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LV12495B - Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity - Google Patents

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

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Publication number
LV12495B
LV12495B LVP-99-153A LV990153A LV12495B LV 12495 B LV12495 B LV 12495B LV 990153 A LV990153 A LV 990153A LV 12495 B LV12495 B LV 12495B
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Latvia
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compound
ethyl
alkyl
methyl
benzoimidazol
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LVP-99-153A
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Latvian (lv)
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LV12495A (en
Inventor
Timothy J. Church
Neil Scott CUTSHALL
Anthony R. GANGLOFF
Thomas E. JENKINS
Martin S. Linsell
Joane Litvak
Kenneth D. RICE
Jeffrey R. Spencer
Vivian Rueywen Wang
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Axys Pharmaceuticals, Inc.
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Publication of LV12495A publication Critical patent/LV12495A/en
Publication of LV12495B publication Critical patent/LV12495B/en

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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
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    • C07—ORGANIC CHEMISTRY
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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Abstract

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

Description

LV 12495
C0MP0UNDS AND COMPOSITIONS FDR TREATING DISEASES ASSOCIATED WITH SERINE PROTEASE, PARTICULARLY TRYPTASE, ACTIVITY
Fieid of the Invcntion:
This application is a continuation-in-part of application Senai No. 08/833,674, filed April 07,1997, which is a continuation-in-part of application Senai No. 08/357,491, filed December 14,1994, which arc herein incorporated by reference, and relates to compounds and compositions for treaiing diseases associated with serine protease, particularly tryptase, activity.
Description of the Fieid:
Tryptase, the predominam protease secreted from human mast celis, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) N. Eng. J. Med. 316:1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific antigen challenge (Castells et al. (1988) J. AUerg. Clin. Immunol. 141:563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase Ievels, a fīnding that provides some support for the hypothesis that release of proteinase from activated mast celis could contribute to lung destruction in smoker’s emphysema. (Celenteron et al. (1988) Chest 94:119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary nbrosis and interstitial lung discase (Ross etal. (1991)./. Clin. Invest. 88:493-499).
Asthma is recognized as an inflammatory disorder (Hood et al. (1984) In: Benjamin-Cummings, ed. īmmunology 2nd ed.) and frequently is characterized by progressive development of hyper-responsivencss of the trachea and bronchi to both immunospecific allergens and generalized Chemical orphysical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic stages. The hyper-responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, which initate and damage the epithelium lining the airway wall and promote pathological thickening of the underiying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall. 2
Allergic responses to inhaled allergens can initiatc the inflammatory sequence. For example, allergens can activate mast celis and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the celi surface. Activated mast celis release a number of preformed or primary Chemical mediators (e.g., histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation (e.g., superoxide, lipid derived mediators, etc.) in situ. In addition, several large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast celis.
The release of these preformed mediators from mast celis probably accounts for the early bronchiolar constriction in the asthmatic reaction to air bome allergens. The early phase of the asthmatic reaction peaks approximately fifteen minūtes after exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function vvhich maximizes six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory celis (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating celis are attracted to the site by release of mast celi derived chemotactic aģents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes.
Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988) J.Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988) J. Pharmacol. Exp. Ther. 248:947-951; and Tam et al. (1990) Am. J Respir. Celi Mol. Biol. 3:27-32) and modulation of bronchial responsiveness to histamine (Sekizawa et al. (1989) J. Clin. Invest. 83:175-179). These fmdings suggest that tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tiyptase cleaves fibrinogen α-chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, administration of tryptase inhibitor protects against development of the late and airway hyper-responsive phases in allergen challenged sheep (Clark et al. (1995) Am. J. Respir. Crit. Care Med. 152: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 3 LV 12495 79(6): 1966-1970). Ali of the above-described findings c!early indicate the applicability of tryptase inhibitors as therapeutic aģents in treating asthma and other disorders associated with inflammation of the respiratory tract.
The disclosures of these and other documents, including patents and patent applications, referred to throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
This application relates to a compound of Formula I:
in vvhich: nlisOorl, n2 is 0,1,2, 3 or 4; n3 is 0, l, 2, 3 or 4; A together with B comprises a fused hcterobicydic radical containing 8 to 12 annular atoms, vvherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X1 and X2 are adjacent annular members of an aromatic ring and X1 is a heteroatom moiety selected from -N=, -NRJ-, -O- and -S-, vvherein R5 is hydrogen, (C!.6)alkyl or hetero(C2.6)alkyl; C comprises a fused heteropolycyclic radical containing 8 to 18 annular atoms, vvherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X4 and X5 are adjacent annular members of an aromatic ring, X5 is a heteroatom moiety selected from -N=, -NR6-, -O- and -S-, vvherein R6 is hydrogen, a group selected from (C,.a)alkyl or hetero(C2.ļ:)alkyl, vvhich group optionally is substituted vvith one to tvvo substituents independently selected from (C,.6)alkanoyloxy, (C|.6)alkylamino, di(C|.e)alkylamino, tri(Cl.6)alkylammonio, (C,.6)alkylcarbamoyl, di(C,.0)alkylcarbamoyl, (C,.6)alkyloxy, (C,.6)alkyloxycarbonyl, (C|.6)alkyloxysulfonyl, amino, carboxy, carbamoyl, (C6.,^)aryl, halo, 4 hetero(Cj.u)aryl, hydroxy and sulfo, or as defined below; and any carbocyclic ketone, thioketone and iminoketone derivative thereof; X3 is -O-, -S-, -S(O)-, -S(0)2-, -0(0)-, -NR7- or -CR7R8-, wherein R7 is hydrogen, (C(.6)alkyl, heterofC^a^l or together with R6 forms (C2^)alkylene or hetero(Cw)alkylene and 5 R8 is hydrogen, (Cu)alkyl or hydroxy or together with R7 forms (C2.6)alkylene or (C|^)alkylidene, wherein any aliphatic or alicyclic moiety comprising R7 and/or R8 optionally are substituted with one to three substituents selected from (CM)alkylamino, di(Cw)alkylamino, tri(Cw)alkylammonio, (C,.6)alkyloxy, (C,.6)alkyloxycarbonyl, (C,.6)alkanoyloxy, amino, caiboxy, carbamoyl, (Ci.6)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, halo and hydroxy; 10 R1 is amino(NM)azolidinyl, amino(NM)azolyl, (NM)azolidinyl, (NM)azolyl, carbamoyl, cyano, -(CH2)XNHC(NR9)R9, -(ΟΗ2)χΝΗΟ(ΝΗ)ΝΚ^9, -C(NR9)R9, -C(NH)NHR'°, -C(NH)NRI0R,° or-(CRnR,l)yNH2 and bonded to any annular atom with an available valence comprising B, wherein x is 0 or 1, y is 0, 1,2 or 3, each R9 independently is hydrogen or (C,^)alkyl, each R‘° is independently (C,.6)alkyl and each R" independently is hydrogen, 15 (C|.3)alkyl or together with another R“ and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moiety comprising R' optionally is substituted with one to two substituents independently selected from (C1.6)alkyloxycarbonyl, (Ci.6)alkanoyloxy, carboxy, carbamoyl, (C1.6)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C,.6)alkylsulfonyl and hydroxy; 20 each R2 independently is (C,^)alkyl, (Ci.6)alkyioxycarbonyl, (C,.6)alkanoyloxy, (C,.6)aIkyloxy, carboxy, carbamoyl, (C|.6)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C|.6)alkylsulfmyl, (C|.6)alkylsulfonyl, (Cu6)alkylthio, halo or hydroxy and bonded to any annular atom with an available valence comprising B, wherein any aliphatic moiety comprising R2 optionally is substituted with one to two substituents independently selected from 25 (C 1.6)alkyloxycarbonyl, (C,.6)alkanoyloxy, carboxy, carbamoyl, (C,.6)alkylcarbamoyl, di(Ci.6)alkylcarbamoyl, (Cw)alkylsulfonyl and hydroxy; each R3 independently is (CM)alkyl, (C,.6)alkyloxy, (Ct.6)alkylthio, cyano, halo, perhalo(C|.6)alkyl or hydroxy and bonded to any annular atom with an available valence comprising C; and 30 R4 is -R12, -OR12, -N(R13)R12, -SR12, -S(0)R12, -S(0)2 R12, -S(0)20 R12, -S(0)2N(RIJ)R12, -N(R13)S(0)2R12, -C(0)R12, -C(0)OR12, -C(0)N(R13)R12, -N(R13)C(0)R12, -0C(0)N(R13)R12, -N(Rl3)C(0)0R12, -<CH2)īN(R13)C(0)N(R13)R12, -0P(0)(0Ri3)0 R12 or 5 LV 12495 -C(0)N(RI4)CH(COOH)R12 and bonded to any annular carbon atom with an available valence comprising C, wherein: zisO, 1 or2, R12 is -R,s or-X6-{R,5)nls, wherein nl5 is 1 or 2, X6 is (C,.l0)alkylene, 5 cyclo(Cj.)0)alkylene, hetero(C2.10)alkylene or heterocyclo(C3.io)alkylenc and each R15 is independently hydrogen, (Ce.M)aryl, cyclo(C3.,4)alkyl, polycyclo(C6.M)aiyl, heteropolycyclo(C6.l4)aiyl, heterocyclo(Cj.,4)alkyl, hetero(Cj.,4)aiyl or as defined below, R13 is hydrogen, (C,.6)alkyl or hetero(C2.e)alkyl; R14 is hydrogen, (C,.6)alkyl or together with X6 and R1J forms (C3-ļ)alkylene; 10 any aliphatic and alicyclic moiety comprising R4 optionally is substituted %vith one to five substituents independently selected from (C,^)alkyl, (Cw)alkylamino, di(C,.*)alkylamino, (C,.6)alkylcarbamoyl, di(C|.4)alkylcafbainoyl, {C,.4)alkyloxy, (C1.6)alkyloxycarbonyl, (C,.6)alkysulfmyl, (C,.e)alkysulfonyl, (C,.6)alkythio, amino, , (C6.|0)arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, balo, hydroxy, mercapto and χ 15 uriedo; and r any aromatic moiety comprising R1J optionally is substituted with one to three :i: substituents independently selected from cyano, guanidino, halo, halo-substituted (C’|.»)alkyl, -R16, -OR16, -SR'6, -S(0)R16, -S(0)2R'6, -S(0)2N(R'3)R16-, -C(0)R16, -C(0)0R16 and -C(0)N(Rl3)R16, wherein R13 is as defined above and R16 is hydrogen, 20 optionally mono-substituted (C,.*)alkyl (wherein the optional substitutent is (C|.6)alkylamino, diiC^jJa^lamino, tri(C1.6)alkylammonio, (C,.6)alkylcarbamoyl, di(C,-i)alkylcarbamoyl, (C,.6)alkyloxycarbonyl, (C,.6)alkyloxysulfonyl, amino, carboxy, carbamoyl, hydroxy or sulfo), cyclo(C3.i)alkyl, hetero(C|.j)alkyl, hetero(C3.6)aryl, heterocyclo(C3.6)alkyl or phenyl; 25 with the proviso that nl is not 0, when n2 is 0 or R2 is (C|.6)alkyl or (C|.6)alkyloxy, n3 is 0 or R3 is (C,^)alkyl or (C,^)alkyloxy and R4 is hydrogen, (C,.i0)alkyl or (CM0)alkyloxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
The present invention also provides for pharmaceutical compositions of the compounds 30 of the invention. These pharmaceutical compositions can be in a variety of forms including oral dosage forms, inhalable forms, as well as injectable and infusible Solutions. When used in inhalant or aerosol form, the compounds of the present invention are used in combination with a 6 pharmaceutically acceptable cairier solution or dry powder which can be converted into aerosol foim. Similarly, when used in oral administration, the compounds of the present invention are used in combination with a pharmaceutically acceptable carrier suitable for such oral administration. When used for the treatment of immunomediated inflammatory skin conditions, 5 the compounds of the present invention are used in combination with a non-toxic, pharmaceutically acceptable topical carrier. The compounds of the present invention can be used in combination with antiinflammatories or other asthma therapies, such as β-adrenergic agonists, antiinflammatory corticosteroids, anticholinergics, bronchodilators such as methyl xanthenes and the Iike. 10 The compounds described herein are useful for the prevention and treatment of immunomediated inflammatory disorders, and particularly those associated with the respiratory tract, including asthma, and particularly the hyper-responsiveness phase associated with chronic asthma, and allergic rhinitis. Thus, the present invention also provides a method for treating immunomediated inflammatory disorders wherein apatient having an immunomediated 15 inflammatory disorder is administered a therapeutically effective dose or amount of a compound of the present invention. Further, the compounds described herein are useful for treating syncytial virai infections.
BRIEF DESCRIPTION OF THE DRAWINGS 20
Figurē 1 compares the specific lung resistance of a control (open squarcs) versus 2-(5-aminomethyl-l/f-benzoimidazoi-2-ylmethyl)-jV-(3-phenylpropyl)-l//-benzoimida2ole-5-carboxamide (Compound 4; closed squares) over time as measured in hours.
Figurē 2 is a bar chart showing the airway hyper-responsiveness (measured as PC400) antigen-challenged sheep treated with Compound 4 by aerosol administration of three 1 mg doses versus sheep treated with a control. 25 7 LV 12495
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
Unless othenvise stated, the following terms used in the specification and claims are 5 defined for the purposes of this application and have the meanings given below: **Alkanoyr means the radical -C(0)R, wherein R is alkyl as defined below, having overall the number of caibon atoms indicated (e.g., (Cw)alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.). 10 “Alicyclic moiety” means any saturated or unsaturated, monocvclic or polycyclic hydrocarbon portion of a radical. For example, alicyclic moiety refers to cycloalkyl, as defmed herein, as well as to alicyclic portions comprising cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloaIkylcaibamoyl, and the like. “Aliphatic moiety” means any straight or branched, saturated or unsaturated hydrocarbon 15 portion of a radical. For example, aliphatic moiety refers to alkyl or heteroalkyl, as defined herein, as well as to aliphatic portions comprising alkyloxy, arylalkyl, heteroarylalkyl, .rit-*. alkylcarbamoyl, alkanoyl, arylalkanoyl, heteroarylalkanoyl, and the like. “Alkyi”, for the purposes of this application, means a straight or branched, saturated or unsaturated aliphatic hydroCarbon radical having the number of carbon atoms indicated, and any 20 ketone, thioketone or iminoketone thereof (e.g., (C,.g)alkyl includes methvl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ier/-butyl, vinyl, allyl, l-propenyl, isopropenyl, l-butenyl, 2- butenyl, 3-butenyl, 2-methylallyl, ethynyl, l-propynyl, 2-propynyl, 3-oxopentyl, 3- thioxopentyl, 3-iminopentyl, etc.). “Alkylene” means a saturated or unsaturated hydrocarbon divaient radical having the 25 number of carbon atoms indicated and any ketone, thioketone, iminoketone and substituted derivative thereof (e.g., (CM0)alkylene includes methylene (-CH2-), ethylene (-CH2CH2-), methylethylene, vinylene, ethynylene, trimethylene (-CH2CH2CH2-), 2-oxotrimethylene (-CH2C(0)CH2-), 2-thiatrimethylene (-CH2C(S)CH2-), 2-iminotrimethylene (-CH2C(NH)CH2-), propenylene (-CH2CH=CH- or -CH=CHCH2-), propanylylidene (=CHCH2CH2-), propendiylene 30 (=CHCH=CH-), l-aminotetramethylene, pentamethylene, etc.). 8 “Alkylidene” means the radical =CRR, wherein each R independently is hydrogen or alkyl, as defined above, having overall the number of carbon atoms indicated (e.g., (Cu)alkylidene includes methylidene, ethylidene, propylidene, isopropylidene, etc.). “Alkyloxy” means the radical -OR, wherein R is alkyl as defined above, having the 5 number of carbon atoms indicated (e.g., (CM)alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, ier/-butoxy, vinyloxy, allyloxy, 1- propenyloxy, isopropenyloxy, l-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, l-propynyloxy, 2-propynyloxy, etc.). “Alkylsulfinyr, “alklsulfonyl” and “alkylthio” mean the radicals -SOR, -S(0)2R and 10 -SR, respectively, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C1.6)alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropyIsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, /err-butylsulfonyl, vinylsulfonyl, allylsulfonyl, l-propenylsulfonyl, isopropenylsulfonyl, l-butenylsulfonyl, 2- butenylsulfonyl, 3-butenylsulfonyl, 2-methylallylsuIfonyl, ethynylsulfonyl, 15 l-propynylsulfonyl, 2-propynylsulfonyl, etc.). “Ammonio” means the radical -NH3+. “Amidino” means the radical -C(NH)NH2. “Amino” means the radical -NH2. "Animal" includes humāns, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, 20 sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.). “Aryl” means an aromatic monocyclic or fused polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 6 annular members (e.gM (C*.l4)aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.). “Arylsulfonyl” mean the radicals -S(0)2R, vvherein R is aryl as defined above, having the 25 number of carbon atoms indicated (e.g., (C6.10)arylsulfonyl includes phenylsulfonyl, naptht-l-ylsulfonyl, etc.). “Aromatic moiety” means any aromatic portion of a radical. For example, aromatic moiety refers to aryl and heteroaryl, as defined herein, as well as the aromatic poitions comprising arylalkyl, heteroarylalkyl, polycycloaryl, heteropolycycloaryl, and the like. 30 “Azolidinyl” means a saturated or unsaturated 5-membered monocyclic radical containing the number of nitrogen atoms indicated. For example, (NM)azolidinyl includes 9 LV 12495 pyrazolidinyl, pyrrolidinyl, imidazolidinyl, trizolidinyl, tetrazolidinyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl and dihydrotriazolyl. “Azolyl” means an aromatic 5-membcred monocyclic radical containing the number of nitrogen atoms indicated. For example, (NM)azolyl includes pyiTolyl, imidazolyl, pyrazolyl, 5 triazolyl and tetrazolyl. “Caibamoyl” means the radical -C(0)NH2. “Caiboxy” means the radical -C(0)0H. “Cyano” means the radical -CN. “Cycloalkyl” means a saturated or unsaturated, monocyclic or fused polycyclic 10 hydrocarbon radical containing the number of carbon atoms indicated, wherein each ring contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone and iminoketone derivative thereof (e.g., (C3.14)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.). 15 “Cycloalkylene” means a saturated or unsaturated, monocyclic or fused poiycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein each ring, contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C3_,0)cycloalkylene includes l,2-cyclopropylene, l,2-cyclobutylene, l,3-cyclobutylene, l,2-cyclopentylene, 20 l,3-cyclopentylene, l,4-cyclopentyiene, l,4-cyclohexylene, 3-cvclohexen-l,2-ylene, 2.5- cyclohexadien-1,4-ylene, 1,4-bicyclo[2.2.2]octylene, 5-oxo-1,3-cyclohexylene, 2.5- dioxo-l,4-cyclohexylene, 5-thioxo-l,4-cyclohexylene, etc.)· "Deprotecting" refers to removing any protective groups present after the selective reaction has been carried out. 25 "Disease" specifically includes any unheaithy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy. "Fused heteropolycyclic radical" includes "fused heterobicyclic radical" and means a heterocyclic radical containing two to three fused rings having the number of annular members 30 indicated, wherein at least two annular members of one ring are common to a second ring (e.g., a heteropolycyclic radical containing from 8 to 18 annular atoms and the carbocyclic ketone and 10 thioketone dcrivatives thereof includes l//-benzimidazol-2-yl, l//-naphtho[2,3-d]imidazol-2-yl, l//-imida2o[4,5-/]quinolin-2-yl, 1 //-imidazo[4,5 -6}pyridin-2-yl, l//-phenanthro[9,10-d]imidazol-2-yl, 1 /f-imidazo[4,5-g]quinoxalin-2-yl, 2,6-dioxo- 2.3.6.7- tetrahydro-l/f-purin-8-yl, 2,6-dithioxo-2,3,6,9-tetrahydro-l//-purin-8-yI, 7/f-purin-8-yl, 5 l,6-dihydrocyclopentaimidazol-2-yl, 4-quinolin-2-yl, etc.). “Guanidino” means the radical -NHC(NH)NH2. “Halo” means fluora, chloro, bromo or iodo. “Heteroatom” means an atom selected frorn N, 0, S and P. “Heteroatom moiety”, unless indicated otherwise, means a moiety selected from -N=, 10 -NR'7-, -O-, -S-, —S(O)-, -S(0)2-, -P(0)(0R17)-, wherein R17 is hydrogen or (Ct.6)alkyl. “Heteroalkyl” means alkyl, as defined above, except one or more of the carbon atoms indicated is replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero(C2.ļ2)alkyl includes methoxy, ethoxy, ethylthio, 2-(2-methoxyethoxy)ethoxy, 15 3-methoxymethoxycarbonylmethoxy, 2-(N-ethyl-7V-methylamino)ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.). “Heteroalkylene” means alkylene, as defined above, except one or more of the carbon atoms indicated is replaced by a heteroatom moiety, as defined in the Detailed Description of the Invention, or any suitable combination thereof (e.g., -0S(0)2-, -S(0)20-, -N(R)S(0)2-, 20 -S(0)2NR17-, -0P(0)(0Rl7)0-, and the like, wherein R'7 is hydrogen or (C|.6)alkyl), and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero(C2.io)alkylene includes azaethylene (-CH2NH-), 2-azapropenylene (-CH2N=CH2-), l-oxatrimethylene (-CH2CH20-), 2-oxo-3-azapentamethylene, 3-aza-2-thiopentamethylene, 2-oxa-3-oxopentamethylene, 3-aza- 2- iminopentamethylene (-CH2CH2NHC(NH)CH2-), 2,4-aza-2-methyl-3,3-dioxo- · 25 3-thiapentamethylene (-CH2NHS(0)2N(CH3)CH2-), 3-hydroxy-2,4-oxa-3-oxo- 3- phosphapentamethyiene (-CH20P(0)(0H)0CH2-), 3-aza-2-oxo-4-carboxyhexamethylene, 4- aza-1 -oxa-3-oxohexamethylene, 1 -thia-3-oxo-4-azahexamethy lene, 1 -thia-1,1,3-trioxo-4-azahexamethylene (-CH2CH2NHC(0)CH2S(0)2-), 3-aza-4-oxoheptamethylene, 1.4.7- trioxaoctamethylene, 6-aza-l-oxa-2,5-dioxooctamethylene 30 (-CH2CH2NHC(0)CH2CH2C(0)0-), 3-aza-4-oxodecamethylene, etc.). “Heteroaryl” means an aromatic monocyclic or fused polycyclic divalent radical having the number of annular atoms indicated, wherein each ring contained therein is comprised of 5 to 11 LV 12495 6 annular members and one or more of the annular atoms is a heteroatom moiety selected from -N=, -NR·7-, -O- or -S-, wherein R17 is hydrogen or (C w)alkyl, and each ring contained therein is comprised of 5 to 6 annular members (e.g., hetero(C5.u)aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo[6]thienyl, isobenzofiiranyl, purinyl, 5 isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.). “Heterocycloalkyr means cycloalkyl, as defined above, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as defmed in the Dētai led Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(Cj.,4)alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, 10 imidazolidmyl, quinuclidinyl, morpholinyl, etc.). “Heterocycloalkylene” means cycloalkylene, as defmed above, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as defmed in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative^ thereof (e.g., the term heterocyclo(C3.M)alkylene includes piperidylene, pyrrolidinylene, 15 pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.). ~ “Heteropolycycloaryl” means polycycloaryi, as deftned below, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as set defined in the ;- ;
Detailed Description of the Invention, and any carbocyclic ketone, thioketone of iminoketone :: derivative thereof (e.g., heteropolycyclo(Cg.|0)alkyl includes 3,4-dihydro-2//-quinolinyl, ^ 20 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2//-[l,8]naphthyridinyl, 2,4-dioxo-3,4-dihydro-2//-quinazolinyl, 3-oxo-2,3-dihydrobenzo[l,4]oxazinyl, etc.). “Hydroxy” means the radical -OH. “Immunomediated inflammatory disorder” means those diseases associated with mast celi mediator release and susceptible to treatment with a tryptase inhibitor (e.g., immediated type 25 hypersensitivity diseases such as asthma, allergic rhinitis, urticaria and angioedema, eczematous anaphylaxis, derraatitis such as atopic dermatitis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disorder, ocular and vemal conjunctivitis, rheumatoid arthritis, inflammatory skin conditions, and the like). “Hyper-responsiveness” means the late phase bronchoconstriction and airway 30 hyperreactivity associated with chronic asthma. Hyper-responsiveness of asthmatic bronchiolar tissue is believed to result from chronic inflammation reactions, which initate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. 12 “Syncytial virai infection” means an infection by a virus, such as a respiratory syncytial vīrus, causing the formation of a cellular protoplasmic mass, i.e. syncytia, via infection. “Imino” means the radical =NH. “Isomers” mean compounds of Formula I having identical molecular formulae but differ 5 in the nature or sequence of bonding of their atoms or in the ajrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “steroisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers”. A carbon atom bonded to four nonidentical substituents is termed a “chiral 10 center”. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a “racemic mixture”. A compound that has more than one chiral center has 2"*1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diasteromer or as a mixture of diastereomers, termed a “diastereomeric mixture”. When one chiral center is present a stereoisomer may be 15 characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog and the absolute descriptor Λ or 5 is cited in parenthesis followed by a hyphen and the Chemical name of the compound. Compounds of Formula I that contain a 20 chiral center can exist as individual stereosiomers or mixtures of steroisomers. For the purposes of the present application when referring to a compound of Formula I by name or by formula and the configuration is not designated, it is to be understood that the referenece is to ali possible configurations of the compound. "Optional" or "optionally” means that the subsequently described event or circumstance 25 may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. Forexample, the phrase "optionally is substituted with one to three radicals" means that the group referred to may or may not be substituted in order to fall within the scope of the invention. ‘W-oxide derivatives” means a derivāti ves of compound of Formula I in which nitrogens 30 are in an oxidized State (i.e., O-N) and which possess the desired pharmacological activity. The N-oxide derivatives of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art 13 LV 12495 “Pathology” of a disease mcans the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes. “Phannaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is ģenerāli safe, non-toxic and neither biologically nor othenvise undesirabale 5 and includes that which is acceptable for veterinary use as well as human pharmaceutical use. “Pharmaceutically acceptable salts" means salts of compounds of Formula 1 which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic 10 acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, l,2~ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 15 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, £. 4-methylbicyclo[2.2.2]oct-2-ene-1 -caiboxylic acid, glucoheptonic aicd, ~ 4,4’-methylenebis(3-hydroxy-2-ene-1 -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiafy butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, >· hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. ;:; 20 Pharmaceutically acceptable salts aiso include base addition salts which may be formed - vvhen acidic protons present are capable of reacting with inorganic or organic bases. Acceptabale inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydoxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. 25 **Polycycloaryr means a fused polycyclic radical containing the number of carbon atoms indicated, wherein at least one, but not ali, of the fused rings comprising the radical is aromatic and each ring contained therein is comprised of five to six annular members, and any carbocyclic ketone and thioketone derivative thereof (e.g., polycyclo(C9_10)aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, l,2-dihydronaphthyl, 2,4-dioxo-l,2,3,4-tetrahydronaphthyl, etc.). 30 “Prodrug derivatives" means derivatives of compounds of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Suitable prodrug derivatives include those compounds of Formula I in which one or more nitrogen and/or oxygen 14 atoms with an available free valence are substituted with a group which is readily cleavable by in vivo processes. For example, prodrug derivatives of compounds of Formula I may contain one or more //-substituted amino groups (e.g., -NH2(R18)) //-substituted nitrogen atoms incoīporated into an aliphatic, alicyclic or aromatic structure (e.g., -N(R18)-), //-substituted imino or amidino 5 groups (e.g., -C(NR‘*)H, -C(NRIS)NH2 or -C(NH)NHRU), N-substituted guanidino groups (e.g., -NHC(NRl8)NHRlg, -NHC(NH)NHR“ or-NHC(NR,s)NH2), and the like, in which R18 is (i) -C(0)R19 or-CH(R20)OC(O)R19, wherein R19 is (CM0)alkyl, (C,.,0)alkyloxy, carbamoyl, (C,.l0)alkylcaibamoyl, di(C1.10)alkylcarbamoyl,cts-2-(C|.|0)alkanoyloxyphenylvinyl, 3-(C|.io)alkanoyloxybutyryl, (C3.l0)cycloalkyl, hetero(Cj.|0)cycloalkyl, (C^a^l or 10 hetero(Cj.|0)aryl and R20 is hydrogen or (C,.,0)alkyl; (ii) -X7-R21, wherein X7 is (C,.,0)alkylene and R21 is carboxy; or (iii) -CiOJOCHtR^OCiOJR23, wherein R22 is hydrogen, (C,.,0)alkyl or (Cj.|0)cycloalkyl and R23 is (C|.10)alkyl or (C3.l0)cycloalkyl. In addition, prodrug derivatives of compounds of Formula I may contain one or more //-hydroxylated imino or amidino groups (e.g., -C(NOR24)H, -C(NOR24)NH2 or -C(NH)NHOR24) or //-hydroxylated guanidino groups 15 (e.g., -NHC(NOR24)NH2, -NHC(NH)NHOR24), in which R24 is hydrogen, methyl, -C(0)R2i or -CH(R26)0C(0)R2S, wherein R25 is (CM0)alkyl or (C3.i0)cycloalkyl and R26 is hydrogen or (C,.,0)alkyl; //-substituted hydroxy groups (e.g.,-OR27), in which R27 is -C(0)R19 or -CH(R20)OC(O)R19, wherein R19 and R20 are as defined above; and/or ester derivatives of carboxylic acids (e.g., -C(0)0R28) wherein R28 is (CM0)aIkyI or (C3.,0)cycloalkyl. 20 "Protective group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a Chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed. "Protected derivatives" means derivatives of compounds of Formula I in which a reactive 25 site or sites are blocked with protective 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 ferf-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981). In particular, a suitable protected derivative of Formula I is exemplified by the 30 compound 2-[5-(l,3-dioxo-l,3-dihydroisoindol-2-ylmethyl)-l//-benzoimida2ol-2-ylmethyl]-4,5,6,7-tetrahydro-l//-benzoimidazole-5-carboxylic acid. 15 LV 12495 “Therapeutically effective amount” means that amount which, when administered to an animal is effective for treating a disease. "Treatment" or "treating" refers to any administration of a compound of the present invention and includes: 5 (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptoms of the disease, (2) inhibiting the disease, i.e., arresting development of its pathology and/or symptoms, or (3) ameliorate the disease, i.e., reversing its pathology and/or symptoms. 10 “Sulfo” means the radical -S(0)0H. “Uriedo” means the radical -NHC(0)NH3.
The compounds of Formula I and the intermediates and starting materiāls used in their preparation are named in accordance with IUPAC rules ofnomenclature. For example, a compound of Formula I in vvhich: 15 A together with B comprises 5-guanidino-l//-benzoimidazol-2-yl, C comprises s 5-(2-naphth-l-ylethylcarbamoyl)-l//-benzoimidazol-2-yl and X3 is -CH2- is named ^ 2-(5-guanidino-l//'-benzoimidazol-2-ylmethyl)-./V-(2-naphth-l-ylethyl-l//-benzoimidazole- 5- carboxamide; * v, A together with B comprises 5-guanidino-l//-benzoimidazol-2-yl, C comprises 20 6-(2-naphth-1 -ylethylcarbamoyl)-1 -methyl-1 //-benzoimidazol-2-y 1 and X3 is -CH2- is named 2-(5-guanidino- l/f-benzoimidazol-2-ylmethyl)-3-methyl-Ar-(2-naphth-1 -y lethyl-3//-benzoimidazole-5-carboxamide; A together with B comprises 5-guanidino-l//-benzoimidazol-2-yl, C comprises 6- [2-(2-carboxyphenyl)ethylcarbamoyl]-1 -(3-sulfopropyl-1 //-benzoimidazol-2-yl and X3 is 25 -CH2- named 2- {2-[2-(5-guanidino-li/-benzoimidazol-2-ylmethyl)-3-(3-sulfopropyl)- 3/f-benzoimidazol-5-ylcarbonylamino]ethyl}benzoic acid; and A together with B comprises 5-guanidino-l/f-benzoimidazol-2-yl, C comprises 6-[2-(2-methoxyphenyl)ethylcarbamoyl]-l-(3-sulfopropyl-l//-benzoimidazol-2-yl and X3 is -CHj-is named 3- {2-(5-guanidino-1 //-benzoimidazol-2-ylmethyl)-30 6-[2-(2-methoxyphenyl)ethylcarbamoy lļbenzoimidazol-1 -yl} propane-1 -sulfonic acid. 16
Certain compounds of Fonnula I exist in tautomeric equilibrium. For example, compounds of Fonnula I in which C comprises 4,5,6,7-tetrahydro-3i/'-imidazo[4f5-c]pyridin-2-yl exist in equilibrium between tautomers of the fo!lowing fonnulae:
and, hence, while the compounds of this invention may be named, illustrated or othenvise described in this application as one possible tautomer, it is to be understood that ali possible 10 tautomers are meant to be encompassed by such names, illustrations and descriptions. Thus, the name ethyl 2-(4-{2-[ l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-l ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate is meant to include its tautomers ethyl 2-(4- {2-[ 1 -(5-guanidino-3//-benzoimidazol-2-yl)ethyl]-l ,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate, ethyl 2-(4- {2-[l-(5-guanidino-15 1 //-benzoimidazol-2-yl)ethyl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl} - 4-oxobutyl)benzoate and ethyl 2-(4-{2-[l-(5-guanidino-3//-benzoimidazol-2-yl)ethyl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl} -4-oxobutyl)benzoate.
