), 8.3 (d), 8.2 (q), 8.1 (d), 7.9 (d), 7.8 (d), 7.6-7.3 (m) 7.2 (s), 7.0 (d), 3.6 (q), 3.3 (t), 3.0 (d).

(g) A mixture containing 3-methylamino-N- (2-naphth-1-ylethyl) -4-nitrobenzamide (21.3 g, 61 mmol), 10% Pd / C (1.0 g), tetrahydrofuran (100 mL). ) and methanol (100 mL) was hydrogenated at 101 kPa (atm), filtered and concentrated in vacuo. There was thus obtained 4-amino-3-methylamino- N - (2-naphth-1-ylethyl) -4-benzamide (18.4 g, 95% yield) as a colorless amorphous solid; 1 H-NMR (300 MHz, DMSO-d ₆ ): 8.3 (d), 8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 ( m), 7.1 (d),

6.9 (s), 6.5 (d), 5.0 (s), 3.5 (q), 3.2 (t), 2.7 (s).

(h) A mixture containing ethyl 5-guanidino-1H-benzoimidazol-2-ylacetate hydrochloride (0.5 g, 1.7 mmol), 4-amino-3-methylamino-N- (2-naphth-1-ylethyl) -4-Benzamide (0.5 g, 1.7 mmol) and dimethylformamide (2 mL) were heated in an oil bath at 185 ° C and stirred under a nitrogen atmosphere for 3.5 hours, cooled to room temperature and poured into stirred acetonitrile ( 150 ml). The resulting precipitate was then washed with acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo. An off-white solid was obtained. The solid was purified by preparative reverse phase HPLC. There was thus obtained 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -3-methyl-37H-benzimidazole-5-carboxylic acid. Boxamide as a white solid (0.5 g) ·············· Boxamide as a white solid (0.5 g) 57%); LRMS (ESI): calcd. found (MH ⁺ ): 517.2.

Example 7

Ethyl 2- (4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5- c] pyridin-5-yl (4-Oxobutyl) benzoate (Compound 29) (a) A solution containing ethyl 2-cyanopropanoate (100 g, 0.29 mol) in ethanol (65 mL) was cooled to 0 ° C and then saturated with dry hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred for 24 hours, cooled to 0 ° C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred for an additional 24 hours. Diethyl ether / hexane (1/1) was then added to the mixture. The resulting precipitate was collected by filtration and dried under vacuum. There was thus obtained ethyl 2- (N-ethoxyamidino) propanoate hydrochloride (119.6 g, 73% yield) as a white solid; 1 H-NMR (300 MHz, DMSO-d 6): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (t, 3H).

(b) A mixture containing 3,4-diaminopyridine (51.7 g, 0.46 mol), ethyl 2- (N-ethoxyamidino) propanoate hydrochloride (125 g, 0.69 mol) and glacial acetic acid (200 mL) was heated to 85 ° C and stirred for 18 hours. Then heated to 120 ° C and stirred for an additional hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was neutralized by addition of 5 M aqueous ammonia and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried (MgSO ₄ ), filtered, and concentrated in vacuo. There was thus obtained ethyl 17H-imidazo [4,5-c] pyridine-2-carboxylate (60.4 g, 58% yield); 1 H-NMR (300 MHz, CDCl ₃ ): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 3, 90 (q, 1H), 1.75 (d, 3H), 1.25 (t, 3H).

(c) A mixture containing ethyl 1/7-imidazo [4,5-c] pyridine-2-carboxylate (34.7 g, 158 mmol), trifluoroacetic acid (50 mL) and platinum oxide (2.5 g) in ethyl acetate. the Parr hydrogenation apparatus was hydrogenated at 50 psi for 24 hours, filtered, and concentrated in vacuo. The oily residue was dissolved in a minimum of ethanol. To this solution was added a solution of dry hydrogen chloride in dioxane (4 M, 120 mL, 475 mmol). Excess diethyl ether was then added to the solution. The resulting precipitate was filtered off and dried in vacuo. There was thus obtained ethyl 1,4,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2-carboxylate dihydrochloride (30.7 g, 66% yield); 1 H-NMR (300 MHz, DMSO-d 6): 10.00 (bs, 2H), 4.35 (q, 1H), 4.20 (bs, 2H), 4.10 (m, 2H), 3 35 (m, 2H), 2.90 (bs, 2H), 1.55 (d, 3H), 1.15 (t, 3H).

(d) A mixture containing ethyl 1,4,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-2-carboxylate dihydrochloride (60.2 g, 0.20 mol), acetonitrile (500 mL). mL) and diisopropylethylamine (100 mL, 0.60 mol) was cooled to 0 ° C. Benzyl chloroformate (58 mL, 0.40 mol) was added slowly with stirring. The mixture was slowly warmed to room temperature, stirred for an additional 16 hours, and concentrated in vacuo. The residue was dissolved in diethyl ether (500 mL) and the solution was washed with 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. A colorless oil was obtained, which was dissolved in ethanol (320 mL) and cooled to 0 ° C. A solution of sodium ethoxide in ethanol (2.6 M, 85 mL, 0.22 mol) was then added slowly. The mixture was stirred at 0 ° C for 1 h and then a solution of hydrogen chloride in dioxane (4 M, 50 mL) was added. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. There was thus obtained 5-benzyl-2-ethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-2,5-dicarboxylate as a yellow amorphous solid (52 g, 72% yield); 1 H-NMR (300 MHz, DMSO-d ₆ ): 11.75 (bs, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (bs, 2H), 4.05 (m, 2H), 3.75 (q, 1H), 3.65 (bs, 2H), 1.40 (d, 3H), 1.15 (t, 3H).

(e) A mixture containing 4-chlorobutyryl chloride (12.6 g, 89.2 mmol), t-butanol (25 mL), pyridine (6.9 g, 86.5 mmol) and 4-dimethylaminopyridine (1.0 g, 8.2 mmol) was heated at 50 ° C under a dry nitrogen atmosphere for 12 hours. The resulting white suspension was partitioned between diethyl ether (250 mL) and water. The organic layer was separated and washed repeatedly with water and then 0.1 M aqueous hydrochloric acid, saturated aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The obtained colorless oil was distilled at 66 Pa (0.5 mmHg) at 51 ° C. There was thus obtained t-butyl 4-chlorobutyrate as a colorless liquid (11.27 g, 73% yield); 1 H NMR (300 MHz, CDCl ₃ ): 3.60 (t, 2H), 2.40 (t, 2H), 2.10 (m, 2H), 1.45 (s, 9H).

(f) A mixture containing ethyl salicylate (3.14 g, 18.9 mmol) and cesium carbonate (6.2 g,

18.9 mmol), dimethylformamide (25 mL) and t-butyl 4-chlorobutyrate (4.08 g, 22.8 mmol) were heated at 70 ° C and stirred for 12 hours. The mixture was then partitioned between diethyl ether (100 mL) and water. The organic layer was separated and washed with water (3x) and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The obtained colorless oil was purified on silica gel by flash chromatography using pure hexane to hexane / ethyl acetate (10/1). Ethyl 2- (3 - / - either) was thus obtained.

Toxicarbonylpropoxy) benzoate (3.6 g, 62% yield) as a colorless oil; 1 H NMR (300 MHz CDCl 3): 7.80 (d, 1H), 7.49 (t, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (t, 2H), 2.50 (t, 2H), 2.10 (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H).

(g) Ethyl 2- (3- t -butoxycarbonylpropoxy) benzoate (3.60 g, 11.7 mmol) was stirred for one hour with excess trifluoroacetic acid at room temperature. The solution was concentrated in vacuo and the oily residue was purified on silica gel by flash chromatography using hexane / ethyl acetate (10/1) to neat diethyl ether. There was thus obtained 4- (2-ethoxycarbonylphenoxy) butanoic acid in the form of a colorless crystalline solid (2.81 g, 95% yield); 1 H NMR (300 MHz, CDCl ₃ ): 7.80 (d, 1H), 7.50 (t, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 ( t, 2H), 2.65 (t, 2H), 2.20 (m, 2H), 1.40 (t, 3H).

(h) A mixture containing benzyl-2-ethoxycarbonylmethyl-1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (1.7 g, 4.8 mmol), N - (3- 1,4-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). The resulting precipitate was washed with acetonitrile and diethyl ether (150 mL), filtered and dried in vacuo. The off-white solid was purified by preparative reverse phase HPLC. Benzyl 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate was thus obtained in as a white solid (1.0 g, 55% yield); LRMS (ESI): calcd. For C24H26N8O2: 458.5; found (MH ⁺ ): 459.2.

(i) A mixture comprising benzyl-2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5- c] pyridine-5- carboxylate (1.0 g, 2.2 mmol), 10% Pd / C (0.5 g), tetrahydrofuran (50 mL), and methanol (50 mL) were hydrogenated at 101 kPa (atm), filtered and concentrated in vacuo. vacuum. There was thus obtained N- {2- (1- (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2-yl) ethyl] -1 H -benzoimidazol-5-yl) guanidine (0.69 g, 97% yield); LRMS (ESI): calcd for C16H20N8: 324.4; found (MH ⁺ ): 325.2.

(j) A mixture containing 4- (2-ethoxycarbonylphenoxy) butanoic acid (155 mg, 0.61 mmol) PyBOP (360 mg, 0.69 mmol), hydroxybenztriazole hydrate (87 mg, 0.64 mmol), N-methylmorpholine ( 0.16 mL, 0.92 mmol) and dimethylformamide (2.5 mL) was stirred at room temperature for 10 minutes, and then N - {2- [1- (4,5,6,7-tetrahydroimidazo [4, 5,6,7-tetrahydroimidazo [4, 5,6,7-tetrahydroimidazo]) was added. 5-c] pyridin-2-yl) ethyl] -3 H -benzoimidazol-5-yl} guanidine (203 mg, 0.63 mmol). The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product was purified by preparative reverse phase HPLC. Combined pure fractions • ·

were then lyophilized. There was thus obtained ethyl 2- (4- {2- [1- (5-guanidino-1H-benzimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine- 5-yl} -4-oxobutyl) benzoate; LRMS (Bioion): calcd for C29H34N8O4 558.6; found: 559.3.

Example 8

2- [1- (5-Hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 30) (a) A solution of t-butyl-2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0 ° C and stirred. Then, diisopropylethylamine (33.8 mL) was added first.

193.9 mmol) followed by dropwise mesyl chloride (13.7 mL, 177.8 mmol). The mixture was allowed to warm to 23 ° C, stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3 M, 3 x 25 mL) and saturated aqueous sodium bicarbonate (2 x 25 mL). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. There was thus obtained tert -butyl-2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI): calcd for C 9 H 11 NO 5 S: 239.08; found (MH ⁺ ): 240.

(b) Lithium bromide (136 g, 1.56 mol) was dissolved in tetrahydrofuran (600 mL) at 0 ° C. The mixture was allowed to warm to 23 ° C and then Z-butyl-2-methylsulfonyloxyethylcarbamate (37.39 g, 156 mmol) was added dropwise. The mixture was stirred at 23 ° C for 18 hours and concentrated in vacuo. The residue was dissolved in hexane and the organic layer was washed with water and brine, dried (Na 2 SO 4) and concentrated in vacuo. There was thus obtained tert -butyl-2-bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI): calcd for C ₇ H ₁₄ BrNO ₂ : 224.10; found (MH ⁺ ) · 225.

(c) A mixture of 2-methoxyphenol (9.8 mL, 89.3 mmol), dimethylformamide (100 mL) and potassium carbonate (61.5 g, 445 mmol) was stirred at 23 ° C and Z-butyl-2- was added. bromoethyl carbamate (20 g, 89.3 mmol). The mixture was stirred for 24 hours and then poured into diethyl ether / hexane (1/1, 400 mL) and washed with water (5 x 50 mL). The aqueous layer was extracted with diethyl ether / hexane (1/1, 3 x 40 mL). The combined organic layers were dried (Na 2 SO 4) and concentrated in vacuo. There was thus obtained n-butyl-2- (2-methoxyphenoxy) ethylcarbamate (23.22 g, 97% yield) as a yellow oil; MS (PB-PCI): calcd for C 14 H 21 NO 4: 267.32; found (MH ⁺ ) 268.

(d) t -Butyl-2- (2-methoxyphenoxy) ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 ° C and a mixture of trifluoroacetic acid and dichloromethane (1 / 1.40 mL) was added dropwise with stirring. The mixture was allowed to warm to 23 ° C, stirred for 2 hours and concentrated in vacuo. Rest dissolved in ·

99 9 9 9 9

Dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium bicarbonate solution (3 x 20 ml) and aqueous sodium hydroxide solution (10%, 3 x 20 ml). ), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. There was thus obtained 2- (2-methoxyphenoxy) ethylamine (13 g, 88% yield) as a light yellow solid; MS (PB-PCI): calcd for C ₉ H ₃ NO ₂ : 167.21; found (MH ⁺ ): 168.

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

(f) A mixture containing 2- (2-methoxyphenoxy) ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) was cooled to 0 ° C and then cooled to 0 ° C. A solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was allowed to warm to 23 ° C over two hours, aqueous hydrochloric acid (3 M, 20 mL) was added, washed with water (3 x 20 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. There was thus obtained N- [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (14 g, 74% yield) as an off-white solid; MS (PB-PCI): calcd for C ₁₇ H ₁₈ N ₂ O ₆ : 346.34; found (MH ⁺ ): 347.

(g) A mixture containing N - [2- (2-methoxyphenoxy) ethyl] -3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 mL) and DMSO (2). ml) was heated in a sealed vial at 110 ° C for 4 hours, cooled and poured into water (25 ml). Addition of 3 M aqueous hydrochloric acid to the solution gave an orange solid which was isolated by filtration. There was thus obtained N- [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI): calcd for C17H19N3O5: 345.35; found (MH ⁺ ): 346.

(h) A mixture containing N - [2- (2-methoxyphenoxy) ethyl] -3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), a Pd / C suspension (10%, 0.5 g) in methanol (100 mL) and tetrahydrofuran (50 mL) were stirred under a hydrogen atmosphere at room pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo. There was thus obtained 4-amino- N - [2- (2-methoxyphenoxy) ethyl] -3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PB-PCI) for C ₇ H ₂ IN ₃ O ₃ calculated: 315.37; found (MH ⁺ ) 316.

(i) A mixture containing 4-amino-3-nitrophenol (5.0 g, 32.4 mmol), Pd / C (10%, 1.0 g) and methanol (50 mL) in a Parr apparatus was hydrogenated at 344 kPa (50 psi) for 3 hours, filtered through celite and concentrated in vacuo. There was thus obtained 3,4-diaminophenol (4.02 g, 91%).

yield) as a dark solid; MS (PB-PCI): calcd for C ₆ H ₃ N ₂ O: 124.16; found (MH ⁺ ): 125.

(j) A mixture of 3,4-diaminophenol (3,661 g, 29.5 mL), ethyl 2- (N-ethoxyamidino) propanoate (7.423 g, 38.4 mmol) and ethanol (30 mL) was heated at reflux 6. hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated aqueous sodium bicarbonate solution (3 x 20 mL) and brine (1 x 20 mL), dried (MgSO ₄ ) and concentrated in vacuo. There was thus obtained ethyl 2- (5-hydroxy-1 H -benzoimidazol-2-yl) propanoate (6.3 g, 91% yield) as a dark solid. The material was further purified on silica gel by flash chromatography (100% ethyl acetate); MS (PB-PCI): calcd for C ₁₂ H ₄ N ₂ O ₃ : 234.28; found (MH ⁺ ): 235.