Presently Preferred Embodiments: 20 While the broadest definition of this Invention is set forth in the Summary of the
Invention, certain aspects of the Invention are preferred. A preferred aspect of the Invention is a compound of Formula I in which A together with B comprises a fused heterobicyclic radical wherein A contains 5 annular members and B contains 6 annular members and X4 and X5 are adjacent members of an oxazol-2-yl, l//-imidazol-2-yl or thiazol-2-yl ring. 17 LV 12495 A preferred aspect of the Invention are compounds of Fomiula II:
in which: 5 the dashed lines independently represent optional bonds; each R2 independently is (C,JaIkyl, (C,.6)alkyloxy, halo or hydroxy; each R3 independently is (Cw)alkyl, (C,^)alkyloxy, halo or hydroxy; X3 is -C(0>- or -CR7RS-, X8 is -CH(R')nl- or -C(R')n,=, wherein R1 is amino(NM)azolidinyl, amino(NM)azolyl, 10 (NM)azolidinyl, (NM)azolyl, -NHC(NH)NR9R9, -C(NR’)R9, -C(NH)NHR'°, -C(NH)NR,0R'° or -{CR1 lRll)yNH:, or X8 is -N= or -NH(R')Bl- wherein R' is -C(NR9)R9, -C(NH)NHR'° or --C(NH)NR'°R10, wherein each R9 independently is hydrogen or (C,.6)alkyl and each R'° independently is (C,.6)alkyl; and X9 is -CH(R4)- or -C(R>, wherein R4 is -R'\ -OR12, -N(RI3)R'2, -SR12, -S(0)R12, -S(0)2 15 R'2, -S(0)20 R'2, -S(0)zN(R13)R12, -N(R13)S(0)2R12, -C(0)R12, -C(0)0R12, -C(0)N(Ru)R12, -N(R13)C(0)R12, -0C(0)N(Rl3)R12, -N(R'3)C(0)0R12, -<CH2)n4N(Rl3)C(0)N(R13)R12, -OP(0)(OR,3)0 R12 or -C(0)N(RU)CH(COOH)R12, or X9 is -N=or-N(R4K wherein R4 is -C(0)R12, -C(0)0R12, -C(0)N(R13)R12, -0C(0)N(R,3)R‘2 or-C(0)N(R'4)CH(COOH)R'\ wherein R12, R13 and R14 are as defined in the Summary of the Invention. 20 A preferred aspect of the invention are compounds of Formula I in which:
Rs is hydrogen or (CM)alkyI, R6 is hydrogen or (CM)alkyl, which alkyl optionally is substituted with one to two substituents independently selected from (CM)alkyloxy, hydroxy and sulfo, R7 is hydrogen or methyl and R* is hydrogen, methyl or hydroxy; X8 is -CH(R4)- or -C(R')n,=, wherein R1 is aminomethyl, l-aminocyclopropyl, 25 2-aminoimidazol-1 -yl, 2-amino-1,1 -dimethylethyl, imidazo!yI, tetrazolyl, -(CH2)XNHC(NR9)R9, -{CH2)XNHC(NH)NR9R9 and -C(NR9)R9, wherein each R9 independently is hydrogen or methyl, or X8 is -N(R‘)nr, wherein R‘ is -CiNR’ļR9, -C(NH)NHR'° or -C(NH)NR‘°R10, wherein each R9 18 independently is hydrogen or methyl and each R10 is methyl, wherein any aliphatic or alicyclic moiety comprising R1 optionally is substituted with one to two substituents independently selected from methylsulfonyl and carboxy; X9 is -C(R>, wherein R4 is -R'2, -OR'2, -C(0)R'2, -C(0)OR‘2, -C(0)N(R'3)R‘2 or 5 -C(0)N(R,4)CH(C00H)R12, wherein R13 and R14 independently are hydrogen or (C,^)alkyl; R12 is -R’5 or -X‘-{R15)nlj, wherein X6 is (CM0)alkylene or hetero(C2.,0)alkylene and each R15 independently is hydrogen, (C6.,4)aryl, cyclo(Cj_l4)alkyl, polycyclo(C6.l4)aryl, heteropolycyclo(C6.,4)aryl, heterocyclo(Cj_,4)alkyl or hetero(Cj.,4)aryl; any aliphatic and alicyclic moiety comprising R4 optionally is substituted with one to five 10 substituents independently selected from (C,.4)alkyloxy, (CM)alkyloxycarbonyl, amino, carbamoyl, carboxy and hydroxy; and any aromatic moiety comprising Rli optionally is substituted with one to three substituents independently selected from (CM)alkyl, (CM)alkyloxy, (CM)alkyloxycarbonyl, carbamoyl, caxboxy, cyano, cyclo(C3.6)alkyloxy, halo, hetero(C,.8)alkyl, 15 hetero(C|.j)aIkylcarbonyl, hetero(Cj.6)aryl and trifluoromethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. A preferred aspect of the invention are compounds of Formula I in which: A together with B comprises 4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl, wherein 20 n2 is 0 and R1 is -C(NR’)R9, or A together with B comprises l//-benzoimidazol-2-yl or 4,5,6,7-tetrahydro-lf/-benzoimidazol-2-yl, wherein R1 is aminomethyl or guanidino and each R2 independently is halo or hydroxy; C comprises 4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl or 1 //-benzoimidazo l-2-yl, wherein R4 is -C(0)X6-R'J, -C(0)0X6-R15 or -C(0)NHX6-R15, wherein X6 is (CM)alkylene or 25 hetero(C2^)alkylene and R15 is (C6.10)aiyl, (C6.,0)aryloxy, polycyclo(C6.10)aryl, hetero(C5.|0)aryl, hetero(C5.,0)aryloxy or heteropolycyclo(C6.,4)aiyl; and any aromatic moiety comprising R,J optionally is substituted with one to three substituents independently selected from (CM)alkyl, (CM)alkyloxy, (CM)alkyloxycarbonyl, carboxy, carbamoyl, halo, hydroxy and tētrazol-l-yl; and the N-oxide derivatives, prodrug 30 derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof. 19 LV 12495 A preferred aspect of the invention are compounds of Formula I in which nl is 0 and each R2 independently is halo or hydroxy, in particular: 2-(2-{2-[l-{4,6,7-trifluoro-l//'-benzoimida2ol-2-yl)ethyl]-3-melhyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid; 5 2-(2-{2-[l-(5,6-difluoro-l/7-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylainino} ethoxy)benzoic acid; butyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//*benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate; propyl 2-(2- {2-[ 1 -(5-hydroxy- l//-benzoimidazol-2-yl)ethy l]-3-methy Ι-ΙΟ 3//-ben2oimidazol-5-ylcarbonylamino}ethoxy)benzoate; and isobutyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoate. A preferred aspect of the invention are compounds of Formula I in which R‘ is guanidino of aminomethyl, in particular. 15 2-(5-guanidino-1 //-benzoimidazol-2-ylmethyl)-3-methyl-/V-(2-naphth-1 -ylethy I)- K. 3//-benzoimidazole-5-carboxamide; ethyl 2-(4- {2-[ 1 -(5-guanidino-lf/-benzoimidazol-2-yl)ethyl]-l,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)ben2oate; 2-(5-guanidino-1 //-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-20 Af-(2-naphth-l-ylethyl)-3//-benzoimidazole-5<arboxamide; 2-(5-guanidino-l//-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl-N-(2-naphth-1 -ylethyl)-3/f-benzoimidazole-5-carboxamide; 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl- N-(2-naphth-l-ylethyI)-3//-benzoimidazole-5-carboxamide; 25 2-(5-guanidino-1 //-benzoimidazol-2-ylmethyl)-3-(2-hydroxy)ethyl- AH2-naphth-l-ylethyl)-3i/-benzoirnidazole-5-carboxarnide; 2-[l -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]-N-[2-(2-carbamoylphenoxy)ethyl]- 3-methyl-3//-benzoimida2ole-5-carboxamide; 2-[ 1 -(5-guanidino-1 tf-benzoimidazol-2-yl)ethyl]-N-[2-(2-carbamoyl-30 4-chlorophenoxy)ethyl]-3-methyl-3čf-benzoimidazole-5-carboxamide; 4-chloro-2-[2-( {2-[ 1 -(5-guanidino- l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonyl} amino)ethoxy]benzoic acid; 20 5‘Chloro-2-[2-({2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonyl} amino)ethoxy]benzoic acid; 2-(5-aminomethyI-l//-bcn2oimidazol-2-ylmethyl)-3-methyl-//-(2-naphth-1 -ylethyl)-3//-benzoimida2olc-5-carboxamidc; and 5 2-(5-aminomethyl-4,5,6,7-tctrahydro-l//’-benzoimidazol-2-ylniethyl)-3-methyl- //-(2-naphth-1 -ylcthyl)-3//-benzoimidazole-5-carboxamide. A preferred aspect of this invention are compounds of Fonnula I in which C comprises 4.5.6.7- tetrahydro-ltf-imidazo[4,5-c]pyridin-2-yl and R1 is -C(NH)R9, in particular: 2-[2-(2-{l-[5-(l-iminoethyI)-4,5,6,7-t€trahydro-l//-iinidazo[4,5-c]pyridin-2-yl]ethyl}- 10 3-methyl-3//-benzoimidazol-5-ylcarbonylaxnino)ethoxy]benzoic acid; 2-[5-( 1 -iminoethy 1)-4,5,6,7-tetrahydro- l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-N-(2-naphth-1 -ylcthyl)-3//-benzoimidazole-5-carboxamide; 2-[5-(l-iminoethyI)-4,5,6,7-tcirahydro-l//'-imidazo[4,5-c]pyridin-2-ylcarbonyl]-3 -methyl-A/'-(2-naphth-1 -ylethyl)-3//’-benzoimidazoIc-5-carboxamide; 15 2-(5-iminomethyl-4,5,6,7-tetrahydro- l//-imidazo(4,5-c]pyridin-2-ylmethyl)*3-methyl- jV-(2-naphth-1 -ylethyl)-3/f-benzoimidazole-5-carboxamide; 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-jV-(2-hydroxy-2-naphth-1 -ylethyl)-3iT-benzoimidazole-5-carboxaxnide; 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyndin-2-ylmethyl]-3-methyl-20 /V-[2-(2-hydroxynaphth-1 -yl)ethyl]-3/f-benzoimidazole-5-carboxamide; 2-[5-( 1 -iminoethyI)-4,5,6,7-tetrahydro- l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-yV-[2-(4-hydroxynaphthal-1 -yl)ethyl]-3//-benzoimidazole-5-carboxamide; 2- {1 -[5-( 1 -iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl} -3-methyl-N-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide; 25 ethyl 2-[2-(2- {1 -[5-( 1 -iminoethyl)-4,5,€,7-tetrahydro- l//-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3if-benzoimidazol-5-yk:arbonyiamino)ethoxy]benzoate; 2-[2-(2- {1 -[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl} -3-(2-methoxyethyl)-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid; 30 ethyl 2-[2-(2- {1 -{5-(l -iminoethyl)-4,5,6,7-tetrahydro- l//-imidazo[4,5-c]pyridin-2-yl}ethyl}- 1.4.6.7- tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino)ethoxy3benzoate; and 21 LV 12495 2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/f-imidazo[4,5-c]pyridm-2-yl]ethyl}- 3-methyl-Af-[2-{2-tetrazolylphenoxy)ethyl]-3//-benzoimidazolc-5-carboxainide.
Pharmacology and Utility: 5 The compounds of this invention are serine protease inhibitors and, as such, are useful in treating diseases associated with increased serine protease activity. In particular, the compounds of this invention are tryptase inhibitors and are useful in treating diseases associated with increased tryptase activity. In vitro protocols for screening potential inhibitors as to their ability to inhibit tryptase are known in the art See, e.g., Stuīzebecher et al. (1992) Biol Chem. 10 Hoppe-Seyler 373:1025-1030. Typically, these assays measure the enzyme-induced hydroiysis of peptide-based chromogenic substances. Details of an exemplary procedure for measuring tryptase inhibitory activity are described below.
In addition, the activity of the compounds of the present invention can be evaluated in vivo in one of numerous animal models of asthma. See, Larson, "Experimental Models of 15 Reversible Airway Obstruction", in The Lung: Scientific Foundations, Crystal, West et al./ eds., Raven Press, New York, 1991; Wamer et al. (1990) Am. Rev. Respir. Dis. 141:253-257. An ideal animal modei would duplicate the chief clinical and physiological features of human asthma, including: airway hyper-responsiveness to Chemical mediators and physicai stimuli; : reversai of airway obstruction by drugs useful in human asthma (β-adrenergics, methylxanthines, 20 corticosteroids, and the like); airway inflammation with infiltration of activated leukocytes; and chronic inflammatory degenerative changes, such as basement membrane thickening, smooth muscle hypertrophy, and epithelial damage. Species used as animal models include mice, rats, guinea pigs, rabbits, dogs, and sheep. Ali have some limitations, and the proper choice of animal modei depends upon the question which is to be addressed. 25 The initial asthmatic response can be evaluated in guinea pigs, and dogs, and particularlv, with a basenji-greyhound cross strain which develops nonspecific airway hyper-responsiveness to numerous nonallergenic substances, such as methacholine and citric acid. Certain selected sheep exhibit a dual response after antigen challenge with Ascaris proteīns. In dual responding animals, the initial asthmatic response (IAR) is folIowed by a late asthmatic response (LAR) at 30 6-8 hours post-exposure. Hypersensitivity to the cholinergic agonist carbachol increases at 24 hours after antigen challenge in those animals which exhibit LAR. 22
The allergic sheep modei (see below) was used to evaluate the potential antiasthmatic efFects of the compounds of the present invention. Administration of compositions comprising the compounds of the present invention to allergic sheep in both oral and inhalant or aerosol formulations, prior to or following exposure to specific allergens demonstrates that such 5 compositions substantially lessen or abolish the late asthmatic response and consequent hyper-responsiveness.
The compounds of this invention are also useful for the treatment of other immunomediated inflammatory disorders in which tryptase activity contributes to the pathological condition. Such diseases include inflammatory diseases associated with mast celis, 10 such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflammatory bowel disease, peptic ulcers and various skin conditions. Further, the compounds of the present invention can be used to treat syncytial virai infections.
The efficacy of the compounds of the present invention for the treatment of the vast 15 majority of immunomediated inflammatory disorders can be evaluated by either in vitro or in vivo procedures. Thus, the anti-inflammatory efficacy of the compounds of the present invention can be demonstrated by assays well known in the art, for example, the Reversed Passive Arthus Reaction (RPAR)-PAW technique (see, e.g., Gangly et ai (1992) U.S. Patent No. 5,126,352). Assays for determining the therapeutic value of compounds in the treatment of various skin 20 conditions, such as hyperpro!iferative skin disease, are well known in the art, for example, the Arachidonic Acid Mouse Ear Tēst (Id.). The compounds of the present invention can be evaluated for their antiulcer activity according to the procedures described in Chiu et ai (1984) Archives Intemationales de Pharmacodynamie et de Therapie 270:128-140.
The efficacy of the compounds of the present invention in blocking celi fusion caused by 25 a syncytial virus infection can be evaluated by the methods generally set forth in Tidwell, et ai, 1 Med. Chem. 26:294-298 (1983).
Compositions and Admininstration:
According to this invention, a therapeutically or pharmaceutically effective amount of a 30 compound of the invention is administered to a patient suffering from an immunomediated inflammatory disorder. According to one embodiment, the compositions of the present invention are useful for preventing or ameliorating asthma. In using the compositions of the present 23 LV 12495 invention in a treatment of asthma, the compounds may be administered prophylactically prior to exposure to allergen or other precipitating factor, or after such exposure. The compounds of the present invention are particularly useful in ameliorating the late-phase tissue destruction seen in both seasonal and perennial rhinitis. Another aspect of the present invention is directed to the prevention and treatment of other immunomediated inflammatory disorders associated with mast celis such as urticaria and angioedema, and eczematous dermatitis (atopic dermatitis), and anaphylaxis, as well as hypetproliferative skin disease, peptic ulcers, and the like. In stili a further embodiment, the compounds of the present invention are used to treat syncytial virai infections, particularly infections of respiratory syncytial virus.
The compositions containing the compounds can be administered for therapeutic and/or prophylactic treatments. In therapeutic applications, compositions are administered to a patient already suffering from a disease, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount or dose." Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. ::
In prophylactic applications, compositions containing the compounds of the invention are administered to a patient susceptible to or othenvise at risk of a particular disease in an amount sufficient to prevent or ameliorate the onset of symptoms. Such an amount is defined to be a £ "prophylactically effective amount or dose." These can be administered orally or by inhalation.
In this use, the precise amounts again depend on the patient's State of health, weight, and the like.
Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a funetion of the symptoms, to a Ievel at which the improved condition is retained. When the symptoms have been alleviated to the desired Ievel, treatment can cease. Patients can, however, require inteimittent treatment on a long-term basis upon any recurrence of the disease symptoms.
In general, a suitable effective dose of the compounds of the present invention will be in the range of 0.05 to 1000 milligram (mg) per recipient per day, preferably in the tange of 0.1 to 100 mg per day. The desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervāls throughout the day. These subdoses can be 24 administered as unit dosagc forms, for example, containing 0.01 to 1000 mg, preferably 0.01 to 100 mg of active ingredient per unit dosage form.
The composition used in these therapies can be in a variety of fonns. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, enteric-coated tablets, pilis, 5 powders, liquid Solutions or suspensions, liposomes, injectable and infusible Solutions. Inhalable preparations, such as aerosols, are also included. Preferred formulations are those directed to oral, intranasal, topical and parenteral applications, but it will be appreciated that the preferred form will depend on the particular therapeutic appiication at hand. Especially preferred formulations are oral or aerosol. The methods for the formulation and preparation of therapeutic 10 compositions comprising the compounds of the invention are well known in the art and are described in, for«xample, Remington's Pharmaceutical Sciences and The Merck Index 11* Ed., (Merck & Co. 1989).
While it is possible to administer the active ingredient of this invention alone, it is preferable to present it as part of a pharmaceutical formulation. The formulations of the present 15 invention comprise at least one compound described herein in a therapeutically or pharmaceutically effective dose together with a pharmacologically acceptable carrier. The pharmaceutical compositions will thus contain the compounds of the present invention in concentrations sufficient to deliver an appropriate dose. For example, where the appropriate dose is 0.05 mg per day, the concentration of the compound of the invention in the pharmaceutical 20 composition would be 0.05 mg per dose, where one dose per day is used. For inhalant or aerosol compositions, the concentration of the compounds of the present invention in the composition will generally depend upon the amount of the dose. Typical concentrations of the compounds of the present invention in inhalant or aerosol compositions would be from about 0.01 to about 30 mg/mL. The formulation may include other clinically useful compounds, such as β-adrenergics 25 (e.g·., albuterol, terbutaline, formoterol, fenoterol, and prenaline) and corticosteroids (e.g., beclomethasome, triamcinolone, flunisolide, and dexamethasone).
Chemistry:
Generally, the compounds of the present invention are synthesized using Standard 30 techniques and reaģents known to and used by those of skill in the art. It will be noted that the linkages between the various functional groups generally comprise carbon linked to the nitrogen of an amide or carbamate, the oxygen of a carbamate or the carbon of a carbonyl. Those of skill 25 LV 12495 5 in the art will recognize that methods and reaģents for forming these bonds are well known and readily available. See, e.g., March, Advanced Organic Chemistry, 4th Ed. (Wiley 1992), Larock, COMPREHENSIVE ORGANIC Transformations (VCH 1989); and Fumiss, et ai, VOGEL'S ΤΕΧΤΒΟΟΚ OF PRACnCAL ORGANIC CHEMISTRY 5th ed. (Longman 1989), each of which is incorporated herein by reference.
Compounds of Formula I in which X4 and Xs are adjacent members of an oxazol-2-yl, l//-imidazol-2-yl or thiazol-2-yl ring can be prepared by the methods depicted in the following reaction scheme:
Scheme 1 10
in which L is a leaving group, D together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein 15 each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom, R29 is -OH, -NHR6 or -SH, X* is -O-, -NR6- or -S- and n2, n3, n4, A, B, X‘, X2, X3, XJ, R1, R2, R3, R4 and R6 are as defined in the Summary of the Invention.
Compounds of Formula I in which X4 and X5 are adjacent members of an oxazol-2-yl, li/-imidazol-2-yl or thiazol-2-yl ring (Formula I(a)) can be prepared by reacting a compound of 20 Formula 1, or a protected derivative thereof with a compound of Formula 2, or a protected derivative thereof, and then deprotecting if necessary. The reaction between the compounds of 26
Foimulae 1 and 2 may be carried out ncat, but preferably is carried out in thc prcscncc of 1,3 -dimethy 1-3,4,5,6-tetrahydro-2( 1 //)-pyrimi dinone (DMPU) or polyphosphoric acid, at 160 to 200eC, prefcrably 180-190°C, and requires 1 to 5 hours to complete (e.g., sce Examples 4(d), 6(h), 8(k), 9(d) and 10(d), infra.). Deprotection can be effected by any means which removes the 5 protective group and gives the desired product in reasonable yield (e.g., see Example 2(g), infra.).
In a similar fashion, compounds of Formula I in which X1 and X2 adjacent members of an oxazol-2-yI, l//-imidazol-2-yl or thiazoI-2-yl ring can be prepared by the methods depicted in the following reaction scheme: 10 Scheme 2
in which L is a leaving group, R30 is -OH, -NHR5 or -SH, X® is -O-, -NR6- or -S- and n2, n3, n4, 15 B, C, X1, X3, X4, X5, R‘, R2, R3, R4 and R6 are as defined in the Summary of the Invention (e.g., see Examples 2(e) and 7(h), infra.).
Isolation and purifrcation of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purifrcation procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or 20 thick-layer chromatography, high-pressure liquid chromatography (HPLC), or a-combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had 27 LV 12495 by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, be used. Nuclear magnetic resonance (NMR) spectra were recorded on a General Electric "QE Plus" spectromcter (300 MHz). Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 Fourier Transform IR (FTIR). Analytical HPLC was perfoimed on a 5 Ultrafast Microprotein Analyzer, Michrom BioResources, Inc. equipped with a PLRP column, lmm x 150mm. Preparative HPLC was perfoimed on a Gilson LC using a VYDAC 1x25 cm Cu reverse phase (RP) column or a Waters Prep LC2000 system using a Vydac 5x25 cm Ct8 RP column. Mass spectra (MS) were obtained on a Finnigan SSQ 710 with an ESI source by direct infusion or by HPLC MS (Ultrafast Microprotein Analyzer, CIS column 2mm X 150 mm). 10 Unless othenvise noted, ali reaģents and equipment were either prepared according to published procedures or were purchased from commercial sources, such as Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (Sl Louis, MO) and ICN Chemical Co. (Irvine, CA).
The techniques Used to perform the syntheses described below will be recognized by those of skill in the art as routine (see, e.g., March, Larock, or Fumiss, supra). 15
Additional Processes for Preparing Compounds of Formula I:
Compounds of Formula I may be prepared as phaimaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a phannaceutically acceptable inorganic or organic acid. Altematively, the pharmaceutically acceptable base 20 addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the phaimaceutically acceptable salts of compounds of Formula I are set forth in the defrnitions section of this application. Altematively, the salt forms of the compounds of Formula I may be prepared using salts of the 25 starting materiāls or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of 30 Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc). 28
The jV-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art For example, A-oxides can be prepared by treating an unoxidized forrn of the compound of Formula I with an oxidizing aģent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, mem-chloroperoxybenzoic acid, etc.) in a suitable inert 5 organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0°C. Altematively, the N-oxides of the compounds of Fomiula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from //-oxides of compounds of Formula I by treating with a reducing aģent (e.g., sulfur, sulfur dioxide, triphenyl 10 phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80°C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., see Example 12, infra.). For further details on prodrugs and their preparation see Saulnier et a/.(l 994), Bioorganic and Medicīnai Chemistry Letters. 15 4:1985)..
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. 20 Compounds of Formula 1 can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving aģent to form a pair of diastereoisomeric comounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be cairied out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline 25 diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these disimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving aģent, by any practical means that would 30 not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean 29 LV 12495
Jacques Andre Collet, Samuel H. Wilen, Enantiomcrs, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).
In summary, an aspect of this Invention is a process for preparing a compound of Formula I, which process comprises: 5 (a) reacting a compound of Formula 1:
10 or a protected derivative thereof, with a compound of Formula 2:
15 or a protected derivative thereof, in which L is a leaving group, D together with the vinylene moiety to which it is fiised comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom, R29 is -OH, -NHR6 or -SH and nl, n2, n3, A, B, X‘, X2, X3, R‘, 20 R2, R3, R4 and R6 are as defined in the Summary of the Invention, and then deprotecting if necessary to give a compound of Formula I in which X4 and Xs are adjacent members of an oxazol-2-yl, l#-iraidazol-2-yl or thiazol-2-yl, ring; or 30 (b) reacting a compound of Formula 3:
5 or a protected derivative tbcreof, with a compound of Formula 4:
or a protected derivative thereoi; in which L is a leaving group, R30 is -OH, -NHR5 or -SH and 10 nl, n2, n3, B, C, X3t X4, X3, R't R\ R3, R4 and R5 are as defined in the Summaiy of the Invention, and then deprotecting if necessary to give a compound of Formula I in which X1 and X2 are adjacent members of an oxazol-2-yl, l/f-imidazoI-2-yl or thiazol-2-yl ring; (c) optionally further converting a compound of Formula I into a phannaceutically acceptable salt; 15 (d) optionally further converting a salt form of a compound of Formula I to non-salt form; (e) optionally further converting an unoxidized form of a.compound of Formula I into a pharmaceutically acceptable N-oxide; (f) optionally further an N-oxide form of a compound of Formula I its unoxidized form; (g) optionally further converting a non-derivatized compotmd of Formula I into a 20 pharmaceutically prodrug derivative; and (h) optionally further converting a prodrug derivative of a compound of Formula I to its non-derivatized form. £xamples: 25 The following examples are provided merely for the purposes of illustration and are not to be construed in any way as iimiting the scope of the present invention. Those skilled in the art will recognize that certain variations and modifications can bc practiccd within the scope of the invention. 31 LV 12495 EXAMPLE 1 2-Naphth-2-ylethylamine A solution comprising 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) was 5 combined under nitrogen with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) and l,8-diazaabicyclo[5.4.0Jundec-7-ene (0.47 mL. 3.14 mmol). The mixturewas heated at 65°C for 3 hours and then partitioned bctween water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3 N hydrochloric acid and then saturated sodium bicarbonate, dried (MgS04), filtered and 10 concentrated by rotary evaporation. The residue was dissolved in THF (5 mL) and the solution was combined with triphenylphosphine (1 g, 3.81 mmol), stirred for 2 hours at room temperature, diluted with water (0.100 mL), stinred 3 hours, diluted with concentrated hydrochloric acid (0.33 mL) to give a precipitate, treated with ethanol (5 mL) to dissolve the precipitate and treated with diethyl ether, added slowly, to give a white precipitate. The while 15 precipitate was isolated by filtration, washed with diethyl ether and dried under vacuum to provide 2-naphth-2-ylethylamine hvdrochloride (0.447 g, 75% yield); Ή-NMR (300Mhz, DMSO-d6): 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). 20 Proceeding as in Example 1 the foilowing intermediate amines were prepared: 2- naphth-l-ylethylamine, yield=56%, Ή-NMR (300Mhz, DMSO-d6): 8.26 (br s, 3H), 8.16 (d, 1H, J = 8.1 Hz), 7.92 (dd, 1H, J=1.5,7.8 Hz), 7.81 (dd, 1H, J=1.2,7.5 Hz), 7.40-7.56 (m, 4H), 3.37 (m, 2H), 3.05 (t, 2H, J=7.4 Hz); 3- cyclohexylpropylamine, yield=40%, Ή-NMR (300Mhz, CDCL3): 2.68 (t, 2H, J-7.2 25 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%, 'Η-NMR (300Mhz, DMSO-d6): 8.39 (br s, 3H), 7.26-7.41 (m, 5H), 6.72 (d, 1H, J = 16.2 Hz), 6.29 (dt, 1H, J=16.2,6.6 Hz), 3.56 (d, 2H, J = 6.6 Hz); 3-phenyl-2-propynylamine, yield=62%, Ή-NMR (300Mhz, DMSO-d6): 8.67 (br s, 2H), 30 7.38-7.42 (m, 5H), 3.91 (m, 2H); and 3,3-diphenylpropylamine, yield=50%, Ή-NMR (300Mhz, DMSO-d6): 8.10 (br s, 3H), 7.30 (m, 8H), 7.19 (m, 2H), 4.11 (t, 1H, J=7.9 Hz), 2.52 (m, 2H) 2.33 (m, 2H). 32 EXAMPLE2 2-(5-Arninomethyl-l//-benzoimidazol-2-ylmethyl)-/V-(4-phenylbutyl)-1 //-benzoimidazole- 5-carboxamide trifluoroacetate (Compound 1) 5 (a) Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was combined under nitrogen with anhydrous ethanol (6 mL, 105 mmol), The mixture was cooled to 10°C (ice/acetone) and bubbled 20 minūtes with dry hydrogen chloride gas. The mixture was slowly warmed to room temperature, sealed and stirred for approximately 18 hours. The mixture vvas 10 diluted with diethyl ether (400 mL) and Iet stand for 5 hours at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to provide ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; ‘Η-NMR (300Mhz, CDCL3): 7.84 (d, 1H, J - 10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H, J = 6.5 Hz), 1.89 (m, 4H). 15 (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 30 minūtes at 110°C under nitrogen. The mixture was poured over crushed ice (50 mL) and stirred 30 minūtes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether 20 and dried under vacuum to provide 2-ethoxycarbonylmethyl-l//-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); Ή-NMR (300Mhz, DMSO-dJ: 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J = 7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J=7.1 Hz). (c) A mixture of dinitrophenylmethanol (22 g, 111 mmol), triphenylphosphine (34.5 g,
25 131 mmol) and phthalimide (17.6 g, 119 mmol) in THF (450 mL) was stirred at -10°C (ice/acetone) under nitrogen while diethyl azodicarboxylate (20.7 mL, 131 mmol) was added dropwise. The mixture was stirred 2 hours at -10°C and then diluted with diethyl ether (900 mL) and stored at -20°C for approximately 18 hours to give a crystalline solid. The solid was isolated by filtration and washed to provide 2-(3,4-dinitrobenzyl)isoindole-l,3-dione (24.6 g, 67% yield) 30 as an off-white crystalline solid; Ή-NMR (300Mhz, DMSO-d6): 7.87-7.94 (m, 5H), 7.74-7.82 (m, 2H), 4.96 (s, 2H). 33 LV 12495 (d) A mixture of 2-(3,4-dinitrobenzyl)isoindole-l ,3-dione (8 g, 24.4 mmol), prepared as in
Exarople 1, and 10% palladium on carbon (300 mg) was combined with anhydrous ethanol (200 mL, anhydrous THF (100 mL) and glacial acetic acid (30 mL) undcr a continuous stream of nitrogen. The mixture then was stirred vigorously 15 hours at room teraperature under hydrogen, 5 filtered and concentrated to a volume of approximately 30 mL by rotary evaporation. The mixture was diluted with water (100 mL) and ammonium hydroxide was added togive an orange precipitate. The precipitate was isolated by filtration and washed several times with water to provide 2-(3,4-diaminobenzyl)isoindole-l,3-dione (6 g, 91% yield); Ή-NMR(300Mhz, DMSO-d6): 7.76-7.85 (m, 4H), 6.31-6.43 (m, 3H), 4.51 (broad s, 4H), 4.47 (s, 2H). 10 (e) A fmely ground mixture of 2-(3,4-diaminobenzyl)isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethy 1-1 //-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated 1 hour at 185°C under nitrogen. The mixture was suspended in 1:1 methylene chloride/ethanol (20 mL) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with 1:1 methylene chloride/ethanol (3 x 20 mL) and dried to provide 15 2-[5-( 1,3-dioxo-1,3-dihydroisoindol-2-ylroethyl)-l//-benzoimidazol-2-ylmethyl]- 1 //-benzoimidazole-5-carboxyl ic acid (0.98 g, 29% yield); Ή-NMR (300Mhz, DMSO-d6): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J=7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J=7.2 Hz), 4.82 (s, 2H), 4.48 (s, 2H). : (0 2-(5-( 1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)- ltf-benzoimidazol-2-ylmethyl]- 20 l//-benzoimidazole-5-carboxylic acid (0.05g, 0.11 lmmol) was dissolved in anhydrous dimethylfonnamide (0.5mL) and the solution was combined with l-hydroxybenzotriazole hydrate (0.017g, 0.126mmol), benzotriazole-l-yloxytrispyrrolidinophosphoniumhexafluoro-phosphate (0.063g, 0.121mmol) and N-methylmorpholine (0.013mL, 0.118mmol) at room temperature under an atomosphere of dry N2. After 2 minūtes 4-phenylbutylamine (0.02mL, 25 0.127mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a sparatory funnel containing 20% ethanol/ethyl acetate solution (7mL), 0.2 N Hcl (3.5mL) and saturated aqueous NaCl (3.5mL). The aqueous phase was extracted once with 20% ethanol/ethyl acetate solution (7mL) and the combined organic phases were washed with a solution containing 0.2 N HC1 (3.5mL) in saturated aqueous NaCl (3.5 mL) 30 followed by a final washing with saturated aqueous sodium bicaibonate solution (7mL). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness on arotary evaporator to provide 2-(5-(1,3-dioxo-l,3-dihydroisoindol-2-ylmethyl)- 34 17/-benzoimidazol-2-ylmethyI]-//-(3-phenylpropyl)-l//-benzoimidazoIe-5-carboxamide as crude material (0.14g). (g) 2-[5-( l ,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)-1 //-benzoimidazol-2-ylmethyI]- N-(3-phenylpropyl)-lH-benzoiinidazole-5-carboxannde (0.14g, crude material) was dissolved in 5 anhydrous ethanol (0.5mL) and the solution combined with anhydrous hydrazine (0.15mL, 0.48mmol). The mixture was heated at reflux under N2 for 1 hour and then concentrated on a rotary evaporator. The residue was place under vacuum (0.15 torr) for 2 hours to remove excess hydrazine. The residue was diluted with 3 M HC1 (0.5mL) and the mixture was heated at 50°C for 20 minūtes. The reaction mixture was cooled to room temperatūra and stirred for an 10 additional 20 minūtes to give a soiid precipitate. The precipitate was isolated by filtration and washed with water (4x 1.5mL). The filtrates were combined and washed with 20% ethanol/ethyl acetate solution (2x 7mL). The combined aqueous phases were lyophilization to give crude product as a hydrochloride salt. The crude material was purified by preparative reverse phase HPLC to provide 2-(5-(1,3-dioxo-l,3-dihydroisoindol-2-ylmethyI)-15 l/f-benzoimidazol-2-ylmethyl]-N-(3-phenylpropyl)-l//-benzoimidazole-5-carboxamide (0.04g, 0.07mmol) as a white soiid; 'H-NMR (300Mhz, CD3OD): 8.14 (s, 1H), 7.84-7.89 (m, 2H), 7.77 (d, 1H, J—8.1 Hz), 7.71 (d, 1H, J-8.1 Hz), 7.56 (d, 1H, J=8.1 Hz), 7.12-7.27 (m, 5H), 4.29 (s, 2HV3.43 (t, 2H, J=7.2 Hz), 2,66 (t, 2H, 3=7.2 Hz), 1.69 (m, 4H). 20 Proceeding as in Example 2 the following compounds of the invention were prepared: 2-(5-aminomethyl- l//-benzoimidazol-2-ylmethyl)-//-naphth-1 -ylmethyl-l//-benzoimidazole-5-carboxamide (Compound 2), Ή-NMR (300Mhz, CD3OD): 8.13 (m, 2H), 7.88 (m, 2H), 7.80 (m, 2H), 7.73 (d, 1H, J=7.9 Hz), 7.67 (d, 1H, J=7.9 Hz), 7.38-7.54 (m, 5H), 5.01 (s, 2H), 4.26 (s, 2H); 25 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-jV-benzyl-l/f-benzoimidazole- 5-carboxamide (Compound 3), 'H-NMR (300Mhz, CD3OD): 8.18 (s, lh), 7.91 (d, 1H, J-7.9 Hz), 7.82 (s, 1H), 7.76 (d, 1H, J-7.9), 7.72 (d, 1H, J=7.9 Hz), 7.54 (d, 1H, J=7.9 Hz), 7.23-7.38 (m, 5H), 4.60 (s, 2H), 4.28 (s, 2H); 2-(5-aminomethyl-l/f-benzoimidazol-2-ylmethyl)-N-(3-phenylpropyl)-30 l//-benzoimidazole-5-carboxamide (Compound 4), Ή-NMR (300Mhz, CD3OD): 8.14 (s, 1H), 7.87 (d, 1H, J=8.6 Hz), 7.8 (s, 1H), 7.76 (d, 1H, J=8.6 Hz), 7.71 (d, 1H, J=8.6 Hz), 7.54 (d, 1H, 35 LV 12495 J=8.6 Hz), 7.24 (ra, 4H), 7.16 (m, 1H), 4.28 (s, 2H), 3.46 (t, 2H, J=7.9 Hz), 2.95 (t, 2H, J=7.9 Hz), 1.62 (quintet, 2H, 7.9 Hz); 2-(5-aminomethyl-1 //-benzoimidazol-2-ylmethyl)-N-(2-phenylethyl)-l//-benzoimidazole-5-carboxamide (Compound 5), Ή-NMR (300Mhz, DMSO-d6): 8.12 (s, 1H), 5 7.83 (m, 2H), 7.78 (d, 1H, J=9.3 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.55 (d, 1H, J = 9.3 Hz), 7.29 (m, 4H), 7.22 (m, 1H), 4.29 (s, 2H), 3.65 (t, 2H, J=7.9 Hz), 2.95 (t, 2H, J=7.9 Hz); 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-./V-(3-aminomethyl)benzyl-l//-benzoimidazole-5-carboxamide (Compound 6), Ή-NMR (300Mhz, DMSO-dj): 9.31 (t, 1H, 1=5.7 Hz), 8.58 (br s, 3H), 8.41 (br s, 3H), 8.28 (s, IH), 7.97 (m, 2H), 7.79 (d, 1H, J=9.3 Hz), 10 7.75 (d, 1H, J=9.3 Hz), 7.59 (d, 1H, J=9.3 Hz), 7.43 (s, 1H), 7.35 (s, 3H), 5.07 (s, 2H), 4.50 (m, 2H), 4.18 (m, 2H), 3.97 (m, 2H); 2-(5-aminomethyl-1 //-benzoimidazol-2-ylmethyl)-iV-(2-aminoethyl)-1 -methyl-l//-benzoimidazole-5-carboxamide (Compound 7), Ή-NMR (300Mhz, DMSO-d6): 8.86 (br, 1H), 8.50 (br s, 3H), 8.24 (s, 1H), 8.08 (br s, 3H), 7.93 (m, 2H), 7.77 (d, 1H, J = 8.7 Hz), 7.55 (<Ļ 15 1H, J=9.2 Hz), 5.02 (br, s, 2H), 4.16 (m, 2H), 3.94 (s, 2H), 3.50 (m, 2H), 2.96 (m, 2H); y 2-(5-aminomethyl-1 tf-benzoimidazol-2-ylmethyl)-W-(2-aminoethyl)-1 //-bcnzoimidazole* 5-carboxamide (Compound 8), Ή-NMR (300Mhz, DMSO-d6): 8.97 (t, 1H, J=4.3 Hz), 8.58 (br s, 3H), 8.31 (s, 1H), 8.16 (br s, 3H), 7.97 (m, 2H), 7.79 (d, 1H, J=10 Hz), 7.73 (d, 1H, J=10 Hz), 7.59 (d, 1H, J=10 Hz), 5.09 (s, 1H), 4.19 (m, 2H), 3.54 (m, 2H), 2.99 (m, 2H); 20 2-(5-aminomethyl-1 //,-benzoimidazol-2-ylmethyl)-/V'-(4-aminobutyl)-1 //-bcnzoimidazole- 5-carboxamide (Compound 9), Ή-NMR (300Mhz, DMSO-d6): 8.77 (t, 1H, J=5.7 Hz), 8.61 (br s, 3H), 8.24 (s, 1H), 7.90-8.02 (m, 5H), 7.78 (d, 1H, J=9.3 Hz), 7.74 (d, 1H, J=9.3 Hz), 7.60 (d, 1H, J=9.3 Hz), 5.09 (s, 1H), 4.18, (m, 2H), 3.28 (m, 2H), 2.78 (m, 2H), 1.12 (m, 4H); 2-(5-aminomethyl-l/i-benzoimidazol-2-ylmethyl)-/*/'-(3-aminopropyl)-25 l#-benzoimidazole-5-carboxamide (Compound 10), Ή-NMR (300Mhz, DMSO-d6): 8.9 (t, 1H, J=5.0 Hz), 8.53 (br s, 3H), 8.23 (s, 1H), 7.97 (br s, 3H), 7.94 (s, 1H), 7.89 (d, 1H, J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.71 (d, 1H, J=8.6), 7.57 (d, 1H, J=8.6 Hz), 5.03 (s, 2H(, 4,40 (m, 2H), 3,34 (m, 2H), 2.81 (m, 2H), 1.81 (m, 2H); and 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-A/-cyclohexylmethyl-30 1 //-benzimidazole-5-carboxamide (Compound 11), Ή-NMR (300Mhz, CDjOD): 8.15 (s, 1H), 7.88 (d, 1H, J=7.6 Hz), 7.84 (s, 1H), 7.76 (d, 1H, J=7.6 hz), 7.72 (d, 1H, J=7.6 Hz), 7.54 (d, 1H, 36 J=7.6 Hz), 4.29 (s, 2H), 3.26 (d, 2H, J=7.2 Hz), 1.64-1.86 (m, 6H), 1.20-1.37 (m, 3H), 0.95-1.09 (m, 2H). EXAMPLE3 5 2-(5-Aimnomethyl-l//-benzoimidazol-2-ylmethyl)-//-(3-aminopropyl)-l-methyl- l//-benzoimidazole-5-carboxamide (Compound 12) (a) A mixture comprising 3-nitro-4-chlorobcnzoic acid (1.3 g, 6.45 minol), 10 10% methylamine and water (10 mL) in a sealed tube was heated at 100°C for 11 hours, concentrated to 1 mL and then diluted with concentrated hydrochloric acid to give a yellow precipitate. The precipitate was isolated by filtration, washed with water and then diethyl ether and dried to provide 3-nitro-4-methylaminobenzoic acid (2.1 g, 86% yield); Ή-NMR (300Mhz, CDCL,): 8.56 (d, 1H, J = 2.1 Hz), 8.52 (q, IH, J=8.6 Hz), 7.94 (dd, 1H, 9.3, 15 2.1 Hz), 7.00 (d, 1H, J=9.3 Hz), 2.97 (d, 3H, J = 8.6 Hz). (b) Ethyl alcohol (1 OOmL) was added to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09g, I0.7mmol) and 10% Pd/C (30mg) under a steady stream of N2. The mixture was stirred under hydrogen for 16 hours, filtered through a milipore 0.22 μτη type GV filter disc and concentrated on a rotary evaporator. The residue was dried under vaccum to provide 3-amino- 20 4-methylaminobenzoic acid (1.1 g, 61 % yield). (c) Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 3-amino-4-methylaminobenzoic acid under conditions similar to that set forth in Example 2(b) to provide 2-ethoxycarbonylmethyl-l-methyl-l#-benzoimdazole-5-carboxylic acid (71% yield); ’H-NMR (300Mhz, DMSO-d6): 7.18 (dd, 1H, J=8.1 Hz), 7.11 (d, 1H, J-1.2 Hz), 6.33 (d, 1H, 25 J=8.1 Hz), 5.28 (br s, 1H), 4.67 (br s, 1H), 3.34 (br s, 2H), 2.72 (s, 3H). (d) 2-(3,4-Diaminobenzyl)isoindole-l,3-dione, prepared as in Example 2(d), was reacted with 2-ethoxycarbonylmethyl-l-methyl-l/f-benzoimidazole-5-carboxylic acid under conditions similar to that set forth in Example 2(e) to provide 2-[5-(l,3-dioxo- l,3-dihydroisoindol-2-ylmethyI)-l//-benzoimidazol-2-ylmethyl]-l-methyl-l//-benzoimidazole-5-carboxylic acid (48% yield); lH-NMR (300Mhz, DMSO-d6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J=10.0 Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H). 30 37 LV 12495 (e) 2-[5-( 1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)- l//-benzoimidazol-2-ylmethyl]- 1 -methyl- l//-benzoimidazole-5-carboxylic acid (0.05g, 0.108mmol), l-hydroxybenzotriazole (0.016g, 0.118mmol), l-(3-dimethylaminopropyl)-3-cthylcaibodinnide hydrochloride (0.023g, 0.12mmol) and the mono-BOC protected derivative of 1,3-diaminopropane werc dissolved at 5 0eC in methylene chloride (lmL) and DMF (minimal amount sufficient to effect a solution).