(k) A mixture containing ethyl 2- (5-hydroxy-1H-benzimidazol-2-yl) propanoate (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 (1 H) -pyrimidone (0.5 mL) was stirred at room temperature to give of a homogeneous solution, degassed by vacuum and concentrated by heating at 170 ° C for 2 hours under a stream of N ₂ . The residue was cooled to room temperature and washed with excess diethyl ether. The amorphous material obtained was taken up in 50% aqueous acetonitrile and purified by reverse phase preparative HPLC (2-50% CH ₃ CN / H ₂ O). This gave 2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-37H-benzimidazole-5- carboxamide (40 mg, 13% yield) as a light pink solid; MS (Biolone): Calcd. For C H ^H ^NsCl: 485.59; found (MH ⁺ ): 486.5.

The following compounds of the invention were prepared as in Example 8: methyl 2- (2- {2- [1- (5-fluoro-177-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazole-5- ylcarbonylamino} ethoxy) benzoate (Compound 31), MS (Biolone): calcd for C C HH ^ NNsCLF: 515.54; found (MH ⁺ ): 516;

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

ethyl 2- (2- {2- [1- (5-hydroxy-17 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 33 MS (Biolone) calcd. For C C ^H ^N ^Os: 527.58; found (MH ⁺ ): 528.1;

ΦΦ φ φ φ φ φ φ · · φ

2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 34 MS (Biolone) calcd. For C27H25N5O5: 499.53; found (MH ⁺ ): 500.1;

And ^t-ethyl-2- [l- (5-hydroxy-l / i-benzimidazol-2-yl) ethyl] -3-methyl-3H-benzimidazole-5-carboxamide (Compound 35), MS (Biolon) for C20H21N5O2 calculated: 363.42; found (MH ⁺ ): 364.1;

2- [1- (5-hydroxy-177-benzoimidazol-2-yl) ethyl] -N- (2-methoxyethyl) -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 36), MS (Biolon): for C21H23N5O3: 393.45; found (MH ⁺ ): 394.1;

butyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 37), MS (Biolone): calcd for C 31 H 33 N 5 O 5 555.64; found (MH ⁺ ): 555.7;

3- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid (Compound 38), MS (LCMS): calcd. For C30H35N8O6S: 635.72; found (MH ⁺ ): 635.4;

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

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxyphenoxy) ethyl] -3-methyl-3Z-benzoimidazole-5-carboxamide (Compound 40 MS (Biolone) calcd. For C29H31N5O4: 513.61; found (MH ⁺ ): 514.5;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide ( Compound 41), MS (Biolone): calcd. For C29H31N5O4: 513.61; found (MH ⁺ ): 514.2;

propyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 42 MS (ESI): calcd. For C30H31N5O5: 541.61; found (MH ⁺ ): 542.2;

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

ethyl 4- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylaminobutanoate (Compound 44), MS (Biolon) for C24H27N5O4 calculated:

449.51; found (MH ⁺ ): 449.9;

4- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} butanoic acid (Compound 45), MS (Biolon): for C22H23N5O4: 421.46; found (MH ⁺ ): 422.1;

Isopropyl 2- (2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 46) , MS (ESI): calcd for C30H31N5O5: 541.61; found (MH ⁺ ): 542.2;

N- {2- [2- (1-ethyl-propoxy) -phenoxy] -ethyl} -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-37 H -benzoimidazole-5 -carboxamide (Compound 47), MS (Biolone): calcd for C31H35N5O4: 541.65; found (MH ⁺ ): 542.5;

ethyl 2- (2- {2- [1- (5-fluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 48) MS (Biolon) for _C2 9H2 ₈ N ₅ O4F calculated: 529.57; found (MH ⁺ ): 529.5;

2-Methoxyethyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 49), MS (Biolone): calcd for C30H31N5O6: 557.61; found (MH ⁺ ): 558.2;

N- (3-methoxypropyl) -2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide (Compound 50), MS (Biolon) ): calcd for C22H2SN5O3: 407.47; found (MH ⁺ ): 408.0;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -77- [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 51), MS (Biolone): calcd for C28H29N5O4: 499.57; found (MH ⁺ ): 499.8;

N - [2- (2-ethoxymethylphenoxy) ethyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 52), MS (Biolone): calcd for C 29 H 31 N 5 O 4 513.60; found (MH ⁺ ): 514.1;

ethyl 2- (2- {2- [1- (6-fluoro-5-hydroxy-1H-benzimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 53), MS (ESI): calcd. for C29H28N5O5F: 545.57; found (MH ⁺ ): 546.3;

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

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-propoxymethylphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 55), MS (Biolone) calcd for C 30 H 33 N 5 O 4 527.62; found (MH ⁺ ): 527.6;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-isopropoxymethylphenoxy) ethyl] -3-methyl-3H-benzoimidazole-5-carboxamide ( Compound 56), MS (Biolone): calcd. For C30H33H5O4: 527.62; found (MH +): 527.9;

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-377-benzoimidazole-5- carboxamide (Compound 57), MS (Biolone): calcd for C30H33N5O5: 543.62; found (MH ⁺ ): 543.4;

2- [1- (1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxymethylphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 58), MS ( Biolone): calcd for C28H29N5O3: 483.57; found (MH ⁺ ): 484;

N- [2- (2-ethoxymethylphenoxy) ethyl] -2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 59), MS (Biolone): calcd for C29H31N5O3: 497.6; found (MH ⁺ ): 498.3;

2- [l- (177-benzoimidazol-2-yl) ethyl] -3-methyl- _J N- [2- (2-propoxymethylfenoxy) -ethyl] -3 / 7-benzimidazole-5-carboxamide (Compound 60), MS (Biolone): calcd. For C30H33N5O3: 511.62; found (MH +): 511.5;

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

2- [1- (1H-benzimidazol-2-yl) ethyl] -N- {2- [2- (2-methoxyethoxymethyl) phenoxy] ethyl} -3-methyl-377-benzoimidazole-5-carboxamide (Compound 62 MS (Biolone): calcd. For C30H33N5O4: 527.62; found (MH ⁺ ): 527.7;

2- [1- (5-hydroxy-177-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -377-benzoimidazole-5-carboxamide ( compound 63), MS (Biolon) for C ₃₀ H32N ₆ O4 calculated: 540.73; found (MH ⁺ ): 541.8;

N - (2-phenylsulfonylethyl) -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H- benzoimidazole-5-carboxamide (Compound 64), MS (Biolon ): calcd for C26H25N5O4S: 503.59; found (MH ⁺ ): 504.2;

2- (2- {2- [1- (6-fluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid acid (Compound 65), MS (ESI): calcd. for C27H24N5O5F: 517.52; found (MH ⁺ ): 518.2;

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

2- [1- (5-fluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-morpholin-4-ylphenoxy) ethyl] -37 H -benzoimidazole-5-carboxamide (Compound 67), MS (Biolone). for C ₃ oH iN ₆ 0 ₃ F ₃ Calculated: 542.62; found (MH ⁺ ): 543.4;

N - (2-phenylsulfonylethyl) -2- [1- (5-fluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 68), MS (Biolone): calcd for C ₂₆ H ₂₄ N ₅ O ₃ FS: 505.58; found (MH ⁺ ): 506.5;

ethyl 2- (2- {2- [1- (4,6-difluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy ) benzoate (Compound 69), MS (Biolone): calcd for C ₂₉ H ₂₇ N ₅ O ₅ F ₂ : 563.52; found (MH ⁺ ): 563.4;

2- (2- {2- [1- (4,6-Difluoro-5-hydroxy-1H-benzimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 70), MS (Biolone): calcd for C ₂₇ H ₂₃ N ₅ O ₅ F ₂ : 536.51; found (MH ⁺ ): 563;

ethyl 2- (2- {2- [1- (4,6-difluoro-5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole 5-ylcarbonylamino} ethoxy) benzoate (compound 71), MS (Biolon) for C ₃₂ H 9 N ₂ O ₇ F _{2 4} calculated: 613.62; found (MH ⁺ ): 614.3;

2- [1- (5-guanidino-177-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2- (3-methyl [1,2,4] oxadiazole-5- yl) phenoxy] ethyl} -3 H -benzoimidazole-5-carboxamide (Compound 72), MS (Biolone): calcd for C ₃₀ H ₃₀ N ₁₀ O ₃ : 578.63; found (MH ⁺ ): 579.4; and

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-1- N - {2- [2- (3-methyl [1,2,4] ] oxadiazol-5-yl) phenoxy] ethyl} -3 // - benzoimidazole-5-carboxamide (compound 73), MS (Biolon) for C ₃₂ H 9 N ₂ O _{3 9} calculated: 587.64; found (MH + ¹ ): 588.2.

Example 9

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-Methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 74)

a) A solution containing 3,4-diaminopyridine (51.7 g, 0.46 mol) in acetic acid (400 mL) was heated to 85 ° C and diethyl-methyl-1 was added in three equal portions over 6 hours. -iminomalonate (125 g, 0.60 mol). The mixture was heated at 85 ° C for 12 hours and at 120 ° C for an additional hour, cooled and concentrated under reduced pressure. The residue was cooled to 0 ° C and neutralized with 5 N aqueous ammonia. The aqueous layer was extracted several times with ethyl acetate. The combined extracts were washed successively with sodium bicarbonate and sodium chloride, dried (Na ₂ SO 4), filtered, and concentrated under reduced pressure. Ethyl 2- (1H-imidazo [4,5-c] pyridin-2-yl) propanoate (60.4 g, 58%) was thus obtained as an amber salt. 99 99

9

9

9,999,999 yellow solid; 1 H NMR (300 MHz, CDCl ₃ ): 9.00 (s, 1H), 8.35 (d, 1H, J = 9.4 Hz), 7.50 (d, 1H,> 9.4 Hz) 4.25 (m, 3H), 1.78 (d, 3H, J = 7.8 Hz), 1.30 (t, 3H, > 4.7 Hz).

(b) A solution containing ethyl 2- (1H-imidazo [4,5-c] pyridin-2-yl) propanoate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 mL) was hydrogenated at 50 ksi in the presence of PtO ₂ (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 diethyl ether, filtered and dried. Solutions containing the residue (15-20 g each) were hydrogenated in fresh trifluoroacetic acid (50 mL each) at 50 psi in the presence of PtO ₂ (5 g each) for 24 hours. The mixtures were filtered and concentrated under reduced pressure. The residues were azeotroped with toluene / ethanol ~ 1: 1, with 4M HCl / dioxane, suspended in diethyl ether, isolated by filtration, and dried on a vacuum line. There was thus obtained ethyl 2- (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2-yl) propanoate dihydrochloride (61.80 g, 75% yield); 1 HNMR (300 MHz, DMSO-d ₆ ): 10.00 (bs, 2H), 4.35 (q, 1H,> 7.1 Hz), 4.25 (bs, 2H), 4.15 (m (2H), 3.35 (m, 2H), 2.90 (bs, 2H), 1.60 (d, 3H, > 7.1 Hz), 1.20 (t, 3H, > 6.9 Hz) ).

(c) A solution containing ethyl 2- (4,5,6,7-tetrahydroimidazo [4,5-c] pyridin-2-yl) propanoate dihydrochloride (60.2 g, 0.20 mol) in acetonitrile (400 mL) ) was cooled to 0 ° C under a nitrogen atmosphere. Then ΛζΥ-diisopropylethylamine (35 mL, 0.20 mol) was added, and the solution cooled to ca. -5 ° C (ice / acetone), and then benzylchloroformate (58 mL, 0.41 mol) and N, N -diisopropylethylamine (70 mL, 0.40 mol) were added in portions over 30 minutes. The mixture was cooled to -5 ° C for one hour and allowed to warm to 20 ° C. After 16 hours, it was concentrated under reduced pressure. The residue was suspended in diethyl ether and the suspension was subsequently washed with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na ₂ SO 4), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 mL) and the solution cooled to -5 ° C under a nitrogen atmosphere, and then sodium ethoxide (21 wt%, 85 mL, 0.22 mol) was added dropwise over one hour at the reaction mixture temperature. kept below 0 ° C. The mixture was cooled to -5 ° C for one hour, 50 mL of 4 M hydrochloric acid was adjusted to pH neutral and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate and sodium chloride, dried (Na ₂ SO 4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / fraction / ethyl acetate). There was thus obtained benzyl 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (52 g, 72%) as a light yellow oil; 1 HNMR (300 MHz, DMSO-d 6): 11.72 (bs, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (bs, 2H), 4.02 (q, 2H, fl fl = 9,3 Hz), 3,77 ( q, 1H,> 8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H,> 8.3 Hz), 1.13 (t, 3H,> 9.3 Hz).

(d) A mixture containing benzyl 2- (1-ethoxycarbonylethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino- 3- (N-methylamino) benzoic acid (2.70 g, 0.016 mol) and DMPU (20 mL) were briefly degassed on a vacuum line, heated at 185 ° C under a nitrogen atmosphere for 4 hours, cooled and added to an equal volume of benzene. Subsequent addition of diethyl ether gave a precipitate. The precipitate was collected by filtration, briefly dried on a vacuum line and purified by recrystallization from hot ethanol / water. The precipitate was collected by filtration and dried. This gave 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-3/7 -benzoimidazole-5-carboxylic acid (4.73 g, 58%); 1 H NMR (300 MHz, DMSO-d ₆ ): 12.70 (bs, 1H), 11.80 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H,> 8) 3 Hz), 7.64 (d, 1H, > 8.3 Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (q, 1H, > 5.2 Hz) ), 4.32 (bs, 2H), 3.78 (s, 3H), 3.65 (bs, 2H), 2.52 (bs, 2H), 1.73 (d, 3H,> 5.2) Hz).

(e) A mixture comprising 2- [1- (5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl) ethyl] -3-methyl-3 H- 7-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) was cooled under a nitrogen atmosphere to -40 ° C, EDC (0.32 g, 1.6 mmol) and N, N -diisopropylethylamine (0.29 mL, 1 mL) were added. , 6 mmol) and after 15 minutes more N-N-diisopropylethylamine (0.29 mL). The mixture was allowed to warm to 20 ° C and stirred for 16 hours. The mixture was then cooled to -40 ° C and EDC (0.080 g) and MV-diisopropylethylamine (0.050 mL) were added, stirred for 15 minutes at -40 ° C and 2 hours at 20 ° C and concentrated by short distillation. The residue was partitioned between chloroform and sodium bicarbonate. The organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried (Na ₂ SO 4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl 3 / MeOH / AcOH 95/5/1). Benzyl-2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) -1,4,6,7- tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (0.69 g, 66%) as a brown glassy foam; 1 H NMR (300 MHz, DMSO-d 6): 11.92 (s, 1H), 8.49 (t, 1H,> 5.0 Hz), 8.02 (s, 1H), 7.69 (d 1 H,> 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H,> 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1H > 9.9 Hz), 6.99 (t, 1H,> 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H,> 8.8 Hz), 4.30 (bs, 2H), 4.20 (t, 2H, > 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2, 55 (bs, 2H), 1.67 (d, 3H, > 8.8 Hz).