The solution was adjusted to pH-8 with //-methylmorpholine and the mixture was allowed to slowly warm to room temperature and then stirred for 20 hours. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with 0.1 N HC1 solution and then saturated NaHC03 solution, dried over sodium sulfate, filtered and concentrated. The residue 10 was purified by preparatory TLC (10% methanol/ethyl acetate) to provide 2-[6-( 1,3-dioxo- 1,3-dihydroisoindol-2-ylmethyl)-1 //-benzoimidazol-2-ylmethyl]-1 -methyl-Ar-(3-aminopropyl)-l//-benzoimidazole-5-carboxamide (0.02g, 28% yield); Ή-NMR (300Mhz, CDCL3): 7.75-7.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (br s, 1H), 7.27 (d, 1H, J-8.6 Hz), 7.15 (d, 1H, J=9.3 Hz), 5.10 (br t, 1H), 4.90 (br s, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 15 (q, 2H, 1=7.2 Hz), 3.24 (q, 2H, J=7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H); (f) The 2-[6-(l,3-dioxo-l,3-dihydroisoindol-2-ylmethyl)-l//-benzoimidazol-2-ylmethyl]- l-methyl-N-(3-aminopropyl)-l//-benzoimidazole-5-carboxainide was deprotected under ~ conditions ’similar to that set forth in Example 2(g) to provide 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-/l/-(3-axninopropyI)-l-methyl-l//-benzoimidazole-5-carboxamide: 20 (20% yield); Ή-NMR (300Mhz, DMSO-d6): 8.85 (t, 1H, J=5.7 Hz), 8.55 (br s, 3H), 8.20 (s, 1H), 8.01 (br s, 3H), 7.74 (m, 2H), 7.80 (d, 1H, J = 6.6 Hz), 5.07 (s, 2H), 4.16 (m, 2H), 3.96 (s, 3H), 3.32 (m, 2H), 2.79 (m, 2H), 1.80 (ra, 2H).
Proceeding as in Example 3 the following compounds of the invention were prepared: 25 3-[2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-//-(2-naphth-l-ylethyl)- l//-benzoimidazole-5-carboxamide (Compound 13), ’H-NMR (300Mhz, CD3OD): 8.25 (d, 1H, J= 8.1 Hz), 8.09 (s, 1H), 7.67-7.86 (m, 6H), 7.37-7.54 (m, 5H), 4.27 (s, 2H), 3.73 (t, 2H, J = 7.4 Hz), 3.41 (t, 2H, J=7.4 Hz); 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-Ar-(3,3-diphenylpropyl)-30 l//-benzoimidazoIe-5-carboxamide (Compound 14), ’H-NMR (300Mhz, CD3OD): 8.11 (s, 1H), 7.77-7.86 (m, 3H), 7.70 (d, 1H, J=9.3), 7.56 (d, 1H, J=9.3 Hz), 7.23-7.39 (m, 8H), 7.13-7.19 (m, 2H), 4.30 (s, 2H), 4.07 (t, 1H, J=7.2 Hz), 3.40 (t, 2H, J=7.2 Hz), 2,44 (q, 2H, J=7.2 Hz); 38 2-(5-aminomethyl-lf/-benzoimidazol-2-ylmethyl)-/'/-(2-naphth-2-ylethyl)-177-benzoimidazole-5-carboxamide (Compound 15), Ή-NMR (300Mhz, CDjOD): 8.10 (s, 1H), 7.67-7.86 (ra, 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); 5 2-( l//-benzoimidazol-2-ylmethyl)-^-[2-(l/f-indol-3-y l)ethyi]-1 //-benzoimidazole- 5-carboxamide (Compound 16), Ή-NMR (300Mhz, CDjOD): 8.09 (s, 1H), 7.81-7.84 (m, 2H), 7.74 (d, 1H, J=8.6 Hz), 7.67 (d, 1H, >8.6 Hz), 7.52-7.58 (m, 2H), 7.30 (d, 1H, J=7.9), 7.01-7.08 (m, 2H), 6.94 (t, 1H, >7.9 Hz), 4.26 (s, 2H), 3.68 (t, 2H, >6.8 Hz), 3.06 (t, 2H, >6.8 Hz); 2-(5-aminomethyl-l//’-benzoimidazol-2-ylmethyl)-/V'-[2-(5-methoxy)indol-3-yl]-10 l/f-benzoimidazole-5-carboxamide (Compound 17), Ή-NMR (300Mhz, CDjOD): 8.10 (s, 1H), 7.81-7.85 (m, 2H), 7.76 (d, 1H, J=8.2 Hz), 7.69 (d, 1H, >8.2 Hz), 7.54 (d, 1H, >8.2 Hz), 7.20 (d, 1H, J=8.2 Hz), 7.07 (m, 2H), 6.70 (dd, 1H, J=10.0,2.2 Hz), 4.27 (s, 2H), 3.65-3.71 (m, 5H), 3.04 (t, 2H, J=7.2 Hz); 2-(5-aminomethy 1-1#-benzoimidazol-2-ylmethyl)-A/-(2,3,4,5,6-pentahydroxyhexyl)-15 1 //-benzoimidazole-5-carboxamide (Compound 18), Ή-NMR (300Mhz, CD30D/D20 (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-(5-3minomethyl-l//-benzoimidazol-2-ylmethyl)-iV-(2-phenoxyethyl)-l//-benzoimidazole-5-carboxamide (Compound 19), Ή-NMR (300Mhz, CD3OD): 8.16 (s, 1H), 20 7.88 (d, 1H, >9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, >9.3 Hz), 7.71 (d, 1H, >9.3 Hz), 7.55 (d, 1H, >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-l//-benzoimidazol-2-ylmethyl)-iV-(3-phenylprop-2-ynyl)-l/f-benzoimidazole-5-carboxamide (Compound 20), Ή-NMR (300Mhz, CD3OD): 8.18 (s, 1H), 25 7.91 (d, 1H, >9.3 Hz), 7.84 (s, 1H), 7.76 (d, 1H, >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-l//-benzimidazol-2-ylmethyl)-Ar-(£-3-phenylallyl)-l//-benzimidazole-5-carboxamide (Compound 21), Ή-NMR (300Mhz, CD3OD): 8.19 (s, 1H), 7.92 (d, 1H, >9.3 Hz), 7.86 (s, 1H), 7.76 (d, 1H, >9.3 Hz), 7.71 (d, 1H, >9.3 Hz), 7.55 (d, 1H, >9.3 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, 6.1 Hz), 4.27 (s, 2H), 4.17 (d, 2H, >6.1 Hz); 30 39 LV 12495 2- (5-aminomethyl-1 #-benzoimidazol-2-ylmethyl)-//-(3-cyclohexylpropyl)- 1 //-benzoimidazole-5-carboxamide (Compound 22), Ή-NMR (300Mhz, CD3OD): 8.13 (s, 1H), 7.86 (d, 1H, J=9.3 Hz), 7.81 (s, 1H), 7.74 (d, 1H, J=9.3 Hz), 7.69 (d, 1H, J=9.3 Hz), 7.53 (d, 1H, J=9.3 Hz), 4.27 (s, 2H), 3.36 (t, 2H, J=7.2 Hz), 1.61-1.78 (m, 7H), 1.19*1.32 (m, 6H). 0.90 (m, 5 2H); 3- [2-(5-aminomethy I-1 //-benzoimidazol-2-ylmcthyI)-//-oct-1 -yl- l//-benzimidazole-5-carboxamide (Compound 23), Ή-NMR (300Mhz, CD3OD): 8.13 (s, 1H), 7.86 (d, 1H, J=9.7 Hz), 7.82 (s, 1H), 7.74 (d, 1H, J=9.7 Hz), 7.69 (d, 1H, J=9.7), 7.49 (d, 1H, J=9.7 Hz), 4.27 (s, 2H), 3.39 (t, 2H, J=7.2 Hz), 1.64 (m, 2H), 1.26-1.43 (m, 11 H), 0.88 (m, 2H); 10 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-/V'-methyl-iV’-(2-phenylethyl)- l//-benzimidazole-5-carboxamide (Compound 24), Ή-NMR (300Mhz, CD3OD): 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 (brs), 4.19 (s), 3.72 (t), 3.47 (t), 3.22 (s), 3.08 (s), 2.87 (t), 2.76 (t); and 2-(5*aminomethyl-17/-benzoimidazol-2-ylmethyI)-A/-( 1 -methyl-3-phenylpropyl)-15 lfl-benzoimidazole-5-carboxamide (Compound 25), Ή-NMR (300Mhz, CD3OD): 8.05 (s, 1H), 7.79 (d, 1H, J=9.3 Hz), 7.75 (s, 1H), 7.68 (d, 1H, J=9.3 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.46 (d, 1H, 1*9.3 Hz), 7.09-7.17 (m, 4H), 7.03 (m, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 2.61 (t, 2H, J=7.9 Hz), 1.17-1.93 (m, 2H), 1.18 (d, 3H, J=7.2 Hz). 20 EXAMPLE 4 C- (2-[5-(4-phenylbutoxy)-1 //-benzoimidazol-2-ylmethyl]-1 //-benzoimidazol-5-yl} methylamine (Compound 26) (a) 4-Phenyl-l-butanol (lmL, 6.49mmol) in THF (3mL) was combined under dry nitrogen 25 with sodium hydride (0.26g, 6.5mmol) in a 60% mineral oil dispersion. The mixture was stirred vigorously for 5 minūtes, combined with 3,4-dinitrochIorobenzene (1.3g, 6.42mmol) and then stirred 10 hours at room temperature. The mixture was partitioned between diethyl ether and 3 N hydrochloric acid. The aqeuous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgS04), filtered and concentrated by rotary 30 evaporation. The residue was purfied by flash chromatography (9:1 hexanes/diethyl ether) to provide 4-(4-phenylbutoxy)-l,2-dinitrobenzene (1.16g, 72% yield); Ή-NMR (300Mhz, CDCL3): 40 7.84 (d, 1H, J - 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, J = 6.5 Hz), 1.89 (m,4H). (b) Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 2-(3,4-diaminobenzyl)isoindoie-l,3-dione under conditions similar to that set forth in 5 Example 2(b) to provide ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)- l//-benzoimidazol-2-ylacetate (71% yield); Ή-NMR (300Mhz, DMSO-d6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J=9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J = 7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J=7.2 Hz). (c) 4-(4-Phenylbutoxy)-1,2-dinitrobenzene was reduced under conditions similar to that set 10 forth in Example 3(b) to provide 4-(4-phenylbutoxy)benzene-1 ,2-diamine (86% crude yield). (d) A mixture of 5-(4-phenylbutoxy)benzene-l,2-diamine (0.06 g, 0.234 mmol) and ethyl 5-( 1,3-dioxo-l ,3-dihydroisoindol-2-ylmethyl)-lH-benzoimidazol-2-ylacetate (0.1 g, 0.234 mmol) was heated 1 hour at 185eC under nitrogen. The mixture was suspended in diethyl ether, stiiTed vigorously for 1 hour. The solīds were collected by filtration, washed with diethyl 15 ether and dried to provide 2- {2-(5-(4-phenylbutoxy)-1 tf-benzoimidazol-2-ylmethyl]-37/-benzoimidazol-5-ylmethyl}isoindole-l,3-dione (0.1 g, 0.18 mmol). (e) The 2-{2-[5-(4-phenylbutoxy)-l//-benzoimidazol-2-ylmethyl]-3/f-benzoimidazol-5-ylmethyl} isoindole-l,3-dione was deprotected under conditions similar to that set forth in Example 2(g) to provide C-{2-[5-(4-phenylbutoxy)- 20 l//-benzoimidazol-2-ylmethyl]-l//-benzoimidazol-5-yl}methylamine (0.05 g, 55% yield); Ή-NMR (300Mhz, CD3OD): 7.83 (d, 1H, J = 8.6 Hz), 7.76 (s, 1H), 7.69 (d, 1H, J = 10.0 Hz), 7.48 (d, 1H, J=8.6 Hz), 6.99-7.16 (m, 5H), 6.92 (d, 1H, J = 10.0 Hz), 6.80 (t, 1H, J=7.2 Hz), 4,44 (s, 2H), 3.93 (t, 2H, J=6.5 Hz), 2.56 (t, 2H, J = 7.2 Hz), 1.72 (m, 2H). 25 EXAMPLE 5 2-Phenylethyl 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-l/ī-benzoimidazole- 5-carbamate trifluoroacetate (Compound 27) 30 2-[5-(l,3-Dioxo-l,3-dihydroisoindol-2-ylmethyl)-l//-benzoimidazol-2-ylmethyl]- l/7-benzoimidazole-5-carboxylic acid (0.060g, 0.133mmol) in phenethanol (0.160mL, 1.34mmol) was combined vvith diphenylphosphoryl azide (0.034mL, 0.158mmol) and 41 LV 12495 triethylamine (0.022mL, 0.158mmol) at room tcmperature under nitrogen. The mixture was stirred 1 hour at 120eC, cooled to room temperature and combined with ethanol (0.5 mL) and hydrazine (0.020 mL, 0.637 rrnnol). The mixture was stirred 45 minūtes ai 95 CC, cooled to room temperature and diluted with with 3 N hydrochloric acid (0.5 mL). The mixture \vas stirred 5 20 minūtes at 55eC and then filtered. The filtered solids were washed wūh 3 N hydrochloric acid and the combined filtrates were washed with ethyl acetate (15 mL) and lvophilized. The residue was purified by preparative reverse phase HPLC to provide the desired product (0.008 g, 11% yield); Ή-NMR (300Mhz, CD3OD): 8.10 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H, J = 9.3 Hz), 7.63 (d, 1H, J=9.3 . Hz), 7.38-7.44 fln, 2H), 7.19-7.32 (m, 5H), 4.36 (t, 2H J = 6.8 Hz), 4.23 (s, 10 2H), 1.98 (t, 2H, J=6.8 Hz). EXAMPLE 6 2-(5-Guanidino-1 //-benzoimidazol-2-ylmethyl)-N-(2-naphthalen-1 -ylethyl)-3-methyl- 3//-benzoimidazole-5-carboxyamide 15 (Compound28) (a) A solution comprising 2-nitro-l,4-phenylenediamine (21.0g, 137mmol) in ethanol (350mL) and 4.0 M hydrogen chloride in dioxane (30.8mL, 123mmol) \vas stirred at room temperature for 15 minūtes and then diethyl ether (1L) was added to give a precipitate. The 20 precipitate was collected by filtration, washed with additional diethyl ether and dried in vacuo to provide 2-nitro-i,4-phenylenediamine hydrochloride (23.3g, 100% yield). (b) Amixture comprising 2-nitro-l,4-phenylenediamine hydrochloride (15.0g, 79.1mmol) cyanamide (25.0g, 595mmol) and water (5mL) was heated at 60°C and stirred for 1.5 hours, allowed to cool to room temperature and then excess diethyl ether was slowly added to give a 25 precipitate. The precipitate was collected by filteration, washed with additional diethyl ether and dried in vacuo to provide N-(4-amino-3-nitrophenyl)guanidine hydrochloride (18.0g, 98% yield); Ή-NMR (300 MHz, DMSO-d6): 9.7 (s), 7.8 (s), 7.6 (s), 7.5 (s), 7.3 (d). 7.1 (d). (c) A mixture comprising N-(4-amino-3-mtrophenyl)guanidine hydrochloride (12.0g, 51.8mmol), 10%palladium on carbon (l.Og), tetrahydrofuran (lOOmL) and methanol (lOOmL) 30 was hydrogenated at one atmosphere, filtered and concentration in vacuo to provide /V-(3,4-diaminophenyl)guanidine hydrochloride (10.3g, 98% yield) as a dark solid; 'H-NMR (300 MHz, DMSO-de): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s). 42 (d) A mixture comprising N-(3,4-diaminophenyl)guanidine hydrochioride (9.9g, 49mmol), ethoxycarboniīnidoyIacetic acid ethyl ester hydrochIoride (12.4g, 59mmoI) and acetic acid (20mL) was heated in an oil bath at 110°C and stirred for 1.5 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol (15mL) and then ethyl acetate 5 (1 OmL) was added to the solution to give a precipitate in suspension. The suspension was filtered and an excess of ethyl ether was added to the filtrate to give a second precipitate. The precipitate was collected by filtration, washed with additional ethyl ether and dried in vacuo to provide ethyl 5-guanidino-l//-benzoimidazol-2-ylacetate hydrochloride (14.lg, 94% yield) as an off white solid; 'H-NMR (300 MHz, DMSO-d6): 10.2 (s), 7.8 (d), 7.7 (m), 7.3 (d), 4.5 (s), 4.2 10 (q), 1.2 (t). (e) A mixture comprising 4-nitro-3-methoxybenzoic acid (5.0g, 25.4mmol) and aqueous methylamine (40%, 15mL) is a sealed tube was heated in an oil bath at 100°C for 12 hours, a!lowed to cool to room temperature, and then poured into a stirring slurry oflM aqueous hydrochloric acid and ice to give an orange precipitate. The precipitate was collected by 15 filtration, rinsed with water and recrystallized from hot ethanol to provide 3-methylamino- 4-nitrobenzoic acid as a bright red crystalline solid (3.6g, 73% yield); 'H-NMR (300 MHz, DMSO-d6): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d). (0 A mixture comprising 3-methylamino-4-nitrobenzoic acid (13.0g, 66.3mmol), PyBOP (38.0g, 73.0mmol), hydroxybenztriazole hydrate (9.9g, 73.0mmol), dimethylformamide (lOOmL) 20 and N-methyImorpholine (18.3mL) was stirred at room temperature for 15 minūtes and then 2-naphthylene-l-ylethylamine (13.8g, 66.3mmol) was added. The mixture v/as stirred for an additional 30 minūtes and concentrated in vacuo. The residue was partioned between water and ethvl acetate and the organic layer was washed with water, 0.1M aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated aqueous sodium chloride, dried 25 (magnesium sulfate), filtered and concentrated in vacuo. The residue was purined by recrystallization from hot ethanol to give 3-methylamino-A;-(2-naphthalene-l-yl-ethyl)-4-nitrobenzamide as a bright red crystalline solid (21.3g, 92% yield); 'H-NMR (300 MHz, DMSO-d6): 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). 30 (g) A mixture comprising 3-methylarnino-N-(2-naphth-l-ylethyl)-4-nitrobenzamide (21.3g, 61mmol), 10% palladium on carbon (l.Og), tetrahydrofuran.(100 mL) and methanol (100 mL) was hydrogenated at one atmosphere, filtered and concentration in vacuo to provide 4-amino- 43 LV 12495 3-methylamino-iV-(2-naphth-l-ylethyl)-4-benzamide (18.4g, 95% yield) as a discolored amorphous solid; ’H-NMR (300 MHz, DMSO-d6): 8.3 (d), 8.2 (t), 7.9 (d), 7.8 (d), 7.6-7.4 (m), 7.1 (d), 6.9 (s), 6.5 (d), 5.0 (s), 3.5 (q), 3.2 (t), 2.7 (s). (h) A mixture comprising ethvl 5-guanidino-l//-benzoimidazol-2-ylacetate hydrochloride 5 (0.5g, 1.7mmol), 4-amino-3-methylamino-/vr-(2-naphth-l-ylethyl)-4-benzamide (0.5g, 1.7mmoI) and dimethyiformamide (2mL) 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 stining acetonitrile (150mL) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150mL), collected by filtration and dried in vacuo to give an off white solid. The 10 solid was purified by preparative reverse phase HPLC to provide of 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-jV-(2-naphth-l-ylethyl)-3-methyl-3//-benzoimidazole-5-carboxamide as a white solid (0.5g, 57 %); LRMS(ESI): Calculated for C30H2gNgO: 516.6; Found (ΜΗ*): 517.2. 15 EXAMPLE 7
Ethvl 2-(4-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate (Compound 29) 20 (a) A solution comprising ethyl 2-cyanopropionate (lOOg, 0.29mol.) in ethanol (65mL) wāš cooled to 0®C and then saturated with dry hydrogen chloride gas. The mixture was allowed to warm to room temperature, stirred for 24 hours, cooled to 0°C and saturated with hydrogen chloride gas. The mixture was allowed to warm to room temperature and stirred another 24 hours. Ethyl ether:hexane (1:1), was added to the mixture to give a precipitate. The precitipate 25 was isolated by filtration and dried in vacuo to provide ethyl 2-(iV-ethoxyamidino)propionate hydrochloride (119.6g, 73% yield) as a white solid; Ή NMR (300 MHz, DMSO-d6): 12.05 (br s, 2H), 4.50 (q, 2H), 4.15 (m, 3H), 1.30 (m, 6H), 1.20 (tr, 3H). (b) A mixture comprising 3,4-diaminopyridine (51.7g, 0.46mol), ethyl 2-(jV-ethoxyamidino)propionoate hydrochloride (125g, 0.69mol) and glacial acetic acid (200mL) 30 was heated at 85°C and stirred for 18 hours and then heated at 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 an excess of 5M aqueous ammonium hydroxide and the 44 mixture was extracted with ethvl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then saturated aqueous sodium chloride, dried (MgSO*), filtered and concentrated in vacuo to provide ethyl l//-imidazo[4,5-c]pyridine-2-carboxylate (60.4g, 58% yield); Ή NMR (300 MHz, CDC13): 9.00 (s, 1H), 8.45 (d, 1H), 7.50 (d, 1H), 4.25 (q, 2H), 5 3.90 (q, 1H), 1.75 (d, 3H), 1.25 (tr, 3H). (c) A mixture comprising ethyl l//-imidazo[4,5-c]pyridine-2-carboxylate (34.7g, 158mmol), trifluoroacetic acid (50mL) and platinum oxide (2.5g) in a 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 and dry hydrogen chloride in dioxane solution (4M, 120mL, 10 475mmol) was added to the solution. An excess of ethyl ether was added to the solution to give a precipitate. The precipitate was collected by filtration and dried itt vacuo to provide ethyl l,4,6,7-tetrahydro-l//-imidazo[4,5-c]pyridine-2-carboxylate dihvdrochloride (30.7g, 66% yield); Ή NMR (300 MHz, DMSO-ds): 10.00 (br s, 2H), 4.35 (q, 1H), 4.20 (br s, 2H), 4.10 (m, 2H), 3.35 (m, 2H), 2.90 (brs, 2H), 1.55 (d, 3H), 1.15(tr,3H). 15 (d) A mixture comprising ethvl l,4,6,7-tetrahydro-l//-imidazo[4,5-c]pyridine-2-carboxylate dihydrochloride (60.2g, 0.20mol), acetonitrile (500mL) and diisopropylethylamine (lOOmL, 0.60mol) was cooled to 0°C and stirred while benzylchloroformate (58mL, 0.40mol) was added slow!y. The mixture was slowly vvarmed to room temperature, stirred an additional 16 hours and concentrated in vacuo. The residue \vas dissolved in ethyl ether (500mL) and the solution was 20 \vashed with 0.1M aqueous hvdrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhvdrous sodium sulfate, filtered and concentrated in vacuo to provide a colorless oil. The residue was dissolved in ethanol (320mL) and the solution was cooled to 0°C and then sodium ethoxide in ethanol solution (2.6M, 85mL, 0.22mol.) was slowly added. The mixture was stinred for one hour at 0°C and then hydrogen 25 chloride solution in dioxane (4M, 50mL) was added. The mixture was concentrated in vacuo and the residue was dissolved in ethvl acetate (250mL) and saturated aqueous sodium hvdrogen carbonate. The organic layer was separated and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 5-benzyl 2-ethyl l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-2,5-dicarboxylate as ayellow amorphous material (52g, 72% yield); Ή NMR (300 MHz, DMSO-d6): 11.75 (brs, 1H), 7.30 (s, 5H), 5.10 (s, 2H), 4.40 (br s, 2H), 4.05 (m, 2H), 3.75 (q, 1H), 3.65 (br s, 2H), 1.40 (d, 3H), 1.15 (tr, 3H). 30 45 LV 12495 (e) A mixture comprising 4-chlorobutyryl chloride (12.6gf 89.2mmol), ierf-butanol (25mL), pyridine (6.9g, 86.5mmol) and 4-dimethylaminopyridine (l.Og, 8.2ramol) was heated at 50°C under an atmosphere of dry nitrogen for 12 hours to give a white suspension. The suspension was partitioned between ethyl ether (250mL) and water and the organic layer was separated and washed repeatedly with water then 0.1M aqueous hydrochloric acid, saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a colorless oil. The oil was distilled at 0.5 mmHg (51 eC) to provide fert-butyl 4-chlorobutyrate as a colorless liquid (11.27g, 73% yield); lH NMR (300 MHz, CDClj): 3.60 (tr, 2H), 2.40 (tr, 2H), 2.10 (m, 2H), 1.45 (s, 9H). (f) A mixture comprising ethyl salicylate (3.14g, 18.9mmol) and cesium carbonate (6.2g, 18.9mmol), dimethylformamide (25mL) and ierf-butyl 4-chlorobutyrate (4.08g, 22.8mmol) was heated at 70 °C and stirred for 12 hours. The mixture was panitioned between ethyl ether (1 OOmL) and water and the organic layer was separated and washed with additional water (3x) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a colorless oil. The residue was purified by silica gel flash chromatography using pure hexane to (10:1) hexane:ethyl acetate to provide ethyl 2-(3-teri· butoxycarbonylpropoxy)benzoate (3.6g, 62% yield) as a colorless oil; 'H NMR (300 MHz, CDClj): 7.80 (d, 1H), 7.49 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.10 (tr, 2H), 2.50 (tr, 2H), 2.10, (m, 2H), 1.45 (s, 9H), 1.40 (tr, 3H). (g) Ethyl 2-(3-ierr-butoxycarbonylpropoxy)benzoate (3.60g, 11.7mmol) was treated with an excess of trifluoroacetic acid at room temperature over one hour. The solution vvas concentrated in vacuo and the oiiy residue purified by silica gel flash chromatography using (10:1) hexane:ethyl acetate to pure ethyl ether to provide 4-(2-ethoxycarbonylphenoxy)butyric acid as a colorless crystalline solid (2.8 lg, 95% yield); Ή NMR (300 MHz, CDCl·,): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H). (h) A mixture comprising benzyl 2-ethoxycarbonylmethyl-l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (1.7g, 4.8mmol), Ar-(3,4-diaminophenyl)guanidine hydrochloride (0.8g, 4.0mmol) and dimethylformamide (2mL) heated in an oil bath at 185°C and stirred under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature and poured into stirring acetonitrile (150mL) to give a precipitate. The precipitate was washed with additional acetonitrile and diethyl ether (150mL), collected by filtration and dried in vacuo to give an off white solid. The solid was purified by 46 preparative reverse phasc HPLC to provide benzyl 2-[ 1 -{5-guanidino- l//-benzoimidazoI-2-yI)ethyl]-l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate as a white solid (l.Og, 55% yield); LRMS(ESI): Calculated for C24H26N,02: 458.5; Found (ΜΗ*): 459.2. (i) A mixture comprising bcnzyl 2-[l-(5-guanidino-l/f-benzoimidazol-2-yI)ethyl]- 5 1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxyIate (1 .Og, 2.2mmoI), 10% palladium on carbon (0.5 g), tetrahydrofuran (50mL) and methanol (50mL) was hydrogenated at one atmosphere, filtered and concentrated irt vacuo to provide jV-{2-[1 -(4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)ethyI]-l//-benzoimidazol-5-yl)-guanidine (0.69g, 97% yield); LRMS(ESI): Calculated for C,6H20Ng: 324.4; Found (MH*): 10 325.2. (j) A mixture comprising 4-(2-ethoxycarbonylphenoxy)butyric acid (155mg, 0.61 mmol), PyBOP (360mg, 0.69mmol), hydroxybenztriazoIe hydrate (87mg, 0.64mmol), jV-methvlmorpholine (0.16mL, 0.92mmol) and dimethylformamide (2.5mL) was stīrred at room temperature for 10 minūtes and then 15 jV*{2-[l-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)ethyl]-37/-benzimidazol-5-yl}guanidine (203mg, 0.63mmol) was added. The mixture was stirTed for 3 hours at room temperature and concentrated in vacuo. The residue was dissolved in 5% aqueous acetonitrile and the product purified by preparative reverse phase HPLC. The combined pure fractions were then lyophillized to provide ethyl 2-(4-{2-[l-(5-guanidino-lH-benzoimidazol-2-yl)ethyl]-20 l,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oxobutyl)benzoate; LRMS (Bioion): alculated for C29H34Ng04: 558.6; Found: 559.3. EXAMPLE 8 2-[ 1 -(5-Hydroxy-l//~benzoimidazol-2-yl)ethyl]-jV-[2-(2-methoxyphenoxy)ethyl]- 3-methyl-25 3//-benzoimidazole-5-carboxamide (Compound 30) (a) Asolutionof rm-butyl 2-hydroxyethylcarbamate (25mL, 161.6mmol) in dichloromethane (60mL) was cooled to 0°C and stirred while first diisopropylethylamine 30 (33.8mL, 193.9mmol) was added and then mesyl chloride (13.7mL, 177.8mmol) then was added dropvvise. The mixture was allovved to warm to 23°C, stirred for 18 hours, poured into dichloromethane (200mL) and washed with aqueous hydrochloric acid (3M, 3.x 25mL) and 47 LV 12495 saturated aqueous sodium hydrogencarbonate (2x 25mL). The organic layer was separated, dried (MgS04) and concentrated in vacuo to provide ierr-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C,H17NOjS m/e calc 239.08; found 240 (ΜΗ*)· 5 (b) Lithium bromide (136g, 1.56mol.) was dissolved in tetrahydrofuran (600mL) at 0°C.
The mixture was allowed to warm to 23 °C and then rer/-butyl 2-methylsulfonyloxyethylcarbamate (37.39g, 156mmol) was added dropwise. The mixture was stirred at 23 °C for 18 hours and concentrated in vacuo. The residue was dissolved in hexanes and the organic layer was washed with water and brine, dried (Na2S04) and concentrated 10 in vacuo to provide ter/-butyl 2-bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI) C7H,4BrN02 m/e calc 224.10; found 225 (MH*). (c) A mixture of 2-methoxyphenol (9.8mL, 89.3mmol), dimethylformamide (lOOmL) and potassium carbonate (61.5 g, 445 mmol) was stirred at 23 °C while as ferr-butyl 2-bromoethylcarbamate (20g, 89.3mmol) was added. The mixture was stirred for 24 hours and 15 then poured into ethyl ether:hexanes (1:1,400mL) and was washed with water (5x 50mL). The · aqueous layer was extracted with ethyl ether:hexanes (1:1,3x 40mL) and the combined organic layers were dried (Na2S04) and concentrated in vacuo to provide ferr-butyl »· 2-(2-methoxyphenoxy)ethylcarbamate (23.22g, 97% yield) as a yellow oil; MS (PB-PCI) C,4H2,N04 m/e calc 267.32; found 268 (MH*). 20 (d) tert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8g, 89mmol) was cooled to 0°C and stirTed as a mixture of trifluoroacetic acid:dichloromethane (1:1,40mL) was added dropwise.
The mixture was alIow to warm to 23 °C, stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 mL) and the soiution was washed with saturated aqueous sodium hydrogen carbonate (3x 20mL) and aqueous sodium hydroxide (10%, 25 3x 20mL), dried (Na2S04), filtered and concentrated in vacuo to provide 2- (2-methoxyphenoxy)ethylamine (13g, 88% yield) a light yellow solid; MS (PB-PCI) C9HtJN02 m/e calc 167.21; found 168 (MH*). (e) A heterogeneous mixture comprising 3-methoxy-4-nitrobenzoic acid (15.42g, 78.2mmol) and thionyl chloride (70mL, 391mmol) was heated at reflux for one hour. The excess thionyl 30 chloride was removed by distillation and the residue was concentrated in vacuo to provide 3- methoxy-4-nitrobenzoyl chloride (16.8g, 99% yield) as a light yellow solid; MS (PB-PCI) CSH6C1N04 m/e calc 215.59; found 216 (MH*). 48 (f) A mixture comprising 2-(2-methoxyphenoxy)ethylamine (lOg, 59.9mmo!), diisopropylethylamine (13.9mL, 81.6mmol) and dichloromethane (80mL) was cooled to 0°C and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76g, 54.4mmol) in dichloromethane (50mL) was added dropvvise. The mixture was allowed to warm to 23 °C over two hours, 5 quenched with aqueous hydrochloric acid (3M, 20mL), washed with water (3x 20mL), dried (Na2S04) and concentrated in vacuo to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (14g, 74% yield) an off white solid; MS (PB-PCI) C17H)8N206 m/e calc 346.34; found 347 (MH*). (g) A mixture comprising jV-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide 10 (4.0g, 11.6mmol), aqueous methylamine (40%, 1 OmL) and DMSO (2mL) in a sealed tube was heated at 110°C for 4 hours, cooled and then poured into water (25mL). The dilution was treated \vith 3M aqueous hvdrochloric acid to give an orange solid. The solid was isolated by filtration to provide /'/-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56g, 89% yield); MS (PB-PCI) C17H19N305 m/e calc 345.35; found 346 (MH*). 15 (h) A mixture comprising iV-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56g, 10.3mmol), suspended palladium on carbon (10%, 0.5g) in methanol (lOOmL) and tetrahvdrofuran (50mL) was stirred under a hvdrogen atmosphere at ambient pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to provide 4-amino-A-[2-(2-methoxyphenoxy)ethyl]-3-methylaminobenzamide (3.37g, 100% yield) as a 20 green foam; MS (PB-PCI) C,7H21N303 m/e calc 315.37; found 316 (MH*). (i) A mixture comprising 4-amino-3-nitrophenol (5.0g, 32.4mmol), palladium on carbon (10%, l.Og) and methanol (50mL) in a Parr apparatus was hydrogenated at 50 psi for 3 hours, filtered through celite and concentrated in vacuo to provide 3,4-diaminophenol (4.02g, 91% yield) as a dark solid; MS (PB-PCI) C6H8N20 m/e calc 124.16; found 125 (MH*). 25 (j) A mixture comprising of 3,4-diaminophenol (3.661g, 29.5mL), ethyl 2-(/V-ethoxyamidino)propionate (7.423g, 38.4mmol) and ethanol (30mL) was heated at reflux for 6 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (200mL) and the solution was washed with saturated aqueous sodium hydrogencarbonate (3x 20mL) and brine (lx 20mL), dried (MgS04) and concentrated in vacuo to provide ethyl 2-(5-hydroxy-30 l/f-benzoimidazol-2-yl)propionate (6.3g, 91% yield) as a dark solid. The solid was further purified by silica gel flash chromatography (100% ethyl acetate); MS (PB-PCI) Ci2H,4N203 m/e calc 234.28; found 235 (MH*). 49 LV 12495 (k) A mixture comprising ethy 12-(5-hydroxy-1 /f-benzoimidazol-2-yI)propionate (148mg, 0.63mmol), 4-amino-Ar-[2-(2-methoxyphenoxy)ethyl]-3-mcthylaminobenzamide (200mg, 0.63mmol) and l,3-dimethy]-3,415,6-tetrahydro-2(l//)-pyrimidone (0.5mL) was stirred ai room temperatūra until homogeneous, degassed under vacuum and concentrated by heating at 170°C 5 for 2 hours under a stream of N2. The residue was cooled to room temperatūra and rinsed with an excess of ethyl ether. The resulting amorphous material was taken up in 50% aqueous acetonitrile and purified by preparative reverse phase HPLC (2-50% CH3CN/H20) to provide 2-[l-(5-hydroxy-l/f-ben2oimidazol-2-yI)ethyl]-//-[2-(2-methoxyphenoxy)ethyl]-3-methyI-3//-benzoimidazole-5-carboxamide (40mg, 13% yield) as a light pink solid; MS (Biolon) 10 ^7Η27Ν504 m/e calc 485.59; found 486.5 (MH+).
Proceeding as in Example 8 the following compounds of the invention were prepared: methyl 2-(2-{2-[l-(5-fluoro-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3tf*benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 31), MS (Biolon) 15 C2gH26N504F m/e calc 515.54; found 516 (MH+); 2-(2- {2-[ 1 -(5-fluoro-1 if-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoic acid (Compound 32) MS (Biolon) C^HjiNjČiF m/e calc 501.52; found 502.1 (MH+); ethyl 2-(2- {2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-20 3//-benzoimazo!-5-ylcarbonylamino} ethoxy)benzoate (Compound 33), MS (Biolon) CjņH^NjOj m/e calc 527.58; found 528.1 (MH*); 2-(2- (2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 34), MS (Biolon) C27H25N505 m/e calc 499.53; found 500.1 (MH~); 25 N-ethyl-2-[ 1 -(5-hydroxy- l#-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazole- 5-carboxamide (Compound 35), MS (Biolon) C2oH2|N302 m/e calc 363.42; found 364.1 (MFT); 2-[ 1 -(5-hydroxy-1 //-benzoimidazoI-2-yl)ethyl]-yV-(2-methoxyethyl)-3-methyl-3tf-benzoimidazole-5-carboxamide (Compound 36), MS (Biolon) C2|H23N503 m/e calc 393.45; found 394.1 -(ΜΗ*); 30 butyl 2-(2- {2-[ 1 -(5-hydroxy-1 /f-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 37), MS (Biolon) C31H33NA m/e calc 555.64; found 555.7 (MH*); 50 3- {2-[ 1 -(5-guanidino- li/-benzoimidazole-2-yl)ethyl]-6-[2-(2-methoxyphenoxy)ethylcarbamoyl]benzimidazol-l -yl}propane-1 -sulfonic acid (Compound 38), MS (LCMS) C30H35NgO6S m/e calc 635.72; found 635.4 (MH*);
Ar-[2-(2-ethoxyphenoxy)ethyl]-2-[l-(5-hydroxy-l//-bcnzoimidazol-2-yl)ethyl]-3-methyl-5 3//-benzoimidazole-5-carboxamide (Compound 39), MS (Biolon) C2gH29Nj04 m/e calc 499.58; found 500.4 (MH*); 2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-Ar-[2-(2-isopropoxyphenoxy)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 40), MS (Biolon) C29Hj,N504 m/e calc 513.61; found 514.5 (MH*); 10 2-[l -(5-hydroxy- l//-benzoimidazol-2-yl)ethyl]-3-methyl- /V-[2-(2-propoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 41), MS (Biolon) CmH3iN,04 m/e calc 513.61; found 514.2 (MH*); propyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-bcnzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 42), MS (ESI) c30h31 n5o3 15 m/e calc 541.61; found 542.2 (MH*); isobutyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol'5-ylcarbonylamino}ethoxy)benzoate (Compound 43), MS (Biolon) Cjt^NjOs m/e calc 555.64; found 556.3 (MH*); ethyl 4- {2-[ 1 -(5-hydroxy-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-20 3//-benzoimidazol-5-ylcarbonylaminobutyrate (Compound 44), MS (Biolon) C24H27Nj04 m/e calc 449.51; found 449.9 (MH*); 4- {2-[ 1 -(5-hydroxy-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}butyric acid (Compound 45), MS (Biolon) C22H23N504 m/e calc 421.46; found 422.1 (MH*); 25 isopropyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 46), MS (ESI) Ο30Η3|Ν5θ5 m/e calc 541.61; found 542.2 (MH*); N- {2-[2-( 1 -ethylpropoxy)phenoxy]ethyl} -2-[ 1 -(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 47), MS (Biolon) C3lH,5N504 m/e calc 541.65; found 542.5 (MH*); 30 51 LV 12495 ethyl 2-(2- {2-[L-(5-fluoro-l//-benzoimidazol-2-yI)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 48), MS (Biolon) CmHmNAF m/e calc 529.57; found 529.5 (MH*); 2-methoxyethyl 2-(2- (2-[l -(5-hydroxy-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-37/-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 49), MS (Biolon) C30H3lN5Oi m/e calc 557.61; found 58.2 (MH*);
Ar-(3-methoxypropyl)-2-[l-(5-hydroxy-l/7-benzoimidazol-2-yl)ethyl]-3-methyl-3tf-benzoimidazole-5-carboxamide (Compound 50), MS (Biolon) C22H2JN503 m/e calc 407.47; found 408.0 (MH*); 2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-iV-[2-(2-methoxymethylphenoxy)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 51), MS (Biolon) C2gH29Nj04 m/e calc 499.57; found 499.8 (MH*);
Ar-[2-(2-ethoxymethylphenoxy)ethyl]-2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 52), MS (Biolon) C29H3!N504 m/e calc 513.60; found 514.1 (MH+); ethyl 2-(2-{2-[l-(6-fluoro-5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoate (Compound 53), MS (ESI) C29H2iNjOjF· m/e calc 545.57; found 546.3 (MH*); ethyl 2-(2- (2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)cyclohexanecarboxyate (Compound 54), MS (Biolon) C29H35N505 m/e calc 533.63; found 534 (MH*); 2-( 1 -(5-hydroxy- l//-benzoimidazol-2-yl)ethyl]-3-methyl-A-(2-(2-propoxymethylphenoxy)ethyl]-37/-benzoimidazole-5-carboxamide (Compound 55), MS (Biolon) CjoHjjNA m/e calc 527.62; found 527.6 (MH*); 2-[ 1 -(5-hydroxy-1 H-benzoimidazol-2-yl)ethyl]-Ar-[2-(2-isopropoxymethylphenoxy)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 56), MS (Biolon) C30H33N5O4 m/e calc 527.62; found 527.9 (MH*); 2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]- A'-{2-[2-(2-methoxyethoxymethyl)phenoxy]ethyl}-3-methyl-3//-benzoimidazole-5-carboxamide, (Compound 57), MS (Biolon) C30H33N5O5 m/e calc 543.62; found 543.4 (MH*); 52 2-[l-(l//-benzoimidazol-2-yl)ethyl]-/V-[2-(2-methoxymethylphenoxy)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 58), MS (Biolon) C2gH29Nj03 m/e calc 483.57; found 484 (MH*);
Ar-[2-(2-ethoxymethylphenoxy)ethyl]-2-[ 1 -(l/7-benzoimidazol-2-yl)ethyl]-3-methyl-5 3//-benzoimidazole-5-carboxamide (Compound 59), MS (Biolon) C29Hj,Nj03 m/e calc 497.6; found 498.3 (MH+); 2-[l-(l//-benzoimidazol-2-yI)ethyl]-3-methyl-Ar-[2-(2-propoxymethylphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 60), MS (Biolon) ¢3^33^03 m/e calc 511.62; found 511.5 (MIT); 10 2-[l-(l//-benzoimidazol-2-yI)ethyl]-Ar-[2-(2-isopropoxymethylphenoxy)ethyl]-3-methyl- 3//-benzoimidazole-5-carboxamide (Compound 61), MS (Biolon) CjoH33Nj03 m/e calc 511.62; found 511.6 (ΜΗ’); 2-[l-(l/f-benzoimidazol-2-yl)ethyI]-A/-{2-[2-(2-methoxyethoxymethyl)phenoxy]ethyl}-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 62), MS (Biolon) Csoī^NsC^ m/e calc 15 527.62; found 527.7 (MH+); 2-[l-(5-hydroxy-l/f-benzoimidazol-2-yl)ethyl]-3-methyl-yV-[2-(2-morpholin-4-ylphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 63), MS (Biolon) C30H32N6O4 m/e calc 540.73; found 541.8 (MĪT); .Y-(2-phenylsulfonylethyl)-2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-20 3//-benzoimidazole-5-carboxamide (Compound 64), MS (Biolon) C26H2JNs04S m/e calc 503.59; found 504.2 (MH*); 2-(2- {2-[ 1 -(6-fluoro-5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy]benzoic acid (Compound 65), MS (ESI) C27H24N503F m/e calc 517.52; found 518.2 (MH+); 25 ethvl 2-hydroxy-5-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonyamino}benzoate (Compound 66), MS (Biolon) C27H23NjOj m/e calc 499.52; found 500.2 (MH+); 2*[ 1 -(5-fluoro-1 /7-benzoimidazol-2-yl)ethvl]-3-methy 1-/V-[2-(2-morpholin-4-ylphenoxy)ethyl]-3//-benzoimidazoIe-5-carboxamide (Compound 67), MS 30 (Biolon) C30H3|N6O3F m/e calc 542.62; found 543.4 (MH+); 53 LV 12495 /V-(2-phenylsulfonylethyl)-2-[l -(5-fluoro-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3/f-benzoimidazole-5-carboxamide (Compound 68), MS (Biolon) C2iH24Nj03FSm/e calc 505.58; found 506.5 (MH+); ethyl 2-(-2- {2-[l-(4,6-difluoro-5-hydroxy- l//-benzoimidazol-2-yI)ethyl]-3-methyl-
I 5 3//-benzoimidazoI-5-ylcarbonylamino}ethoxy)benzoate (Compound 69), MS (Biolon) C,9H27NsOjF2 m/e calc 563.52; found 563.4 (MH+); 2-(2-{2-[l-(4,6-difluoro-5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3tf-benzoimidazol-5-ylcarbonylamino)ethoxy)benzoic acid (Compound 70), MS (Biolon) C27H23NjOjF2 m/e calc 536.51; found 563 (MH+); 10 ethyl 2-(-2-{2-[l-(4,6-difluoro-5-imidazol-l-yl-l//-benzoimidazol-2-yl)ethyl]-3-methyl- 3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 71), MS (Biolon) Cj2H29N704F: m/e calc 613.62; found 614.3 (MH*); 2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-methyI- /V-{2-[2-(3-methyl-[l,2,4]oxadiazol-5-yl)phenoxy]ethyl}-3//-benzoimidazoIe-5-carboxamide 15 (Compound 72), MS (Biolon) C3oH30N1003 m/e calc 578.63; found 579.4 (MH*); and 2-[ 1 -(5-imidazol-1 -yl-1 //-benzoimidazol-2-yl)ethyl]-3-methyI-jV-{2-[2-(3-methyl[l,2,4]oxadiazol-5-yl)phenoxy]ethyl}-3tf-benzoimidazole-5-carboxamide (Compound 73), MS (Biolon) C32H:9N903 m/e calc 587.64; found 58S.2 (ΜΣΓ). 20 EXAMPLE 9 2-[2-(2-{l-[5-(l-Iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 74) 25 (a) A solution comprising 3,4-diaminopyridine ((51.7 g, 0.46 mol) in acetic acid (400 mL) was heated to 85 °C and then diethyl methyl-1-iminomalonate (125 g, 0.60 mol) was added in 3 equivalent portions over 6 hours. The mixture was heated at 85°C for 12 hours and at 120°C for another hour, cooled and concentrated under reduced pressure. The residue was cooled to 0°C and neutralized with 5 N ammonium hydroxide. The aqueous laver was extracted with several 30 portions of ethyl acetate and the combined extracts were washed successively with sodium bicarbonate and sodium chloride, dried (Na:S04), filtered and concentrated under reduced pressure to provide ethyl 2-(l//-imidazo[4,5-c]pyridin-2-yl)propionate (60.4 g, 58%) as an amber 54 solid. Ή-NMR (300 ΜΗζ, CDC13) d ppm: 9.00 (s, 1H), 8.35 (d, 1H, J = 9.4 Hz), 7.50 (d, 1H, J = 9.4 Hz), 4.25 (m, 3H), 1.78 (d, 3H, J = 7.8 Hz), 1.30 (t, 3H, J =» 4.7 Hz). (b) A solution comprising ethyl 2-(ltf-imidazo[4,5-c]pyridin-2-yl)propionate (60.4 g, 0.28 mol) in trifluoroacetic acid (100 mL) was hydrogenation at 50 psi in the presence of 5 platinum (IV) oxide (5 g) for 2 days. The mixture was filtered and concentrated under reduced pressure. The residue was cooled to 0°C, treated with 4 M HCl/dioxane, suspended in ether, isolated by filtration and dried. Solutions comprising the residue (15-20g each) in fresh trifluoroacetic acid (50 mL each) were hydrogentated at 50 psi in the presenced of platinum (IV) oxide (5 g each) for 24 hours. The mixtures were filtered and concentrated under reduced 10 pressure. The residues were azeotropically dried with a mixture of toluene/ethanol -1:1, with 4 Ό M HCl/dioxane. suspended in ether, isolated by filtration and dried on the vacuum line to provide ethyl 2-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)propionate dihydrochloride (61.80 g, 75% vield); 'H-NMR (300 MHz, DMSO-d4) d ppm: 10.00 (br s, 2H), 4.35 (q, 1H, J = 7.1 Hz), 4.25 (br s, 2H), 4.15 (m, 2H), 3.35 (m, 2H), 2.90 (br s, 2H), 1.60 (d, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 6.9 Hz). (c) A solution comprising ethvl 2-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin*2-yl)propionate · dihvdrochloride (60.2 g, 0.20 mol) in acetonitrile (400 mL) was cooled to 0°C under nitrogen, treated with V,A-diisopropyIethylamine (35 mL, 0.20 mol), further cooled to - -5°C (ice/acetone) and then treated with benzvl chloroformate (58 mL, 0.41 mol) and 20 Ar.A-diisopropylethylamine (70 mL, 0.40 mol) in altemating portions over 30 minūtes. The mixture \vas cooled at -5°C for I hour and allov/ed to warm to 20 °C and, after 16 hours, concentrated under reduced pressure. The residue was suspended in ether and the suspension was washed successively with sodium bicarbonate, sodium chloride, 0.1 M hydrochloric acid and sodium chloride, dried (Na,S04), filtered and concentrated under reduced pressure. The residue 25 was dissolved in ethanol (320 mL) and the solution was cooled to -5 °C under nitrogen and then sodium ethoxide (21 wt %, 85 mL, 0.22 mol) was added dropwise over 1 hour while the reaction temperature was maintained below 0°C. The mixture \vas cooled at -5°C for 1 hour, adjusted to neutral pH with 50 mL of 4 M hvdrochloric acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was uashed with sodium bicarbonate and 30 sodium chloride, dried (Na,S04), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes/ethyl acetate) to provide benzvl 2-(l-ethoxycarbonylethyI)-l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (52 g, 72%) 55 LV 12495 as a pale yellow oil; 'H-NMR (300 MHz, DMSO-rf4) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H), 4.02 (q, 2H, J = 9.3 Hz), 3.77 (q, 1H, J = 8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H, J = 8.3 Hz), 1.13 (t, 3H, J « 9.3 Hz). (d) A mbcture comprising benzyl 2-( 1 -ethoxycarbonylethyl)-l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (6.37 g, 0.018 mol), 4-amino-3-(iV-methylamino)benzoic acid (2.70 g, 0.016 mol) and DMPU (20 mL) was degassed briefly on a vacuum line, heated heated at 185 eC under nitrogen for 4 hours, cooled and combined with an equivalent voiume of benzene. Ether was then added to the mixture to give a precipitate. The precipitate was isolated by filtration, dried briefly on a vacuum line and further purified by a reprecipitation from hot ethanolAvater. The precipitate was isolated recovered by filtration and dried to provided 2-[l-(5-benzyloxycarbonyl-4,5,6,7-tetrahydro- l/f-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-3//-benzoimidazole-5-carboxylic acid (4.73 g, 58 %); 'H-NMR (300 MHz, DMSO-</6) d ppm: 12.70 (br s, 1H), 11.80 (s, 1H), 8.15 (s, 1H), 7.78 (d, 1H, J - 8.3 Hz), 7.64 (d, 1H, J = 8.3 Hz), 7.31 (s, 5H), 5.09 (s, 2H), 4.66 (q, 1H, J = 5.2 Hz), 4.32 (br s, 2H), 3.78 (s, 3H), 3.65 (br s, 2H), 2.52 (br s, 2H), 1.73 (d, 3H, J - 5.2 Hz). (e) A mixture comprising 2-[ 1 -(5-benzyloxycarbonyl-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-3//'-benzoimidazole-5-carboxylic acid (0.75 g, 1.6 mmoi), 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 nitrogen to -40°C, treated with EDC (0.32 g, 1.6 mmol) and M/V-diisopropylethylamine (0.29 mL, 1.6 mmol) and 15 minūtes later with additional yV,A-diisopropylethylamine (0.29 mL), allowed to warm to 20SC and stirrcd for 16 hours. The mixture then \vas cooled to -40°C, treated with additional EDC (0.080 g) and /'/,jV-diisopropylethylamine (0.050 mL), stirred for 15 minūtes at -40°C and 2 hours at 20°C and concentrated by shortpath distillation. The residue was partitioned between chloroform and sodium bicarbonate and the organic layer was washed with sodium chloride, 0.5 M potassium sulfate and sodium chloride, dried (Na,S04), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3/MeOH/'AcOH : 95/5/1) to provide benzvl 2-(l-{6-[2-(2-methoxycarbonylphenoxy)ethylcarbamoyI]-l-methyl-l//-benzoimidazol-2-yl}ethyl)-l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (0.69 g, 66 %) as a glassy brown foam; ’H-NMR (300 MHz, DMSO-rf4) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J = 5.0 Hz), S.02 (s, 1H), 7.69 (d, 1H, J = 9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H, J = 8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1H, J = 9.9 Hz), 6.99 (t, 1H, J = 8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J = 8.8 Hz), 4.30 (br s, 56 2Η), 4.20 (t, 2H, J = 5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J = 8.8 Hz). (f) A solution comprising benzyl 2-(l-{6-[2-(2-methoxycarbonylphenoxy)ethylcarbamoyl]-1 -methyl-1 W-benzoimidazoI-2-yl} ethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridineo-carboxylate 5 (0.69 g, 1.1 mmol) in THF (2 mL) and water (2 mL) vvas cooled to 0°C under nitrogen, treated with 2 H lithium hydroxide (1.1 mL, 2.2 mmol), allovved to warm to 20°C and stirred for 8 hours. The mixture then was cooled to 0°C, treated with additional 2 N lithium hydroxide (1.1 mL), allovved to vvarm to 20°C, stirred for 6 hours, cooled to 0°C, adjusted to pH 7 vvith 1 M hydrochloric acid and concentrated under reduced pressure. The residue vvas carefully 10 vvashed with cold sodium chloride and vvater and then dried on the vacuum line to provide 5-benzyloxycarbonyl-2-(2-{3-methyl-2-(l-(4,5,6,7-tetrahydro- lH-imidazo(4,5-c]pyridin-2-yl)ethyl]-3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (0.56 g, S3 %) as a glassy residue; ‘H-NMR (300 MHz, DMSO-4) d ppm: 11.87 (br s. 1H). 9.74 (s, 1H), S.45 (s, 1H), 7.84 (d, 1H, J = 9.7 Hz), 7.56 (d, 1H, J = 9.7 Hz), 7.42 (d, 1H, J = 7.7 15 Hz), 7.32 (s, 5H), 7.23 (t, IH, J = 7.7 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.90 (t, IH. J = 7.7 Hz), 5.08 (s, 2H), 4.63 (q, IH, J = 7.7 Hz), 4.32 (s, 2H), 4.19 (m, 2H), 3.84 (s, 3H), 3.64 (m, 4H), 2.55 (s, 2H), 1.71 (d, 3H, J = 7.7 Hz). (g) A solution comprising 5-benzyloxycarbonyl-2-(2-{3-methyl-2-[l-(4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl)ethyl]-3//-benzoimidazolo-ylcarbonylamino}ethoxy)benzoic 20 acid (0.561 g, 0.90 mmol) in glacial acetic acid (2 mL) was neated under nitrogen in a vvater bath to 10°C, treated with hydrogen bromide in acetic acid (2 mL of a 30 % solution) and allovved to vvarm to 20°C and, one hour later, concentrated vvith a stream of nitrogen. The residue vvas dissolved in a small quantity of ethanol and the solution vvas added dropvvise to stirring ether to give a pale brovvn precipitate. The precipitate vvas isolated by filtration and dried to provide 25 2-(2-{3-methyl-2-[4,5,6,7-tetrahydro-l/7-imidazo(4,5-c]pyridin-2-yI)ethyl]- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid hydrobromide (0.651 g); 'H-NMR (300 MHz, DMSO-d6) d ppm: 9.31 (br s, 2H), 8.63 (m, 1H), 8.24 (s, 1H), 7.79 (d, 1H, J = 7.9 Hz), 7.63 (m, 2H), 7.47 (t, IH, J = 7.9 Hz), 7.21 (d, IH, J = 7.9 Hz), 7.00 (t, IH, J = 7.9 Hz), 5.21 (q, IH, J = 6.3 Hz), 4.29 (s, 2H), 4.21 (s, 2H), 3.91 (s, 3H), 3.6S (m, 2H), 3.43 (m, 2H), 2.89 (s, 30 2H), 1.79 (d, 3H,J = 6.3 Hz). (h) A solution comprising 2-(2-{3-methyl-2-[4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl)ethyl]-37/-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic 57 LV 12495 acid hydrobromide (0.30 g, 0.46 mmol) in DMF (1.5 mL) was cooled undsr nitrogen to 0°C, treated with ethyl acetimidate (0.12 g, 0.92 mmol) and jV,/V-diisopropylethylamine (0.25 mL, 1.4 mmol), cooled at 0eC for 30 minūtes and then allowed to warm to 20°C and stirred for 20 hours. The mixture then was cooled to 0°C, treated with additional ethyl acetimidate (0.06 g) and of MN-diisopropylethylamine (0.16 mL), allowed to warm to 20°C and stirred for 2 hours. The mixture was cooled to 0°C, treated with additional ethyl acetimidate (0.03 g), allowed to \varm to 20°C and stirred for 2 hours. The mixture then was added dropvvise to stirring ether to give a precipitate. The precipitate was isolated by decantating away the solvent and dried on a vacuum line. The residue was precipitated from ethanol/ether and purified by preparative RP-HPLC: 2 50 % MeCN/H20 (20 mM HC1) over 50 minūtes. The fractions were lyophi!ized to provide 2-[2-(2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-ltf-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (0.145 g, 52 %); ’H-NMR (300 MHz, DMSO-c/,) d ppm: 9.77 (s, 1H), 9.34 (2s, 1H), 8.81 (m, 1H), 8.36 (s, 1H), 7.89 (d, IH, J = 8.6 Hz), 7.71 (d, 1H, J = 8.6 Hz), 7.60 (d, 1H, J = 7.7 Hz), 7.49 (t, 1H, J = 7.7 Hz), 7.21 (d, 1H, J = 7.7 Hz), 6.99 (t, 1H, J = 7.7 Hz), 5.37 (m, 1H), 4.71 (2s, 2H), 4.23 (s, 2H), 3.97 (s, 3H), 3.S2 (s, 1H), 3.66 (m, 2H), 2.S3 (m, 2H), 2.49 (s, 1H), 2.40 (d, 3H, J = 3.5 Hz), 1.85 (d, 3H, J = 5.1 Hz). MS (ESI) GjH^NA m/e calcd. 529.61, observed 530.3 (MH~). EXAMPLE 10 ethvl 2-(2-{2-[ 1-(4,6,7-trifluoro-l/f-benzoimidazol-2-yl)ethyl]-3-methyl-3//-bcnzoimidazol-5-carbonylamino} ethoxy} benzoate (Compound 75) (a) A solution comprising 2,3,4,6-tetrafluoronitrobenzene (0.6 g, 3.1 mmol) and ammonia in dioxane (Aldrich, 0.5 M, 7.5 mmol) was stirred at room temperature for 3 hours to givc a finc whitc precipitate. The mixture was diluted with an equal volume of \vater to dissolve the white precipitate and give yel!ow crystals. The crystals were isolated were collected and dried to provide 2,3,5-trifluoro-6-nitroaniline (307 mg, 51%) as yello\v needles; m.p. 66°C; ’H NMR (CDC13) δ 6.4 (1H, m), δ 6.0 (2H, s). (b) A mixture of 2,3,5-trifluoro-6-nitroaniline (300 mg, 1.56 mmol) and 10% palladium on carbon in absolute ethanol was hvdrogenated ovemight at atmospheric pressure, filtered under nitrogen and concentrated to provide l,2-diamino-3,4,6-trifluorobenzene (219 mg, 87% yield) as 58 a purple crystalline solid; MS M' 162.7, +41.+82 (+ ACN, +2ACN). (calcd for C6H5F3N2: 162.11). (c) A mixture of 1,2-diamino-3,4,6-triiluorobenzene (l.92 g, 11.8 mmol), ethyl 2-ethoxycarbonimidoylpropionate (3.1 g, 14.7 mmol) and absolute ethanol (6 ml) was heated at 5 reflux untii no further progression of the reaction was indicated by TLC indicated the reaction was not progressing further, filtered ffom NH4C1 and concentrated. The residue was purified by chromatography on silica (hexane: methylene chloride: ethyl acetate, 5:5:1) to give ethyl 2-(4,6,7-trifluoro-l//-benzoimidazol-2-yl)propionate (1.37 g, 42%) as a tan crystalline solid; NMR (CDClj): δ 10.35 (s, 1/2 Η), δ 7.05 (s, 1/2 H), 6.7 (m, 1H), δ 4.25 (dd, 2H), δ 4.15 (dd, 10 1H), δ 1.73 (d, 3H), δ 1.31 (t, 3H); M* 272.9 (calcd for C,2HnF3N202: 272.23). (d) Ethyl 2-(4,6,7-trifluoro-l//-benzoimidazol-2-yl)propionate (988 mg, 3.63 mmol) and ethyl 2-[2-(4-amino-3-methylaminobenzoy!amino)ethoxy]benzoate (1.3 g, 3.63 mmol) were combined and placed under vacuum for 4 hours and then further combined vvith DMPU (4 ml). The mixture was stirred untii in soiution, evacuated ovemight under high vacuum to remove 15 residual gases, heated to 195°C under a nitrogen stream for 4 hours, cooled to room temperature and partitioned betvveen ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue \vas purified by chromatography on silica (stepvvise gradient of 100% hexane to 100% ethyl acetate) and further purified by crvstallization from MeOH/THF/water to provide ethvl 2-(2-(2-( 1-(4,6,7-trifluoro-20 l//-benzoimidazol-2-yl)ethyl]-3-methyl-3/f-benzoimidazol-5-carbonylamino}ethoxy}benzoate (l .0 g, 49%) as a white crystallinc solid: NMR (CDClj): δ 6.84-8.07 (m, SH), δ 4.93 (dd, 1H), δ 4.34 (dd, 2H), 0 4.27 (m, 2H), δ 3.95 (m, 2H), δ 3.9 (s, 3H), δ 1.93 (d, 3H), δ 1.78 (s, 2H), δ 1.3S (t, 3H); LCMS M* 566.2 Biolon M* 565.7 (calcd for C2yH26F3NjO.,: 565.55). 25
Proceeding as in Example 10 the following compounds of the invention wcre prepared: ethvl 2-(2-{2-[l-(5,6-difluoro-l//-benzoimidazoI-2-yl)ethyl]-3-methyl-3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 76), MS (Biolon) CI9H27N504F2 m/e calc 547.56; found 54S.1 (MH*); 30 ethyl 2-(2-{2-[l-(4,6-difluoro-l//-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 77, MS (LCMS) C2,H27F2N504 m/e calc 547.56; found 54S.3 (MH*); 59 LV 12495 ethyl 2-(2- {2-[ 1 -(4,5,6-trifluoro-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 78), MS (LCMS) C3,H26F3N50, m/e calc 565.55; found 566.2 (ΜΗ*); and ethyl 2-{2-[3-methyl-2-(4,6,7-trifluoro-l//-benzoimidazol-2-ylmethyl)-3//-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 79), MS (Biolon) C2sH,4F3Nj04 m/e calc 551.52; found 551.2. EXAMPLE11 2-(2- {2-[ 1 -(4,6,7-T rifluoro-1 £f-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonyIamino}ethoxy)benzoic acid (Compound 80) A mixture comprising ethyl 2-(2-{2-[ 1-(4,6,7-trifluoro-l//-benzoimidazo l-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-carbonylamino}ethoxy}benzoate (118 mg, 0.21 mmol), methanol (4 ml) and 2N sodium hydroxide (2.1 ml) was stirred at room temperature for 4 hours, neutralized with 2N hydrochloric acid (2.1 ml) and partitioned between ethyl acetate and saturated ammonium chloride. The aqueous layer \vas separated and extracted with ethyl acetate (X3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to a white solid. The residue was dissolved in \varm ethanol (10 ml) and 4M hvdrogen chloride/dioxane solution. The solution was diluted with ethyl ether to give a precipitate. The precipitate vvas isolated and dried to give 2-(2-{2-[ 1-(4,6,7-trifluoro-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid as a \vhite solid; MS (LCMS) C37H3IF3N504 m/e calc 537.50; found 53S.4 (ΜΗ'*.
Proceeding as in Example 11 the following compounds of the invention were prepared: 2-(2-(2-[l-(5,6-difluoro-17/-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazoI-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 81), MS (LCMS) C37H23N504F, m/e calc 519.51; found 520.2 (MH*); 2-(2- {2-[ 1 -(4,6-difluoro-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 82), MS (LCMS) C:7H:3F2N504 m/e calc 519.51; found 520.2 (ΜΗ*); and 60 2-(2- (2-[ 1 -(4,5,6-trifluoro-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-carbonylamino}ethoxy)benzoic acid (Compound 83), MS (Biolon) C27H:,F3N504 m/e calc 537.5; found 537.7 (MH+). 5 EXAMPLE12
Ethvl 2-(2-{2-[l-(l-isobutyryl-5-methoxycarbonyloxy-l//-benzoimidazol-2-yl)ethyl]-3-methyI-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 84) 10 A mixture comprising ethyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]- 3-methyl-3//-benzoimidazol-5-carbonylamino}ethoxy)benzoate (0.50g, 0.95 mmol), dimethylformamidc (5mL), cesium carbonate (0.93g, 2.85 mmol) and isobutvric anhvdride (0.17 mL, 1.05 mmol) was stirred for 2 hours, then diluted with dichloromethane (50 mL) and passed through a celite pad. The solvents were removed in vacuo and the residue was dissolved 15 in dichloromethane (5 mL). The solution was combined vvith diisopropylethylamine (0.47 mL, 2.7 mmol) and methy! chioroformate (0.1 mL, 1.3 mmol) and the mixture was stirred for l hour. The solvents were removed in vacuo and the residue \vas purified by silica gel chromatography using ethanoi and dichloromethane as eluent to provide ethvl 2-(2-(2-(1-(1 -isobutyrI-5-methoxycarbonyloxy-l/jr-benzoimidazol-2-yl)ethyl]-3-methyI-20 3Ar-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (0.20g, 32% yield) as a colorless amorpnous solid; MS (Biolon) C^jHjjNjOg m/e calc 655.72; found 656.1 (MH*).
Proceeding as in Example 12 the follovving prodrug derivatives of the invention were prepared: 25 methyl 2-(l-{6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-l-methyl- l//-benzoimidazol-2-yl}ethyl)-5-hydroxybenzoimidazole-l-carboxylate (Compound S5), MS (ESI) C3|H3iN507 m/e calc 585.62; found 586.2 (MH*); ethvl 2-( 1 - (6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-1 -methyl-lW-benzoimidazol-2-yl}ethyl)-5-methoxycarbonyloxybenzoimidazole-l-carboxylate (Compound S6), MS (ESI) C33H33N5O7 m/e calc 643.66; found 644.2 (MH+); 30 61 LV 12495 ethyl 2-(2- {2-[ 1 -(5-hydroxy-1 -isobutyryl-1 /f-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 87), MS (ESI) C33H3iNs06 m/e calc 597.68; found 598.2 (MH+); ethyl 2-(2- (2-[ 1 -(1 -benzoyl-5-hydroxy-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-5 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 88), MS (ESI) C36H33Nj06 m/e calc 631.69; found 632.3 (ΜΗ*); ethyl 2-(2- {2-[ 1 -(1 -dimethylcarbamoyl-5-hydroxy- l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazoI-5-ylcarbonylamino)ethoxy}benzoate (Compound 89), MS (ESI) C32H34N605 m/e calc 598.66; found 599.3 (MH*); 10 ethyl 2-(2- {2-[ 1 -(1 -acetoxymethyl-5-hydroxy- l//-benzoimidazoI-2-yI)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 90), MS (Biolon) C„HmNj07 m/e calc 599.65; found 600.7 (MH*); ethyl 2-(2-(2- {1 -[ 1 -(2,2-dimethylpropionyloxymethyl)-5-hydroxy-lAr-benzoimidazol-2-yl]ethyl}-3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoate 15 (Compound 91), MS (ESI) C3JH39N307 m/e calc 641.74; found 642.3 (MH*); ethyl 2-(2-{2-[l-(l-isobutyrl-5-methoxycarbonyloxy-l//-benzoimidazol-2-yl)ethyl]-3-methyI-3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 92), MS (Biolon) C35H37N503 nL'e calc 655.72; found 656.1 (MH~); ethyl 5-ethoxycarbonyloxy-2-(l-{6-[2-(2-ethoxycarbonylphenoxy)ethylcarbamoyl]-20 l-methyl-l//-benzoimidazol-2-yl}ethyl)benzoimidazoIe-l-carboxylate (Compound 93), MS (ESI) C3jH37N509 m/e calc 671.72; found 672.4 (MH*); isopropyl 2-( 1 - {6-[2-(2-etho.\ycarbonylphenoxy)ethylcarbamoy 1]-1 -mechyl-l//-benzoimidazol-2-yl}ethyl)-5-isopropoxycarbonyloxy-benzoimidazole-l-carboxylatc (Compound 94), MS (ESI) m/e calc 699.79; found 700.4 (MH*); and 25 ethyl 2-(2-{2-(1-( l-acetyl-5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 95), MS (ESI) C3|H3|Ns06 m/e calc 569.62; found 570.1 (MH*).