• 9 9 · 99 9 9 · ·

9 · · · · · · · · · · · · · · · · 9 9 · ·

(F) A solution containing benzyl-2- (1- {6- [2- (2-methoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-17 H -benzoimidazole-2- yl} ethyl) -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (0.69 g, 1.1 mmol) in THF (2 mL) and water (2 mL) was cooled to 0 ° C under a nitrogen atmosphere, 2N lithium hydroxide (1.1 mL, 2.2 mmol) was added, allowed to warm to 20 ° C and stirred for 8 hours. The mixture was then cooled to 0 ° C, 2N lithium hydroxide (1.1 mL) was added, allowed to warm to 20 ° C, stirred for 6 hours, cooled to 0 ° C, adjusted to pH 7 with 1M hydrochloric acid and concentrated under reduced pressure. pressure. The residue was carefully washed with cold sodium chloride and water and then dried on a vacuum line. There was thus obtained 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl)) -ethyl] -37Y-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.56 g, 83%) as a glassy residue; 1 HNMR (300 MHz, DMSO-d ₆ ): 11.87 (bs, 1H), 9.74 (s, 1H), 8.45 (s, 1H), 7.84 (d, 1H,> 9), 7 Hz), 7.56 (d, 1H, > 9.7 Hz), 7.42 (d, 1H, > 7.7 Hz), 7.32 (s, 5H), 7.23 (t, 1H > 7.7 Hz), 7.06 (d, 1H,> 7.7 Hz), 6.90 (t, 1H,> 7.7 Hz), 5.08 (s, 2H), 4.63 (q, 1H, > 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, > 7.7 Hz).

(g) A solution containing 5-benzyloxycarbonyl-2- (2- {3-methyl-2- [1- (4,5,6,7-tetrahydro-1H) -imidazo [4,5-c] pyridin-2) -yl) ethyl] -37 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.561 g, 0.90 mmol) in glacial acetic acid (2 mL) was heated at 10 ° C under a nitrogen atmosphere in a water bath. To the mixture was added hydrogen bromide in acetic acid (2 mL of a 30% solution), and the mixture was allowed to warm to 20 ° C. After an hour, the mixture was concentrated with a stream of nitrogen. The residue was dissolved in a small amount of ethanol and the solution was added dropwise to stirred diethyl ether. The resulting light brown precipitate was collected by filtration and dried. 2- (2- {3-Methyl-2- [4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3] hydrobromide was thus obtained. t -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.651 g); 1 H NMR (300 MHz, DMSO-d ₆ ): 9.31 (bs, 2H), 8.63 (m, 1H), 8.24 (s, 1H), 7.79 (d, 1H,> 7) 9 Hz), 7.63 (m, 2H), 7.47 (t, 1H, > 7.9 Hz), 7.21 (d, 1H, > 7.9 Hz), 7.00 (t, 1H,> 7.9 Hz), 5.21 (q, 1H,> 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, > 6.3 Hz).

(h) A solution containing 2- (2- {3-methyl-2- [4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ethyl] hydrobromide -3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (0.30 g, 0.46 mmol) in DMF (1.5 mL) was cooled to 0 ° C under a nitrogen atmosphere, ethyl acetimidate (0.12) was added g, 0.92 mmol) and N, N -diisopropylethylamine (0.25 mL, 1.4 mmol). The solution was cooled to 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, additional ethyl acetate imidate (0.06 g) and N-diisopropylethylamine (0.16 mL) were added, allowed to warm to 20 ° C and stirred for 2 hours. The mixture was cooled to 0 ° C, additional ethyl acetate imidate (0.03 g) was added, allowed to warm to 20 ° C and stirred for 2 hours. The mixture was then added dropwise to stirred diethyl ether. The resulting precipitate was isolated by decantation and dried on a vacuum line. The residue was precipitated from ethanol / ether and purified by preparative RP-HPLC: 2-50% MeCN / H ₂ O (20 mM HCl) for 50 minutes. Fractions were lyophilized. 2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl] was thus obtained. 3-Methyl-3H-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (0.145 g, 52%); 1 H NMR (300 MHz, DMSO-d ₆ ): 9.77 (s, 1H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s, 1H), 7, 89 (d, 1H, J = 8.6Hz), 7.71 (d, 1H, J = 8.6Hz), 7.60 (d, 1H, J = 7.7Hz), 7.49 ( t, 1H, J = 7.7 Hz), 7.21 (d, 1H, J = 7.7 Hz), 6.99 (t, 1H, J = 7.7 Hz), 5.37 (m, 1H), 4.71 (2s, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.82 (s, 1H), 3.66 (m, 2H), 2, 83 (m, 2H), 2.49 (s, 1H), 2.40 (d, 3H, J = 3.5Hz), 1.85 (d, 3H, J = 5.1Hz), MS ( ESI) for C 8 H ₃₁ N _{2 7} O4 calculated: 529.61; found (MH ⁺ ): 530.3.

Example 10 Ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H- benzoimidazole-5-carbonylamino} ethoxy} benzoate (Compound 75) (a) A solution containing 2,3,4,6-tetrafluomitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5 M, 7.5 mmol) was The mixture was diluted with an equal volume of water to dissolve the white precipitate to give yellow crystals, and the crystals were isolated and dried to give 2,3,5-trifluoro-6-nitroaniline (307). mg, 51%) as yellow needles: mp 66 ° C 1 H NMR (CDCl 3): 6.4 (1H, m), 6.0 (2H, s).

(b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% Pd / C in absolute ethanol was hydrogenated overnight at room pressure, filtered under a nitrogen atmosphere, and concentrated. There was thus obtained 1,2-diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as a violet crystalline solid; MS: M ⁺ 162.7, +41, +82 (+ ACN, + 2 ACN) (calcd for C ₆ H ₅ F ₃ N ₂ : 162.11).

(c) A mixture of 1,2-diamino-3,4,6-trifluorobenzene (1.92 g, 11.8 mmol), ethyl 2-ethoxycarbimidoyl propanoate (3.1 g, 14.7 mmol) and absolute ethanol (6). mL) was heated at reflux until completion of the reaction indicated by TLC, filtered from NH 4 Cl and concentrated. The residue was purified by silica gel chromatography (hexane / methylene chloride / ethyl acetate 5: 5: 1) to give ethyl 2- (4,6,7-trifluoro-1 H -benzoimidazol-2-yl) propanoate (1.37 g) , 42%) in the form of • ·

brownish crystalline solids; NMR (CDC1 _3): 10.35 (s, 2.1 H), 7.05 (s, 1.2 H), 6.7 (m, 1H), 4.25 (dd, 2H), 4, 15 (dd, 1 H), 1.73 (d, 3 H), 1.31 (t, 3 H); M ⁺ 272.9 (for C ₁₂ H ₁₈ F ₃ N ₂ O ₂ calculated 272.23).

(d) Ethyl 2- (4,6,7-trifluoro-1 H -benzoimidazol-2-yl) propanoate (988 mg, 3.63 mmol) and ethyl 2- [2- (4-amino-3)]. -methylaminobenzoylamino) ethoxy] benzoate (1.3 g, 3.63 mmol) was mixed and kept under vacuum for 4 hours. DMPU (4 mL) was then added and the mixture was stirred to dissolve and degassed by high vacuum evacuation overnight, heated to 195 ° C under a stream of nitrogen for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (stepwise gradient from 100% hexane to 100% ethyl acetate) followed by crystallization from MeOH / THF / water. There was thus obtained ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5- carbonylamino} ethoxy} benzoate (1.0 g, 49%) as a white crystalline solid; NMR (CDCl ₃ ): 6.84-8.07 (m, 8H), 4.93 (dd, 1H), 34 (dd, 2H), 4.27 (m, 2H), 3.95 (m, 2H), 3.9 (s, 3H), 1.93 (d, 3H), 1.78 (s, 2H) ), 1.38 (t, 3H); LCMS M ⁺ 566.2 ⁺ 565.7 Biolon M (for C ₂ 9H ₂ 6F NsO4 ₃ calculated: 565.55).

The following compounds of the invention were prepared as in Example 10: ethyl 2- (2- {2- [1- (5,6-difluoro-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3) / benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 76), MS (Biolon) for C, gH _{2 2 2} 7F N5O4 calculated: 547.56; found (MH ⁺ ): 548.1;

ethyl 2- (2- {2- [1- (4,6-difluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (compound 77), MS (LCMS): calcd for C ₂₇ F 9 N _{2 2} NsO4 calculated: 547.56; found (MH ⁺ ): 548.3;

ethyl 2- (2- {2- [1- (4,5,6-trifluoro-1H-benzimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate ( compound 78), MS (LCMS): calcd for C 9 H _{2 2 3} NsO4 6F calculated: 565.55; found (MH ⁺ ): 566.2; and ethyl 2- {2- [3-methyl-2- (4,6,7-trifluoro-1H-benzoimidazol-2-ylmethyl) -3H-benzoimidazol-5-ylcarbonylamino) ethoxy} benzoate (Compound 79), MS (Biolon) for C 8 H ₂₄ F ₂ N _{5 3} O4 calculated: 551.52; found: 551.2.

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9 ·· ·

Example 11

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

Mixture containing ethyl 2- (2- {2- [1- (4,6,7-trifluoro-1 H -benzoimidazol-2-yl) ethyl) -3-methyl-3 H -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 2 N hydrochloric acid (2.1 mL) and partitioned between ethyl acetate and saturated ammonium chloride solution. The aqueous layer was separated and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residual white solid was dissolved in hot ethanol (10 mL) and a 4M solution of hydrogen chloride in dioxane. This solution was diluted with diethyl ether and the resulting precipitate was collected and dried. 2- (2- {2- [1- (4,6,7-Trifluoro-1 H -benzoimidazol-2-yl) ethyl) -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino} was obtained. ethoxy) benzoic acid as a white solid; MS (LCMS): calcd. For C27H22F3N5O4: 537.50; found (MH ⁺ ): 538.4.

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

2- (2- {2- [1- (5,6-Difluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 81 MS (LCMS) calcd. For C27H23F2N5O4: 519.51; found (MH ⁺ ): 520.2;

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

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

Example 12

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

A mixture containing ethyl 2- (2- {2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl) -3-methyl-37 H -benzoimidazole-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 dilute with dichloromethane (50 mL) and filter through a pad of celite. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (5 mL). The solution was mixed with diisopropylethylamine (0.47 mL, 2.7 mmol) and methyl chloroformate (0.1 mL, 1.3 mmol) and the mixture was stirred for an hour. The solvents were removed in vacuo and the residue was purified by silica gel chromatography using ethanol and dichloromethane as eluent. Ethyl 2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5- was thus obtained. ylcarbonylamino} ethoxy) benzoate (0.20 g, 32% yield) as an amorphous colorless solid; MS (Biolone): calcd for C35H37N5O8: 655.72; found (MH ⁺ ): 656.1.

The following prodrug derivatives of the invention were prepared as in Example 12: methyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-177-benzoimidazol-2-yl} ethyl) -5- hydroxybenzoimidazole-1-carboxylate (Compound 85), MS (ESI): calcd for C31H31N5O7: 585.62; found (MH ⁺ ): 586.2;

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

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

ethyl 2- (2- {2- [1- (1-benzoyl-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 88), MS (ESI): calcd for C36H33N5O6: 631.69; found (MH ⁺ ): 632.3;

ethyl 2- (2- {2- [1- (1-dimethylcarbamoyl-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino) ethoxy} benzoate (Compound 89), MS (ESI): calcd for C32H34N6O6: 598.66; found (MH ⁺ ): 599.3;

ethyl 2- (2- {2- [1- (1-acetoxymethyl-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 90), MS (Biolone): calcd for C32H33N5O7: 599.65; found (MH ⁺ ): 600.7;

ethyl 2- [2- (2- {1- [1- (2,2-dimethylpropanoyloxymethyl) -5-hydroxy-1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazole -5-ylcarbonylamino) ethoxy] benzoate (Compound 91), MS (ESI): C 35 H 39 N 5 O 7 calculated: 641.74; found (MH ⁺ ): 642.3;

ethyl 1-2- (2- {2- [1- (1-isobutyryl-5-methoxycarbonyloxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 92), MS (Biolone): calcd for C 35 H 37 N 5 O 8 655.72; found (MH ⁺ ): 656.1;

• 9

9 «• 9 <

• · 9

9 9 9 · Ethyl-5-ethoxycarbonyloxy-2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl] -1-methyl-1H-benzoimidazol-2-yl} ethyl) benzoimidazole-1-carboxylate (Compound 93), MS (ESI): calcd for C 35 H 37 N 5 O 9 671.72; found (MH ⁺ ): 672.4;

Isopropyl 2- (1- {6- [2- (2-ethoxycarbonylphenoxy) ethylcarbamoyl) -1-methyl-1H-benzoimidazol-2-yl} ethyl) -5-isopropoxycarbonyloxybenzoimidazole-1-carboxylate (Compound 94), MS (ESI): calcd for C37H41N5O9: 699.79; found (MH ⁺ ): 700.4; and ethyl-2- (2- {2- [1- (1-acetyl-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 95), MS (ESI): calcd for C31H31N5O6: 569.62; found (MH ⁺ ): 570.1.

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

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

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

C- [2- (5-methyl-1 H -benzoimidazol-2-ylmethyl) -1 H -benzoimidazol-5-yl] methylamine (Compound 98), MS (Biolone): calcd for C 17 H 17 N 5: 291.4; found (MH ⁺ ): 292.3;

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

3- [2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -1H-benzoimidazol-5-ylcarbonylamino] propanoic acid (Compound 100), 1 H-NMR (300 MHz, CD ₃ OD): 1 92 (m, 2H, &gt; 7.2 Hz), 2.38 (t, 2H, > 7.2 Hz), 3.47 (t, 2H, > 7.2 Hz), 4.30 (s, 2H), 7.54 (d, 1H, > 10.0 Hz), 7.69 (d, 1H, > 8.6 Hz), 7.75 (d, 1H, > 10.0 Hz), 7, 81 (s, 1H), 7.87 (d, 1H, > 8.6 Hz), 8.12 (s, 1H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -N- (2-naphth-1-ylethyl) -1H-benzoimidazole-5-carboxamide (Compound 101), * HNMR (300 MHz, CD ₃ OD): 3.42 (t, 2H,> 7.5 Hz), 3.75 (t, 2H,> 7.5 Hz), 7.39-7.81 (m, 12H), 8, 08 (s, 1H), 8.27 (d, 1H, > 10.0 Hz);

2- (5-Aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 102), 1 H NMR (300 MHz, CD 3 OD): 3.41 (t, 2H,> 7.4 Hz), 3.72 (t, 2H,> 7.4 Hz), 3.96 (s, 3H), 4.27 ( s, 2H), 7.37-7.54 (m, 5H), 7.67 (d, 1H, > 8.7 Hz), 7.71-7.77 (m, 2H), 7.80- 7.85 (m, 2H), 8.70 (d, 1H, > 0.9 Hz), 8.24 (d, 1H, > 8.1 Hz);

• φ «·· ·· ······· ·· ··

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -377-benzoimidazole-4-carboxamide (Compound 103), * HNMR (300 MHz, CD ₃ OD): 3.45 (t, 2H,> 7.2 Hz), 3.74 (s, 3H), 3.83 (t, 2H,> 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,> 8.1 Hz);

(S) -2- [2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -1 H -benzoimidazol-5-ylcarbonylamino] -3-indol-3-ylpropanoic acid (Compound 104), 1 HNMR (300 MHz, CD ₃ OD): 3.36 (dd, 1H,> 14.6 and 8.1 Hz), 3.53 (dd, 1H,> 14.6 and 5.0 Hz), 3.92 (s, 3H), 4.27 (s, 2H), 6.97 (t, 1H, > 7.4 Hz), 7.07 (t, 1H, > 7.4 Hz), 7.16 (s (1H), 7.33 (d, 1H > 7.8 Hz), 7.51 (dd, 1H, > 8.4 and 1.5 Hz), 7.60-7.66 (m, 2H), 7.73-7.80 (m, 3H), 7.96 (d, 1H, > 0.9 Hz), 8.39 (d, > 7.5 Hz, partially replaced);

(R) -2- [2- (5-Aminomethyl-1 H -benzoimidazol-2-ylmethyl) -1 H -benzoimidazol-5-ylcarbonylamino-3-indol-3-ylpropanoic acid (Compound 105), 1 HNMR (300 MHz, CD ₃ OD): 3.35 (dd, 1H,> 14.5 and 8.1 Hz), 3.51 (dd, 1H,> 14.4 and 4.8 Hz), 3 90 (s, 3H), 4.23 (s, 2H), 6.96 (t, 1H, > 7.4 Hz), 7.06 (t, 1H, > 7.4 Hz), 7.14 (s, 1H), 7.31 (d, 1H, > 7.8 Hz), 7.44 (d, 1H, > 7.8 Hz), 7.58-7.74 (m, 5H), 7 94 (s, 1H); 8.33 (d,> 8.1 Hz, partially replaced);

2- (177-benzoimidazol-2-ylmethyl) - N - (2-naphth-1-ylethyl) -1 H -benzoimidazole-5-carboxamide (Compound 106), 1 H NMR (300 MHz, CI) ₃ OD): 3.42 (t, 2H,> 7.4 Hz), 3.76 (t, 2H,> 7.4 Hz), 3.97 (s, 3H), 7.38-7.60 (m, 5H) ), 7.65 (d, 1H, > 8.7 Hz), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, > 8.6 and 1.5 Hz), 8, 04 (d, 1H, > 1.2 Hz), 8.26 (d, 1H, > 8.4 Hz);

2- (5-aminomethyl-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (4-aminobutyl) -37 H -benzoimidazole-4-carboxamide (Compound 107), MS (Biolon): for C22H27N7O requires 405.4; found (MH ⁺ ): 406.5;

2- [1- (5-Aminomethyl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 108), MS (Biolone): calcd. For C ₃₁ H ₃₀ N ₆ O: 502.6; found (MH ⁺ ): 503.3;

2- (1H-imidazo [4,5-c] pyridin-3-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 109) MS (Biolone): calcd for C28H24N6O: 460.5; found (MH ⁺ ): 461.3;

2- (5-Aminomethyl-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N- (2-naphth-1-ylethyl) -377-benzoimidazole-5-carboxamide (Compound 110), MS (Biolon) : C for ₃ oH26Nó02 calculated: 502.6; found (MH ⁺ ): 503.6;

2- (5-carbamoyl-1 // - benzoimidazol-2-ylmethyl) ^-N - (2-naphth- 1-ylethyl) -1 // - benzoimidazole-5-carboxamide (Compound 111);

2- (5-Aminomethyl-4,5,6,7-tetrahydro-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -377-benzoimidazole-5 -carboxamide (Compound 112) 1 H NMR (300 MHz, CD ₃ OD): 1.67 (m, 1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd) (1H,> 15.3 and 9.3 Hz), 2.76 (m, 2H), 2.90 (dd, 1H,> 15.7 and 7.5 Hz), 3.05 (d, 2H, > 6.9 Hz), 3.41 (t, 2H,> 7.4 Hz), 3.75 (t, 2H,> 7.4 Hz), 3.90 (s, 3H), 7.35- 7.53 (m, 5H), 7.61 (d, 1H,> 8.4 Hz), 7.72-7.75 (m, 2H), 7.85 (dd, 1H,> 8.1 and 1.2 Hz), 7.99 (d, 1H, > 0.9 Hz), 8.26 (d, 1H, > 8.4 Hz);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (3-phenylpropyl) -377-benzoimidazole-5-carboxamide (Compound 113), 1 H NMR (300 MHz) CD3OD): 1.98 (m, 2H), 2.72 (t, 2H, &gt; 7.6 Hz), 3.46 (t, 2H, > 7.2 Hz), 4.01 (s, 3H) ), 4.29 (s, 2H), 7.12-7.17 (m, 1H), 7.217.28 (m, 4H), 7.56 (d, 1H,> 8.1 Hz), 7, 70 (d, 1H, > 8.7 Hz), 7.77 (d, 1H, > 8.4 Hz), 7.857.88 (m, 2H), 8.16 (s, 1H, >1H);

2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 114), * HNMR (300 MHz, CD ₃ OD): 3.80 (t, 2H,> 5.0 Hz), 3.99 (s, 3H), 4.17 (t, 2H,> 5.0 Hz), 4.27 (s, 2H), 6.88 (t, 1H, > 7.5 Hz), 6.92 (d, 2H, > 7.5 Hz), 7.22 (t, 2H, > 7.5 Hz), 7, 55 (d, 1H, > 8.7 Hz), 7.68 (d, 1H, > 6.6 Hz), 7.77 (d, 1H, > 8.4 Hz), 7.84 (s, 1H) 7.88 (d, 1H, > 8.7 Hz), 8.18 (s, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-N - (2-naphth- 1-ylethyl) - 37 H -benzoimidazole-5-carboxamide (Compound 115), 1 H NMR (300 MHz, CD 3 OD): 2.45 (2.43, s, 3H), 2.96 (m, 2H), 3, 42 (t, 2H, > 7.4 Hz), 3.75 (t, 2H, > 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, > 1.5 Hz), 8, 08 (s, 1H); 8.26 (d, 1H, > 8.0 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1-yl) -ylethyl) -3 H -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, > 7.4 Hz), 3.74 (t, 2H, > 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, > 7.8 Hz);

2- (5-Iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl) ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 117), 1 H NMR (300 MHz, CD 3 OD): 2.95 (m, 2H), 3.40 (t, 2H,> 7.4 Hz), 3.74 (t, 2H,> 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, > 8.4 Hz);

2- (5-aminomethyl-4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbonyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole- 5-carboxamide (Compound 118), * HNMR (300 MHz,

CD 3 OD): 1.69 (m, 1H), 2.15 (m, 1H), 2.20 (m, 1H), 2.55 (dd, 1H,> 15.0 and 11.4 Hz), 2 , 81 »· · · · · 4 4 4 • • • • 4 4 4 4

3.08 (m, 5H), 3.44 (t, 2H, J = 7.5Hz), 3.74 (m, 2H), 4.23 (s, 3H), 7.39-7.52 (m, 4H), 7.75 (dd, 1H, > 6.1 and 3.2 Hz), 7.83-7.88 (m, 2H), 7.97 (d, 1H, > 8.7 Hz), 8.10 (s, 1H, 8.27 (d, 1H,> 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) 13 -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, &gt; 5.6 Hz), 3.95 (s, 3H), 3.98 (m, 2H), 4.17 (t, 2H, > 5.6 Hz), 4.71 (4.81, s, 2H), 6.89 (t, 1H,> 7.3 Hz), 6.93 (d, 2H,> 8.6 Hz), 7.23 (dd, 2H,> 8) 7.6 and 7.3 Hz), 7.66 (d, 1H, > 7.8 Hz), 7.85 (d, 1H, > 7.8 Hz), 8.13 (s, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-benzo) [1,3] dioxol-4-ylethyl) -377-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,> 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,> 7.8 Hz), 7.76-7.79 (m, 1H), 8.06 (m, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (benzoimidazol-1-yl) Ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 121), 1 H NMR (300 MHz, CD 3 OD): 2.46 (2.44, s, 3H), 2.96 (m, 2H), 3, 92 (s, 3H), 3.95-4.01 (m, 4H), 4.73 (4.79, s, 2H), 4.80 (m, 2H), 7.54-7.64 ( m, 4H), 7.83 (dd, 1H, > 6.5 and 2.2 Hz), 7.93 (s, 1H), 7.98 (dd, > 6.5 and 2.1 Hz), 9.49 (s, 1H);

N- [2- (5-hydroxy-177-indol-2-yl) ethyl] -2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4, 5-c] pyridin-2-ylmethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 122) 1 H NMR (300 MHz, CD 3 OD): 2.42 (2.39, s, 3H) 2.90 (m, 2H), 2.99 (t, 2H, > 7.1 Hz), 3.67 (t, 2H, > 7.1 Hz), 3.75 (s, 3H), 3 93 (m, 2H), 4.66 (4.76, s, 2H), 6.61 (dd, 1H, > 8.5 and 2.3 Hz),

6.94 (d, IH, > 2.3 Hz), 7.06 (s, IH), 7.12 (d, IH, > 8.5 Hz), 7.59 (d, IH, > 8.4 Hz) 7.76 (dd, 1H, > 8.4 and 1.2 Hz), 7.87 (d, 1H, > 1.2 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-N - [2- ( 2-chlorophenoxy) ethyl] -377-benzoimidazole-5-carboxamide (Compound 123), MS (BioIon): calcd for C 26 H 28 ClN 7 O 2 506.0; found (MH ⁺ ): 506.3;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-N - [2- ( 3-chlorophenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 124), MS (BioIon): calcd for C 26 H 28 ClN 7 O 2 506.0; found (MH ⁺ ): 506.7;

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-naphthyl) 1-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 125), 1 HNMR (300 MHz, CD 3 OD): 2.48 (2.46, s, 3H), 3.00 (m, 2H) 3.60 (t, 2H,> 6.6 Hz), 3.90-4.05 (m, 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,> 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 - (2-hydroxy- 2-naphth-1-ylethyl) -377-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,> 13.6 and 8.3 Hz), 3,913.99 (m, 6H), 4.70 (4.80, s, 2H), 5.78 (dd, IH) > 8.3 and 3.6 Hz), 7.44-7.54 (m, 3H), 7.66 (d, 1H,> 8.4 Hz), 7.76-7.88 (m, 4H), 8.08 (m, 1H), 8.39 (d, 1H,> 8.4Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - [2- (2 -hydroxynaphth-1-yl) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 127), 1 H NMR (300 MHz, CD ₃ OD): 2.43 (2.41, s, 3H), 2, 92 (m, 2H), 3.41 (t, 2H, > 7.1 Hz), 3.69 (t, 2H, > 7.1 Hz), 3.85 (s, 3H), 3.93- 3.96 (m, 2H), 4.68 (4.78, s, 2H), 7.11 (d, 1H, > 8.7 Hz), 7.21 (t, 1H, > 7.5 Hz) 7.38 (dt, 1H,> 1.2 and 7.6 Hz), 7.50-7.61 (m, 2H), 7.69-7.75 (m, 2H), 7.93 (s, 1H), 8.07 (d, 1H,> 8.4 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4- hydroxynaphth-1-yl) ethyl) -3 H -benzoimidazole-5-carboxamide (Compound 128), 1 HNMR (300MHz, CD ₃ OD): 2.42 (2.40, s, 3H), 2.89 ( m, 2H), 3.27 (m, 2H), 3.69 (t, 2H, > 7.2 Hz), 3.82 (3.83, s, 3H), 3.93 (m, 2H) 4.64 (4.76, s, 2H), 6.72 (d, 1H, > 7.8 Hz), 7.17 (d, 1H, > 7.5 Hz), 7.37 (t, IH,> 7.5 Hz), 7.46 (dt, IH,> 0.9 and 6.9 Hz), 7.62 (d, IH,> 8.5 Hz), 7.77 (d, IH > 8.5 Hz), 7.95 (s, 1H), 8.12 (d, 1H,> 8.4 Hz), 8.17 (d, 1H,> 8.4 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl- _{N -} [2- ( 2-methoxyphenoxy) ethyl] -3 H -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,> 5.4 Hz), 4.71 (4, 81, s, 2H), 6.85-7.00 (m, 4H), 7.66 (d, 1H, > 8.7 Hz), 7.84 (m, 1H), 8.13 (s, IH);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N-naphth-2-ylmethyl -3 H -benzoimidazole-5-carboxamide (Compound 130), 1 H NMR (300MHz, CD 3 OD): 2.44 (2.42, s, 3H), 2.92 (m, 2H), 3.91 (s 3H), 3.95 (m, 2H), 4.68 (4.78, s, 2Η), 4.77 (s, 2H), 7.41-7.44 (m, 2H), 7, 50 (dd, 1H, > 8.6 and 1.1 Hz), 7.67 (d, 1H, > 8.4 Hz), 7.78-7.83 (m, 4H), 7.90 (m 1 H, 8.16 (m, 1H);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-a] pyridin-2-ylmethyl) -3-methyl-N- (3-pyridin-4) -ylpropyl) -377-benzoimidazole-5-carboxamide (Compound 131), 1 H NMR (300 MHz, CD 3 OD): 2.11 (m, 2H), 2.46 (2.43, s, 3H), 2, 96 (m, 2H), 3.06 (t, 2H, > 7.7 Hz),

fc 0

3.51 (t, 2H,> 6.8 Hz), 3.98 (m, 5H), 4.72 (4.82, s, 2H), 7.67 (d, 1H,> 8.5 Hz) ), 7.83 (dd, IH, > 8.5 and 1.3 Hz), 8.00 (d, 2H, > 6.6 Hz), 8.15 (d, IH, > 1.3 Hz) 8.70 (d, 2H,> 6.6 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ylethyl) -3Z-benzoimidazole-5-carboxamide (Compound 132), MS (Biolone): calcd for C32H32N8O3: 576.6; found (MH ⁺ ): 577.5; ^! 1 HNMR (300 MHz, CD 3 OD): 3.41 (t, 2H,> 7.5 Hz), 3.58-3.76 (m, 4H), 4.05 (m, 1H), 4.45 (dd) (IH, > 14.9 &amp; 8.5 Hz), 4.61 (dd, IH, > 14.9 &amp; 3.2 Hz), 7.36-7.52 (m, 4H), 7.66- 7.85 (m, 4H), 8.14 (s, 1H), 8.25 (d, 1H, &gt; 7.8 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-N- [2- ( 4-methoxyphenoxy) ethyl] - 37 H -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,> 5.6 Hz),

3.95 (s, 3H), 3.98 (m, 2H), 4.12 (t, 2H,> 5.6 Hz), 4.71 (4.81, s, 2H), 6.78- 6.89 (m, 4H), 7.66 (d, 1H, > 8.4 Hz), 7.84 (m, 1H), 8.13 (d, 1H, > 1.2 Hz);

2- (5-guanidino-17 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 134), MS (Biolone): calcd for C 32 H 30 N 7 O 4 590.6; found (MH ⁺ ): 590.7; ¹ H-NMR (300 MHz, CD 3 OD): 3.42 (t, 2H,> 7.4 Hz), 3.74 (t, 2H,> 7.4 Hz), 4.00 (d, 2H,> 4.2 Hz), 4.38 (t, 1H,> 11.7 Hz), 4.56 (dd, 1H,> 12.5 and 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,> 1.2 Hz), 8.25 (d, 1H,> 8.1 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl] -3-methyl-[- [2- ( 1,2,3,4-tetrahydronaphth-1-yl) ethyl] -377-benzoimidazole-5-carboxamide (Compound 135), 1 HNMR (300 MHz, CD 3 OD): 1.69-2.11 (m, 6H) 2.45 (2.43, s, 3H), 2.73 (m, 2H), 2.88 (m, 1H), 2.95 (m 2H), 3.52 (t, 2H,> 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, > 8.7 Hz), 7.82-7.86 (m, 1H), 8.14 (d, 1H, > 0.9 Hz);