Proceeding as described in this application or by methods knovvn to those of ordinary 30 skill the following additional compounds of the invention were prepared: C-[2-(5-aminomethyl-1 //-benzoimidazol-2-ylmethyl)-3//-benzoimidazol-5-yl]methylamine (Compound 96); 62 C-[2-(ltf-naphtho[2,3y]imidazol-2~ylmethyl)-l//-benzoimidazol-5-yl]methylamine (Compound 97), MS (Biolon) C20HI7N5 m/e calc 327.4; found 328.1 (MPT); C-[2-(5-methyl-l//-benzoimidazol-2-ylmethyl)-l//-benzoimidazol-5-yl]rnethylamine (Compound 98), MS (Biolon) C17H,7N5 m/e calc 291.4; found 292.3 (MH*); 5 2-(5-aminomethyl-l//-benzoimidazol-2-ybnethyl)-l/f-benzoimidazoIe-5-carboxylic acid (Compound 99); 3-[2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-l/i-benzoimidazol-5-ylcarbonylamino]propionic acid (Compound 100), Ή-NMR (300Mhz, CD3OD): 1.92 (m, 2H, J=7.2Hz), 2.3S (t, 2H, J = 7.2 Hz), 3.47 (t, 2H, >7.2 10 Hz), 4.30 (s, 2H), 7.54 (d, 1H, J=10.0 Hz), 7.69 (d, 1H, J = 8.6 Hz), 7.75 (d, 1H, J=10.0 Hz), 7.81 (s, IH), 7.87 (d, 1H, >8.6 Hz), 8.12 (s, 1H); 2-(5-aminomethyl-l//-bcnzoimidazol-2-ylmethyl)-N-(2-naphth-l-ylsthyl)-l//-benzoimidazole-5-carboxamide (Compound 101), Ή-NMR (300Mhz, CD3OD): 3.42 (t, 2H, J=7.5 Hz), 3.75 (t, 2H, J = 7.5 Hz), 7.39-7.S1 (m, 12H), 8.0S (s, 1H), 8.27 (d, 1H, >10.0 Hz); 15 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-3-methyl-Ar-(2-naphth-l-ylethyl)- 3/i-benzoimidazole-5-carboxamide (Compound 102), Ή-NMR (300Mhz, CD3OD): 3.41 (t, 2H, >7.4 Hz), 3.72 (t, 2H, J=7.4 Hz), 3.96 (s, 3H), 4.27 (s, 2H), 7.37-7.54 (m, 5H), 7.67 (d, 1H, >S.7 Hz), 7.71-7.77 (m, 2H), 7.S0-7.S5 (m, 2H), S.70 (d, 1H, >0.9 Hz), S.24 (d, IH, J = 8.1 Hz); 20 2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-3-methyl-/V-(2-naphth-l-ylethyl)- 37/-benzoimidazole-4-carboxamidc (Compound 103), Ή-NMR (300Mhz, CD3OD): 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, IH, J=S.l Hz); (6)-2-[2-(5-aminomethyl-l//-benzoimidazol-2-ylmethyl)-25 l//-benzoimidazol-5-ylcarbonylamino]-3-indol-3-ylpropionic acid (Compound 104), Ή-NMR (300Mhz, CD3OD): 3.36 (dd, IH, J = 14.6, 8.1 Hz), 3.53 (dd, IH, >14.6, 5.0 Hz), 3.92 (s,3H), 4.27 (s,2H), 6.97 (t, 1H,J = 7.4 Hz), 7.07 (t, IH, >7.4 Hz), 7.16 (s, IH), 7.33 (d, IH >7.8 Hz), 7.51 (dd, IH, J = 8.4, 1.5 Hz), 7.60-7.66 (m, 2H), 7.73-7.80 (m, 3H), 7.96 (d, IH, >0.9 Hz), 8.39 (d, J = 7.5 Hz, partiallv exchanged); 30 (R)-2-[2-(5-aminomethyl-l//-benzoimidažol-2-ylmethyl)- ltf-benzoimidazol-5-ylcarbonylamino]-3-indol-3-ylpropionic acid (Compound 105), Ή-NMR (300Mhz, CD3OD): 3.35 (dd, IH, J = 14.5, 8.1 Hz), 3.51 (dd, IH, >14.4, 4.S Hz), 3.90 63 LV 12495 (s, 3H), 4.23 (s, 2H), 6.96 (t, 1H, J = 7.4 Hz), 7.06 (t, 1H, J=7.4 Hz), 7.14 (s, 1H), 7.31 (d, 1H, >7.8 Hz), 7.44 (d, 1H, J = 7.8 Hz), 7.58-7.74 (m, 5H), 7.94 (s, 1H), 8.33 (d, J=8.1 Hz, partially exchanged); 2-(l//-benzoimidazol-2-ylmethyl)-Ar-(2-naphth-l-ylethyl)-l//-benzoimidazole-5-carboxamide (Compound 106), Ή-NMR (300Mhz, CD3OD): 3.42 (t, 2H, >7.4 Hz), 3.76 (t, 2H, J = 7.4 Hz), 3.97 (s, 3H), 7.38-7.60 (m, 5H), 7.65 (d, 1H, >8.7Hz), 7.72-7.79 (m, 4H), 7.85 (dd, 1H, J=8.6,1.5 Hz), 8.04 (d, 1H, J—1.2 Hz), 8.26 (d, 1H, >8.4 Hz); 2-(5-aminornethyl-l//-benzoimidazol-2-ylmethyl)-3-methyl-/'/-(4-aminobutyl)-3//-benzoimidazole-4-carboxamide (Compound 107), MS (Biolon) C22H27N70, m/e calc 405.4; found 406.5 (MH*)‘. 2-[l-(5-aminomethyl-l//-benzoimidazol-2-yl)ethyl]-3-methyl-iV-(2-naphth-l-ylethyl)-37/-benzoimidazole-5-carboxamide (Compound 108), MS (Biolon) C3,H3oN60, m/e calc 502.6; found 503.3 (ΜΗ1-); 2-(l//-imidazo[4,5-c]pyridin-2-ylmethyl)-3-methyl-Ar-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamidc (Compound 109), MS (Biolon) C28H24N60, m/e calc 460.5; found 461.3 (MH*); 2-(5-aminomethyl-l//-benzoimida2ol-2-ylcarbonyl)-3-methyl-/V-(2-naphth-l-ylethyl)-3f/-ben2oimidazole-5-carboxamide (Compound 110), MS (Biolon) C3(}H26N502 m/e calc 502.6; found 503.6 (MH*); 2-(5-carbamoyl-l//-benzoimidazol-2-ylmethyl)-/V-(2-naphth-l-ylethyl)-l//-benzoimidazole-5-carboxamide (Compound 111), 2-(5-aminomethyl-4,5,6,7-tetrahydro-l//-benzoimidazol-2-ylmethyl)-3-methyl-.'V-(2-naphtn-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 112), Ή-NMR (300.Mhz, CD3OD): 1.67 (m, 1H), 2.14 (m, 1H), 2.24 (m, 1H), 2.47 (dd, 1H, J=15.3, 9.3 Hz), 2.76 (m, 2H), 2.90 (dd, 1H, J = 15.7, 7.5 Hz), 3.05 (d, 2H, J=6.9 Hz), 3.41 (t, 2H, J=7.4 Hz), 3.75 (t, 2H, J=7.4 Hz), 3.90 (s, 3H), 7.35-7.53 (m, 5H), 7.61 (d, 1H, J=8.4 Hz), 7.72-7.75 (m, 2H), 7.85 (dd, 1H, J = 8.1, 1.2 Hz), 7.99 (d, 1H, J=0.9 Hz), S.26 (d, 1H, J=8.4 Hz); 2-(5-aminomethyl-li:/-benzoimida2ol-2-ylmethyl)-3-methyl-.V-(3-phenylpropyl)-3//-benzoimidazole-5-carboxamide (Compound 113), Ή-NMR (300Mhz, CD3OD): 1.98 (m, 2H), 2.72 (t, 2H, >7.6 Hz), 3.46 (t, 2H, >7.2 Hz), 4.01 (s, 3H), 4.29 (s, 2H), 7.12-7.17 (m, 1H), 7.21-7.2S (m, 4H), 7.56 (d, 1H, >8.1 Hz), 7.70 (d, 1H, >8.7 Hz), 7.77 (d, 1H, >8.4 Hz), 7.S5-7.88 (m, 2H), 8.16 (s, 1H, >1H); 64 2-(5-aminomethyl-l//-bsnzoimidazol-2-ylmethyl)-3-methyI-A'-(2-phenoxyethyl)-3//-benzoimidazole-5-carboxamide (Compound 114), Ή-NMR (300Mhz, CD3OD): 3.S0 (t, 2K, J=5.0 Hz), 3.99 (s, 3H), 4.17 (t, 2H, J=5.0Hz), 4.27 (s, 2H), 6.S8 (t, 1H, J=7.5Hz), 6.92 (d, 2H, J=7.5 Hz), 7.22 (ί, 2H, J=7.5 Hz), 7.55 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=6.6 Hz), 7.77 (d, 1H, Ο J = 8.4 Hz), 7.84 (s, 1H), 7.88 (d, 1H, J=S.7 Hz), 8.18 (s, 1H); 10 2-[5-(l-iminoethyI)-4,5,6,7-tetrahydro-l//-imidazo[4,5-<:]pyridin-2-ylmethy!]-3-methyl-A,-(2-naphth-l-ylethyl)-3//-bsnzoimidazole-5-carboxamids (Compound 115), Ή-NMR (300Mhz, CDjOD): 2.45 (2.43, s, 3H), 2.96 (m, 2H), 3.42 (t, 2H, J=7.4 Hz), 3.75 (t, 2H, J=7.4 Hz), 3.93 (s, 3H), 3.98 (m, 2H), 4.70 (4.S0, s, 2H), 7.3S-7.53 (m, 4H), 7.63-7.S7 (m, 4H), S.04 (d, J=1.5 Hz, 3.08, s, 1H), 8.26 (d, 1H, J=S.O Hz); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-irnidazo[4,5-c]pyridin-2-ylcarbonyl]-3-methyl-/V-(2-naphth-l-ylethyl)-37/-bsnzoimidazols-5-carboxamide (Compound 116), ‘H-NMR (300Mhz, CD3OD): 2.45 (2.43. s, 3H), 3.03 (m, 2H), 3.41 (t, 2H, J=7.4 Hz), 3.74 (t, 2H, J=7.4 Hz), 3.97 (m, 2H), 4.1S (4.18, s, 3H), 4.66 (4.S0, s, 2H), 7.3S-7.54 (m, 4H), 7.72-7.92 (m, 4H), !5 3.04(5, lH),S.26(d, 1H, J=7.S Hz); 20 2-(5-iminomeīhyl-4,5,6,7-tetrahydro-l//-imidazo[4,5-cjpyridin-2-ylmethyl)'3-methyl-Ar-(2-napruh-l-ylethyl)-3//-benzoimidazole-5-carboxamīde (Compound 117), ‘H-NMR (300Mhz, CDjOD): 2.95 (η, 2H), 3.40 (t, 2H, J=7.4 Hz), 3.74 (t, 2H, J - 7.4 Hz), 3.90 (3.89, s, 3H), 3.98 (m, 2H), 4.70 (4.82, s, 2H), 7.39-7.52 (m, 4H). 7.63-7.S4 (m, 4H), 8.03 (s, IH), S.16 (S.1S, 5, 1H), 8.24 (d, 1H, J=S.4 Hz); 2-(5-aminomethyi-4,5,6,7-isirahydro-l/i-benzoimidazo!-2-ylcarbonyi)-3-mathyl-;V-(2-naphth-l-ylsthyl)-3//-benzoimidazols-5-carboxamide (Compound 118), 1 H-NMR (300Mhz, CD3OD): 1.69 (m, 1H), 2.15 (m, IH), 2.20 (m, 1H), 2.55 (dd, iH, J=15.0, 11.4 Hz), 2.81-3.08 (m, 5H), 3.44 (t, 2H, J=7.5 Hz), 3.74 (m, 2H), 4.23 (s, 3H), 7.39-7.52 (m, 4H), 7.75 Γdd, iH. J=6.1, 3.2 Hz), 7.S3-7.38 (m, 2H), 7.97 (d, IH, J=8.7 Hz), S.10 (3, IH), 8.27 (d, IH, J=S.l Hz); 2-[5-( 1 -iminoetnyl)-4,5,6,7-tctrahydro-17/-imidazo[4.5-c]p>Tidin-2-ylmethyl'i-3-msthvl-.Y-(2-phenoxyethyl)-3//-bcnzoimidazoie-5-ca:boxarnide ('Compound 119). Ή-NMR NOOMhz. CD3OD): 2.45 62.43, s, 3H). 2.95 (m, 2H). 3.S0 (:, 2H, J=5.6 Hz). 3.95 is, 3H). 3.9S (m, 2H), 4.17 (;, 2H, J=5.6 Hz), 4.71 (4.81, s, 2H), 6.89 (t, IH, J=7.3 Hz), 6.93 (d. 2H. J=$.6 Hz), 7.23 1 dd. 2H. J=S,6. 7.3 Hz), ".66 (d. IH, j=7.S Hzi, 7.35 (d. IH, J=7.S Hz). 3.13 (3, IH); 65 LV 12495 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-//-(2-benzo[l,3]dioxol-4-ylethyl)-3#-benzoimidazole-5-carboxamide (Compound 120), lH-NMR (300Mhz, CD3OD): 2.45 (2.43, s, 3H), 2.89-2.97 (m, 4H), 3.65 (t, 2H, J = 7.1 Hz), 3.94 (s, 3H), 3.98 (m, 2H), 4.71 (4.81, s, 2H), 5.83 (s, 2H), 6.65-6.74 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 7.76-7.79 (m, 1H), 8.06 (m, 1H); 2-[5-( l -iminoethyl)-4,5,6,7-tetrahydro-1 #-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-//-(-benzoimidazol-1 -ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 121), 'H-NMR (300Mhz, CDjOD): 2.46 (2.44, s, 3H), 2.96 (m, 2H), 3.92 (s, 3H), 3.95-4.01 (m, 4H), 4.73 (4.79, s, 2H), 4.80 (m, 2H), 7.54-7.64 (m, 4H), 7.83 (dd, 1H, J=6.5,2.2 Hz), 7.93 (s, 1H), 7.98 (dd, J=6.5, 2.1 Hz), 9.49 (s, 1H); A7-[2-(5-hydroxy-ltf-indol-2-yl)ethyl]-2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-3#-benzoimidazole-5-carboxamide (Compound 122), Ή-NMR (300Mhz, CD3OD): 2.42 (2.39, s, 3H), 2.90 (m, 2H), 2.99 (t, 2H, J=7.1 Hz), 3.67 (t, 2H, J=7.1 Hz), 3.75 (s, 3H), 3.93 (m, 2H), 4.66 (4.76, s, 2H), 6.61 (dd, 1H, J=8.5,2.3 Hz), 6.94 (d, 1H, J=2.3 Hz), 7.06 (s, 1H), 7.12 (d, 1H, J=$.5 Hz), 7.59 (d, 1H, J=8.4 Hz), 7.76 (dd, 1H, J=8.4, 1.2 Hz), 7.87 (d, IH, J-1.2 Hz); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/:i-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-/V-[2-(2-chlorophenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 123), MS (Biolon) C:6H23N702CI m/e calc 506.0; found 506.3 (MH*); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyndin-2-ylmethyI]-3-methyl-/V-[2-(3-chlorophenoxy)ethyl]-3//-benzoimidazole-5-carboxamidc (Compound 124), MS (Biolon) m/e calc 506.0; found 506.7 (MH”); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-i:]pyndin-2-ylmethyl]-3-methyl-A'-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 125), Ή-NMR (300Mhz, CDjOD): 2.4S (2.46, s, 3H), 3.00 (m, 2H), 3.60 (t, 2H, J=6.6 Hz), 3.90-4.05 (m, 7H). 4.76 (4.76, s, 2H), 6.64 (6.66, s, partially exchanged), 7.45-7.95 (m, 9H), 8.02 (m, partially cchanged), 8.17 (d, 1H, 1=8.1 Hz), 8.96 (s, partially exchanged); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l#-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-A-(2-hydroxy-2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 126), Ή-NMR (300Mhz, CD3OD): 2.45 (2.43, s, 3H), 2.94 (m, 2H), 3.55 (dd, 1H, J=13.6, 8.3 Hz), 3.91-3.99 (m, 6H), 4.70 (4.80, s, 2H), 5.78 (dd, 1H, J=8.3, 3.6 Hz), 7.44-7.54 (m, 3H), 7.66 (d, 1H, J=8.4 Hz), 7.76-7.88 (m, 4H), 8.08 (m, 1H), 8.39 (d, 1H, J=8.4Hz); 66 2-(5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-Ar-[2-(2-hydroxynaphth-l-yl)ethyl]-3/7-benzoimidazole-5-carboxamide (Compound 127), Ή-NMR (300Mhz, CD3OD): 2.43 (2.41, s, 3H), 2.92 (m, 2H), 3.41 (t, 2H, J=7.1 Hz), 3.69 (t, 2H, J—7.1 Hz), 3.85 (s, 3H), 3.93-3.96 (m, 2H), 4.68 (4.78, s, 2H), 7.11 (d, 1H, J=8.7 Hz), 7.21 5 (t, 1H, J=7.5 Hz), 7.38 (dt, 1H, J=l.2,7.6 Hz), 7.50-7.61 (m, 2H), 7.69-7.75 (m, 2H), 7.93 (s, 1H), 8.07 (d, 1H, J=8.4 Hz); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-ylmethyl]-3-methyI-/V-[2-(4-hydroxynaphthaI-l -yl)ethyI]-3//-benzoimidazole-5-carboxamide (Compound 128), Ή-NMR (300Mhz, CD3OD): 2.42 (2.40, s, 3H), 2.89 (m, 2H), 3.27 (m, 2H), 3.69 (t, 2H, J=7.2 10 Hz), 3.82 (3.83, s, 3H), 3.93 (m, 2H), 4.64 (4.76, s, 2H), 6.72 (d, IH, J=7.S Hz), 7.17 (d, 1H, J=7.5 Hz), 7.37 (t, IH, J=7.5 Hz), 7.46 (dt, IH, J=0.9, 6.9 Hz), 7.62 (d, 1H, J=8.5 Hz), 7.77 (d, IH, J=S.5 Hz), 7.95 (s, IH), 8.12 (d, IH, J=8.4 Hz), 8.17 (d, IH, J = 8.4 Hz); 2-(5-(1-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-ylmethyl]-3-methyl-yV-[2-(2-methoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 129), ’H-NMR 15 (300Mhz, CD3OD): 2.45 (2.43, s, 3H), 2.95 (m, 2H), 3.S0 (m, 5H), 3.95 (s, 3H), 3.9S (rņ, 2H), 4.17 (t, 2H, J=5.4 Hz), 4.71 (4.81, s, 2H), 6.85-7.00 (m, 4H), 7.66 (d, IH, J = 8.7 Hz), 7.84 (m, IH), S.13 (s, IH); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-irnidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-/V-naphth-2-ylmethyl-3//-benzoimidazole-5-carboxamide (Compound 130), 20 Ή-NMR (300Mhz, CD3OD): 2.44 (2.42, s, 3H), 2.92 (m, 2H), 3.91 (s, 3H), 3.95 (m, 2H), 4.6S (4.7S, s, 2H), 4.77 (s, 2H), 7.41-7.44 (m, 2H), 7.50 (dd, lh, J=8.6, 1.1 Hz), 7.67 (d, IH, J=8.4 Hz), 7.78-7.83 (m, 4H), 7.90 (m, IH), 8.16 (m, IH); CO ΙΟ 2-(5-( l-iminoethyl)-4,5,6,7-tetrahydro-l //-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-/V-(3-pyrid-4-ylpropyl)-3//-benzoimidazole-5-carboxamide (Compound 131), 'H-NMR 5 (300Mhz, CD3OD): 2.11 (m, 2H), 2.46 (2.43, s, 3H), 2.96 (m, 2H), 3.06 (t, 2H, J=7.7 Hz), 3.51 (t, 2H, J=6.8 Hz), 3.98 (m, 5H), 4.72 (4.82, s, 2H), 7.67 (d, IH, J=S.5 Hz), 7.83 (dd, IH, J=8.5, 1.3 Hz), S.00 (d, 2H, J=6.6 Hz), 8.15 (d, IH, J=1.3 Hz), 8.70 (d, 2H, J=6.6 Hz); 2-(5-guanidino-l//-benzoimidazol-2-ylmethy!)-3-(2,3-dihydroxy)propyl-/V-(2-naphth-l-y!ethyl)-3//-benzoimidazole-5-carboxamide (Compound 132), MS (Biolon) 0 CjīHjjNjOj m/e calc 576.6; found 577.5 (MH’); Ή-NMR (300Mhz, CD3OD): 3.41 (t, 2H, J=7.5 Hz), 3.58-3.76 (m, 4H), 4.05 (m, IH), 4.45 (dd, IH, J=14.9, 8.5 Hz), 4.61 (dd, IH, J - 14.9, 3.2 Hz), 7.36-7.52 (m, 4H), 7.66-7.85 (m, 4H), 8.14 (s, IH), 8.25 (d, IH, J=7.S Hz); 67 LV 12495 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l.tf-imidazo[4,5^yridin-2-ylrnethyl]-3-methyl-7/-[2-(4-methoxyphenoxy)ethyI]-3//-benzoimidazole-5-carboxamide (Compound 133), Ή-NMR (300Mhz, CD3OD): 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-l/f-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl-yV-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 134), MS (Biolon) C3:H30N7O4 m/e calc 590.6; found 590.7 (MH*); Ή-NMR (300Mhz, CD3OD): 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, 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, >1.2Hz), 8.25 (d, 1H, >8.1 Hz); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-/V-[2-(l,2,3,4-tetrahydronaphth-l-yl)ethyl]-3W-benzoimidazole-5-carboxamide (Compound 135), Ή-NMR (300Mhz, CD3OD): 1.69-2.11 (m, 6H), 2.45 (2.43, s, 3H), 2.73 (m, 2H), 2.88 (m, 1H), 2.95 (m 2H), 3.52 (t, 2H, >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, >S.7 Hz), 7.82-7.86 (m, 1H), 8.14 (d, 1H, J = 0.9 Hz); 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/7-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl-/V-[2-(3-methoxyphenoxy)ethyl]-3tf-benzoimidazole-5-carboxamide (Compound 136), Ή-NMR (300Mhz, CD3OD): 2.45 (2.42, s, 3H), 2.95 (m, 2H), 3.71 (s, 3H), 3.7S (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.S3 (m, 1H), 8.12 (m, 1H, >1.2 Hz); 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-//-(3-phenylpropyl)-l//-benzoimidazole-5-carboxamide (Compound 137), 2-(5-guanidino-l//-bcnzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl-/V-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 138), 'H-NMR (300Mhz, CDjOD): 2.09 (m, 2H), 3.44 (t, 2H, >7.4 Hz), 3.58 (t, 2H, >5.6 Hz), 3.77 (t, 2H, >7.4 Hz), 4.55 (t, 2H, J = 7.1 Hz), 7.32 (dd, IH, >8.6, 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), S.28 (d, 1H,>8.1Hz); 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-A;-[2-(2-methoxy)phenoxyethyl]-3//-benzoimidazole-5-carboxamide (Compound 139), MS (Biolon) C,9H32N805 m/e calc 572.62; found 573.3 (MH*); Ή-NMR (300Mhz, CD3OD): 3.5S-3.69 (m, 2H), 3.S0 (m, 5Η), 4.07 (m, 1H), 4.17 (t, 2H, >5.3 Hz), 4.47 (dd, 1Η, >15.0, S.4 Hz), 68 4.64 dd, 1H, J=15.0, 3.0 Hz), 6.66-7.00 (m, 4H), 7.38 (dd, 1H, J=8.6,1.7 Hz), 7.66 (d, IH, J=1.7Hz), 7.70 (d, 1H, J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.87 (dd, 1H, J=8.6, 1.5 Hz), 8.24 (d, 1H, J=1.5Hz); 2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-(2,3-dihydroxypropyl)-5 //-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 140), MS (Biolon) C33H34Ns03 m/e calc 590.7; found 591.3 (MH+); 2-(5-guanidino-l//-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxypropyl)-/V-[2-(2-methoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 141), MS (Biolon) C:,H30N8O6 m/e calc 586.6; found 587.5 (MH*); Ή-NMR (300Mhz, CD3OD): 3.33 (m, 10 1H), 3.81 (m, 5H), 3.98 (d, 2H, J=4.5 Hz), 4.18 (t, 2H, J=5.4 Hz), 4.38 (t, 1H, J=12.0 Hz), 4.57 (dd, 1H, J=12.0, 3.5Hz), 6.85-7.00 (m, 4H), 7.30 (dd, 1H, J=8.7,2.2 Hz), 7.60 (d, 1H, J=2.2Hz), 7.64 (d, 1H, J=S.4 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.S0 (dd, 1H, J=8.4, 1.5 Hz), 8.14 (d, IH, J=1.5 Hz); 2-(5-( 1-iminoethyl)aminomethyl-l//-benzoimidazol-2-ylmethyl]-15 3-(2,3-dihydroxy)propyl-/V-[2-(2-methoxy)phenoxyethyl]-3//-benzoimidazole-5-cafboxamide (Compound 142), Ή-NMR (300Mhz, CD3OD): 2.28 (s, 3H), 3.64 (m, 2H), 3.S0 (s, 3H), 3.79-3.85 (m, 2H), 4.05 (m, 1H), 4.18 (t, 2H, J=5.4 Hz), 4.46 (dd, 1H, J=15.0, 8.7 Hz), 4.62-4.66 (m 3H), 6.S6-7.00 (m, 4H), 7.53 (dd, IH, J=8.7, 1.2 Hz), 7.68 (d, 1H, J=8.4 Hz), 7.77-7.SO (m, 2H), 7.S4 (dd, IH, J=S.4, 1.4 Hz), S.2I (d, IH, J=1.4 Hz); 20 methvl 2-{2-[2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)- 3-methyl-3tf-benzoimidazol-5-y!carbonylamino]ethoxy}benzoatc (Compound 143), MS (Biolon) C2sH:sN304 m/e calc 54.56; found 541.4 (MH+); 2- {-2-[2-(5-guanidino- l//-benzoimidazol-2-ylmethyl)-3-methyl-3//-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoic acid (Compound 144); 25 methyl 3-{-2-[2-(5-guanidino-l//-benzoimidazoI-2-ylmethyl)- 3-methyl-3//-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 145), MS (Biolon) C2sH:jNs04 m/e calc 540.5; found 541.4 (MH+); 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-methyl-yV-[2-(2,6-dimethoxy)phenoxyethyl]-3//-benzoimidazole-5-carboxamide (Compound 146), Ή-NMR (300Mhz, CD3OD): 3.71 (t, 2H, J=5.3 Hz), 3.73 (s, 6H), 4.01 (s, 3H), 4.13 (t, 2H, J= Hz), 6.63 (d, 2H, J=8.4 Hz), 6.99 (t, IH, J=8.4 Hz), 7.33 (dd, IH, J=8.6,1.9 Hz), 7.63 (d, IH, 30 69 LV 12495 J=1.9 Hz), 7.74 (d, 1H, J=8.7 Hz), 7.75 (d, IH, J=8.6 Hz), 7.90 (dd, IH, J=8.7,1.5 Hz), 8.21 (d, IH, J=l.5 Hz); 2-(5-guanidinomethyl-l£f-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyl-A'-(2-(2-methoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 147), 'H-NMR 5 (300Mhz, CD3OD); 3.57-3.69 (m, 2H), 3.80 (m, 5H), 4.05 (m, 1H), 4.17 (t, 2H, J=5.4 Hz), 4.45 (dd, 1H, J=15.0, 8.7 Hz), 4.58-4.65 (m, 3H), 6.85-7.00 (m, 4H), 7.50 (dd, 1H, J=8.7, 1.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.72 (d, 1H, J-1.5 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.82 (dd, 1H, J=8.5,1.4 Hz), 8.19 (d, 1H, 1=1.4 Hz); 2-(5-iminomethylaminomcthyl-l//-benzoimidazol-2-yimethyI)-3-(2,3-dihydroxy)propyl-10 A'-[2-(2-methoxy)phenoxyethyl]-3//-benzoimidazole-5-carboxamide (Compound 148), 'H-NMR (300Mhz, CDjOD): 3.58-3.70 (m, 2H), 3.81 (m, 5H), 4.06 (m, 1H), 4.19 (t, 2H, J=5.4 Hz), 4.46 (dd, 1H, J=15.0, S.7 Hz), 4.64 (dd, 1H, J=15.0, 3.0 Hz), 4.69 (4.73, s, 2H), 6.86-7.01 (m, 4H), 7.51 (dd, 1H, 1=8.1,1.5 Hz), 7.69 (d, 1H, J=8.6 Hz), 7.76-7.79 (m, 2H), 7.84 (dd, 1H, J=8.6, 1.3 Hz), 7.96 (8.12, s, 1H), 8.21 (d, 1H, J=1.3Hz); 15 2-(5-guanidino- l//-benzoimidazol-2-ylmethyl)-3-methyl-iV-(2-hydroxy- 2-quinol-4-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 149), Ή-NMR (300Mhz, CD3OD): 3.60 (dd, 1H, J-13.8,7.5 Hz), 3.97-4.06 (m, 4H), 5.99 (dd, 1H, J=7.5, 3.6 Hz), 7.35 (dd, 1H, J=S.7,2.0 Hz), 7.65 (d, 1H, J=2.0 Hz), 7.69 (d, 1H, J=S.7 Hz), 7.77 (d, IH, J=S.7 Hz), 7.84 (dd, 1H, J=8.7,1.5 Hz), 7.99 (m, 1H), S.H-S.18 (m, 2H), 8.26 (d, 1H, 20 J=S.4 Hz), 8.33 (d, IH, J=5.7Hz), 8.88 (d, IH, J=8.7 Hz), S.15 (d, IH, J=5.7 Hz); 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-methyl-A/-(2-(3-methyl-2,4-dioxoquinazolin-l-yl)ethyl]-3//-bcnzoimidazole-5-carboxamide (Compound 150), MS (Biolon) Cv,H:sN10O3 m/e calc 564.6; found 565.5 (MH+); methvl 2-{2-[2-(5-guanidino-l//-benzoimidazol-2-ylcarbonyl)-3-methyl-25 3//-benzoimidazol-5-yIcarbonyIamino]ethoxy}benzoate (Compound 151), MS (Biolon) C:sH24Nj03 m/e calc 554.5; found 554.8 (MH*); 2-(5-guanidino-I/7-benzoimidazol-2-ylmethyl)-3*(2-hydroxy)ethyl-/V-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 152), 'H-NMR (300Mhz, CDjOD): 3.44 (t, 2H, J=7.4 Hz), 3.77 (t, 2H, J=7.4 Hz), 3.95 (t, 2H, J=4.9 Hz), 4.56 (t, 30 2H, J = 4.9 Hz), 7.32 (dd, 1H,J=8.7, l.S Hz), 7.40-7.54 (m, 4H), 7.61 (d, 1H,J= 1.8 Hz), 7.67-7.89 (m, 5H), 8.09 (d, IH, J=1.2 Hz), S.2S (d, IH, J=8.1 Hz); 70 2-(5-guanidino-l/7-benzoimidazoI-2-ylmethyI)-3-methyl-jV-[2-(3-oxo-2,3-dihydrobenzo[l,4]oxazin-4-yl)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 153); 2-(5-guanidino-l//-benzoimidazol-2-ylcarbonyI]-3-(2-hydroxyethyI)-5 yV-(2-naphth-2-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 154), Ή-NMR (300Mhz, CD3OD): 3.42 (t, 2H, J=7.3 Hz), 3.75 (t, 2H, J=7.3 Hz), 4.48-4.51 (m, 2H), 7.29 (dd, 1H, J=8.6,1.9 Hz), 7.38-7.52 (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-l//-benzoimidazol-2-ylcarbonyl)-3-methyl-iV-(2-naphth~l-ylethyl)-10 3//-benzoimidazole-5-carboxamide (Compound 155), 2-(5-guanidino-l//-benzoimidazol-2-yIcarbonyl)-3-(3-hydroxypropyl)-/V-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 156); 2-(5-imidazol-l-yl-l//-benzoimidazoI-2-ylmethyl)-3-methyl-Y-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 157); 15 2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-methyl-A-(2-naphth-l-ylethyl)- 3//-benzoimidazole-5-carboxamide (Compound 158), MS (Biolon) C3,Hj0NjO, m/e calc 530.6; found 531.1 (MH*); 2-[ 1 -(5-imidazol-1 -yl-1 /f-benzoimidazol-2-yI)ethyl]-3-methyl-JV-(2-naphth- l-ylethyl)-3i¥-bcnzoimidazole-5-carboxamide (Compound 159), MS (Biolon) CsjHjņNjO, m/e calc 539.6; 20 found 540.1 (MH*); 2- {1 -[5-(2-aminoimidazo l-1 -yl)-1 //-benzoimidazol-2-yl]ethyl} -3-methyl-,Y-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 160), MS (Biolon) CjjHjoNjO, m/e calc 554.7; found 555.2 (MH+); 1 -(5-guanidino- l//-benzoimidazol-2-yl)-3-hydroxy-1 -methyl-Y-(2-naphth-1 -y lethyl) 25 3,4-dihydro-l//-2-oxa-4a,9-diazafluorene-6-carboxamide (Compound 161); 2- ( 1 -(5-guanidino-1 /f-benzoimidazol-2-yl)ethyl]-3-(4-hydroxybuty 1)-/V-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 162), MS (Biolon) Cj^Hj^jOi m/e calc 588.7; found 589.3 (MH+); 3- [2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]- 30 6-(2-naphth-l-ylethylcarbamoyl)benzoimidazol-l-yl]propane-l-sulfonic acid (Compound 163), MS (Biolon) Cjj^NgC^S m/e calc 638.7; found 639.2 (ΜΗ*); 71 LV 12495 3-[2-[ 1 -(5-imidazol-1 -yl-1 //-benzoimidazol-2-y I)ethyl]-6-(2~naphth-1 -ylethylcarbamoyl)benzoimidazol-1 -yl]propane-1 -sulfonic acid (Compound 164), MS (Biolon) C3JH33N7O4S m/e calc 647.8; found 648.2 (MH*); 2-[ 1 -(5-guanidino- lif-benzoimidazol-2-yl)-2-methylpropyl]-3-methyl-5 /V-(2-naphth-l-y]ethyl)-3//-benzoimidazole-5-carboxamide (Compound 165), MS (Biolon) CjjH^NgO, m/e calc 558.7; found 559.6 (ΜΗ*); 2-[ 1 -(1 //-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-/V:-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 166), MS (Biolon) C:9Hi6N60, m/e calc 474.6; found 475.2 (MH*); 10 2-(5-{ 1 -(//-methylimino)ethyl]-4,5,6,7-tetrahydro- l//-imidazo[4,5-c]pyridin-2-ylmethyl}-3-methyl-N-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 167), MS (Biolon) C31H33N7O m/e calc 519.71; found 520.9 (MH*); imino(2- {1 -(l -methy l-6-(2-naphth-1 -ylethy lcarbamoy 1)-1 //-benzoimidazol-2-y l]ethy l} -l,4,6,7-tctrahydroimidazo[4,5-c]pyridin-5-yl)acetic acid (Compound 168), MS (Biolon) 15 C3,H3,N703 m/e calc 549.6; found 550.2 (MH*); 2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-i//-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-yV-(2-naphth-l-ylethyl)-3/3’-benzoimidazole-5-carboxamide (Compound 169), MS (Biolon) €3|Η33Ν70ι m/e calc 519.6; found 520.3 (MH*); 2-{l-[5-(/V-methylamidino)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl}-20 3-methyl-yV-(2-naphth-I-ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 170), MS (Biolon) C31H34N3O, m/e calc 534.7; found 535.1 (MH*); 2-(2- {2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yl)ethyI]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)-5-methoxybenzoic acid (Compound 171), MS (Biolon) CjHjoNA m/e calc 570.6; found 571.2 (MH*); 25 2-(2- (2-[ 1 -(5-guanidino-1 if-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)isophthalic acid (Compound 172), MS (Biolon) C2,H30N3O5 m/e calc 570.6; found 571.3 (MH*); 2-(2- {2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yI)-1 -hydroxyethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)-6-methoxybenzoic acid (Compound 173), MS 30 (Biolon) CjoHjoNjOs m/e calc 586.6; found 5S7.2 (MH*); 72 ethyl 2-(2-(2- {l-(5-(A-acetylguanidino)-l.i/-benzoimidazol-2-yl]ei:hyl}-3-methyl-3#-benzoimidazol-5-ylcarbonylamino)ethox· ;benzoate (Compound 174), MS (Biolon) C31H3:Ns03 m/e calc 596.6; found 597.2 (ΜΗ*); 2-{1 -[5-(Ar^-dimethylamidmo)-4,5,6,7-tetrahydro-l/f-imidazo[4,5-c]pyridin-2-yl]ethyl} -3-methyl-Ar-(2-naphth-l-ylethyl)-3#-benzoimidazole-5-carboxamide (Compound 175); 2- (1 -[5-(2-amino-1,1 -dimethylethyl)- l#-benzoimidazol-2-yl]ethyl} -3-methyI-/V-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide (Compound 176); 2- {1 -[5-( 1 -iminoethyl)-4,5 f6,7-tetrahydro- lH-imidazo(4,5-c]pyridin-2-yl]ethyl} -A-ethyl-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 177); 2-(2-(2- {1 -(5-(N-acetylguanidino)-l//-benzoimidazol-2-yl]ethyl} -3-methyl-3H-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 178), MS (Biolon) CjoHjoNjOj m/e calc 582.6; found 5S3.3 (MH*); 2-(2-(2-{1-(5-( l-aminocyclopropyl)-l//-benzoimidazol-2-yl]ethyl}-3-methyl-3H-bcnzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 179), MS (Biolon) CjoHjoNA m/e calc 538.6; found 539.3 (MH*); 2-( 1 -(5-imidazol-1 -y 1-1 H-benzoimidazol-2-yl)ethyl]-3-methyl-A-(3-methylbutyl)-3//-bcnzoimidazole-5-carboxamide (Compound 180), MS (Biolon) C26H29N7O1 m/e calc 455.6; found 456.2 (MH*); 2-(l#-benzoimidazol-2-ylethyl)-3-methyl-Ar-(2-pher.oxyethyI)-3H-benzoimidazole-5-carboxamids (Compound 181), MS (Biolon) CisH^NA m/e calc 439.5; found 440.2 (MH*); ethyl 2-(2-(2-( 1-(5-( l-iminoethyl)-4,5,6,7-tetrahydro-1 H-imidazo [4,5-c]pyridin-2-yl] ethyl} -3 -methy 1- 3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoate (Compound 182); 2-(l-(5-guanidino-lH-benzoimidazol-2-yl)ethyl]-3-methyl-A'-[2-(2,4-dioxo-3,4-dihydro-2//-quinazolin-]-yl)ethyi]-3//-benzoimidazole-5-carboxamide (Compound 183); 2- {1 -(5-( 1 -iminoethyl)-4,5,6,7-tetrahydro-1 //-imidazo[4,5-c]pyridin-2-yl]ethyl} -Af-(3-methoxypropyl)-3-methyl-3H-benzoimidazole-5-carboxamide (Compound 184); A,'-ethyl-2-[l-(5-imid2Zol-l-yl-lil/-ben2oimida2ol-2-yl)ethyl]-3-methyl-3H-bcnzoimidazole-5-carboxamide (Compound 185), MS (Biolon) C23H23N7O1 m/e calc 413.5; found 414.1 (MH*); 73 LV 12495 2-[ 1 -(5-imidazol-1 -yl- i//-benzoimidazol-2-yl)ethyl]-/V-(2-methoxyethyl)-3-methyl-3H-benzoimidazole-5-carboxamide (Compound 186), MS (Biolon) C24H25N702 m/e calc 443.5; found 444.2 (ΜΗ*); I -(2-[ I -(5-imidazol-1 -yl-1 //-benzoimidazol-2-yl)ethyl]-3-methyI-3//-benzoimidazol-5-ylcarbonyIamino)-4-methylpentanoic acid (Compound 1S7), MS (Biolon) C27H29N702 m/e calc 499.6; found 500.3 (MH*); 2-(2-(2-(1-(5-imidazol-l-yl-l//-benzoimidazol-2-yI)ethyl]-3-methyl-3f/-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound ĪSS), MS (Biolon) C30H27N7O4 m/e calc 549.6; found 550.2 (MH*); 2-(2-{l-(5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-yl]ethyI}-3-methyl-3//-benzoimidazol-5-yicarbonylamino)-4-methylpentanoic acid (Compound 189); 2- {1 -[5-(/V,A/-dimethy lamidino )-4,5,6,7-tetrahydro-1 //-imidazo[4,5-c]pyridin-2-yl]ethyl} -3-methyI-3//-bcnzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 190), MS (Biolon) mIt calc 558.6; found 559.3 (MH*); i 2-[2-(2-{l-(5-(2-carboxy-l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-yl]ethyI) - % 3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 1S1), MS i (Biolon) C29H3|N706 m/e calc 573.6; found 530.3 (MH*), loss of C02; 2-(2-{2-(l-(5-imidazol-l-yl-l//-benzoimidazol-2-yl)ethyl]-3-(2-methoxyethyl)-3//-benzoimidazoI-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 192), MS (Biolon) C32H3|N705 m/e calc 593.6; found 594.2 (MH*); 2-[l-(5-imidazol-1-yl-l//-benzoimidazol-2-yl)ethyl]-3-(2-methoxyethyl)-/V-(2-methoxyethyi)-3//'-benzoimidazole-5-carboxamide (Compound 193), MS (Biolon) C26H,,N703 m/e calc 487.6; found 488.2 (MH*); 2- (2-(2-{l-(5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-(2-methoxyethyl)-3//-benzoimidazoI-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 194); 3- (2-{2-(l-(5-guanidino-ltf-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonyiamino}ethoxy)benzoic acid (Compound 185), MS (Biolon) C2sH23Ns04 m/e calc 540.6; found 541.3 (MH*); 74 2-(2-{2-[l-(5-guanidino-l#-benzoimidazol-2-yl)ethyl]-3-(2-methoxyethyl)-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 196), MS (Biolon) CjoHjzNjOj m/e calc 584.6; found 585.3 (MH+); 2-(2-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-(3-sulfopropyl)-5 3tf-benzoimidazol-5-yIcarbonylamino}ethoxy)benzoic acid (Compound 197), MS (Biolon) CjoHjjNjOtS m/e calc 648.7; found 649.6 (MH+); 2-(2-{2-[l-(5-imidazol-l-yl-l/f-benzoimidazol-2-yl)ethyl]-3-(3-sulfopropyl)-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 198), MS (Biolon) C32H21N707S m/e calc 657.7; found 658.4 (MH+); 10 2-(2-{2-[l-(5-imidazol-l-yl-3-methyl-3tf-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonyiamino}ethoxy)benzoic acid (Compound 199), MS (Biolon) C3|H29N704 m/e calc 563.6; found 564.2 (MET); 2-(2-{2-[l-(5-imidazol-l-yl-l//-benzoimidazol-2-yl)ethyl]-3-(2-hydroxypropyl)-3//-bcnzoimidazol-5-ylcarbonyIamino}ethoxy)benzoic acid (Compound 200), MS (Biolon) 15 C32H31N705 m/e calc 593.6; found 594.3 (MH*); 2-{2-[2-(l-{5-[l-(yV-hydroxyimino)ethyl]-4,5,6,7-tstrahydro- ltf-imidazo[4,5-c]pyridin-2-yl}ethyl)-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoic acid (Compound 201); ethyl 2-(2- (2-[ 1 -(5-guanidino-1 /f-benzoimidazol-2-yl)ethyl]-3-methyl-20 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 202), MS (Biolon) C30H3:NsO., m/e calc 568.6; found 569.5 (MH+); ethyl 2-[2-(2- {1 -[5-(l -iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl}- 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino)ethoxy]benzoate (Compound 203), 25 MS (Biolon) C2sHJ6N304 m/e calc 549.0; found 548.2 (MH‘); ethy 14- {2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}butyrate (Compound 204), MS (Biolon) C23H30NsO3 m/e calc 490.57; found 491.3 (MH~);