2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-a] pyridin-2-ylmethyl] -3-methyl-N '- [2- (3-methoxyphenoxy) ethyl] -3 H -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,> 5.6 Hz), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 (t (2H, > 5.6 Hz), 4.71 (4.80, s, 2H), 6.46-6.54 (m, 3H), 7.12 (t, 1H, > 8.0 Hz) 7.66 (d, 1H, > 8.4 Hz), 7.83 (m, 1H), 8.12 (m, 1H, > 1.2 Hz);

2- (5-guanidino-177-benzoimidazol-2-ylmethyl) -N- (3-phenylpropyl) -1H-benzoimidazole-5-carboxamide (Compound 137);

2- (5-guamidino-1 H -benzoimidazol-2-ylmethyl) -3- (3-hydroxy) propyl-N- (2-naphth-1-ylethyl) -37 H -benzoimidazole-5-carboxamide (Compound 138 1 HNMR (300 MHz, CD ₃ OD): 2.09 (m, 2Η), 3.44 (t, 2H,> 7.4 Hz), 3.58 (t, 2Η,> 5.6 Hz) ), 3.77 (t, 2Η,> 7.4 Hz), 4.55 (t, 2Η,> 7.1) · ¢ · ¢ 3 ··· ·· ··· · · ·· · · ··

Hz), 7.32 (dd, 1H, > 8.6 and 1.9 Hz), 7.37-7.55 (m, 4H), 7.61 (d, 1H, > 1.9 Hz), 7.69 (d, 1H, > 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 H -benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3 H -benzoimidazole-5- carboxamide (Compound 139), MS (Biolone): calcd for C29H32N8O5: 572.62; found (MH ⁺ ): 573.3; 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,> 15.0 and 8.4 Hz), 4.64 dd, 1H,> 15.0 and 3.0 Hz), 6.66-7.00 (m (4H), 7.38 (dd, 1H, > 8.6 and 1.7 Hz), 7.66 (d, 1H, > 1.7 Hz), 7.70 (d, 1H, > 8.6 Hz), 7.78 (d, 1H, > 8.6 Hz), 7.87 (dd, 1H, > 8.6 and 1.5 Hz), 8.24 (d, 1H, > 1.5 Hz) );

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5 -carboxamide (Compound 140), MS (Biolone): calcd for C 33 H 34 N 8 O 3 590.7; found (MH ⁺ ): 591.3;

2- (5-guanidino-17 H -benzoimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) - N - [2- (2-methoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide ( Compound 141), MS (Biolone): calcd for C29H30N8O6: 586.6; found (MH ⁺ ): 587.5; 1 H-NMR (300 MHz, CD ₃ OD): 3.33 (m, 1H), 3.81 (m, 5H), 3.98 (d, 2H,> 4.5 Hz), 4.18 ( t, 2H,> 5.4 Hz), 4.38 (t, 1H,> 12.0 Hz), 4.57 (dd, 1H,> 12.0 and 3.5 Hz), 6.85-7 .00 (m, 4H), 7.30 (dd, 1H, > 8.7 and 2.2 Hz), 7.60 (d, 1H, > 2.2 Hz), 7.64 (d, 1H, > 8.4 Hz), 7.74 (d, 1H,> 8.7 Hz), 7.80 (dd, 1H,> 8.4 and 1.5 Hz), 8.14 (d, 1H,> 1.5 Hz);

2- [5- (1-Iminoethyl) aminomethyl-1H-benzoimidazol-2-ylmethyl] -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3H-benzimidazole- 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,> 5.4 Hz), 4.46 (dd, 1H,> 15.0 and 8.7 Hz) ), 4.62-4.66 (m 3H), 6.86-7.00 (m, 4H), 7.53 (dd, 1H,> 8.7 and 1.2 Hz), 7.68 ( d, 1H, > 8.4 Hz), 7.77-7.80 (m, 2H), 7.84 (dd, 1H, > 8.4 and 1.4 Hz), 8.21 (d, 1H > 1.4 Hz);

methyl 2- {2- [2- (5-guanidino-1 H -benzoimidazol-2-ylmethyl) -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (Compound 143), MS ( Biolone): calcd. For C28H28N8O4: 540.56; found (MH ⁺ ): 541.4;

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

methyl 3- {2- [2- (5-guanidino-1 H -benzoimidazol-5-ylmethyl) -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (Compound 145), MS (Biolon) ): calcd. for C28H28N8O4: 540.5; found (MH ⁺ ): 541.4;

• * • Ht

2- (5-guanidino-lH-benzoimidazol-2-ylmethyl) -3-methyl-7V- [2- (2,6-dimethoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide (Compound 146) ^l H- NMR (300 MHz, CD ₃ OD): 3.71 (t, 2H,> 5.3 Hz), 3.73 (s, 6H), 4.01 (s, 3H), 4.13 (t, 2H) > 5.3 Hz), 6.63 (d, 2H,> 8.4 Hz), 6.99 (t, 1H,> 8.4 Hz), 7.33 (dd, IH,> 8.6) and 1.9 Hz), 7.63 (d, IH, > 1.9 Hz), 7.74 (d, IH, > 8.7 Hz), 7.75 (d, IH, > 8.6 Hz) 7.90 (dd, 1H, > 8.7 and 1.5 Hz), 8.21 (d, 1H, > 1.5 Hz);

2- (5-guanidinomethyl-1H-benzimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxyphenoxy) ethyl] -377-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, > 5.4 Hz),

4.45 (dd, 1H,> 15.0 and 8.7 Hz), 4.58-4.65 (m, 3H), 6.85-7.00 (m, 4H), 7.50 (dd, IH) > 8.7 and 1.5 Hz), 7.67 (d, IH,> 8.5 Hz), 7.72 (d, IH,> 1.5 Hz), 7.76 (d, IH, &Gt; 8.7 Hz), 7.82 (dd, 1H, > 8.5 and 1.4 Hz), 8.19 (d, 1H, > 1.4 Hz);

2- (5-Iminomethylaminomethyl-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- [2- (2-methoxy) phenoxyethyl] -3H-benzoimidazole-5-carboxamide ( Compound 148) ¹ H-NMR (300 MHz, CD 3 OD): 3.58-3.70 (m, 2H), 3.81 (m, 5H), 4.06 (m, 1H), 4.19 ( t, 2H,> 5.4 Hz),

4.46 (dd, 1H, > 15.0 and 8.7 Hz), 4.64 (dd, 1H, > 15.0 and 3.0 Hz), 4.69 (4.73, s, 2H), 6 , 86-7.01 (m, 4H), 7.51 (dd, 1H, > 8.1 and 1.5 Hz), 7.69 (d, 1H, > 8.6 Hz), 7.76- 7.79 (m, 2H), 7.84 (dd, 1H, > 8.6 and 1.3 Hz), 7.96 (8.12, s, 1H), 8.21 (d, 1H, > 1.3 Hz);

2- (5-guanidino-1H-benzimidazol-2-ylmethyl) -3-methyl-N- (2-hydroxy-2-quinol-4-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 149); 1 H-NMR (300 MHz, CD ₃ OD): 3.60 (dd, 1H,> 13.8 and 7.5 Hz), 3.97-4.06 (m, 4H), 5.99 (dd, IH,> 7.5 and 3.6 Hz), 7.35 (dd, IH,> 8.7 and 2.0 Hz), 7.65 (d, IH,> 2.0 Hz), 7.69 (d, IH, > 8.7 Hz), 7.77 (d, IH, > 8.7 Hz), 7.84 (dd, IH, > 8.7 and 1.5 Hz), 7.99 ( m, 1H), 8.11-8.18 (m, 2H), 8.26 (d, 1H, > 8.4 Hz), 8.33 (d, 1H, > 5.7 Hz), 8, 88 (d, 1H, > 8.7 Hz), 8.15 (d, 1H, > 5.7 Hz);

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3-methyl-N- [2- (3-methyl-2,4-dioxoquinazolin-1-yl) ethyl] -3H-benzoimidazol-5- carboxamide (Compound 150), MS (Biolone): calcd for C29H28N10O3: 564.6; found (MH ⁺ ): 565.5;

methyl 2- {2- [2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino] ethoxy} benzoate (Compound 151), MS ( Biolone): calcd for C28H26N8O5: 554.5; found (MH ⁺ ): 554.8;

2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxy) ethyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 152), ¹ H-NMR (300 MHz, CD 3 OD): 3.44 (t, 2H,> 7.4 Hz), 3.77 (t, 2H,> 7.4 Hz), 3.95 (t, 2H,> 4.9 Hz), 4.56 (t, 2H,> 4.9 Hz), 7.32 (dd, IH,> 8.7 and 1.5 Hz), 7.40-7.54 (m, 4H), 7.61 (d, 1H, > 1.8 Hz), 7.67-7.89 (m, 5H), 8.09 (d, 1H, > 1.2 Hz), 8 28 (d, 1H,> 8.1 Hz);

Fe fe fe fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe

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

2- (5-guanidino-1 H -benzoimidazol-2-ylcarbonyl) -3- (2-hydroxyethyl) - N - (2-naphth-2-ylethyl) - 37 H -benzoimidazole-5-carboxamide (Compound 154) 1 H-NMR (300 MHz, CD ₃ OD): 3.42 (t, 2H, J = 7.3 Hz), 3.75 (t, 2H, J = 7.3 Hz), 4.48- 4.51 (m, 2H), 7.29 (dd, 1H, J = 8.6 and 1.9 Hz), 7.38-7.52 (m, 4H), 7.58 (d, 1H, J = 1.9 Hz), 7.62 (d, 1H, J = 8.7 Hz), 7.71-7.76 (m, 3H), 7.86 (d, 1H, J = 8.6) Hz), 8.06 (s, 1H), 8.26 (d, 1H, J = 8.1 Hz);

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

2- (5-guanidino-177-benzoimidazol-2-ylcarbonyl) -3- (3-hydroxypropyl) -N- (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 156);

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

2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 158 MS (Biolone) calcd. For C ₃₁ H ₃₀ N ₅ O: 530.6; found (MH ⁺ ): 531.1;

2- [1- (5-imidazol-1-yl-1H-benzimidazol-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5- carboxamide (compound 159), MS (Biolon) for C ₃₃ H 9 N ₂ O ₇ calculated: 539.6; found (MH ⁺ ): 540.1;

2- {1- [5- (2-Aminoimidazol-1-yl) -1H-benzoimidazol-2-yl] ethyl} -3-methyl-N- (2-naphth-1-ylethyl) -3ZH- benzoimidazole-5-carboxamide (compound 160), MS (Biolon) for C ₃₃ H ₃ oN 0 ₈ calculated: 554.7; found (MH ⁺ ): 555.2;

- (5-guanidino-1H-benzoimidazol-2-yl) -3-hydroxy-1-methyl- N - (2-naphth-1-ylethyl) -3,4-dihydro-177-2-oxa-4a 9-diazafluorene-6-carboxamide (Compound 161);

2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3- (4-hydroxybutyl) - N - (2-naphth-1-ylethyl) -3 H -benzoimidazole-5- carboxamide (compound 162), MS (Biolon) for C 4 H _{3 2 36} N8O calculated: 588.7; found (MH ⁺ ): 589.3;

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

3- {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 (Biolon): for

C 5 H ₃₃ N ₃ O4S _7: calculated: 647.8; found (MH ⁺ ): 648.2;

fc • fc fcfc fc

Fc fc fc fc fc fcfc fcfc fcfc fcfcfc fcfc fcfcfc fcfc fcfc fcfc fcfc

2- [1- (5-guanidino-177-benzoimidazol-2-yl) -2-methylpropyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide (Compound 165), MS (Biolone): calcd for C33H34N8O: 558.7; found (MH ⁺ ): 559.6;

2- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole- 5-carboxamide (Compound 166), MS (Biolone): calcd for C 29 H ₂₆ N ₆ O: 474.6; found (MH ⁺ ): 475.2;

2- {5- [1- (N-methylimino) ethyl] -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl} -3-methyl- N - (2-naphth-1-yl-ethyl) -3 H -benzoimidazole-5-carboxamide (Compound 167), MS (Biolone): calcd for C 31 H 33 N 7 O: 519.71; found (MH ^4): 520.9;

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

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-1H - (2-naphth-1-ylethyl) -3,7-benzoimidazole-5-carboxamide (Compound 169), MS (Bioion): calcd for C31H33N7O: 519.6; found (MH ^4): 520.3;

2- {1- [5- (N-methylamidino) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-N - ( 2-naphth-1-ylethyl) -3 H -benzoimidazole-5-carboxamide (Compound 170), MS (Bioion): calcd for C 31 H 34 N 8 O: 534.7; found (MH ⁺ ): 535.1;

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) -5-methoxybenzoic acid (Compound 171), MS (Biolone): calcd for C29H30N8O5 570.6; found (MH ⁺ ): 571.2;

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 172), MS (Biolone) calcd for C 29 H 30 N 8 O 5 570.6; found (MH ⁺ ): 571.3;

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) -1-hydroxyethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) -6 -methoxybenzoic acid (Compound 173), MS (Biolone): calcd for C 29 H 30 N 8 O 6 586.6; found (MH ⁺ ): 587.2;

ethyl 2- [2- (2- {1- [5- (N-acetylguanidino) -1 H -benzoimidazol-2-yl) ethyl} -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino) ethoxy ] benzoate (Compound 174), MS (Biolone): calcd for C31H32N8O5: 596.6; found (MH ⁺ ): 597.2;

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

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

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

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

2- [2- (2- {1- [5- (1-Aminocyclopropyl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 179), MS (Biolone): calcd for C30H30N6O4: 538.6; found (MH ⁺ ): 539.3;

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

2- (1H-benzoimidazol-2-ylethyl) -3-methyl-N- (2-phenoxyethyl) -3H-benzoimidazole-5-carboxamide (Compound 181), MS (Biolon): calcd for C26H25N5O2: 439 , 5; found (MH ⁺ ): 440.2;

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

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

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

N-ethyl-2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl) -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 185), MS (Biolone): calcd for C23H23N7O: 413.5; found (MH ⁺ ): 414.1;

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

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

• • • • • •

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

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

189);

2- {l- [5- _(7V>? V-dimethylamidino) -4,5,6,7-tetrahydro-l / 7-imidazo [4,5-c] pyridin-2-yl] -ethyl} -3- methyl-317-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound

190), MS (Biolon) C39H34N for ₈ O4 Calculated: 558.6; found (MH ⁺ ): 559.3;

2- [2- (2- {1- [5- (2-Carboxy-1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-377-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 191), MS (Biolon): calcd for C29H31N7O6: 573.6; found (MH ⁺ ): 530.3 - loss of CO ₂ ;

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3H-benzoimidazol-5-ylcarbonylamino ethoxy) benzoic acid (Compound 192), MS (Bioion): calcd for C32H31N7O5: 593.6; found (MH ⁺ ): 594.2;

2- [1- (5-imidazol-1-yl-1H-benzimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -N- (2-methoxyethyl) -37H-benzoimidazole-5-carboxamide ( Compound 193), MS (Biolone): calcd for C 26 H 29 N 7 O 3 487.6; found (MH ⁺ ): 488.2;

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3- (2-methoxyethyl) -377-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 194);

3- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 195), MS (Biolone): calcd. For C28H28N8O4: 540.6; found (MH ⁺ ): 541.3;