2-[l -(5-guanidino- l//-benzoimidazol-2-yl)ethyl]-3-methyl-0 //-[2-(2-tetrazol-l-ylphenoxy)ethyl)-3//-benzoimidazole-5-carboxamide (Compound 205), MS (Biolon) C23H2SN1202 m/e calc 564.56; found 565.3 (MH‘); 75 LV 12495 2-[2-(2-{l-[5-(l-iminoethylamino)-l//-benzoimidazol-2-yl]ethyl}-3-methyI- * 3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 206), MS (Biolon) C3lH„N704 m/e calc 567.6; found 568.4 (MH*); ethyl 4-(2-{2-[l-(5-guanidino-lif-benzoimidazol-2-yl)ethyl]-3-methyl-5 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 207), MS (Biolon)
CjoHnNA m/e calc 568.6; found 569.4 (MET); 5-(2- (2-[ 1 -(5-guanidino- l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)isophthalic acid (Compound 208), MS (Biolon) CmH2SNj06 m/e calc 584.6; found 585.3 (MH*); 10 4-(2-{2-(l-(5-guanidino-li/-benzoimidazol-2-yl)ethyl]-3-methyl- 3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 209), MS (Biolon) C28H2sN804 m/e calc 540.6; found 541.2 (MH*); 2-(2- {2-[ 1 -(5-guanidino-1 tf-benzoimidazo I-2-yl)ethy 1]-3-(2-hydroxypropyl)-3//-benzoimidazol-5-yIcarbonylamino}ethoxy)benzoic acid 15 (Compound 210), MS (Biolon) CļoK^NjOj m/e calc 584.6; found 5S5.4 (MH'); 2-[l-(5-imidazoI-i-yl-l//-benzoimidazol-2-yl)ethyl]-3-methyl-A/’-[2-(2-methoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 211), MS (BioIon)'CjoH29N702 m/e calc 535.6; found 536.3 (MH'); 2-(2- {2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-20 3//-benzoimidazol-5-yIcarbonylamino}ethoxy)benzoic acid (Compound 212), MS (Biolon) C27H,6Ng04 m/e calc 526.6; found 527.2 (MH*); 2-( 1 -(5-imidazol-l -yl-1 tf-benzoimidazol-2-yl)ethyl]-3-methyl-/V-(2-phenoxyethyl)-3//-benzoimidazole-5-carboxamide (Compound 213), MS (Biolon) C2,H27N70j m/e calc 505.6; found 506.2 (MH*); 25 2-(2- (2-[ 1 -(5-imidazol-1 -yl-1 //-benzoimidazol-2-yl)ethylj- 1 //-benzoimidazol-5-ylcarbonylamino} ethoxy)benzoic acid (Compound 214), MS (Biolon) C,,H2jN704 m/e calc 535.6; found 536.4 (MH*); ethyl 2-(2-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3if-benzoimidazol-5-ylcarbonylamino}ethoxy)-4-methylbenzoate (Compound 215), MS 30 (Biolon) C3|Hj4Ns04 m/e calc 582.7; found 583.5 (MH*); 76 2-(2- {2-[l -(5-guanidino-l//-benzoimidazoI-2-yI)ethyl]-3-methyl-benzoimidazol-5-ylcarbonyiamino}ethoxy)-4-methylbenzoic acid (Compound 216), MS (Biolon) CsņHjoNgO* m/e calc 554.6; found 555.5 (MH*); 2-[2-(2- (1 -[5-( 1 -iminoethyl)-4,5,6,7-tetrahydro-1 if-imidazo[4,5-c]pyridin-2-yI]ethyl} -5 l,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino)ethoxy]benzoate (Compound 217), MS (ESI) CjsHhNA m/e calc 520.58; found 521.3 (MH*); ethyl 2-(2-{2-[5-(Ar-methylamidino)-l//-benzoimidazol-2-ylrncthyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 218), MS (Biolon) C30H3,N7O4 m/e calc 553.6; found 554.3 (MH*); 10 2-[2-(2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/f-imidazo[4,5-c]pyridin-2-yl]ethyl}- 3-(3-sulfopropyl)-3/7-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 219), MS (Biolon) C3oHjjN707 nv'e calc 637.7; found 638.3 (MH*); ethyl 2-(2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/f-imidazo[4,5-c]pyridin-2-yI]ethyl}-3-methyl-3if-benzoimidazol-5-ylcarbonylamino)-4-methylvalerate (Compound 220); 15 ethyl 2- {2-[2-( 1 - {5-[ 1 -(N-hydroxyimino)ethyl]-4,5,6,7-tetrahvdro- l//-imidazo[4,5-c]pyridin-2-yl}ethyl)-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino]ethoxy}benzoate (Compound 221); 2-[l-(l//-benzoimidazol-2-yl)ethyl]-3-methyl-Ar-[2-(2-methoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 222), MS (Biolon) ^7Η:7Ν503 m/e calc 469.5; 20 found 469.5 (MH*); 2-(2-ethoxycarbonylphenoxy)ethyl 2-[ 1 -(6-guanidino-1 //-benzoimidazol-2-yl)ethyI]-l,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxyate (Compound 223), MS (Biolon) C;3H3:N30j m/e calc 560.62; found 561.3 (MH*); 4- {2-[ 1 -(5-guanidino-1 H-benzoimidazol-2-yl)ethyl]-3-methyl- 25 3//-benzoimidazol-5-ylcarbonylamino)butyric acid (Compound 224), MS (Biolon) C23H26N303 m/e calc 462.52; found 462.S (MH*); 2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl-yV-[2-(2-tetrazolylphenoxy)ethyl]-3/f-benzoimidazole-5-carboxamide (Compound 225), MS (ESI) C23H3|Nn02 m/e calc 553.6; found 553.5 (MH*); 30 isopropyl 2-(2-{2-[l-(5-imidazol-l-yl-l//-benzoimidazol-2-yl)cthylļ-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 226), MS (Biolon) ChHmN70, m/e calc 591.3; found 591.4 (MH*); 77 LV 12495 2- {1 -[5-(l -iminoethyl)-4,5,6,7-tetrahydro- l//-imidazo[4,5-c]pyndin-2-yI]ethyl} * 3-methyl-/V-[2-(3-tetrazolylphenoxy)ethyl]-3/i-benzoimidazole-5-carboxamide (Compound 227), MS (Biolon) C2gH31Nn02 m/e calc 553.59; found 553.5 (MH*); 2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/f-imidazo(4,5-c]pyridin-2-yl]ethyl}-3-methyl-/V-[2-(4-tetrazoIylphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 228), MS (ESI) C2gH3IN[102 m/e calc 553.59; found 553.5 (MH*); cyclohexyl 2-(2- {2-[ 1 -(5-imidazol-1 -yl)-l//-benzoimidazol-2-yl]ethyl}-3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxybenzoate (Compound 229), MS (ESI) C36H37N704 m/e calc 631.3; found 631.5 (ΜΗ*); 2-[2-(2- {1 -[5-(/V-methylamidino)-1 if-benzoimidazol-2-yl]ethyl} -3-methyl-3/f-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 230), MS (Biolon) C2SH27N704 m/e calc 525.6; found 525.5 (MH*); 2-[2-(2- {1 -[5-( 1 -iminoethylamino)-l//-benzoimidazoI-2-yl]ethyl} -3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid (Compound 231), MS (Biolon) C2,H2,N704 m/e calc 539.6; found 539.8 (MH*); 2-(3-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]- 1.4.6.7- tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonyl}propoxy)benzoic acid (Compound 232), MS (Biolon) C27H30N804 m/e calc 530.60; found 531.7 (MH*); 2-(2- (2-[ l -(5-guanidino-1 //-benzoimidazol-2-yI)ethyl]- 1.4.6.7- tetrahydroimidazo[4,5-c]pyridin-5-ylformyloxy}ethoxy)benzoic acid (Compound 233), MS (Biolon) C26H28N805 m/e calc 532.56; found 533.2 (MET); 2-methoxyethyI 2-(2- {2-( 1 -(5-imidazol-1 -yl-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 234), MS (Biolon) C33H33N703 m/e calc 607.3; found 607.4 (MH+); isobutyl 2-(2- {2-[ 1 -(5-imidazol-1 -yl-l//-benzoimidazol-2-yl)ethyI]-3-methyl-3//-benzoimidazol-5-ylcarbonyiamino}ethoxy)benzoate (Compound 235), MS (Biolon) C34H33N704 m/e calc 605.3; found 605.4 (MH*); 2-(2-methoxyethoxy)ethyl 2-(2-{2-[l-(5-imidazol-l-yI-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 236), MS (Biolon) C35H37N706 m/e calc 651.3; found 651.3 (MH‘); 78 butyl 2-(2-{2-[l-(5-imidazol-l-yl-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-yIcarbonylamino}ethoxy)benzoate (Compound 237), MS (Biolon) C34H35N704 m/e calc 605.3; found 605.4 (MH+); 2-( 1 -(1 ff-benzoimidazol-2-yl)ethyl]-3-methyl- 5 /V-[2-(3-oxo-2,3-dihydrobenzo[ 1,4]oxazin-4-yl)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 238), MS (Biolon) 023Η26Ν603 m/e calc 494.2; found 494.5 (MH*); 2-[ 1 -(l //-benzoimidazol-2-yl)ethyl]-3-methyI-Ar-[2-(2-fluorophenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 239); 2-(l-(l//-benzoimidazol-2-yl)ethyl]-3-methyl-yV-[2-(3-fluorophenoxy)ethyl]-10 3tf-benzoimidazole-5-carboxamide (Compound 240); 2-[l-(lif-benzoimidazol-2-yl)ethyl]-3-methyl-7/-[2-(2-isopropoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 241), MS (Biolon) C29H3lNj03 m/e calc 497.2; found 497.6 (MH*); 2-[l-(lf/-benzoimidazol-2-yl)ethyl]-3-methyl-/V-[2-(2-methylphenoxy)ethyl]-15 3/jr-benzoimidazole-5-carboxamide (Compound 242), MS (Biolon) C27H27Nj02 m/e calc 453.2; found 453.5 (MH*); 2-[l-(l//-benzoimidazol-2-yl)ethyl]-3-methylwV-[2-(2-ethoxyphenoxy)ethyl]-3//-benzoimidazoIe-5-carboxamide (Compound 243), MS (Biolon) C23H2,N503 m/e calc 483.2; found 4S3.5 (MH*); 20 2-[ l -(5-guanidino- l//-benzoimidazol-2-yl)ethyl]-3-methyl- /V-[2-(2-methoxyphenoxy)ethyl]-3//-benzoimidazole-5-carboxamide (Compound 244), MS (Biolon) C2gH30īsrsO3 m/e calc 526.6; found 526.8 (MH*); ethyl 2-(2-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino}ethoxy)benzoate (Compound 245), 25 MS (Biolon) C2gH33N904 m/e calc 559.6; found 559.6 (MH*); 2-methoxyethyl 2-(2-{2-[l-(l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazoI-5-ylcarbonylamino}ethoxy)benzoate (Compound 246), MS (Biolon) C30H3,NsO4 m/e calc 541.6; found 541.5 (MH”); ethyl 2-{2-{2-[l-(5-guanidino-l//-benzoimidazol-2-yI)ethyI]-3-methyl-3//-benzoimidazoI-5-ylcarbonylamino}ethoxy)benzoate (Compound 247), MS (Biolon) C29H30NgO4 m/e calc 554.6; found 555.4 (MH*); 30 79 LV 12495 2-{2-{2-[1-(5-guanidino-l//-benzoimidazol-2-yI)ethyl]-3-methyl-3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 248), MS (Biolon) C2gH23Ns04 m/e calc 540.6; found 541.3 (MH+); 2-[ 1 -(5-guanidino- l//-benzoimidazol-2-yl)ethyl]-N-[2-(2-caibamoylphenoxy)ethyl]- Οι Ο Οι Ο Οι 3- methyl-3//-benzoimidazole-5-carboxamide (Compound 249), MS (Biolon) Cjg^NoOj m/e calc 539.6; found 540.5 (MH*); 2-(l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-W-[2-(2-carbamoyl- 4- chlorophenoxy)ethyI]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 250), MS (Biolon) C:gH,gN9OjCl m/e calc 574.0; found 574.2 (MH+); 4- chIoro-2-(2- {2-[ l -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}cthoxy)benzoic acid (Compound 251), MS (Biolon) C:3H:7Ns04C1 m/e calc 575.0 found 575.2 (MH*); 5- chloro-2-(2-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 252), MS (Biolon) C2sH27NgO.,Cl m/e calc 575.0; found 575.2 (MH"); 6- chloro-2-(2-{2-[l-(5-guanidino-1//-benzoimidazol-2-yI)ethyl]-3-mcthyl-3//-benzoimidazol-5-yIcarbonylamino}ethoxy)benzoic acid (Compound 253), MS (Biolon) CjjHj^jOjCI m/e calc 575.0; found 575.2 (MH"); 4,6-dichloro-2-(2-{2-(l-(5-guanidino-l//-benzoimidazol-2-yl)ethy l]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 254), MS (Biolon) CjjHmNACIī m/e calc 609.5; found 609.1 (MH*); ethyl 2-(2-{2-[l-(l//-benzoimidazoI-2-yl)ethyI]-3-methyl-3//-benzoimidazole-5-carbonylamino}ethoxy)benzoate (Compound 255), MS (Biolon) C^HjgNjO.» m/e calc 511.6; found 512.2 (MH*); 2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-A/- {2-[2,4-dioxo-3-(2-trimethylsilanylethyl)-3,4-dihydro-2//-quinazolin-l-yl]sthyl}-3//-benzoimidazole- 5- carboxamide (Compound 256), MS (Biolon) C34H40N,0O3Si m/e calc 664.8; found 665.4 (MH'); 2-[l-(5-guanidino-l//-benzoimidazol-2-yI)ethyI]-3-methyI-,/V-{2-[2,4-dioxo-30 3,4-dihydro-2//-quinazoIin-l-yl]ethyl}-3//-benzoimidazole-5-carboxamide (Compound 257), MS (Biolon) C29H23Nt0O3 m/e calc 564.6; found 565.2 (MH*); 80 2-[l-(l/f,-benzoimidazol-2-yl)ethyl]-M-[2-(2-cyanophenoxy)ethyl]-3-methyl-3/7-berizoimidazole-5-carboxamide (Compound 258), MS (Biolon) C27H24N602 m/e calc 454.5; found 465.1 (MH+); 5-(2-{2-[ 1-(l//-ben2oimidazol-2-yl)ethyl]-3-methyl-5 3//-benzoimidazol-5-yIcarbonylamino}ethoxy)isophthalic acid (Compound 259), MS (Biolon) C>sH2JN506 m/e calc 527.5; found 528.4 (MH+); 2-(2-methoxyethoxy)ethyl 2-(2-{2-[l-(l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazoi-5-ylcarbonylamino}ethoxy)benzoate (Compound 260), MS (Biolon) C32H35N506 m/e calc 585.7; found 585.4 (MH*); 10 2-(2-{2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethylj- 1,4,6,7-tetrahydroimidazo[4,5-c]pyrid-5-ylcarbonylamino} ethoxy)benzoic acid (Compound 261), MS (Biolon) C2oH2,N904 m/e calc 531.6; found 531.5 (MH*); 2-[ 1 -(l//-imidazo[4,5-c]pyridin-2-yl)ethyl]-//-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3/f-benzoimidazole-5-carboxamide (Compound 262), MS (Biolon) C26H26N603 m/e čalc 470.54; 15 found 471.4 (MH*); 2-[l-(5-fluoro-l//-benzoimidazol-2-yl)ethyl]-/V-[2-(2-methoxyphenoxy)ethyl]-3-methyI-37/-benzoimidazoIe-5-carboxamide (Compound 263), MS (Biolon) C27H26Nj03F m/e calc 487.54; found 48S.1 (MH"); 2-[ 1 -(5-imidazol-1 -yl-1 //-benzoimidazol-2-yl)ethyl]-3-methyl-/V-(2-tetrazol-1 -ylethyl)- 20 3//-benzoimidazole-5-carboxamide (Compound 264), MS (ESI) C24HI3N||0 m/e calc 481.47; found 4S2.6 (MH"); 2- [l-(4-hydroxy-l//-benzoimidazol-2-yl)ethyl]-Ar-[2-(2-methoxyphenoxy)ethyl]-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 265), MS (Biolon) C27H27N504 m/e calc 485.59; found 486.3 (MH"); 25 2-[ 1 -(4-aminobenzoxazol-2-yl)ethyl]-yV-[2-(2-methoxyphenoxy)ethyl]-3-methyl- 3/7-benzoimidazoIe-5-carboxamide (Compound 266), MS (Biolon) C27H27N504 m/e calc 485.59; found 486.1 (MH"); 3- {2-[ 1 -(1 //-benzoimidazo!-2-yl)ethyI]- 6-[2-(2-methoxyphenoxy)ethylcarbamoyIjbenzoimidazol-1 -yl} propane-1 -sulfonic acid (Compound 267), MS (Biolon) C2,H3ļN500S m/e calc 577.66; found 577.4 (MH"); 30 81 LV 12495 3- {2-[ 1 -(5-imidazol-1 -yl-1 //-benzoimidazol-2-y l)ethyl]-6-[2-(2-methoxyphenoxy)ethylcarbamoyl]benzoimidazol-l -yl} propane-1 -sulfonic acid (Compoand 268), MS (Biolon) C32H33N706S m/e calc 643.72; found 644.6 (MH*); ethyl 2-[2-(2- {1 -[ 1 -(2-methoxyethyl)-1 /7-benzoimidazol-2-yl]ethyl} -3-methyl-5 3//-benzoimidazole-5-carbonylamino)ethoxy]benzoate (Compound 269), MS (Biolon)
CjjHjjNjOj m/e calc 569.66; found 570.5 (MH+); benzyl 2-(l-(5-imidazol-l-yl-l//-benzoimidazol-2-yl)ethyl]-/ 1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (Compound 270), MS (Biolon) C,9HjoNg06 m/e calc 586.6; found 587.2 (MFT); 10 ethyl 2-(4-{2-[l-(l//-benzoimidazoI-2-yl)ethyI]- l,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-oxobutoxy)benzoate (Compound 271); 1- {2-[l-(l/7'-benzoimidazol-2-yl)ethyl]-l,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl}-4-(2-methoxyphenoxy)butan-l-one (Compound 272); 2- (5-guanidino-1 //-benzoimidazol-2-ylmethyl)- 15 /V-(2-naphth-l-ylethyl)imidazo[l,2-a]pyridine-6-carboxamide (Compound 273); A43-(2-ethoxyphenyl)propyl]-2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyI-3//-benzoimidazole-5-carboxamide (Compound 274), MS (Biolon) C:9H3,N503 m/e calc 497.62; found 497.4; /V-[3-(2-butoxyphenyl)propyl]-2-(l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyI-20 3//-benzoimidazole-5-carboxamide (Compound 275), MS (Biolon) CjļHjjNjOj m/e calc 525.65; found 526.3; 2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-/V-[3-(2-propoxyphenyl)propyl]-3/7-benzoimidazole-5-carboxamide (Compound 276), MS (Biolon) C3oH33N303 m/e calc 511.62; found 512.3; 25 2-[ l -(5-hydroxy-1 //-benzoimidazol-2-yl)ethyl]-Ar- (2-(2-(3-methyl- [l,2,4]oxadiazol-5-yl)phenoxy]ethyl}-3-methyl-3//-benzoimidazole-5-carboxamide (Compound 277), MS (Biolon) C19H27N7O4 m/e calc 538.1; found 537.58; ethvl 2-(2-(2-(1 -(4-fluoro-5-hydroxy-l//-benzoimidazol-2-yl)cthyI]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 27S), MS (ESI) ^9Η23Ν505 m/e 30 calc 545.57 found 545.6; 82 2-(2-{2-[l-(4-fluoro-5-hydroxy-lH-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 279), MS (Biolon) 027Η24Ν305Ρ m/e calc 517.52 found 517.4; ethyl 2-(2- {2-[ 1 -(6-fluoro-4-hydroxy-1 tf-benzoimidazol-2-yl)ethyI]-3-methyl-5 3Ar-benzoimidazol-5-yicarbonylamino}ethoxy)benzoate (Compound 280), MS (Biolon) 0291^3^0^ m/e calc 545.57 found 545.9; 2-(2-(2-( l-(6-f]uoro-4-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl-3//-benzoimidazoI-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 280), MS (Biolon) CjjH^NjOjF m/e calc 517.52 found 517.6; 10 ethyl 2-(2-(2-(1-(4,5-difluoro-7-hydroxy-ltf-benzoimidazol-2-yl)ethyl]-3-methyl- 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate (Compound 281), MS (Biolon) CjiH^NjOjFi m/e calc 563.56 found 563.9; and 2-(2- {2-[ 1 -(4,5-difluoro-7-hydroxy-1 //-benzoimidazol-2-yI)ethyl]-3-methyl-3tf-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (Compound 282), MS (ESI) CijH^NjOjF: 15 m/e calc 536.1 found 535.51. LV 12495 S3 EXAMPLE 13
In vitro Tryptase Inhibition Assay
Tryptase solution (60g/mL) was prepared by dissolving tryptase purified from human lung or skin tissue preparations or human mast celi line (HMC-1) or obtained from commercial sources, e.g., ICN Biomeidals, Irvine, Califomia, Athens Research & Technology, Athens, Georgia, etc., in a solvent mixture compnsing: iOmM 2-/V-morpholinoethane sulfonic acid, 2mM CaCU, 20% glycerol and 50 g/mL heparin. Substrate solution containing 2mM synthetic tripeptide (tosyl-Gly-Pro-Lys-/?-nitroaniIide) was obtained from Sigma. Tēst Compound Solutions were prepared by dituting a stock solution (1 mg of tēst Compound in 200 pL of dimethylsulfoxide (DMSO)) by ten-fold into assay buffer (compnsing: Tris-HCl (pH 8.2), 50mM; NaCl, lOOmM; 0.05% polyoxyethylenesorbitan monolaurate (Tween-20®); and zinc chloride, 150 μΜ) and then making seven additional three-fold dilutions into 10% DMSO in assay buffer.
Aliquots (50 pL) from each of the eight dilutions of tēst compound solution were added to separate wells in a 96-well U-bottom microtiter plate. Typtase solution (25 pL) was added to each well and the Solutions \vere mixed 1 hour at room temperature. Substrate solution (25 pL) \vas added to initiate the enzymatic reaction and the microtiter plates were immediately transferrred to a LTV/ΜΑΧ Kinetic Microplate Reader (Molecular Devices). The hydrolysis of the chromogenic substrate \vas followed spectrophotometrically at 405 nanometers for five minūtes. Initial velocity measuremcnts \vere calculated from the progress curves by kinetic analysis program (BatchKi; Petr Kuzmic, University of Wisconsin, Madison, WI). Apparent inhibition constants (KJ were calculated from the enzyme progress curves using Standard mathematical models.
Proceeding as described in this application or by methods known to those of ordinary skill the follov/ing compounds of the invention were tested for tryptase inhibitory activitv:
Compound 1, Ki=0.09pM; Compound 12, Κ(=29μΜ; Compound 26, K,=33pM; Compound 27, Kj=0.6pM; Compound 28, K,=0.00007pM; Compound 29, Kj=0.0008pM; Compound 30, Κ;=0.009μΜ; Compound 37, K,=0.002pM; Compound 42, Κ~0.008μΜ; Compound 43, Kj=0.002pM; Compound 74, K,=0.006pM; Compound 75, K,=0.03pM; Compound 80, Kj-0.01pM; Compound 81, K.=0.01pM; Compound 84, K,=2.6pM; 84
Compound 102, K.j=0.00007pM; Compound 112, Κ;=0.00005μΜ; Compound 115, Κ(=0.003μΜ; Compound 116, Κ;=0.006μΜ; Compound 117, Κ=0.008μΜ; Compound 126, Kj=0.008pM; Compound 127, Κ^Ο.ΟΟβμΜ; Compound 128, Κ=0.002μΜ; Compound 169, Κ—Ο.ΟΟΙμΜ; Compound 132, Kj=0.00002pM; Compound 134, Κ;=0.00002μΜ;
Compound 138, Kj=0.0002pM; Compound 152, Κ~0.0005μΜ; Compound 182, Κ~0.004μΜ; Compound 194, Κ^Ο.ΟΟΟμΜ; Compound 203, Kj=0.008piVi; Compound 225, Κ~0.008μΜ; Compound 249, Kr=0.0007pM; Compound 250, Κ~0.0004μΜ; Compound 251, Κ—Ο.ΟΟΟδμΜ; and Compound 252, Kj=0.0004pM. 10 EXAMPLE 14
Sheep Modei of Asthma
The allergic sheep modei of asthma was employed for the in vivo evaluation of the compounds of the invention as antiasthmatics. These methods have been published previously 15 (see Ābraham et al. (19S3) Am. Rev. Respir. Dis. 128:839-844; AUegra et al. (1983) J. Appl.
Physiol. 55:726-730; Russi et al. (1985) J. Appl. Physiol. 59:1416-1422; Soler et ai ((1989)7. Appl. Phvsiol. 67:406-413. Each sheep serves as its own control. Body weights for these animals ranged from 20-50 kilograms.
In these studies, 1 mg of Compound 13 was dissolved in 3 mL distilled water, and the 20 total solution delivered as an aerosol 0.5 hours before, 4 hours after, and 24 hours after antigen challcnge (total dose = 1 mg; n = 3). The results of these experiments are summarized in Figurē 1.
Twenty-four hours after antigen challenge in both the control and drug trial, the sheep developed ainvav hyper-responsiveness. Ainv'ay hvper-responsiveness is expressed as PC400, 25 the concentration of carbachol that causes a 400% inerease in SRL; therefore, a dserease in PC400 indicates hyper-responsiveness. Compound 13 was found to block the onset of hyper-responsiveness. As shown in Figurē 2, this compound maintained the PC400 at substantially the baseline value of 15 breath units. The number of breath units fell to 7 for those animals in the control group. Thus, treatment vvith Compound 13 resulted in a signifieant 30 improvement in ainvav funetion in antigen challenged sheep.
Thus, the present invention provides compounds and compositions that are useful for the prevention and treatment of immunomediated inflammatory disorders, particularly those LV 12495 85 associated with the respiratory tract, including asthma, and the hyper-responsiveness phase associated with chronic asthma, in addition to allergic rhinitis. The present invention is also recognized as providing a method for treating immunomediated inflammatory disorders that are susceptible to treatment with a compound of the present invention.
It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon revievving the above description. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. 86 LV 12495 WE CLAIM: 1. A compound of Formula I:
in which: nl is Oor 1, n2 is 0, l, 2, 3 or4; n3 is 0, 1, 2, 3 or4; A together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X1 and X: are adjacent annular members of an aromatic ring and X1 is a heteroatom moiety selected from -N=, -NR5-, -0- and -S-, \vherein R5 is hydrogen, (C,.6)alkyl or hetero(C2.6)alkyl; C comprises a fused heteropolycyclic radical containing S to IS annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X4 and X3 are adjacent annular members of an aromatic ring, X3 is a heteroatom moictv selected from -N=, -NR6-, -0- and -S-, wherein R6 is hvdrogen, a group selected from (C|.3)alkyl or hetero(C2.I2)alkyl, which group optionally is substituted with one to two substituents independentlv selected from (C..6)alkanoyloxy, (C,.6)alkylamino, di(Ct.6)alkylamino, tri(C,.6)alkylammoniol (C,.6)aIkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C,,fi)alkyloxy, (C|.6)alkyloxycarbonyl, (C,.6)alkyloxysulfonyl, amino, carboxy, carbamoyl, (C6.M)aryl, halo, hetero(C5.u)arvl, hvdroxy and sulfo, or as defined below; and any carbocyclic ketone, thioketone and iminoketone derivative thereof; X3 is -0-, -S-, -S(O)-, -S(0)2-, -C(O)-, -NR7- or -CR7R3-, wherein R7 is hvdrogen, (C,.6)alkyl, hetero(C2.u)alkyl or together with R6 forms (C2.Jalkylene or hetero(C2.4)alkylcne and R3 is hvdrogen, (C,.6)alkyl or hydroxy or together with R7 forms (C2.6)alkylene or (C,.6)alkylidene, wherein anv aliphatic or alicvclic moiety comprising R7 and/or R3 optionally are 87 29 substituted with one to three substituents selected from (C|.6)alkylamino, di(C|.6)alkyIamino, 30 tri(C,.6)alkylammonio, (C|.4)alkyloxy, (Cl.6)alkyioxycarbonyl, (C,.6)alkanoyloxyt amino, 31 carboxy, carbamoyl, (C,.6)alkylcarbamoyl, di(Ct.6)alkylcarbamoyI, halo and hydroxy; 32 R' is amino(NM)azolidinyl, amino(NM)azolyl, (N,.4)azolidinyl, (NM)azolyl, carbamoyl, 33 cyano,-(CH2)xNHC(NR9)R,, -{CH2)xNHC(NH)NR9R9I-C(NR9)R97 -C(NH)NHR10, 34 -C(NH)NR'°R10 or -{CR1 ‘R")yNH2 and bonded to any annular atom with an available valence 35 comprising B, wherein x is 0 or 1, y is 0,1,2 or 3, each R9 independently is hydrogen or 36 (C,.6)alkyl, each R10 is independently (Ct.6)alkyl and each R" independently is hydrogen, 37 (C,.3)alkyl or together with another R11 and a carbon atom to which both are attached forms 3S cycIopropyl, v/herein any aliphatic or alicyclic moiety comprising R1 optionally is substituted 39 with one to t\vo substituents independently selected from (C|.6)alkyloxycarbonyl, 40 (C|.fl)alkanoyloxy, carboxy, carbamoyl, (C|.4)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, 41 (C|.6)alkylsulfonyl and hydroxy; 42 each R2 independently is (Ci.6)alkyl, (C,.6)alkyloxycarbonyl, (Cl.4)alkanoyloxy, 43 (Ct.6)aIkyloxy, carboxy, carbamoyl, (C,.6)alkylcarbamoyl, di(C,.<;)alky]carbamoyl, 44 (C,.6)alkylsulfmyl, (C1.6)alkylsulfony!, (C,.6)alkylthio, halo or hydroxy and bonded to any 45 annular atom with an available valence comprising B, wherein any aliphatic moiety comprising 46 R2 optionally is substituted with one to t\vo substituents independentlv selected from 47 (C,.6)alkyloxycarbonyl, (Ci.6)aIkanoyloxy, carboxy, carbamoyl, (C,.6)alkylcarbamoyl, 4S di(C,.6)alkyIcarbamoyl, (C,.6)alkylsuIfonyl and hydroxy; 49 each R3 independently is (C,.6)alkyl, (C,.6)alkyloxy, (C|.6)alkylthio, cyano, halo, 50 perhalo(C,.6)alkyl or hydroxy and bonded to any annular atom \vith an available valence 51 comprising C; and
52 53 -N(R13)S(0):R,2) -C(0)R12, -C(0)0R':, -C(0)N(R,3)R12, -N(Ri3)C(0)R12, -0C(0)N(R,3)Ri:, 54 -N(Ri3)C(0)0R12, -{CHjJ^R^ļCiOJNCR^iR12, -0P(0)(0R,3)0 R12 or 55 -C(0)N(Rl4)CH(C00H)R12 and bonded to any annular carbon atom with an available valence 56 comprising C, vvherein: 57
5S z is 0, 1 or 2, R12 is -R15 or -Xs-{Rls)nl5, \vherein nl5 is 1 or 2, X4 is (C,.10)aikylene, 59 cyclo(C3.l0)alkylene, hetero(C2.|0)aIkyIene or heterocyclo(C3.i0)alkylene and each RIS is 88 LV 12495 60 independently hydrogen, (C6.|4)aryl, cyclo(C3.|4)alkyl, poIycyclo(C4.u)aryl, 61 heteropolycyclo(C6.u)aryl, heterocyclo(C3.u)alkyl, hetero(C5.u)aryl or as defrned below, 62 R13 is hydrogen, (C,.6)alkyl or hetero(C2.6)aIkyl; 63 R14 is hydrogen, (C!.6)alkyl or together with X6 and R15 forms (C3.4)alkylene; 64 any aliphatic and alicyclic moiety comprising R4 optionally is substituted with one 65 to five substituents independently selected from (C|.6)alkyl, (C|.4)alkylamino, 66 di(C,.4)alkylamino, (C,.4)alkylcarbamoyl, di(C,.4)alkyIcarbamoyl, (C,.4)alkyioxy, 67 (C|.6)alkyloxycarbonyl, (C,.6)alkysulfinyl, (C1.4)alkysulfonyl, (C,.6)aIkvthio, amino, 68 (C4.10)arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and 69 uriedo; and 70 any aromatic moiety comprising R13 optionally is substituted \vith one to three 71 substituents independently selected from cyano, guanidino, halo, halo-substituted 72 (C1.J)alkyl, -R16, -OR16, -SR14, -S(0)R16, -S(0);R16, -S(0)2N(R13)R16-, -C(0)R16, 73 -C(0)0R16 and -C(0)N(Rl3)R16, wherein R13 is as defmed above and Rl& is hvdrogen, 74 optiona!ly mono-substituted (C,.s)alkyl (wherein the optional substitutent iš 75 (C,.4)alkyIamino, di(C|.4)alkylamino, tri(C,.4)alkylammonio, (C,.4)alkvlcarbamoyl, 76 di(C,.4)alkylcarbamoyl, (C1.4)alkyloxycarbonyl, (C|.4)alkyloxysulfonyl, amino, carboxy, 77 carbamoyl, hydroxy or sulfo), cyclo(C3.4)alkyl, hetero(C1.3)alkyI, hetero(C5.4)aryl, 78 heterocyclo(C3.6)alkyl or phenyl; 79 with the proviso that nl is not 0, when n2 is 0 or R1 2 is (C,.6)aikvl or (Ct.4)alkyloxy, n3 is 0 or R3 4 80 is (C|.4)alkyl or (C|.6)alkyloxy and R4 is nydrogen, (C|.|0)alkyi or (CM0)aIkyloxy; and the /V-oxide 81 derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers 82 and pharmaceutically acceptable salts thereof. 1 2. The compound of Claim 1 in which A contains 5 annular members and B contains 2 6 annular members and X1 and X3 are adjacent members of an oxa2ol-2-yl, l//-imidazol-2-yl or 3 thiazol-2-yl ring; and the /V-oxide derivatives, prodrug derivatives, protected derivatives, 4 individual isomers, mixtures of isomers and pharmacsuticallv acceptable salts thereof. 3.
The compound of Claim 2 \vhich a compound of Formula II:
in which: the dashed lines independently represent optional bonds; each R2 independently is (Cl.4)alkyl, (C|.fi)alkyloxy, halo or hydroxy; each R3 independently is (C,.6)alkyl, (C|.6)alkyloxy, halo or hydroxy; X3 is -C(O)- or -CR1R3-; X1 is -CH(R')n[- or -C(R')nl=, wherein R2 is amino(N,.4)azolidinyl, amino(NM)azolyl, (NM)azolidinyl, (NM)azolyl, -NHC(NH)NR3R’, -C(NR3)R3, -CCNH)NHR4 5, -C(NH)NR4R4 or -{CRuRM)yNH2, or X3 is -N= or -NK(R')e|-, wherein R' is -C(NR3)R3, -C(NH)NHR'° or -CCNH)NR4R4, wnerein each R3 independently is hydrogen or (C,.6)alkyl and each R4 independently is (C,.6)alkyl; and X3 is -CH(R')- or -C(R>, wherein R6 is -Ri2, -OR!2, -N'(RI3)R,:, -SR12, -S(0)R12, -S(O), R12, -S(0)20 R12, -S(0)2N(R,3)R12, -N(R,3)S(0)2R!2, -C(0)R!2, -C(0)0R12, -C(0)N(R13)R12, -N(Rl3)C(0)R'\ -0C(0)N(Rl3)R12, -N(Rl3)C(0)0R12, -(CH2)n4N(R,3)C(0)N(R,3)R,2> -0P(0)(0Rl3)0 Rp* or -C(0)N(R14)CH(C00H)R12, or X3 is -N= or -N(R4)-, wherein R6 is -C(0)R12, -C(0)0R12, -C(0)N(R13)R12, -0C(0)N(R,3)R12 or -C(0)N(R|4)CH(C00H)R,;!. 1 sulfo, R1 is hydrogen or methyl and R2 is hydrogen, methyl or hydroxy; 2 X2 is -CCR1)*^, wherein R7 is aminomethyI, l-aminocyclopropyl, 2-aminoimidazol-l-yl, 3 2-amino-l,l-dimethylethvl, imidazolyl, tetrazolyl, -(CH^NHCfNR^R3, 4 -{CH2),NHC(NH)NR3R3 and -C(NR3)R3, wherein each R3 independently is hydrogen or methyl, 5 or X2 is -N(R')nl- wherein R1 is -C(NR3)R3, -C(NH)NHR4 or -CCNH)NR4R4, wherein each R3 6
The compound of Claim 3 in which: 7 substituted \vith one to two substituents independently selected from (CM)alkytoxy, hydroxy and 90 LV 12495 9 independently is hydrogen or methyl and each R10 is methyi, wherein any aliphatic or aiicyclic 10 moiety comprising R1 2 optionallv is substituted with one to two substituents independently 11 selected from methylsulfonyl and carboxy; 12 X9 is -C(R>, wherein R4 is -R'2, -OR12, -C(0)R'2, -C(0)OR12, -C(0)N(Rl3)R12 or 13 -C(0)N(R|4)CH(C00H)R12, wherein R'3 and R14 independently are hydrogen or (C,.4)alkyl; R12 14 is -R15 or -X6-(Rl5)nij. wherein X6 is (C,.,0)alkylene or hetero(C2.10)alkylene and each R15 15 independently is hydrogen, (C4.l4)aryl, cyclo(C3.14)alkyl, polycyclo(C4.14)aryl, 16 heteropolycyclo(C4.M)aryI, heterocyclo(C3.u)alkyl or hetero(C5.u)aryl; 17 any aliphatic and alicvclic moiety comprising R4 optionally is substituted with one to five 18 substituents independentlv selected from (CM)alkyloxy, (C,.4)alkyloxvcarbonyl, amino, 19 carbamoyl, carboxy and hydroxy; and 20 any aromatic moiety comprising R15 optionally is substituted \vith one to three 21 substituents independently selected from (C|.4)alkyl, (C|.4)alkyloxy, (C|.4)alkyloxycarbonyl, 22 carbamoyl, carboxy, cyano, cyclo(C3.s)alkyloxy, halo, hetero(C|.s)alkyl, hydroxy, 23 hetero(C|.3)alkylcarbonyl, hetero(Ci.4)aryl and trifluoromethyl; and the yV-oxide derivatives, 24 prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and 25 pharmaceuticallv acceptable salts thereof. 1 5. The compound of Claim 4 in which: 2 A together vvith B comprises 4,5,6,7-tetrahydro-I//-imidazo[4,5-c]pyridin-2-yi, wherein 3 n2 is 0, R1 is -C(NR’)R9 and R5 is hvdrogen, or A together with B comprises 4 l//-benzoimidazol-2-yI or 4,5,6,7-tetrahydro-l//-benzoimidazoI-2-yI, wherein R1 is aminomethyl 5 or guanidino and each R: independently is halo or hydroxy; 6 C comprises 4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl or l//-benzoimidazol-2-yl, 7 \vherein R4 is -C(0)X6-R15, -C(0)0X6-R1S or -€(0)ΝΗΧ^15, wherein X6 is (CM)alkylene or 8 hetero(C2.4)alkylene and R15 is (C6.I0)aryl, (C6.l0)aryloxy, polycyclo(C6.l0)aryl, hetero(C5.,0)aryl, 9 hetero(C5.|0)aryloxy or heteropolycyclo(C6.I4)aryl; and 10 any aromatic moiety comprising R15 optionally is substituted \vith one to three 2 substituents independently selected from (CM)alkyl, (C|.4)alkyloxy, (CM)alkyloxycarbonyl, 12 carboxy, carbamoyl, halo, hydroxy and tetrazol-l-yl; and the /V-oxide derivatives, prodrug 13 derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically 14 acceptable salts thereof. 91 1 6. The compound of Claim 5 in which A together with B comprises 2 17/-benzoimidazol-2-yl and each R1 independently is halo or hydroxy; and the N-oxide 3 derivatives, prodrug derivatives, protecied derivatives, individual isomers, mixtures of isomers 4 and phanmaceutically acceptable salts thereof. 1 7. The compound of Claim 6 in vvhich nl is 0; and the iV-oxide derivatives, prodrug 2 derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically 3 acceptable salts thereof. 1 8. The compound of Claim 7 vvhich is selected from: 2 2-(2- (2-[ 1 -(4,6,7-trifiuoro- l//-benzoimidazol-2-yl)ethyl]-3-methyl- 3 3W-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid; 4 2-(2-{2-[l-(5,6-difluoro-l//-benzoimidazo!'2-yl)ethyl]-3-methyl- 5 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid; 6 butyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyI]-3-methyl- 7 3iV-bcnzoimidazol-5-ylcarbonylamino}ethoxy)benzoate; S propyl 2-(2- {2-[ 1 -(5-hydroxy-lf/-benzoimidazol-2-yl)ethyl]-3-methyl- 9 3ff-benzoirmdazol-5-ylcarbonylamino}ethoxy)benzoate; and 10 isobutyl 2-(2-{2-[l-(5-hydroxy-l//-benzoimidazol-2-yl)ethyl]-3-methyl- 11 3//-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoate; and the yV-oxide derivatives, prodrug 12 derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically 13 acceptable salts thereof. 1 9. The compound of Claim 5 in vvhich R2 is guanidino or aminomethvi, and the 2 N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of 3 isomers and pharmaceutically acceptable salts thereof. 3 1 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-methyl-iV-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide; 2 10. The compound of Claim 9 vvhich is selected from: 92 LV 12495 4 ethyl 2-(3-{2-(l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]- 5 l,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino}propoxy)benzoate; 6 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-(2,3-dihydroxy)propyi- 7 /V-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide; 8 2-(5-guanidino-l//-benzoimidazol-2-ylcarbonyl)-3-(2,3-dihydroxy)propyl- 9 /V-(2-naphth-1 -ylethyl)-3/7-bcnzoimidazole-5-carboxamide; 10 2-(5-guanidino-l/f-benzoimidazol-2-ylmethyl)-3-(3-hydroxy)propyl- 11 /V-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide; 12 2-(5-guanidino-l//-benzoimidazol-2-ylmethyl)-3-(2-hydroxy)ethyl- 13 /V-(2-naphth-l-ylethyl)-3Ar-benzoimidazole-5-carboxamide; 14 2-[ 1 -(5-guanidino-1 //-benzoimidazo l-2-y l)ethyl]-/V-[2-(2-carbamoy lphenoxy)ethyl]- 15 3-methyl-3//-benzoimidazole-5-carboxamide; 16 2-[ 1 -(5-guanidino-1 //-benzoimidazol-2-yl)ethyl]-yV-(2-(2-carbamoyl- 17 4-chlorophenoxy)ethyl]-3-methyl-37/-benzoimidazole-5-carboxamide; 1S 4-chloro-2-(2-( {2-[ 1 -(5-guanidino- l//-benzoimidazol-2-yl)ethyl]-3-methyI- 19 3//-benzoimidazol-5-ylcarbonyl}amino)ethoxy]benzoic acid; 20 5-chloro-2-[2-({2-[l-(5-guanidino-l//-benzoimidazol-2-yl)ethyl]-3-msthyl- 21 3//-benzoimidazoI-5-ylcarbonyl}amino)ethoxy]benzoic acid; 22 2-(5-aminomethyI-l//-benzoimidazoI-2-ylmethyl)-3-methyl-iV-(2-naphth-l-yiethyl)- 23 3//-benzoimidazole-5-carboxamide; and 24 2-(5-aminomethyl-4,5,6,7-tetrahydro-l//-benzoimidazol-2-ylmethyl)-3-methyl- 25 Ar-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamidc; and the Ar-oxide derivātives, prodrug 26 derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically 27 acceptable salts thereof. 93 1 12. The compound of Claim 11 which is selected from: 2 2-[2-(2-{l-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/7-imidazo[4,5-c]pyridin-2-yl]ethyl}- 3 3-methyl-3//-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoic acid; 4 2-(5-(l-iminoethyl)-4,5,6,7-tetrahydiO-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl- 5 iV-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide; 6 2-[5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyndin-2-ylcarbonyl]- 7 3-methyl-/7-(2-naphth-l-ylethyl)-3tf-benzoimidazole-5-carboxamide; 8 2-(5-iminornethyl-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-ylmethyl)-3-rnethyl- 9 ,'V-(2-naphth-1 -ylethyl)-3//-benzoimidazole-5-carboxamide; 10 2-(5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-ylmethyl]-3-methyl- 11 /V-(2-hydroxy-2-naphth-l-ylethyl)-3//’-benzoimidazoIe-5-carboxamide; 12 2-(5-(l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-ylmethyl]-3-methyl- 13 /V-[2-(2-hydroxynaphth-l-yl)ethyl]-3//-benzoimidazole-5-carboxamide; 14 2-(5-(l-iminoethyl)-4,5,6,7-tetrahydro-l/f-imidazo(4,5-c]pyridin-2-ylmethyl]-3-methyl- 15 Ar-[2-(4-hydroxynaphthaI-1 -yl)ethyl]-3//’-benzoimidazole-5-carboxamide; 16 2-{1-(5-( l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo(4,5-c]pyridin-2-yl]ethyl}- 17 3-methyl-Ar-(2-naphth-l-ylethyl)-3//-benzoimidazole-5-carboxamide; 1S ethyl 2-(2-(2-{1-(5-(l-iminoethyl)-4,5,6,7-tetrahydro- 19 l//-imidazo[4,5-c]pyridin-2-yl]ethy!}-3-methyI- 20 37/-benzoimidazol-5-ylcarbonylamino)ethoxy]benzoate; 21 2-(2-(2-(1-(5-( l-iminoethyl)-4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl}- 22 3-(2-methoxyethyl)-3//-benzoimidazol-5-yIcarbonylamino)ethoxy]benzoic acid; 23 ethyl 2-(2-(2-{l-(5-(l-iminoethyl)-4,5,6,7-tetrahydro- 24 1 //-imidazo[4,5-c]pyndin-2-yl]ethyl} - 25 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-ylcarbonylamino)sthoxy]benzoate; and 26 2- {1 -(5-(1 -iminoethyl)-4,5,6,7-tetrahydro- l//-imidazo(4,5-c]pyridin-2-yl]ethyl} - 27 3-methyl-/V-(2-(2-tctrazoIylphenoxy)ethyI]-37/-benzoimidazolc-5-carboxamide; and thc /V-oxide 28 derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers 29 and pharmaceuticallv acceptable salts thereof. 1 13. The compound of Claim 12 which is 2-(2-(2- {l -(5-(1 -iminoethyI)- 2 4,5,6,7-tetrahydro-l//-imidazo[4,5-c]pyridin-2-yl]ethyl}-3-methyl- 94 LV 12495 3 3if-benzoimidazoI-5-ylcarbonylamino)ethoxy]benzoic acid; and the /V-oxide derivatives, prodrug 4 derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically 3 acceptable salts thereof. 1 14. A pharmaceutical composition comprising the compound of Claim 1 in 2 combination with a pharmaceutically acceptable carrier. 1 15. The pharmaceutical composition in accordance with Claim 14, further comprising 2 a β-adrenergic agonist compound. 1 16. The pharmaceutical composition in accordance with Claim 14, wherein said 2 β-adrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, 3 formoterol, fenoterol and prenaline. 1 17. The pharmaceutical composition in accordance with Claims 14, wherein said 2 composition comprises a pharmaceutically acceptable topical carrier. 1 18. The pharmaceutical composition in accordance \vith Claims 14, \vherein said 2 composition comprises a pharmaceutically acceptable oral carrier. 1 19. The pharmaceutical composition in accordance with Claims 14, wherein said 2 composition comprises a pharmaceutically acceptable aerosol carrier. 1 20. An aerosol device, comprising the compound of Claim 1 in a pharmaceutically 2 acceptable carrier solution or dry powder, and a means for converting said solution or dry 3 powder into an aerosol form suitable for inhalation. 1 21. A method for treating an immunomediated inflammatory disorder in a mammai, 2 said method comprising administering to said mammai a therapeutically effective amount of the 3 compound of Claim 1. 22. A method of treating rheumatoid arthritis in a mammai, comprising administering to said mammai a therapeuticaliy effective amount of a compound of Claim 1. 23. A method of treating conjunctivitis in a mammai, said method comprising administering to said mammai a therapeutically effective amount of the compound of Claim 1. 24. A method of treating syncytial vīrus infections in a mammai said method comprising administering to said mammai a therapeutically effective amount of the compound of Claim 1. 25. A method for treating an immunomediated inflammatory disorder of the rcspiratory tract of a mammai, said method comprising administering to said mammai a therapeutically effective amount of a compound of Claim 1. 26. A process for preparing a compound of Formula I:
in which: nl is 0 or 1, n2 is 0,1,2, 3 or 4; n3 is 0, 1, 2, 3 or 4; A together with B comprises a fused heterobicycIic radical containing 8 to 12 armular atoms, \vherein each ring contains 5 to 7 annular members, each artnular atom optionally is a heteroatom, X1 is a heteroatom moiety selected ffom -N=, -0- and -S- and X1 and X2 are adjacent annular members of an oxazol-2-yl, l/f-imidazol-2-yl or thiazol-2-yl ring, \vherein an annular member of the l//-imidazol-2-yl ring optionally is -NR3-, wherein R3 is hydrogen, (C,.6)alkyl or hetero(C2.6)alkyl; or 96 LV 12495 C comprises a fused heteropo[ycyclic radical containing 8 to 18 annular atoms, v/herein each ring contains 5 to 7 annular members, each annular atom optionallv is a heteroatom, X5 is a heteroatom moiety selected from -N=, -O- and -S- and X4 and X5 are adjacent annular members of an oxazol-2-yt, l//-imidazol-2-yl or thiazol-2-yl ring, wherein an annular member of the l//-imidazol-2-yl ring optionally is -NR6-, wherein R6is hydrogen, a group selected from (C|.3)alkyl or hetero(C2.I2)alkyl, which group optionally is substituted with one to two substituents independently selected from (C,.6)alkanoyloxy, (C,.6)alkylamino, di(C,.6)alkylamino, tri(C,.6)alkylammonio, (C,.6)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C,.6)alkyloxy, (C,.6)alkyloxycarbonyl, (C,.6)alkyloxysulfonyl, amino, carboxy, carbamoyl, (Ct|4)aryl, halo, hctero(C5.|4)aryl, hydroxy and sulfo, or as derincd beIow and any carbocvclic ketone, thioketone and iminoketone derivative thereof; X1 is -0-, -S-, -S(O)-, -S(0)2-, -C(O)-, -NR7- or -CR7RS-, wherein R7 is hydrogen, (C|.6)alkyl, hetero(C2.ļ2)alkyl or together with R6 forms (C>.4)alkylene or hetero(C2.4)alkylene and R3 is hydrogen, (C,.4)alkyl or hydroxy or together \vith R7 forms (C2.4)alkylene or (C,.4)alky ūdens, wherein any aliphatic or alicvclic moietv comprising R7 and/or R3 optionallv are substituted \vith one to three substituents selected from (C,.6)alkylamino, di(C,.6)alkylamino, tri(C|.6)alkylammonio, (C|.6)alkyloxy, (C|.4)alkyloxycarbonyl, (C,.4)aIkanoyloxy, amino, carboxy, carbamoyl, (C,.6)alkylcarbamoyl, di(C|.6)aIkylcar'oamoyi, halo and hydroxy; R1 is amino(N,.4)azolidinyl, amino(N,.4)azolyl, (N,.4)azolidinyl, (N,.4)azolyl, carbamovl, cyano, -(CH2)XNHC(NR9)R9, -(CK2)XNHC(NH)NR9R9, -C(NR9)R9, -C(NH)NHR10, -C(NH)NRI0R10 or -{CRllR")yNH2 and bonded to any annular atom with an available valence comprising B, \vherein x is 0 or 1, y is 0, 1, 2 or 3, each R9 independentlv is hydrogen or (C|.0)a!kyl, each R10 is independently (C,.6)alkyl and each R11 independent!y is hydrogen, (C,.3)alkyl or together with another R" and a carbon atom to which both are attached forms cyclopropyl, wherein any aliphatic or alicyclic moietv comprising R1 optionallv is substituted with one to two substituents independently selected from (C,.5)aikyloxycarbonyl, (C,.4)aIkanoyloxy, carboxy, carbamovl, (C,.4)alkylcarbamoyl, di(C,.4)alkylcarbamoyl, (C,.4)alkylsulfonyl and hydroxy; each R2 independently is (C,.4)alkyl, (C,.4)alkyioxycarbonyl, (C16)alkanoyIoxy, (C,.6)alkyloxy, carboxy, carbamoyl, (C,.4)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C,.6)alkylsulfmyl, (Cļ.Jalkvlsulfonvl, (C,.4)alkylthio, halo or hydroxv and bonded to any annular atom with an available valence comprising B, \vherein anv aliphatic moiety comprising 97 9748495051 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 6S 69 70 71 72 73 74 75 76 77 78 R2 optionally is substituted with one to t\vo substituents independently selected from (C1.4)alkyloxycarbonyl, (C,.6)alkanoyloxy, carboxy, carbamoyl, (C|.6)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C,.6)alkylsulfonyl and hydroxy; each R3 independently is (C,.6)alkyl, (C,.6)alkyloxy, (C,.4)alkyIthio, cyano, halo, perhalo(C,.4)alkyl or hydroxy and bonded to any annular atom with an available valence comprising C; and R4 is -R'2, -OR12, -N(R13)R'2, -SR'2, -S(0)R12, -S(O), R12, -S(0)20 R'2, -S(0),N(R'J)R12, -N(Rl3)S(0)2R12, -C(0)R12, -C(0)0R12, -C(0)N(R13)R12, -N(R'3)C(0)R12, -0C(0)N(R13)R12, -N(R13)C(0)0R12, -{CH2)zN(R!3)C(0)N(RI3)R12, -0P(0)(0R13)0 R12 or -C(0)N(Rl4)CH(C00H)R12 and bonded to any annular carbon atom with an available valence comprising C, wherein: z is 0, 1 or 2, R12 is -R15 or-X6-(Rl5)nl5, wherein η 15 is 1 or 2, Xs is (CM0)a!kylene, cyclo(C3.10)alkylene, hetero(C2.,o)alkylene or heterocyclo(C3.,0)alkylene and each R15 is independently hvdrogen, (C6.u)aryl, cyclo(C3_m)alkyl, polycyclo(C6.u)aryl, heteropolycyclo(C4.u)aryl, heterocyclo(C3.u)alkyl, hetero(C3.u)aryl or as defined below, R13 is hydrogen, (C,.4)alkyl or hetero(C2_4)alkyl;
Ru is hvdrogen, (C,.6)alkyl or together with X6 and R15 forms (C3J)alkylene; any aliphatic and alicvclic moietv comprising R4 optionallv is substituted \vith one to five substituents independently selected from (CI.6)alkyl, (C,.s)alkylamino, di(C|.4)aikylamino, (C,.6)alkylcarbamoyl, di(C|.4)alkylcarbamoyl, (C,.6)alkyloxy, (C,.4)alkyloxycarbonyl, (C,.4)alkysulfmyl, (C,.4)alkysuIfonyl, (C,.4)alkythio, amino, (C4.10)arylsulfonyl, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto and uriedo; and any aromatic moiety comprising R15 optionally is substituted with one to three substituents independently selected from cyano, guanidino, halo, halo-substituted (C,.3)alkyl, -R16, -OR16, -SR16, -S(0)R16, -S(0):R16, -SiOi.NCR'^R'6-, -C(0)R16, -C(0)0R16 and -C(0)N(Rl3)R16, wherein R13 is as deftned above and R16 is hydrogen, optionallv mono-substituted (C,.g)alkyl (\vherein the optionai substitutent is (C,.4)alkylamino, di(C|.4)alkylamino, tri(Cl·4)alkylammonio, (C,.4)alkylcarbamoyl, di(C,.4)alkylcarbamoyl, (Ct.4)alkyloxycarbonyl, (C,.4)alkyloxysulfonyl, amino, carboxy, 98LV 12495 79 80 81 82 83 84 85 86 87 carbamoyl, hydroxy or sulfo), cyclo(C3.6)alkyl, hetero(C1.3)alkyl, hetero(C5.6)aryl, heterocyclo(C3.6)aIkyI or phenyl; with the proviso that nl is not 0, when n2 is 0 or R2 is (C(.6)alkyl or (Ct.6)alkyloxy, n3 is 0 or R3 is (C,.6)aikyl or (Cl.i)alkyloxy and R4 is hydrogen, (C,.|0)alkyl or (C,.l0)alkyloxy; and the N-oxide derivatives, prodmg derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof; vvhich process comprises: (a) reacting a compound of Formula 1:
SS 89 90 91 92 93 or a protected derivative thereof, vvith a compound of Formula 2:
94 95 96 97 98 99 100 101 102 103 104 105 or a protected derivative thereof, in vvhich L is a leaving group, D together vvith the vinyiene moiety to vvhich it isfused comprises a monocyclic or fused bicyclic divalent radical containing firom 5 to 15 annular atoms, vvherein each ring contains 5 to 7 annular atoms and each annular atom optionally is a heteroatom, R2’ is -OH, -NHR6 or -SH, vvherein R6 is hydrogen or a group selected firom (C1.8)alkyl or hetero(C2.i2)alkyl, vvhich group optionallv is substituted vvith one to tvvo substituents independently selected from (C,.6)alkanoyloxy, (C,.6)alkylamino, di(C|.,;)alkyIamino, tri(C,.6)alkylammonio, (C,.6)alkylcarbamoyl, di(C,.6)alkylcarbamoyl, (C,.6)alkyloxy, (C,.6)alkyloxycarbonyl, (C1.i)alkyloxysulfonyl, amino, carboxy, carbamoyl, (C6.|4)aryl, halo, hetero(C3.u)aryl, hydroxy and sulfo, and nl, n2, n3, A, B, X1, X2, X3, R1, R2, R3, R4 and R6.are as defined above, and then deprotecting if necessary; or 99 99 10c (b) rcacting z compound of rormula 3:
107 10S
109 110 111 112 1 i-2 114 115 116 117 11S 119 120 121 122 123 124 125 or z orotsctcd dcrivativc thcrcof, with a compound of Formula 4:
or a protcctcd dcrivativc thcrcof, in wnich L is a lcaving group, RM is -OK, -NER3 or -SH and nl, n2. n3. B, CT X\ X4, X5, R\ RJ, R3. R4 and R3 arc zs dcfincd abovc, and thcn dcprotccting if ncccssary; (c) . optionaliv furthcr convcrting a compound of Formula I into a phurmaccutically aaccptabic salt; (d) optionaliv riirthcr convcrting a salt form of a compound of Formula I to non-salt form; (e) optionaliv furthcr convcrting an unoxidized form of a compound of Formula I into a pharmaccuticallv acccptabie /V-oxidc; (0 optionaliv furthcr an ;V-oxidc form of a compound of Formula I its unoxidizcd form; (g) optionaliv furthcr convcrting a non-dcrivarizcd compound of Formula I into a phannaccutically prodrug dcrivativc; and (h) optionaliv furthcr convcrting a prodrug dcrivativc of a compound of Formula 1 to its ποη-dcrivatizcd form. 126 LV 12495 1/2 compoūnd 13 (1 mg x 3; aerosol) Speciflc Lung Resistance
Central Campound 13
Fig. 1 LV 12495 2/2 compound 13 (1 mg x 3; aerosol) 30 η
Basaline O Post-Antigen PC400 (Breath Unita) 20 -
Controi
Conroound 13
Fig. 2 LV 12495
Abstract
Novel compounds, compositions containing thereof and use thereof for the prevention and treatment of mast-cell mediated inflammatory disorders.
Compounds of Formula (II):
compositions containing thereof and use thereof for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other types of immunomediated inflammatory disorders, such as rheumatoid arthritis, conjunctivitis and inflammatory bovvel disease, dermatological conditions and vīrus diseases. The compounds comprise potent and selective inhibitors of the mast celi protease tryptase.