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3- (2-methoxyethyl) -3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid ( Compound 196), MS (Biolone): calcd for C 30 H 32 N 8 O 5 584.6; found (MH ⁺ ): 585.3;

2- (2- {2- [1- (5-guanidino-17 H -benzoimidazol-2-yl) ethyl] -3- (3-sulfopropyl) -3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 197), MS (Biolone): calcd for C30H32N8O7S: 648.7; found (MH ⁺ ): 649.6;

• ·

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

2- (2- {2- [1- (5-imidazol-1-yl-3-methyl-3 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5- ylcarbonylamino} ethoxy) benzoic acid (Compound 199), MS (Biolone): calcd for C31H29N7O4: 563.6; found (MH ⁺ ): 564.2;

2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3- (2-hydroxypropyl) -3H-benzoimidazol-5-ylcarbonylamino ethoxy) benzoic acid (Compound 200), MS (Bioion): calcd for C32H31N7O5: 593.6; found (MH ⁺ ): 594.3;

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

ethyl 2- {2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonyfamino} ethoxy) benzoate (Compound 202), MS (Biolone): calcd for C30H32N8O4: 568.6; found (MH ⁺ ): 569.5;

ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -1,6,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 203), MS (Biolone): calcd for C28H36N8O4 549.0; found (MH ⁺ ): 548.2;

ethyl 1-4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} butanoate (Compound 204), MS (Biolone): calcd for C25H30N8O3: 490.57; found (MH ⁺ ): 491.3;

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-tetrazol-1-ylphenoxy) ethyl] -3H-benzoimidazole- 5-carboxamide (Compound 205), MS (Biolone): calcd for C28H28N12O2: 564.56; found (MH ⁺ ): 565.3;

2- [2- (2- {1- [5- (1-Iminoethylamino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid acid (Compound 206), MS (Biolone) calcd for C 31 H 33 N 7 O 4 567.6; found (MH ⁺ ): 568.4;

ethyl 4- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 207), MS (Biolone): calcd for C30H32N8O4: 568.6; found (MH ⁺ ): 569.4;

5- (2- {2- [1- (5-Guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 208 ), MS (Biolone): for

C29H28N8O6 calculated: 584.6; found (MH ⁺ ): 585.3;

• · · * · * ♦ ·

4- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl) -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 209 MS (Biolone) calcd. For C28H28N8O4: 540.6; found (MH ⁺ ): 541.2;

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

2- [1- (5-imidazol-1-yl-177-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3H-benzoimidazole-5- carboxamide (Compound 211), MS (Biolone): calcd for C30H29N7O2: 535.6; found (MH ⁺ ): 536.3;

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

2- [1- (5-imidazol-1-yl-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-phenoxyethyl) -3 H -benzoimidazole-5 -carboxamide (Compound 213), MS (Biolone): calcd for C29H27N7O2: 505.6; found (MH ^4): 506.2;

2- (2- {2- [1- (5-Imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 214 MS (Biolone): calcd. For C29H25N7O4: 535.6; found (MH ⁺ ): 536.4;

ethyl 2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) -4- methyl benzoate (Compound 215), MS (Biolone): calcd for C31H34N8O4: 582.7; found (MH ^4): 583.5;

2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methylbenzoimidazol-5-ylcarbonylamino} ethoxy) -4-methylbenzoic acid (Compound 216), MS (Biolone): calcd for C29H30N8O4: 554.6; found (MH ^4), 555.5;

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino) ethoxy] benzoate (Compound 217), MS (ESI): calcd for C26H32N8O4: 520.58; found (MH ^4): 521.3;

ethyl 2- (2- {2- [5- (N-methylamidino) -1 H -benzoimidazol-2-ylmethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 218 MS (Biolone): calcd. For C30H31N7O4: 553.6; found (MH ^4): 554.3;

2- [2- (2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3- (3-sulfopropyl) -3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid (Compound 219), MS (Biolon): calcd for C 30 H 35 N 7 O 7 637.7; found (MH ^4): 638.3;

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

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

2- [l- (177-benzoimidazol-2-yl) ethyl] -3-methyl- _J N- [2- (2-methoxyphenoxy) ethyl] -3 / 7-benzimidazole-5-carboxamide (Compound 222); MS (Biolone): calcd for C27H27N5O3: 469.5; found (MH ⁺ ): 469.5;

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

4- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} butanoic acid (Compound 224), MS (Biolon): for C23H26N8O3: 462.52; found (MH ⁺ ): 462.8;

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl- N - [2- (2-Tetrazolylphenoxy) ethyl] -377-benzoimidazole-5-carboxamide (Compound 225), MS (ESI): calcd for C28H31N11O2: 553.6; found (MH ⁺ ): 553.5;

Isopropyl 2- (2- {2- [1- (5-imidazol-1-yl-177-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 226), MS (Biolone): calcd. For C33H33N7O4: 591.3; found (MH ⁺ ): 591.4;

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-N - [ 2- (3-tetrazolylphenoxy) ethyl] -377-benzoimidazole-5-carboxamide (Compound 227), MS (Biolone): calcd for C28H31N11O2: 553.59; found (MH ⁺ ): 553.5;

2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-1H [2- (4-Tetrazolylphenoxy) ethyl] -377-benzoimidazole-5-carboxamide (Compound 228), MS (ESI): calcd for C28H31N11O2: 553.59; found (MH ⁺ ): 553.5;

Cyclohexyl 2- (2- {2- [1- (5-imidazol-1-yl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-377-benzoimidazol-5-ylcarbonylamino) ethoxybenzoate (Compound 229 MS (ESI): calcd. For C36H37N7O4: 631.3; found (MH ⁺ ): 631.5;

2- [2- (2- {1- [5- (N-methylamidino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid acid (Compound 230), MS (Biolone): for

C28H27N7O4 requires 525.6; found (MH ⁺ ): 525.5;

• ·

2- [2- (2- {1- [5- (1-Iminoethylamino) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid acid (Compound 231), MS (Biolone): calcd for C29H29N7O4: 539.6; found (MH ⁺ ): 539.8;

2- (3- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonyl } propoxy) benzoic acid (Compound 232), MS (Biolone): calcd for C27H30N8O4: 530.60; found (MH ⁺ ): 531.7;

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

2-methoxyethyl-2- (2- {2- [1- (5-imidazol-1-yl-1H-benzimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 234), MS (Biolone): calcd for C33H33N7O5: 607.3; found (MH ⁺ ): 607.4;

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

2- (2-methoxyethoxy) ethyl-2- (2- {2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazole-5 -ylcarbonylamino} ethoxy) benzoate (Compound 236), MS (Bioion): calcd for C35H37N7O6: 651.3; found (MH ⁺ ) · 651.3;

butyl 2- (2- {2- [1- (5-imidazol-1-yl-177-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 237), MS (Biolone): calcd. For C34H35N7O4: 605.3; found (MH ⁺ ): 605.4;

2- [1- (1H-benzimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-oxo-2,3-dihydrobenzo [1,4] oxazin-4-yl) ethyl] -3,7-benzoimidazole-5-carboxamide (Compound 238), MS (Biolone): calcd for C28H26N6O3 494.2; found (MH ⁺ ): 494.5;

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

2- [1- (177-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (3-fluorophenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 240);

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-isopropoxyphenoxy) ethyl] -3H-benzoimidazole-5-carboxamide (Compound 241), MS ( Biolone): calcd for C29H31N5O3: 497.2; found (MH ⁺ ): 497.6;

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methylphenoxy) ethyl] -3H-isoisoimidazole-5-carboxamide (Compound 242), MS (Biolone): calcd for C27H27N5O2: 453.2; found (MH ⁺ ): 453.5;

2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl- N - [2- (2-ethoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 243), MS (Biolone): calcd. For C28H29N5O3: 483.2; found (MH ⁺ ): 483.5;

2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-N- [2- (2-methoxyphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide (Compound 244), MS (Biolone): calcd for C28H30N8O3: 526.6; found (MH ⁺ ): 526.8;

ethyl 2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5- b] pyridine- 5-ylcarbonylamino} ethoxy) benzoate (Compound 245), MS (Biolone): calcd for C28H33N9O4: 559.6; found (MH ⁺ ): 559.6;

2-methoxyethyl-2- (2- {2- [1- (1H-benzimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 246), MS (Biolone): calcd for C30H31N5O4: 541.6; found (MH +): 541.5;

ethyl 2- {2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 247 MS (Biolone): calcd. For C29H30N8O4: 554.6; found (MH ⁺ ): 555.4;

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3ZZ-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid (Compound 248), MS (Biolone): calcd. For C28H28N8O4: 540.6; found (MH ⁺ ): 541.3;

2- [1- (5-guanidino-17 H -benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -3-methyl-37 H -benzoimidazole-5-carboxamide (Compound 249), MS (Biolone): calcd for C28H29N9O3: 539.6; found (MH ⁺ ): 540.5;

2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] - N - [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5- carboxamide (Compound 250), MS (Biolone): calcd for C28H28ClN9O3: 574.0; found (MH ⁺ ): 574.2;

4-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid ( Compound 251), MS (Biolone): calcd. For C28H27ClN8O4: 575.0; found (MH ⁺ ): 575.2;

5-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid acid (Compound 252), MS (Biolone): calcd for C28H27ClN8O4: 575.0; found (MH ⁺ ): 575.2;

• ·

6-chloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid acid (Compound 253), MS (Biolone): calcd for C28H27ClN8O4: 575.0; found (MH ⁺ ): 575.2;

4,6-dichloro-2- (2- {2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy ) benzoic acid (Compound 254), MS (Biolone): calcd for C28H26Cl2N8O4: 609.5; found (MH ⁺ ): 609.1;

ethyl 2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazole-5-carbonylamino} ethoxy) benzoate (Compound 255), MS (Biolon) for C29H29N5O4: 511.6; found (MH ⁺ ): 512.2;

2- [1- (5-guanidino-177-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2,4-dioxo-3- (2-trimethylsilanylethyl) -3,4-dihydro -277-quinazolin-1-yl] ethyl} -3,7-benzoimidazole-5-carboxamide (Compound 256), MS (Biolone): calcd for C 34 H 40 N 10 O 3 Si: 664.8; found (MH ⁺ ): 665.4;

2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- {2- [2,4-dioxo-3,4-dihydro-2H-quinazoline 1-yl] ethyl} -3H-benzoimidazole-5-carboxamide (Compound 257), MS (Biolone): calcd for C29H28N10O3: 564.6; found (MH ⁺ ): 565.2;

2- [1- (1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-cyanophenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 258) MS (Biolone): calcd. For C27H24N6O2: 454.5; found (MH ⁺ ): 465.1;

5- (2- {2- [1- (177-Benzoimidazol-2-yl) ethyl] -3-methyl-37 H -benzoimidazol-5-ylcarbonylamino} ethoxy) isophthalic acid (Compound 259), MS (Biolon): Calcd for C28H25N5O6 527.5; found (MH ⁺ ): 528.4;

2- (2-methoxy ethoxy) ethyl 1-2- (2- {2- [1- (1H-benzoimidazol-2-yl) ethyl) -3-methyl-377-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 260), MS (Biolone): calcd for C32H35N5O6: 585.7; found (MH ⁺ ): 585.4;

2- (2- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino ethoxy) benzoic acid (Compound 261), MS (Biolone): calcd for C29H29N9O4: 531.6; found (MH ⁺ ): 531.5;

2- [1- (1H-imidazo [4,5-c] pyridin-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole -5-carboxamide (Compound 262), MS (Biolone): calcd for C26H26N6O3: 470.54; found (MH ⁺ ): 471.4;

2- [1- (5-Fluoro-17 H -benzoimidazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-377-benzoimidazole-5-carboxamide (Compound 263 ), MS (Biolone): calcd for C27H26FN5O3:

487.54; found (MH ⁺ ): 488.1;

• Φ φ φ

2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -3-methyl-N- (2-tetrazol-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide (Compound 264), MS (ESI): calcd. For C24H23N11O: 481.47; found (MH ⁺ ): 482.6;

2- [1- (4-hydroxy-1 H -benzoimidazol-2-yl) ethyl] - N - [2- (2-methoxyphenoxy) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 265 MS (Biolone) calcd. For C27H27N5O4: 485.59; found (MH ⁺ ): 486.3;

2- [1- (4-aminobenzoxazol-2-yl) ethyl] -N- [2- (2-methoxyphenoxy) ethyl] -3-methyl-377-benzoimidazole-5-carboxamide (Compound 266), MS (Biolon) for C27H27N5O4: 485.59; found (MH ⁺ ): 486.1;

- {2- [1- (1H-benzimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid (Compound 267 MS (Biolone): calcd. For C29H31N5O6S: 577.66; found (MH ⁺ ): 577.4;

- {2- [1- (5-Imidazol-1-yl-177-benzoimidazol-2-yl) ethyl] -6- [2- (2-methoxyphenoxy) ethylcarbamoyl] benzoimidazol-1-yl} propane-1-sulfonic acid acid (Compound 268), MS (Biolone) calcd for C 32 H 33 N 7 O 6 S 643.72; found (MH ⁺ ): 644.6;

ethyl 2- [2- (2- {1- [1- (2-methoxyethyl) -1 H -benzoimidazol-2-yl] ethyl} -3-methyl-377-benzoimidazole-5-carbonylamino) ethoxy] benzoate ( Compound 269), MS (Biolone): calcd for C 32 H 35 N 5 O 5 569.66; found (MH ⁺ ): 570.5;

benzyl-2- [1- (5-imidazol-1-yl-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridine-5-carboxylate (Compound 270), MS (Biolone): calcd for C29H30N8O6: 586.6; found (MH ⁺ ): 587.2;

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

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

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

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

N - [3- (2-butoxyphenyl) propyl] -2- [1- (5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazole-5-carboxamide ( Compound 275), MS (Biolone): calcd for C 31 H 35 N 5 O 3 525.65; found: 526.3;

• · · · ·

I · · ·

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

2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -N- {2- [2- (3-methyl- [1,2,4] oxadiazol-5-yl) phenoxy] ethyl} -3-methyl-3 H -benzoimidazole-5-carboxamide (Compound 277), MS (Biolone): calcd for C 29 H 27 N 7 O 4 538.1; found: 537.58;

ethyl 2- (2- {2- [1- (4-fluoro-5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-3H-benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 278), MS (ESI): for _C2 9H2 ₈ FN ₅ O5 calculated: 545.57; found: 545.6;

2- (2- {2- [1- (4-fluoro-5-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H- benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid acid (Compound 279), MS (Biolone) calcd for C27H24FN5O5: 517.52; found: 517.4;

ethyl 2- (2- {2- [1- (6-fluoro-4-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-37 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate (Compound 280), MS (Biolone): calcd for C29H28FN5O5: 545.57; found: 545.9;

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

ethyl 2- (2- {2- [1- (4,5-difluoro-7-hydroxy-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino ethoxy) benzoate (Compound 282), MS (Biolone): calcd for C29H27F2N5O5: 563.56; found: 563.9; and

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

Example 13

Determination of tryptase inhibition in vitro

Tryptase solution (60 g / ml) was prepared by dissolving tryptase purified from human lung or skin tissue preparations or human living cell culture (HMC-1) or obtained from commercial sources, e.g., ICN Biomeidals, Irvine, Califomia, Athens Research & Technology , Athens, Georgia, etc., in a mixed solvent comprising: 10 mM 2-N-morpholinethanesulfonic acid, 2 mM CaCl ₂ , 20% glycerol and 50 g / ml heparin. A substrate solution containing 2 mM synthetic tripeptide (tosyl-Gly-Pro-Lys-p-nitroanilide) was obtained from Sigma. Test compound solutions were prepared by a 10-fold dilution.

stock solution (1 mg test compound in 200 µL dimethylsulfoxide (DMSO)) in buffer (containing: Tris-HCl (pH 8.2), 50 mM; NaCl, 100 mM; 0.05% polyoxyethylene sorbitan monolaurate (Tween-20®) and zinc chloride, 150 μΜ) and then seven consecutive triple dilutions in 10% DMSO in the above buffer.

Aliquots (60 µL) from each of the eight dilutions of the test compound solution were added to individual wells in a 96-well U-day microtiter plate. Tryptase solution (25 µL) was added to each well and the solutions were stirred for 1 hour at room temperature. Substrate solution (25 µL) was added to initiate the enzymatic reaction and the microtiter plates were transferred to a UV / MAX Kinetic Microplate Reader (Molecular Devices). Hydrolysis of the chromogenic substrate was monitored spectrophotometrically at 405 nm for five minutes. The initial rate of measurement was calculated from the measured hydrolysis course curves by a kinetic analysis program (BatchKr, Petr Kuzmic, University of Wisconsin, Madison, WI). The apparent inhibition constants (K i) were calculated from the measured hydrolysis curves using standard mathematical models.

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

Compound 1, K i - 0.09 µM; Compound 12, K i = 29 pM; Compound 26, K i = 33 pM; Compound27, Kj = 0.6 μΜ; Compound28, K i - 0.00007 µM; Compound29, K; = 0.0008 μΜ, Compound 30, K i = 0.009 pM; Compound 37, K i = 0.002 µM; Compound 42, K i = 0.008 µM; Compound 43, K i = 0.002 µM; Compound 74, K i = 0.006 µM; Compound 75, K i = 0.03 µM; Compound 80, K i = 0.01 pM; Compound 81, K i = 0.01 pM; Compound 84, K i = 2.6 pM; Compound 102, K i = 0.00007 pM; Compound 112, K i = 0.00005 µM; Compound 115, K i = 0.003 µM; Compound 116, K i = 0.006 µM; Compound 117, K i = 0.008 µM; Compound 126, K i = 0.008 µM; Compound 127, K i = 0.006 µM; Compound 128, K i = 0.002 µM; Compound 169, K i = 0.001 µM; Compound 132, K i = 0.00002 µM; Compound 134, K i = 0.00002 µM; Compound 138, K i = 0.0002 µM; Compound 152, K i = 0.0005 µM; Compound 182, K i = 0.004 µM; Compound 194, K i = 0.009 µM; Compound 203, K i = 0.008 µM; Compound 225, K i = 0.008 µM; Compound 249, K i = 0.0007 pM; Compound 250, K i = 0.0004 µM; Compound 251, K i = 0.0008 pM and Compound 252, K i = 0.0004 pM.

··

·· ·

Example 14

Sheep model asthma

The allergic sheep asthma model was used for the in vivo evaluation of the compounds of the invention as antiasthmatics. These methods have been published (see Abraham et al., (1983) Am. Rev. Respir. Dis. 128: 839-844; Allegra et al., (1983) J. Appl. Physiol. 55: 726-730; Russi). et al., (1985) J. Appl Physiol 59: 1416-1422, Soler et al ((1989) J. Appl Physiol 67: 406-413) Each sheep serves as its own control. these animals were in the range of 20-50 kg.

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

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

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

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

Industrial applicability

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 immunologically induced inflammatory disorders such as rheumatoid arthritis,

Claims (26)

PATENT CLAIMS • · 1. Compound of Formula I: where: n 1 is 0 or 1; n 2 is 0,1, 2, 3 or 4; n 3 is 0,1, 2, 3 or 4; A together with B forms a fused heterobicyclic group containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom optionally being a heteroatom, X ¹ and X ² are adjacent ring members of the aromatic ring and X ¹ is a heteroatom group selected from -N =, -NR ⁵ -, -O- and -S-, wherein R ⁵ is hydrogen, (C _1-6 ) alkyl or hetero (C 2-6) alkyl; C is a fused heteropolycyclic group containing 8 to 18 ring atoms, each ring containing 5 to 7 ring members, each ring atom optionally being a heteroatom, X ⁴ and X ⁵ are adjacent ring members of the aromatic ring, X ⁵ is a heteroatom group selected from -N =, -NR ⁶ -, -O- and -S-, wherein R ⁶ is hydrogen, a group selected from (C 1-8) alkyl or hetero (C 2-12) alkyl, which group is substituted with one to two substituents independently selected from one to two; the other of (C _1-6 ) alkanoyloxy, (C _1-6 ) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylammonio, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkyloxy , (C 1-6) alkyloxycarbonyl, (C 1-6) alkyloxy sulfonyl, amino, carboxy, carbamoyl, (C 6-18), halogen, hetero (C 5-14) aryl, hydroxy and sulfo, or as defined below, and any of them keto, thioketo and iminoketo derivatives; X ³ is -O-, -S-, -S (O) -, -S (O) ₂ , -C (O) -, -NR ⁷ - or -CR ⁷ R ⁸ -, wherein R ⁷ is hydrogen, (C 1-6 alkyl, hetero (C 2-12) alkyl or together with R ⁶ form a (C 2-4) alkylene or hetero (C 2-4) alkylene; and R is hydrogen, (C 1-6) alkyl or hydroxy, or together with R form (C 2-6) alkylene or (C 1-6) alkylidene, wherein any aliphatic or alicyclic group R ⁷ and / or R ⁸ is optionally substituted with one to three substituents selected from (C 1-6) alkylamino, di (C 1-6) .6) alkylamino, tri (C1-6) alkylammonio, (C1-6) alkyloxy, (C1-6) alkyloxycarbonyl; ΦΦ Φ · · · Φ · · · · φ »· ΦΦΦ 9 Φ ΦΦΦΦ Φ Φ · Φ ΦΦΦ ΦΦΦ Φ Φ Φ Φ Φ (C1-6) alkanoyloxy, amino, carboxy, carbamoyl, (C1-6) alkylcarbamoyl, di (C1-6) alkylcarbamoyl, halogen and hydroxy; R ¹ is amino (NM) azolidinyl, amino (NM) azolyl, (Ni-Jazolidinyl, (NM) azolyl, carbamoyl, cyano, - (CH 2) _X NHC (NR ⁹ ) R ⁹ , - (CH 2) _X NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , -C (NH) NR ¹⁰ R ^10, or - (CR ¹¹ R ¹¹ ) _y NH 2, and is bonded to any atom of cycle B with available valency, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R ⁹ is independently of one another hydrogen or (C 1-6) alkyl, each R ¹⁰ is independently of one another (C 1-6) alkyl and each R ¹¹ is, independently of one another, hydrogen, (C 1-3) alkyl, or together with another R ¹¹ and the carbon atom to which they are both attached to form cyclopropyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one to two substituents selected independently of one another of (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 of one another (C 1-6) alkyl, (C 1-6) alkyloxycarbonyl, (C 1-6 alkanoyloxy, (C 1-6) alkyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) C _1-6 alkylsulfonyl, (C _1-6 ) alkylsulfonyl, (C 1-6 alkylthio, halogen or hydroxy) and is bonded to any ring B atom with available valency, wherein any aliphatic group R is optionally substituted with one to two substituents selected independently of one another from (C 1-6) 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 of one another (C 1-6) alkyl, (C 1-6) alkyloxy, (C 1-6) alkylthio, cyano, halogen, perhalogen (C 1-6) alkyl or hydroxy and is bonded to any atom of the C ring with available valency; and R ⁴ is -R ¹² , -OR ¹² , -N (R ¹³ ) R ¹² , -SR ¹² , -S (O) R ¹² , -S (O) 2 R ¹² , -S (O) 2 OR ¹² , -S (O) 2N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) R ¹² , -OC (O) N (R ¹³ ) R ¹² , -N (R ¹³ ) C (O) OR ¹² , - (CH ₂ ) _z N (R ¹³ ) C (O) N (R ¹³ ) R ¹² , - OP (O) (OR ¹³ ) OR ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² and is bound to any atom of the C ring with available valency, wherein: z is 0, 1 or 2, R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ 'i5 wherein NL5 is 1 or 2, X ⁶ is a (Ci-io) alkylene, cyclo (C3.io) alkylene, hetero _(C2-IO) alkylene or heterocyclo (C 3-10) alkylene and each R ¹⁵ is, independently of one another, hydrogen, (C 6-14) aryl, cyclo (C 3-14) alkyl, · polycyclo (C ₆ .i ₄₎ aryl, heteropolycycle (C ₆ -i ₄₎ aryl, heterocyclo (C _3.14) alkyl, hetero (C5 and ₄₎ aryl or as defined below, R ¹³ is hydrogen, (C 1-6) alkyl or hetero (C 2-6) alkyl; R ¹⁴ is hydrogen, (C 1-6) alkyl or together with X ⁶ and R ¹⁵ form (C 3-4) alkylene; any aliphatic and alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C _1-6 ) alkyl, (C 1-6) alkylamino, di (C _1-6 ) alkylamino, (C _1-6 ) alkylcarbamoyl, di (C _1-6 ) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C _1-6 ) alkysulfinyl, (C _1-6 ) alkysulfonyl, (C 1-6) alkythio, amino, (C 6-10) arylsulfonyl , carbamoyl, carboxy, cyano, guanidino, halogen, hydroxy, mercapto and ureido; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from cyano, guanidino, halogen, halogenated (C 1-8) alkyl, -R ¹⁶ , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , -S (O) 2 R ¹⁶ , -S (O) ₂ N (R ¹³ ) R ¹⁶ -, -C (O) R ¹⁶ , -C (O) OR ^16, and -C (O) N (R ¹³ ) R ¹⁶ , wherein R ¹³ is as defined above and R ¹⁶ is hydrogen, optionally mono substituted (C 1-8) alkyl (wherein the optional substitutent is (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylammonio, (C 1-6 alkylcarbamoyl, di ( C 1-6 alkylcarbamoyl, (C 1-6) alkyloxycarbonyl, (C 1-6 alkykyxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C 3-6) alkyl, hetero (C 1-8) alkyl, hetero (C 5-6) aryl, heterocyclo (C 3-6) alkyl or phenyl; with the exception that AD is not 0 when n2 is 0 or R ² is (C ójalkyl or (Ci_6) alkyloxy, n3 is 0 or R ³ is (Ci_6) alkyl or (C ójalkyloxy and ^R4 is hydrogen, (C io) alkyl or (C 1-10) alkyloxy, and its A-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 1, wherein A comprises 5 ring members and B contains 6 ring members and X ¹ and X ⁵ are adjacent members of the oxazol-2-yl, 1A-imidazol-2-yl or thiazol-2-yl ring; and its A-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. A compound according to claim 2 which satisfies formula II: where: the dotted lines represent, independently of each other, any bonds; each R ² is independently of one another (C 1-6) alkyl, (C _1-6 ) alkyloxy, halogen or hydroxy; each R ³ is independently of one another (C 1-6 alkyl, (C _1-6 ) alkyloxy, halogen or hydroxy; X ³ is -C (O) -or -CR ⁷ R ⁸ ; X ⁸ is -CH (R ') n - or -C (R ¹ ) n -, wherein R ¹ is amino (Ni-4) azolidinyl, amino (Ni-4) azolyl, (N 4 -solidolidinyl, (N _M ) azolyl, -NHC (NH) NR ⁹ R ⁹ , -C (NR ⁹ ) R ⁹ , -C (NH) NHR ¹⁰ , -C (NH) NR ¹⁰ R ^10, or - (CR ¹¹ R ¹¹ ) y NH 2, or is X ⁸ - N = or -NH (R ') 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 one on the other, hydrogen or (C 1-6) alkyl, and each R ¹⁰ is independently of one another (C 1-6) alkyl; 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) 2 OR ¹² , -S (O) 2 N (R ¹³ ) R ¹² , -N (R ¹³ ) S (O) 2 R ¹² , -C (O) R ^12, -C (O) OR ^12, -C (O) N ^{(R13) R12,} -N ^(R13) C (O) R ^12, -OC (O) N (R ¹³⁾ R ¹² - N (R ¹³ ) C (O) OR ¹² - (CH _{2) n4} -N (R ¹³⁾ C (O) N (R ¹³⁾ -R ^12, -OP (O) (OR ¹³⁾ OR ¹² or -C (O) N ^(R14) 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 ^{I3) R12} or -C (O) N ^(R14) CH (COOH) ^R12 The compound of claim 3, wherein: R ⁵ is hydrogen or (C 1-6 alkyl, R ⁶ hydrogen or (C 1-6 alkyl), the alkyl being optionally substituted with one to two substituents selected independently of one another from (C 1-6 alkyloxy, hydroxy and sulfo, R ⁷ is hydrogen or methyl and R ⁸ is hydrogen methyl or hydroxy; X ⁸ is -CCR 4 n ¹ , wherein R ¹ is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2-amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH ₂ ) _x NHC (NR ⁹ ) R ⁹ , - (CH ₂ ) _x NHC (NH) NR ⁹ R ⁹ and -C (NR ⁹ ) R ⁹ , each R ⁹ being ·· · * · · · · · · · · · · · · Independently of one another hydrogen or methyl, or X ^{8 is} -NCR 4 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 methyl and each R ¹⁰ is methyl, wherein any aliphatic or alicyclic group R ¹ is optionally substituted with one to two substituents selected independently of one another from methylsulfonyl and carboxy ; X ⁹ is -C (R ⁴ ) =, wherein R ⁴ is -R ¹² , -OR ¹² , -C (O) R ¹² , -C (O) OR ¹² , -C (O) N (R ¹³ ) R ¹² or -C (O) N (R ¹⁴ ) CH (COOH) R ¹² , wherein R ¹³ and R ¹⁴ are each independently hydrogen or (C 1-6) alkyl; R ¹² is -R ¹⁵ or -X ⁶ - (R ¹⁵ ) n ¹⁵ , wherein X ⁶ is (C 10) alkylene or hetero (C 2-10) alkylene and each R ¹⁵ is independently of one another hydrogen, (C 6-18) cyclo (C3-i4) alkyl, polycyclo (C6-i4) aryl, heteropolycycle (C6_i ₄₎ aryl, heterocyclo (C3_i4) alkyl or hetero (C5-i4) aryl; any aliphatic and alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C 1-4 alkyloxy, (C _1-4 ) alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy) and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C 1-4) alkyl, (C _1-4 ) alkyloxy, (C _1-4 ) alkyloxycarbonyl, carbamoyl, carboxy, cyano, cyclo (C 3-6) alkyloxy, halogen, hetero (C 1-8) alkyl, hydroxy, hetero (C 1-8) alkylcarbonyl, hetero (C 5-6) aryl and trifluoromethyl, and its N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 4, wherein: A, together with B, forms 4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl, wherein n 2 is 0, R ¹ is -C (NR ⁹ ) R ⁹ and R ⁵ is hydrogen, or A together with B forms 1 H -benzoimidazol-2-yl or 4,5,6,7-tetrahydro-1 H -benzoimidazol-2-yl, wherein R ¹ is aminomethyl or guanidino and each R ² is independently of one another halogen or hydroxy; C is 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl or 1H-benzoimidazol-2-yl, wherein R ⁴ is -C (O) X ⁶ -R ¹⁵ , -C (O) OX ⁶ -R ¹⁵ or -C (O) NHX ⁶ -R ¹⁵ , wherein X ⁶ is (C 1-4) alkylene or hetero (C 2-4) alkylene and R ¹⁵ is (C 6-6) io) aryl, (C 6-10) aryloxy, polycyclo (C 6-10) aryl, hetero (C 5-10) aryl, hetero (C 5-10) aryloxy or heteropolycyclo (C 6-14) aryl; and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from (C 1-4) alkyl, (C 1-4) alkyloxy, (C _1-4 ) alkyloxycarbonyl, carboxy, carbamoyl, halogen, hydroxy and tetrazol-1-yl; and its A-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 5, wherein A together with B forms 1 H -benzoimidazol-2-yl and each R ² is independently of one another halogen or hydroxy; and Tt-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 6, wherein n 1 is 0; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof. The compound of claim 7, wherein the compound is selected from: 2- (2- {2- [1- (4,6,7-trifluoro-1 H -benzoimidazol-2-yl) ethyl] -3-methyl- 37 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5,6-Difluoro-1 H -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-3 H -benzoimidazol-5-ylcarbonylamino} ethoxy) benzoate; propyl 2- {2- {2- [1- (5-hydroxy-1H-benzoimidazol-2-yl) ethyl] -3-methyl-377-benzoimidazol-5-ylcarbonylamino} 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; its N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 5, wherein R ¹ is guanidino or aminomethyl, and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. The compound of claim 9, wherein the compound is selected from: 2- (5-guanidino-1N-benzoimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-yl ethyl) -3H-benzoimidazole-5-carboxamide; ethyl 2- (3- {2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino propoxy) benzoate; 2- (5-guanidino-1N-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxy) propyl-N- (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxypropyl) -N- (2-naphth-1-yl ethyl) -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-1 H -benzoimidazol-2-yl) ethyl] - N - (2- (2-carbamoylphenoxy) ethyl] -3-methyl-3 H- benzoimidazole-5-carboxamide ; 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3H-benzoimidazole- 5-carboxamide; 4-chloro-2- [2- ({2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid; 5-chloro-2- [2- ({2- [1- (5-guanidino-1 H -benzoimidazol-2-yl) ethyl] -3-methyl-3 H -benzoimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid; 2- (5-aminomethyl-1H-benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; and 2- (5-aminomethyl-4,5,6,7-tetrahydro-1 H -benzoimidazol-2-ylmethyl) -3-methyl- N - (2-naphth-1-ylethyl) -3 H -benzoimidazole -5-carboxamide; and its N -oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts. The compound of claim 5, wherein A together with B forms 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl and R ¹ is -C (NH) R ⁹ ; and its A-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 11, wherein the compound is selected from: 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4, 5-c] pyridin-2-yl] -ethyl} -3-methyl-3 H -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-naphth- 1-ylethyl) -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- naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; 2- (5-Iminomethyl-4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-ylmethyl) -3-methyl-N - (2-naphth-1-ylethyl) 13H-benzoimidazole-5-carboxamide; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl- N - (2- hydroxy-2-naphth-1-ylethyl) -3H-benzoimidazole-5-carboxamide; 2- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl N - [2- (2-hydroxynaphth-1-yl) ethyl] -3 H -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-hydroxynaphth-1-yl) ethyl] -3H-benzoimidazole-5-carboxamide; 2- {1- [5- (1-Iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -3-methyl-N - ( 2-naphth-1-yl-ethyl) -3H-benzoimidazole-5-carboxamide; ethyl 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl-3 H -benzoimidazol-5-ylcarbonylamino) ethoxy] benzoate; 2- [2- (2- {1- [5- (1-Iminoethyl) -4,6S, 6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl } -3- (2-methoxyethyl) -3 H -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} -1,4,6,7-tetrahydroimidazo [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-N- [2- (2-tetrazolylphenoxy) ethyl] -3 H -benzoimidazole-5-carboxamide; and its N -oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. The compound of claim 12, wherein the compound is 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5-c]). pyridin-2-yl] ethyl} -3-methyl-377-benzoimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; and its N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 14. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 14 further comprising a compound that is a β-adrenergic agonist. 16. A pharmaceutical composition according to claim 14 wherein the compound that is a β-adrenergic agonist is selected from the group consisting of albuterol, terbutaline, formoterol, phenoterol, and prenalin. A pharmaceutical composition according to claim 14 comprising a pharmaceutically acceptable carrier for administration as an ointment. 18. A pharmaceutical composition according to claim 14 comprising a pharmaceutically acceptable carrier for oral administration. 19. A pharmaceutical composition according to claim 14 comprising a pharmaceutically acceptable carrier for aerosol administration. An aerosol inhaler comprising a compound of claim 1 in a pharmaceutically acceptable carrier, i.e., solution or dry powder, and means for converting the solution or dry powder into an aerosol form suitable for inhalation. A method for treating immunologically induced inflammation in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method of treating rheumatoid arthritis in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method of treating conjunctivitis in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method of treating a syncytial viral infection in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A method for treating immunologically induced inflammation in the respiratory tract of a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. A process for preparing a compound of formula I: (R2) _n2 - ^ X wherein: n 1 is 0 or 1; n 2 is 0,1,2, 3 or 4; n 3 is 0, 1, 2, 3 or 4; A together with B forms a fused heterobicyclic group containing 8 to 12 ring atoms, each ring containing 5 to 7 ring members, each ring atom optionally being a heteroatom, X ¹ is a heteroatom group selected from -N =, -O- and -S- and X ¹ and X ² are adjacent members of the oxazol-2-yl, 1 H -imidazol-2-yl or thiazol-2-yl ring, wherein the 1 H -imidazol-2-yl ring member is optionally -NR ⁵ -, wherein R ⁵ is hydrogen, (C 1-6) alkyl or hetero (C 2-6) alkyl; or C forms a fused heteropolycyclic group containing 8 to 18 ring members, each ring containing 5 to 7 ring members, each ring atom optionally being a heteroatom, X ⁵ is a heteroatom group selected from -N =, -O- and -S-, and X ⁴ and X ⁵ are adjacent members of the oxazol-2-yl, 1 H -imidazol-2-yl or thiazol-2-yl ring, wherein the 1 H -imidazol-2-yl ring member is optionally -NR ⁶ -, wherein: R ⁶ is hydrogen, a group selected from (C 1-6) alkyl or hetero (C 2-12) alkyl, wherein the group is optionally substituted with one to two substituents selected independently of one another from (C 1-6) alkanoyloxy, (C 1-6) alkylamino, di (C _1-6 ) alkylamino, tri (C _1-6 ) alkylammonio, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C _1-6 ) alkyloxy, (C _1-6 ) alkyloxycarbonyl, (C 1-6) a 6alkyloxy-sulfonyl, amino, carboxy, carbamoyl, (C 6-14 aryl, halogen, hetero (C 5-14) aryl, hydroxy and sulfo, or as described below, and any keto, thioketo and iminoketo derivative thereof; X ³ is -O-, -S-, -S (O) -, -S (O) 2 -, -C (O) -, -NR ⁷ - or -CR ⁷ R ⁸ -, wherein R ⁷ is hydrogen , (C 1-6) alkyl, hetero (C 2-12) alkyl or together with R ⁶ form (C 2-6) alkylene or hetero (C 2-6) alkylene and R is hydrogen, (C 1-6 alkyl or hydroxy) or together with R 6 forms (C 2-6) alkylene or (C 1-6) alkylidene, wherein any aliphatic or alicyclic group R and / or R is optionally substituted with one to three substituents selected from (C 1-6) alkylamino, di (C _1-6 ) alkylamino, tri ( Ci. ₆₎ alkylammonium (C, ₆₎ alkyloxy, (Ci. ₆₎ alkyloxycarbonyl, (C, 6) alkanoyloxy, amino, carboxy, carbamoyl, (Cl-6) alkylcarbamoyl, di (Ci.ó) alkylcarbamoyl, halo and hydroxy ; R ¹ is amino (N-4) azolidinyl, amino (Ni_4) azolyl, (Ni_4) azolidinyl, (Ni-jazolyl, carbamoyl, cyano, - (CH2) X NHC ^{(NR9) R9,} - (CH2) _x NHC ( NH) NR ⁹ R ^9, -C ^{(NR9) R9,} -C (NH) NHR ^10, -C (NH) NR ¹⁰ R ^I0 or - (CR ¹¹ R ¹¹⁾ y NH 2, and is attached to any carbon atom of ring B having an available valency, wherein x is 0 or 1, y is 0, 1, 2 or 3, each R ⁹ is independently of one another hydrogen or (C 1-6) alkyl, each R ¹⁰ is independently of one another (C 1-6) ) alkyl and each R ¹¹ is independently of one another hydrogen, (C 1-6) alkyl, or forms together with another R ¹¹ and the carbon to which they are both attached cyclopropyl, wherein any aliphatic or alicyclic group R ¹ is independently of one another optionally substituted with one to two substituents selected independently of one another from (C 1-6) alkyloxycarbonyl, (C 1-6) alkanoyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfonyl and hydroxy; Each R ² is independently of one another (C 1-6) alkyl, (C 1-6) alkyloxycarbonyl, (R ²⁾ is independently of one another. C 1-6) alkanoyloxy, (C 1-6) alkyloxy, carboxy, carbamoyl, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylsulfinyl, (C 1-6) alkylsulfonyl, (C 1-6) alkylthio, halogen or hydroxy, and is bonded to any ring B atom having available valency, wherein any aliphatic R ² group is optionally substituted with one to two substituents independently of one another 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 ³ is independently of one another (C _1-6 ) alkyl, (C 1-6) alkyloxy, (C 1-6 alkylthio, cyano, halogen, perhalo (C 1-6) alkyl or hydroxy, and is bound to any atom of the ring C s by available valency; R ⁴ is -R ¹² , -OR ¹² , -N (R ¹³ ) R ¹² -, -SR ¹² , -S (O) R ¹² -, -S (O) 2 R ¹² , -S (O) 2 OR ¹² , -S (O) 2N ^{(R13) R12,} -N ^(R13) S (O) 2 R ^12, -C (O) R ^12, -C (O) OR ^12, -C (O) N (R ¹³ ) R ¹² -N ^(R13) C (O) R ^12, -OC (O) N (R ¹³⁾ R ^12, -N (R ⁱ³⁾ C (O) OR ^12, - (CH _{2) a} -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 is bonded to any ring C atom with available valency, where: z is 0, 1 or 2; R ¹² is -R ⁶ or -X ¹⁵ - (R ¹⁵⁾ 'i5 wherein NL5 is 1 or 2, X ⁶ is a (Ci-io) alkylene, cyclo (C3.io) alkylene, hetero _(C2 _io) alkylene or heterocyclo (C 3-10) alkylene and each R ¹⁵ is independently of one another hydrogen, (C 6-14) aryl, cyclo (C 3-14) alkyl, polycyclo (C 6-14) aryl, heteropolycyclo (C 1-4) aryl, heterocyclo (C 3-14) alkyl, hetero (C 5-14) aryl or as defined below; R ¹³ is hydrogen, (Ci.6) alkyl or hetero _(C2 _6) alkyl; R ¹⁴ is hydrogen, (C 1-6) alkyl, or together with X ⁶ and R ¹⁵ form (C 3-4) alkylene; any aliphatic or alicyclic group R ⁴ is optionally substituted with one to five substituents selected independently of one another from (C 1-6) alkyl, (C 1-6) alkylamino, di (C 1-6) alkylamino, (C 1-6 alkylcarbamoyl, di (C 1-6) alkylcarbamoyl (C, 6) alkyloxy, (Ci. ₆₎ alkyloxycarbonyl, (Ci. ₆₎ alkylsulfinyl, (Cl-6) alkylsulfonyl, (Ci_6) alkylthio, amino, (C ₆ _io) arylsulfonyl, carbamoyl, carboxy, cyano, guanidino , and any aromatic group R ¹⁵ is optionally substituted with one to three substituents selected independently of one another from cyano, guanidino, halogen, halogen substituted (C 1-6) alkyl, -R ¹⁶ , -OR ¹⁶ , -SR ¹⁶ , -S (O) R ¹⁶ , -S (O) ₂ R ¹⁶ , -O -S (O) ₂ N (R ¹³ ) R ¹⁶ , -C (O) R ¹⁶ , -C (O) OR ¹⁶ and -C (O) N (R ¹³ ) R ¹⁶ , wherein R ¹³ is as defined above, and R ¹⁶ is hydrogen, optionally mono-substituted with (Ci-g) alkyl (wherein the optional substituent is (Ci-s) alkylamino, di (Ci.6) alkylamino, tri (Ci.6) alkylammonium, (Ci.6) alkylcarbamoyl, di (C . ₆₎ alkylcarbamoyl, (Ci. ₆₎ alkyloxycarbonyl, (C ₆₎ alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo (C _6.3) alkyl, hetero (Ci.g) alkyl, hetero (C5 6) aryl, heterocyclo (C 3-6) alkyl or phenyl; with the exception that AD is not 0, when n2 is 0 or R ² is (C-C6) alkyl, or (Ci.6) alkyloxy, n3 is 0 or R ³ is (Ci_6) alkyl or (Ci_6) alkyloxy and R ⁴ is hydrogen, _(Ci-I0) alkyl or (Ci-io) alkyloxy; and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof; wherein the method comprises: (a) reaction of compound 1: or a protected derivative thereof with compound 2: or a protected derivative thereof, wherein L is a leaving group, D together with the vinylene group to which it is fused forms a monocyclic or fused bicyclic divalent group containing from 5 to 15 ring atoms, each ring containing 5 to 7 ring atoms and each ring member is optionally heteroatom, R ²⁹ is -OH, -NHR ⁶ or -SH, wherein R ⁶ is hydrogen or a group selected from (C 1-8) alkyl or hetero (C 2-12) alkyl, wherein the group is optionally substituted with one to two substituents selected independently of one another from (C 1-6) alkanoyloxy, (C 1-6) alkylamino, di (C 1-6) alkylamino, tri (C 1-6) alkylammonio, (C 1-6) alkylcarbamoyl, di (C 1-6) alkylcarbamoyl, (C 1-6) alkylamino; 6) alkyloxy, (C 1-6) alkyloxycarbonyl, (C 1-6) alkyloxysulfonyl, amino, carboxy, carbamoyl, (C ₆ -i ₄₎ aryl, halo, hetero (C ₅ .i ₄₎ aryl, hydroxy and sulfo; and nl, n2, n3, A, Β, X ^1, X ^2, X ^3, R ^1, R ^2, R ^3, R ⁴ and R ⁶ are as defined above, and if necessary, further includes deprotecting; or (b) reacting compound 3: or a protected derivative thereof, with compound 4: or a protected derivative thereof, wherein L is a leaving group, R ³⁰ is -OH, -NHR ⁵ or -SH and n 1, n 2, n 3, B, C, X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above and, if necessary, further include deprotection; (c) optionally further comprising converting a compound of Formula I to a pharmaceutically acceptable salt; (d) optionally further comprising converting the compound of Formula I in salt form to its free form; (d) optionally further comprising converting the non-oxidized form of the compound of Formula I to a pharmaceutically acceptable A-oxide; (e) optionally further comprising converting the A-oxidized form of the compound of Formula I to its non-oxidized form; (f) optionally further comprising converting the non-derivatized form of a compound of Formula I into a pharmaceutical prodrug derivative; and (g) optionally further comprises converting a prodrug derivative of a compound of Formula I into its non-derivatized form.