Claims (4)

1 LV 12495 Izgudrojuma formula 1. Savienojums ar formulu (I):1. A compound of formula (I): kurā: n1 ir 0 vai 1; n2 ir 0,1, 2, 3 vai 4; n3 ir 0,1, 2, 3 vai 4; A kopā ar B veido kondensētu heterobiciklisku grupu, kurā ir 8 -12 cikla atomi, pie tam katrā no cikliem ir 5 - 7 cikla atomi un katrs no cikla atomiem var būt heteroatoms; X1 un X2 ir blakusesošie cikla atomi aromātiskā ciklā un X1 ir heteroatomu ietverošs cikla loceklis no rindas: -N=, -NR5-, -0- un -S-, kur R5 ir ūdeņraža atoms, Ci-6alkilgrupa vai hetero-C2-6alkilgrupa; C ir kondensēta heteropolicikliska grupa, kas saur 8-18 cikla atomus, pie tam katrā no cikliem ir 5 - 7 cikla atomi un katrs no cikla atomiem var būt heteroatoms; X4 un X5 ir blakusesošie cikla atomi aromātiskā ciklā un X5 ir heteroatomu ietverošs cikla loceklis no rindas: -N=, -NR6-, -0- un -S-, kur R6 ir ūdeņraža atoms, Ci_8alkilgrupa vai hetero-C2-i2aIkiIgrupa, pie tam minētās grupas neobligāti aizvietotas ar 1 - 2 aizvietotājiem, kas neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkanoiloksigrupa, C-i^alkilaminogrupa, di-(Ci^alkil)aminogrupa, tri- 2 (Ci-6alkil)amonija grupa, Ci^alkilkarbamoilgrupa, dī-(Ci_6alkil)- karbamoilgrupa, Ci^alkoksigrupa, Ci^alkoksikarbonilgrupa, Cļ.6alk-oksisulfonilgrupa, aminogrupa, karboksilgrupa, karbamoilgrupa, C6-i4arilgrupa, halogēna atoms, hetero-Cs-uarilgrupa, hidroksilgrupa un sulfogrupa, vai arī R6 ir tāds, kā aprakstīts zemāk; kā arī jebkādi grupas C karbocikliskie ketona, tioketona vai iminoketona atvasinājumi; X3 ir -O-, -S-, -SO-, -SO2-, -CO-, -NR7- vai -CR7R8-, kur R7 ir ūdeņraža atoms, Ci^alkilgrupa, hetero-C2-i2alkilgrupa, vai kopā ar R6 veido C2-4alkilēngrupu; R8 ir ūdeņraža atoms, Ci-ealkilgrupa vai hidroksilgrupa, vai kopā ar R7 veido C2^alkilēngrupu vai Ci^alkil-idēngrupu, pie tam jebkura no alifātiskajām vai alicikliskajām R7 un/vai R8 grupām ir neobligāti aizvietota ar 1 - 3 aizvietotājiem no rindas: Ci^alkilaminogrupa, di-(Ci_6alkil)aminogrupa, tri-(Ci^alkil)amonija grupa, Ci^alkoksigrupa, Ci^alkoksikarbonilgrupa, Ci^alkanoiloksi-grupa, aminogrupa, karboksilgrupa, karbamoilgrupa, Ci^alkilkarbamoil-grupa, di-(Ci^alkil)karbamoilgrupa, halogēna atoms un hidroksilgrupa; R1 ir amino(Ni^)azolidinilgrupa, amino(Ni^)azolilgrupa, (Ni_4)azo-lidinilgrupa, (N^Jazolilgrupa, karbamoilgrupa, ciāngrupa, -(CH2)xNH-C(NR9)R9, -(CH2)xNHC(NH)NR9R9, -C(NR9)R9, -C(NH)NHRlb, -C(NH)-NR10R10 vai -(CR11R11)yNH2 un ir pievienots jebkuram no cikla B atomiem, kuram ir brīva valence, pie kam X ir 0 vai 1, y ir 0, 1, 2 vai 3, katrs R9, neatkarīgi viens no otra, ir ūdeņraža atoms vai C^alkilgrupa, katrs R10, neatkarīgi viens no otra, ir Cļ^alkilgrupa un katrs R11, neatkarīgi viens no otra, ir ūdeņraža atoms, Ci.3alkilgrupa vai arī kopā ar otru R11 un oglekļa atomu, kam tie ir pievienoti, veido ciklopropilgrupu, pie tam jebkura no R1 ietilpstošām alifātiskajām vai alicikliskajām grupām grupām ir neobligāti aizvietota ar 1 - 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: C-i-ealkoksikarbonilgrupa, Ci^alkanoiloksigrupa, karboksilgrupa, karbamoilgrupa, Ci-ealkilkarbamoilgrupa, di-(Ci-6alkil)karbamoilgrupa, Ci^alkilsulfonilgrupa un hidroksilgrupa; katrs R2, neatkarīgi viens no otra, ir C^alkilgrupa, Ci^alkoksikarbonil-grupa, Ci^alkanoiloksigrupa, Ci^alkoksigrupa, karboksilgrupa, karbamoilgrupa, Ci^alkilkarbamoilgrupa, di-(Ci^alkil)karbamoilgrupa, Ci^alkilsulfinilgrupa, Ci^alkilsulfonilgrupa, Ci^alkiltiogrupa, halogēna atoms vai hidroksilgrupa, un ir pievienots pie jebkura no cikla B atomiem, kuram ir brīva valence, pie tam jebkura no alifātiskajām grupām, kas ietilpst R2 ir neobligāti aizvietota ar 1 - 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkoksi-karbonilgrupa, Ci^alkanoiloksigrupa, karboksilgrupa, karbamoilgrupa, Ci^alkilkarbamoilgrupa, di-(Ci^alkil)karbamoilgrupa, C-i-ealkilsulfonil-grupa un hidroksilgrupa; katrs R3, neatkarīgi viens no otra, ir Ci^alkilgrupa, C^alkoksigrupa, Ci-ealkiltiogrupa, ciāngrupa, halogēna atoma, perhalogenēta Ci-ealkil-grupa vai hidroksilgrupa, un ir pievienota pie jebkura no cikla C atomiem, kam ir brīva valence; 3 3 LV 12495 R4 ir -R12, -OR12, -N(R13)R12, -SR12, -SOR12, -S02R12, -S020R12, -S02-N(R13)R12, -N(R13)S02R12, -CO-R12, -COOR12, -CON(R13)R12, -N(R13)-CO-R12, -0C(0)N(R13)R12, -N(R13)COOR12, -(CH2)2N(R13)CO- N(R13)R12, -0P(0)(0R13)0R12 vai -CON(R14)CH(COOH)R12, un ir pievienots pie jebkura no cikla C atomiem, kuram ir brīva valence, z ir 0,1 vai 2, R12 ir R15 vai -X6-(R15)ni5, kur n15 ir 1 vai 2, ir Ci.ioalkilēngrupa, ciklo-C3-ioalkilēngrupa, hetero-C2.ioalkilēngrupa vai heterociklo-C3-ioalkilēngrupa un katrs no R15, neatkarīgi viens no otra, ir ūdeņraža atoms, C6-i4arilgrupa, C3.ucikloalkilgrupa, Ce-upolicikioarilgrupa, hetero-C6.Hpolicikloarilgrupa, hetero-C3-ucikloalkilgrupa, hetero- Ce-^arilgrupa, vai arī kāda tā ir aprakstīta zemāk; R13 ir ūdeņraža atoms, Ci^alkilgrupa vai hetero-C2-6alkilgrupa; R14 ir ūdeņraža atoms, Ci^alkilgrupa, vai arī kopā ar X6 un R15 veido C3-4alkilēngrupu; jebkura alifātiskā vai alicikliskā grupa, kas ietilpst R4 ir neobligāti aizvietota ar 1 - 5 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkilgrupa, Cļ^alkilaminogrupa, di-(Ci^alkil)aminogrupa, Ci^alkilkarbamoilgrupa, di-(Ci^alkii)karbamoilgrupa, Ci^alkoksigrupa, Ci^alkoksikarbonilgrupa, C^alkilsulfinilgrupa, Ci^alkilsulfonilgrupa, Ci^alkiltiogrupa, aminogrupa, C6-ioarilsulfonilgrupa, karbamoilgrupa, .karboksilgrupa, ciāngrupa, guanidīngrupa, halogēna atoms, hidroksilgrupa, merkaptogrupa un ureīdgrupa; jebkura aromātiskā grupa, kas ietilpst R15, ir neobligāti aizvietota ar 1 -3 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: ciāngrupa, guanidīngrupa, halogēna atoms, halogēnaizvietota Ci-ealkilgrupa, -R16, -OR16, -SR16, -SOR16, -S02R16, -S020R16, -S02-N(R13)R?6, -CO-R16, -COOR16 un -CON(R13)R16, kur R13 nozīmes ir jau minētās un R16 ir ūdeņraža atoms, ar aizvietotāju, kas ņemts no rindas: Ci-ealkilaminogrupa, di-(Ci^alkii)aminogrupa, tri-(Ci^alkil)amonija grupa, Ci-ealkilkarbamoilgrupa, dKC^alkiOkarbamoilgrupa, Ci.6alk-oksikarbonilgrupa, Cļ^alkoksisulfonilgrupa, aminogrupa, karboksilgrupa, karbamoilgrupa, hidroksilgrupa vai sulfogrupa, neobligāti monoaizvietota Ci^alkilgrupa, C3^cikloalkilgrupa, hetero-C^alkilgrupa, hetero-C5^arilgrupa, hetero-C3^cikloalkilgrupa vai fenilgrupa, ar tādu noteikumu, ka n1 nav 0, kad n2 ir 0 vai R2 ir Ci-ealkilgrupa vai Ci^alkoksigrupa, n3 ir 0 vai R3 ir Ci^alkilgrupa vai Ci^alkoksigrupa un R4 ir ūdeņraža atoms, Ci-i0alkilgrupa vai Ci-ioalkoksigrupa, kā arī šī savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis. 4wherein n1 is 0 or 1; n2 is 0,1, 2, 3 or 4; n3 is 0,1, 2, 3 or 4; A together with B forms a fused heterobicyclic group having 8 to 12 ring atoms, each having 5 to 7 ring atoms and each of the ring atoms may be a heteroatom; X1 and X2 are adjacent ring atoms in the aromatic ring and X1 is a heteroatom-containing ring member from -N =, -NR5-, -O-, and -S-, where R5 is hydrogen, C1-6alkyl, or hetero-C2-6alkyl ; C is a fused heteropolicyclic group that holds 8-18 ring atoms, each having 5 to 7 ring atoms in each ring and each of the ring atoms may be a heteroatom; X4 and X5 are adjacent ring atoms in the aromatic ring and X5 is a heteroatom-containing ring member from -N =, -NR6-, -O-, and -S-, wherein R6 is hydrogen, C1-8alkyl, or hetero-C2-i2alkyl; optionally substituted with 1 to 2 substituents independently selected from the group consisting of C 1-4 alkanoyloxy, C 1-6 alkylamino, di- (C 1-6 alkyl) amino, tri-2 (C 1-6 alkyl) ammonium, C 1-6 alkylcarbamoyl, di- (C 1-6 alkyl) carbamoyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkyloxysulfonyl, amino, carboxyl, carbamoyl, C 6-4 aryl, halo, hetero-C 6 -aryl, hydroxyl and sulpho, or also R6 is as described below; as well as any carbocyclic ketone, thioketone or iminocetone derivatives of Group C; X3 is -O-, -S-, -SO-, -SO2-, -CO-, -NR7-, or -CR7R8-, wherein R7 is hydrogen, C1-6alkyl, hetero-C2-12alkyl, or together with R6 forms a C 2-4 alkylene group; R8 is hydrogen, C1-6alkyl or hydroxy, or together with R7 forms a C2-6 alkylene group or a C1-6alkylidene group, and any of the aliphatic or alicyclic R7 and / or R8 groups is optionally substituted with 1 to 3 substituents from the row: C 1-6 alkylamino, di- (C 1-6 alkyl) amino, tri- (C 1-6 alkyl) ammonium, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-4 alkanoyloxy, amino, carboxyl, carbamoyl, C 1-6 alkylcarbamoyl, di- C 1-4 alkyl) carbamoyl, halogen and hydroxy; R 1 is amino (N 1 -) azolidinyl, amino (N 1 -) azolyl, (N 1-4) azo-lidinyl, (N 1 -Jazolyl, carbamoyl, cyano, - (CH 2) x NH-C (NR 9) R 9, - (CH 2) x NHC ( NH) NR9R9, -C (NR9) R9, -C (NH) NHR1b, -C (NH) -NR10R10, or - (CR11R11) yNH2 and attached to any of the ring B atoms having free valence, wherein X is 0 or 1, y is 0, 1, 2 or 3, each R9, independently of one another, is hydrogen or C1-4alkyl, each R10 independently of one another is C1-4 alkyl and each R11 is independently of one another; is a hydrogen atom, a C 1-3 alkyl group or together with the other R 11 and the carbon atom to which they are attached form a cyclopropyl group, furthermore any of the aliphatic or alicyclic groups of R 1 is optionally substituted with 1 to 2 substituents independently of one another. one is taken from the group consisting of C 1-4 alkoxycarbonyl, C 1-4 alkanoyloxy, carboxyl, carbamoyl, C 1-6 alkylcarbamoyl, di- (C 1-6 alkyl) carbamoyl, C 1-6 alkylsulfonyl and hydro each R 2, independently of one another, is C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkanoyloxy, C 1-4 alkoxy, carboxyl, carbamoyl, C 1-6 alkylcarbamoyl, di- (C 1-6 alkyl) carbamoyl, C 1-6 alkylsulfinyl, C 1-4 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, halogen, or hydroxyl, and attached to any of the B atoms in the ring having free valence, and any of the aliphatic radicals belonging to R 2 is optionally substituted with 1 to 2 substituents independently of one another. from each other are taken from the group consisting of C 1-6 alkoxy-carbonyl, C 1-4 alkanoyloxy, carboxyl, carbamoyl, C 1-6 alkylcarbamoyl, di- (C 1-6 alkyl) carbamoyl, C 1-4 alkylsulfonyl and hydroxy; each R 3, independently of one another, is C 1-6 alkyl, C 1-4 alkoxy, C 1-6 alkylthio, cyano, halogen, perhalogenated C 1-6 alkyl or hydroxy, and is attached to any of the C atoms in the ring having free valence; 3 12 LV 12495 R4 is -R12, -OR12, -N (R13) R12, -SR12, -SOR12, -SO2R12, -SO2R12, -SO2-N (R13) R12, -N (R13) SO2R12, -CO- R12, -COOR12, -CON (R13) R12, -N (R13) -CO-R12, -CO (O) N (R13) R12, -N (R13) COOR12, - (CH2) 2N (R13) CO- N (R13) R12, -OP (O) (OR13) R12 or -CON (R14) CH (COOH) R12, and attached to any of the C atoms in the ring having free valence, z is 0,1 or 2, R12 is R15 or -X6- (R15) ni5, where n15 is 1 or 2, is C1-10alkylene, cyclo-C3-10alkylene, hetero-C2-10alkylene or heterocyclo-C3-10alkylene and each of R15 is independently of one another are hydrogen, C6-aryl, C3-cycloalkyl, Ce-alkylcycloaryl, hetero-C6H-polycycloaryl, hetero-C3-cycloalkyl, hetero-C ar-aryl, or as described below; R 13 is hydrogen, C 1-6 alkyl or hetero-C 2-6 alkyl; R 14 is hydrogen, C 1-4 alkyl, or together with X 6 and R 15 forms a C 3-4 alkylene group; any aliphatic or alicyclic group belonging to R 4 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-4 alkylamino, di- (C 1-4 alkyl) amino, C 1-6 alkylcarbamoyl , di- (C 1-6 alkyl) carbamoyl, C 1-4 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, amino, C 6-10 arylsulfonyl, carbamoyl,. mercaptogroup and urea; any aromatic group belonging to R15 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, guanidine, halogen, halogen-substituted C1-6alkyl, -R16, -OR16, -SR16, -SOR 16, -SO 2 R 16, -SO 2 R 16, -SO 2 -N (R 13) R 6, -CO-R 16, -COOR 16, and -CON (R 13) R 16, wherein R 13 has the meanings already mentioned and R 16 is hydrogen, with a substituent, taken from the group consisting of C1-6alkylamino, di- (C1-6alkyl) amino, tri- (C1-6alkyl) ammonium, C1-6alkylcarbamoyl, dKC1-6alkocarbamoyl, C1-6alkoxycarbonyl, C1-6alkoxysulfonyl, amino, carboxyl, carbamoyl, hydroxyl or sulpho, optionally mono-substituted C 1-6 alkyl, C 3-6 cycloalkyl, hetero-C 1-4 alkyl, hetero-C 5 aryl, hetero-C 3-4 cycloalkyl or phenyl, provided that n 1 is not 0 when n 2 is 0 or R2 is C1-6alkyl or C1-4alkoxy, n3 is 0 or R3 is C1-6 alkyl or C1-4alkoxy and R4 is hydrogen, C 1-10 alkyl or C 1-10 alkoxy, as well as N-oxides of this compound, prodrugs of the drug, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 4 2. Savienojums pēc 1. punkta, kurā cikls A satur 5 cikla locekļus un cikls B satur 6 cikla locekļus un X1 un X5 ir blakus locekli oksazol-2-ilgrupā, 1 H-imidazol-2-iIgrupā vai tiazol-2-ilgrupā, kā arī šī savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis.A compound according to claim 1 wherein the ring A contains 5 ring members and the ring B contains 6 ring members and X 1 and X 5 are adjacent to the oxazol-2-yl group, 1H-imidazol-2-yl or thiazol-2-yl group. as well as N-oxides of this compound, prodrugs of the drug, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 3 vai tā aizsargātā atvasinājuma, iedarbību ar savienojumu (4):3 or a derivative thereof protected by a compound (4): 3- Savienojums pēc 2. punkta, proti, savienojums ar formulu (II):3- A compound according to claim 2, namely a compound of formula (II): kurā: pārtrauktās līnijas apzīmē neobligātās saites, kas var būt vai nebūt neatkarīgi viena no otras; katrs R2, neatkarīgi viens no otra, ir Ci^alkilgrupa, Ci^alkoksigrupa, halogēna atoms vai hidroksilgrupa; katrs R2, neatkarīgi viens no otra, ir Ci-ealkilgrupa, Ci^alkoksigrupa, halogēna atoms vai hidroksilgrupa; katrs R3, neatkarīgi viens no otra, ir Ci^alkilgrupa, Ci^alkoksigrupa, halogēna atoms vai hidroksilgrupa; X3 ir -CO- vai -CR7R8-; X8 ir -CH(R1)ni- vai -C(R1)m= , kur R1 ir amino(Ni^»)azolidinilgrupa, aminoiN^azolilgrupa, (N^azo-lidinilgrupa, (Ni^)azolilarupa, -NHCJNH)NR9R9, -C(NR9)R9, -C(NH)NHR , -C(NH)NR10R1“ vai -(CR"R11)NR10R10, kur katrs R9, neatkarīgi viens no otra, ir ūdeņraža atoms vai C-i^alkilgrupa un katrs R10, neatkarīgi viens no otra, ir Ci^alkilgrupa; X9 ir -CH(R4)- vai -C(R4)=, kur R4 ir -R12, -OR12, -N(R13)R12, -SR12, -SOR12, -S02R12, -S020R12, -S02-N(R13)R12, -N(R13)S02R12, -CO-R12, -COOR12, -CON(R13)R12, -N(R13)-CO-R12, -0C(0]N(R13)R12, vai -N(R13)COOR12, -(CH2)2N(R13)CON(Ri3)R12, -0P(0)(0Rld)0R12 -= -CON(R14)CH(COOH)R12. V. Savienojums pēc 3. punkta, kurā: 5 5 LV 12495 R1 ir ūdeņraža atoms vai Ci^alkilgrupa, R2 ir ūdeņraža atoms vai Ci^alkilgrupa, pie kam minētā aliklgrupa ir neobligāti aizvietota ar 1- 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkoksigrupa, hidroksilgrupa un sulfogrupa; R3 ir ūdeņraža atoms vai metilgrupa; R8 ir ūdeņraža atoms, metilgrupa vai hidroksilgrupa; X8 ir -CH(R1)ni-, kur R1 ir aminometilgrupa, 1-aminociklopropilgrupa, 2-aminoimidazol-1 -ilgrupa, 2-amino-1,1 -dimetiletilgrupa, imidazolilgrupa, tetrazolilgrupa, -(CH2)XNHC(NR9)R9, -(CH2)xNHC(NH)NR9Rf un -C(NR9)R9, kur katrs R9, neatkarīgi viens no otra, ir ūdeņraža atoms vai metilgrupa; vai arī X8 ir -N(R1)nr, kur R1 ir -C(NR9)R9, -C(NH)NHR10- vai -C(NH)-NR10R10, kur katrs R9, neatkarīgi viens no otra, ir ūdeņraža atoms vai metilgrupa un katrs R10 ir metilgrupa, pie kam jebkura R1 ietilpstošā alifātiskā vai alicikliskā grupa ir neobligāti aizvietota ar 1 - 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: metilsulfonilgrupa un karboksilgrupa; X9 ir -C(R4)=, kur R4 ir -R12, -OR12, -CO-R12, -COOR12, -CON(R13)R12 vai -CON(R14)CH(COOH)R12, kur R13 un R14, neatkarīgi viens no otra, ir ūdeņraža atoms vai Ci^alkilgrupa; R12 ir -R15 vai -X2-(R15)„15. kur X2 ir Ci.i0alkilēngrupa vai hetero-CMoalkilēngrupa un katrs R , neatkarīgi viens no otra, ir ūdeņraža atoms, Ce-uarilgrupa, Ca-udkloalkilgrupa, policiklo-Ce-uarilgrupa, heteropoliciklo-Ce-uarilgrupa, hetero-C3-i4Ciklo-alkiigrupa vai hetero-Cs-uarilgrupa; pie tam jebkura R3 ietilpstošā alifātiskā vai alicikliskā grupa in neobligāti aizvietota ar 1- 5 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: C-Malkoksigrupa, C^alkoksikarbonilgrupa, aminogrupa, karbamoilgrupa, karboksilgrupa un hidroksilgrupa; jebkura R15 ietilpstošā aromātiskā grupa ir neobligāti aizvietota ar 1 - 3 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: C-Malkilgrupa, C-Malkoksigrupa, Ci^alkoksikarbonilgrupa, karbamoil-grupa, karboksilgrupa, ciāngrupa, C^cikloalkiloksigrupa, halogēna atoms, hetero-Ci. 8alkilgrupa, hidroksilgrupa, hetero-C-Malkilkarbonil-grupa, hetero-Cs-uarilgrupa un trifluormetilgrupa, kā arī šī savienojuma N-oksīdi, zāju priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis. 1 Savienojums pēc 4. punkta, kurā: 2 A kopā ar B veido 4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilgrupu, 3 kur n2 ir 0, R1 ir -C(NR9)R9 un R1 ir ūdeņraža atoms, vai arī 6 A kopā ar B veido 1H-benzimiazol-2-ilgrupu vai 4,5,6,7-tetrahidro-1H-benzimiazol-2-ilgrupu, kur R1 ir aminometilgrupa vai guanidīngrupa un katrs R2, neatkarīgi viens no otra, ir halogēna atoms vai hidroksilgrupa; C ir 4,5,6,7-tetrahidro-1H-imidazo[4,5-clpiridin-2-ilgrupa vai 1H-benzimiazol-2-ilgrupa, kur R4 ir -C(0)X6-R , -C(0)0X® vai -C(0)NHX6-R15, kur X6 ir Ci^alkilēngrupa vai C2^heteroalkilēngrupa un R15 ir C6-ioarilgrupa, C6-ioariloksigrupa, C6-iopolicikloarilgrupa, C5.i0hetero-ariigrupa, C5.ioheteroariloksigrupa, vai C6.i4heteropolicikloarilgrupa; pie tam R15 ietilpstošā aromātiskā grupa ir neobligāti aizvietota ar 1 - 3 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkilgrupa, CMalkoksigrupa, Ci^alkoksikarbonilgrupa, karboksilgrupa, karbamoilgrupa, halogēna atoms, hidroksilgrupa un tetrazol-1-ilgrupa, kā arī šī savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis.wherein: broken lines denote optional links that may or may not be independent of each other; each R 2, independently of one another, is C 1-6 alkyl, C 1-4 alkoxy, halo, or hydroxy; each R 2, independently of one another, is C 1-6 alkyl, C 1-4 alkoxy, halo, or hydroxy; each R 3, independently of one another, is C 1-6 alkyl, C 1-4 alkoxy, halo, or hydroxy; X3 is -CO- or -CR7R8-; X 8 is -CH (R 1) ni- or -C (R 1) m = where R 1 is amino (N 1 -) azolidinyl, amino N - azolyl, (N 1 - azo-lidinyl, (N 1 -) azolaryl, -NHC 1 NH) NR 9 R 9 , -C (NR9) R9, -C (NH) NHR, -C (NH) NR10R1 'or - (CR " R11) NR10R10 wherein each R9, independently of one another, is hydrogen or C1-6alkyl and each R10 is hydrogen. , independently of one another, is C 1-6 alkyl; X9 is -CH (R4) - or -C (R4) = wherein R4 is -R12, -OR12, -N (R13) R12, -SR12, -SOR12, -SO2R12, -SO2R12, -SO2-N (R13) ) R12, -N (R13) SO2R12, -CO-R12, -COOR12, -CON (R13) R12, -N (R13) -CO-R12, -OC (O] N (R13) R12, or -N ( R13) COOR12, - (CH2) 2N (R13) CON (R13) R12, -OP (O) (ORld) 0R12 - = -CON (R14) CH (COOH) R12. 12495 R1 is hydrogen or C1-6alkyl, R2 is hydrogen or C1-6alkyl, wherein said alkyl is optionally substituted with 1 to 2 substituents independently selected from C1-4 alkoxy. , hydroxyl and sulpho; R3 is hydrogen or methyl; R8 is hydrogen, methyl or hydroxy; X8 is -CH (R1) ni-, wherein R1 is aminomethyl, 1-aminocyclopropyl, 2-aminoimidazol-1-yl, 2- amino-1,1-dimethylethyl, imidazolyl, tetrazolyl, - (CH2) XNHC (NR9) R9, - (CH2) xNHC (NH) NR9Rf and -C (NR9) R9, wherein each R9, independently of one another, is hydrogen atom or methyl; also X 8 is -N (R 1) n, wherein R 1 is -C (NR 9) R 9, -C (NH) NHR 10 - or -C (NH) -NR 10 R 10, wherein each R 9, independently of one another, is hydrogen or methyl and each R10 is methyl, wherein any aliphatic or alicyclic group of R1 is optionally substituted with 1 to 2 substituents independently selected from the group consisting of methylsulfonyl and carboxyl; X9 is -C (R4) = wherein R4 is -R12, -OR12, -CO-R12, -COOR12, -CON (R13) R12 or -CON (R14) CH (COOH) R12, wherein R13 and R14 are independently are hydrogen or C 1-6 alkyl; R 12 is -R 15 or -X 2 - (R 15) "15. wherein X 2 is C 1-10 alkylene or hetero-CMoalkylene and each R independently of one another is hydrogen, C 1-6 aryl, C 1 -C 6 alkyl, polycycloalkyl, heteropolicyclo-C 1-6 alkyl, hetero-C 3-14 cycloalkyl or hetero-C 6 -aryl; furthermore, an aliphatic or alicyclic group of any R3 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C-alkoxy, C 1-4 alkoxycarbonyl, amino, carbamoyl, carboxyl, and hydroxy; any of the R15 aromatic groups is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C-Malkyl, C-alkoxy, C 1-6 alkoxycarbonyl, carbamoyl, carboxyl, cyano, C 1-4 cycloalkyloxy, halogen, hetero-Ci. 8-alkyl, hydroxy, hetero-C-alkylcarbonyl, hetero-C 6 -aryl and trifluoromethyl, as well as N-oxides of this compound, prodrugs, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts. A compound according to claim 4, wherein: 2A together with B forms 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl, 3 wherein n2 is 0, R1 is - C (NR 9) R 9 and R 1 are hydrogen, or 6 A together with B form 1H-benzimiazol-2-yl or 4,5,6,7-tetrahydro-1H-benzimiazol-2-yl, wherein R 1 is aminomethyl or guanidine and each R2, independently of one another, is halogen or hydroxy; C is 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl or 1H-benzimiazol-2-yl, wherein R4 is -C (O) X6-R, -C (0) ) 0X ® or -C (O) NHX 6 -R 15, wherein X 6 is C 1-6 alkylene or C 2-4 heteroalkylene and R 15 is C 6-10 aryl, C 6-10 aryloxy, C 6 iopolicycloaryl, C 5-10 heteroaryl, C 5-10 heteroaryloxy, or C 6 .4heteropolicycloalkyl; the R15 aromatic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, carboxyl, carbamoyl, halogen, hydroxy and tetrazol-1 as well as N-oxides of this compound, prodrugs of the drug, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 6. Savienojums pēc 5. punkta, kurā A kopā ar B veido 1H-benzimiazol-2-ilgrupu un katrs R , neatkarīgi viens no otra, ir halogēna atoms vai hidroksilgrupa, kā arī šī savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis.The compound of claim 5, wherein A together with B forms a 1H-benzimiazol-2-yl group, and each R, independently of one another, is a halogen atom or a hydroxyl group, as well as the N-oxides of this compound, prodrugs, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts. 7. Savienojums pēc 6. punkta, kurā n ir 0, kā arī šī savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis.A compound according to claim 6, wherein n is 0 as well as N-oxides of this compound, prodrugs of the drug, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 8. Savienojums pēc 7. punkta, kas ņemts no rindas, kurā ietilpst: 2-(2-{2[1-(4,6,7-trifluor-1H-benzimidazol-2-il)etiI]-3-metil-3H-benzimidazol-5-il- karbonilamino}etoksi)benzoskābe; 2-(2-{2[1-(5,6-difluor-1H-benzimidazol-2-il)etil]-3-metil-3H-benzimidazol-5-il- karbonilamino}etoksi)benzoskābe; 2-(2-{2[1-(5-hidroksi-1H-benzimidazol-2-il)etil]-3-metil-3H-benzimidazol-5-il-karbonilamino}etoksi)benzoskābes butilesteris; 2-(2-{2[1-(5-hidroksi-1H-benzimidazol-2-il)etil]-3-metil-3H-benzimidazol-5-il-karbonilamino}etoksi)benzoskābes propilesteris; 2-(2-{2[1-(5-hidroksi-1H-benzimidazol-2-il)etil]-3-metil-3H-benzimidazol-5-il-karbonilamino}etoksi)benzoskābes izobutilesteris, kā arī šo savienojumu N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis. 7 7 LV 124958. A compound according to claim 7, taken from the group consisting of: 2- (2- {2- [1- (4,6,7-trifluoro-1H-benzimidazol-2-yl) ethyl] -3-methyl- 3H-benzimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5,6-Difluoro-1H-benzimidazol-2-yl) ethyl] -3-methyl-3H-benzimidazol-5-ylcarbonylamino} ethoxy) benzoic acid; 2- (2- {2- [1- (5-Hydroxy-1H-benzimidazol-2-yl) ethyl] -3-methyl-3H-benzimidazol-5-ylcarbonylamino} ethoxy) benzoic acid butyl ester; 2- (2- {2- [1- (5-Hydroxy-1 H -benzimidazol-2-yl) ethyl] -3-methyl-3 H -benzimidazol-5-ylcarbonylamino} ethoxy) benzoic acid propyl ester; 2- (2- {2- [1- (5-Hydroxy-1H-benzimidazol-2-yl) ethyl] -3-methyl-3H-benzimidazol-5-ylcarbonylamino} ethoxy) benzoic acid isobutyl ester, and this compound N -oxides, drug precursors, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 7 7 EN 12495 9. Savienojums pēc 5. punkta, kurā R1 ir guanidīngrupa vai aminometilgrupa, kā arī šī savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis.The compound of claim 5, wherein R 1 is guanidine or aminomethyl, as well as the N-oxides of this compound, prodrugs of the drug, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts. 10. Savienojums pēc 9. punkta, kas ņemts no rindas, kurā ietilpst: 2-(5-guanidino-1H-benzimidazol-2-ilmetil)-3-metil-N-(2-naft-1-iletil)-3H-benz- imidazol-5-karboksamīds; 2-(3-{2-[1-(5-guanidino-1H-benzimidazol-2-il)etil]-1,4,6,7-tetrahidroimidazo-[4,5-c]piridin-5-ilkarboniIamino}propoksi)benzoskābes etilesteris; 2-(5-guanidino-1H-benzimidazol-2-ilmetil)-3-(2,3-dihidroksipropil)-N-(2-naft-1- iletil)-3H-benzimidazol-5-karboksamīds; 2-(5-guanidino-1H-benzimidazol-2-ilkarbonil)-3-(2,3-dihidroksipropil)-N-(2-naft- 1- iletil)-3H-benzimidazol-5-karboksamīds; 2- (5-guanidino-1H-benzimidazol-2-ilmetil)-3-(3-hidroksipropil)-N-(2-naft-1-il-etil)-3H-benzimidazol-5-karboksamīds; 2-(5-guanidino-1H-benzimidazol-2-ilmetil)-3-(2-hidroksietil)-N-(2-naft-1-iletil)- 3H-benzimidazol-5-karboksamīds; 2-[1-(5-guanidino-1H-benzimidazol-2-il)etil]-N-[2-(2-karbamoilfenoksi)etil]-3- metil-3H-benzimidazol-5-karboksamīds; 2-[1-(5-guanidino-1H-benzimidazol-2-il)etil]-N-[2-(2-karbamoil-4-hlorfenoksi)- etil]-3-metil-3H-benzimidazol-5-karboksamīds; 4- hlor-2-[2-({2-[1-(5-guanidino-1H-benzimidazol-2-il)etil]-3-metil-3H-benzimid-azol-5-ilkarbonil}amino)etoksiJbenzoskābe; 5- hIor-2-[2-({2-[1-(5-guanidino-1H-benzimidazol-2-il)etil]-3-metil-3H-benzimid-azol-5-ilkarbonil}amino)etoksi]benzoskābe; 2-(5-aminometil-1H-benzimidazol-2-ilmetil)-3-metil-N-(2-naft-1-iletil)-3H-benz- imidazol-5-karboksamīds; 2-(5-aminometil-4,5,6,7-tetrahidro-1H-benzimidazol-2-ilmetil)-3-metil-N-(2- naft-1-iletil)-3H-benzimidazol-5-karboksamīds, kā arī šo savienojumu N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālis.10. The compound of claim 9, taken from the group consisting of: 2- (5-guanidino-1H-benzimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H- benzimidazole-5-carboxamide; 2- (3- {2- [1- (5-guanidino-1H-benzimidazol-2-yl) ethyl] -1,4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-ylcarbonylamino} propoxy) benzoic acid ethyl ester; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-ylethyl) -3H-benzimidazole-5-carboxamide; 2- (5-guanidino-1H-benzimidazol-2-ylcarbonyl) -3- (2,3-dihydroxypropyl) -N- (2-naphth-1-yl-ethyl) -3H-benzimidazole-5-carboxamide; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (3-hydroxypropyl) -N- (2-naphth-1-yl-ethyl) -3H-benzimidazole-5-carboxamide; 2- (5-guanidino-1H-benzoimidazol-2-ylmethyl) -3- (2-hydroxyethyl) -N- (2-naphth-1-ylethyl) -3H-benzimidazole-5-carboxamide; 2- [1- (5-guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoylphenoxy) ethyl] -3-methyl-3H-benzimidazole-5-carboxamide; 2- [1- (5-Guanidino-1H-benzoimidazol-2-yl) ethyl] -N- [2- (2-carbamoyl-4-chlorophenoxy) ethyl] -3-methyl-3H-benzimidazole-5-carboxamide ; 4-Chloro-2- [2 - ({2- [1- (5-guanidino-1 H -benzimidazol-2-yl) ethyl] -3-methyl-3 H -benzimidazol-5-ylcarbonyl} amino) ethoxybenzoic acid; 5-Chloro-2- [2 - ({2- [1- (5-guanidino-1H-benzimidazol-2-yl) ethyl] -3-methyl-3H-benzimidazol-5-ylcarbonyl} amino) ethoxy] benzoic acid; 2- (5-Aminomethyl-1H-benzimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzimidazole-5-carboxamide; 2- (5-Aminomethyl-4,5,6,7-tetrahydro-1 H -benzimidazol-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3 H -benzimidazole-5-carboxamide as well as N-oxides of these compounds, prodrugs of the drug, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 11. Savienojums pēc 5. punkta, kurā A kopā ar B veido 4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilgrupu un R1 ir -C(NH)R9, kā arī šī 8 savienojuma N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālīs.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 R1 is -C (NH) R9 as also the N-oxides of this compound, drug precursors, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts. 12. Savienojums pēc 11. punkta, kas ņemts no rindas, kurā ietilpst: 2-[2-(2-{1-[5-(1-iminoetil)-4,5I6I7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3- metil-3H-benzimidazol-5-ilkarbonilamino)etoksi]benzoskābe; 2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil- N-(2-naft-1-iletil)-3H-benzimidazol-5-karboksamīds; 2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilkarbonil]-3- metil-N-(2-naft-1-iletil)-3H-benzimidazol-5-karboksamīds; 2-(5-iminometil-4,5I6I7-tetrahidro-1H-imidazo[4,5-cjpiridin-2-ilmetil)-3-metil-N- (2-naft-1-iletil)-3H-benzimidazol-5-karboksamTds; 2-[5-(1-iminoetil)-4f5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil- N-(2-hidroksi-2-naft-1-iletil)-3H-benzimidazol-5-karboksamīds; 2-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil- N-[2-(2-hidroksinaft-1-il)etil]-3H-benzimidazol-5-karboksamīds; 2-[5-(1-iminoetil)-4l5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-ilmetil]-3-metil· N-[2-(4-hidroksinaft-1-il)etil]-3H-benzimidazol-5-karboksamīds; 2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil- N-(2-naft-1-iletil)-3H-benzimidazol-5-karboksamīds; 2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil-3H-benzimidazol-5-ilkarbonilamino)etoksi]benzoskābes etilesteris; 2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro1H-imidazo[4,5-c]piridin-2-il]etil}-3- (2-metoksietil)-3H-benzimidazol-5-ilkarbonilamino)etoksi]benzoskābe; 2-[2-(2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro1H-imidazo[4,5-c]piridin-2-il]etil}- l^.ej-tetrahidroimidazo^.S-cjpiridin-S-ilkarbonilaminoJetoksļbenzoskābes etilesteris; 2-{1-[5-(1-iminoetil)-4,5,6,7-tetrahidro1H-imidazo[4,5-c]piridin-2-il]etil}-3-metil- N-[2-(2-tetrazolilfenoksi)etil]-3H-benzimidazol-5-karboksamīds; kā arī šo savienojumu N-oksīdi, zāļu priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālīs.12. The compound of claim 11, taken from the group consisting of: 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4.5- c] pyridin-2-yl] ethyl} -3-methyl-3H-benzimidazol-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-yl) -ylethyl) -3H-benzimidazole-5-carboxamide; 2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylcarbonyl] -3-methyl-N- (2-naphth-1-yl) -ylethyl) -3H-benzimidazole-5-carboxamide; 2- (5-iminomethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl) -3-methyl-N- (2-naphth-1-ylethyl) -3H-benzimidazol-5-one carboxamtds; 2- [5- (1-Iminoethyl) -4f5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- (2-hydroxy-2-naphthyl) -1-ylethyl) -3H-benzimidazole-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] -3H-benzimidazole-5-carboxamide; 2- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-ylmethyl] -3-methyl-N- [2- (4-hydroxynaphthalene) 1-yl) ethyl] -3H-benzimidazole-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) -3H-benzimidazole-5-carboxamide; 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3-methyl -3H-benzimidazol-5-ylcarbonylamino) ethoxy] benzoic acid ethyl ester; 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl] ethyl} -3- ( 2-methoxyethyl) -3H-benzimidazol-5-ylcarbonylamino) ethoxy] benzoic acid; 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1 H -imidazo [4,5- c] pyridin-2-yl] ethyl} -1 H 2- (1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-2-yl) ej-tetrahydroimidazo [4,5-b] pyridin-2-ylcarbonylamino; il] ethyl} -3-methyl-N- [2- (2-tetrazolylphenoxy) ethyl] -3H-benzimidazole-5-carboxamide; and N-oxides of these compounds, drug precursors, protected derivatives, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts. 13. Savienojums pēc 12. punkta, proti, 2-[2-(2-{1 -[5-(1 -iminoetil)-4,5,6,7-tetrahidro-1H-imidazo[4l5-c]piridin-2-il]etil}-3-metil-3H-benzimidazol-5-ilkarbonilamino)etoksi]benzoskābe, kā arī šī savienojuma N-oksīdi, zāļu 9 9 LV 12495 priekštečvielas, aizsargātie atvasinājumi, individuāli izomēri, izomēru maisījumi un farmaceitiski pieņemamās sālīs.13. A compound according to claim 12, which is 2- [2- (2- {1- [5- (1-iminoethyl) -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine] 2-yl] ethyl} -3-methyl-3H-benzimidazol-5-ylcarbonylamino) ethoxy] benzoic acid, and N-oxides of this compound, prodrugs of 9 9 EN 12495, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof . 14. Farmaceitiskā kompozīcija, kas ietver savienojumu pēc 1. punkta kopā ar farmaceitiski pieņemamu nesēju.A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier. 15. Farmaceitiskā kompozīcija pēc 14. punkta, kas papildus ietver β-adrenerģiski aktīvu savienojumu.15. The pharmaceutical composition of claim 14, further comprising a β-adrenergic active compound. 16. Farmaceitiskā kompozīcija pēc 14. punkta, kurā minētais β-adrenerģiski aktīvais savienojums ir ņemts no rindas, kas ietver albuterolu, terbutalīnu, formoterolu, fenoterolu un prenalīnu.A pharmaceutical composition according to claim 14, wherein said β-adrenergic active compound is taken from a row comprising albuterol, terbutaline, formoterol, phenoterol and prenaline. 17. Farmaceitiskā kompozīcija pēc 14. punkta, kas ietver farmaceitiski pieņemamu nesēju ārīgai lietošanai.A pharmaceutical composition according to claim 14, comprising a pharmaceutically acceptable carrier for external use. 18. Farmaceitiskā kompozīcija pēc 14. punkta, kas ietver farmaceitiski pieņemamu nesēju iekšķīgai lietošanai.A pharmaceutical composition according to claim 14, comprising a pharmaceutically acceptable oral carrier. 19. Farmaceitiskā kompozīcija pēc 14. punkta, kas ietver farmaceitiski pieņemamu nesēju aerosola formai.A pharmaceutical composition according to claim 14, comprising a pharmaceutically acceptable carrier for aerosol form. 20. Aerosola ierīce, kas satur savienojumu pēc 1. punkta, šķīdinātu farmaceitiski pieņemamā nesējā vai sausu savienojuma pulveri, kā arī līdzekli minētā šķīduma vai sausā pulvera pārvēršanai inhalācijai piemērotā aerosolā.An aerosol device comprising a compound of claim 1 dissolved in a pharmaceutically acceptable carrier or dry compound powder as well as a means for converting said solution or dry powder into an aerosol suitable for inhalation. 21. Savienojuma pēc 1. punkta pielietojums tāda medikamenta ražošanai, kas izmantojams immūnoloģiski izsauktas zīdītāju iekaisuma slimības ārstēšanai.The use of a compound according to claim 1 for the manufacture of a medicament for use in the treatment of an immunologically induced mammalian inflammatory disease. 22. Savienojuma pēc 1. punkta pielietojums tāda medikamenta ražošanai, kas izmantojams zīdītāju reimātiskā artrīta ārstēšanai.Use of a compound according to claim 1 for the manufacture of a medicament for use in the treatment of rheumatic arthritis in mammals. 23. Savienojuma pēc 1. punkta pielietojums tāda medikamenta ražošanai, kas izmantojams zīdītāju konjunktivīta ārstēšanai.Use of a compound according to claim 1 for the manufacture of a medicament for use in the treatment of conjunctivitis in mammals. 24. Savienojuma pēc 1. punkta pielietojums tāda medikamenta ražošanai, kas izmantojams zīdītāju sincitiālā vīrusa infekciju ārstēšanai.The use of a compound according to claim 1 for the manufacture of a medicament for use in the treatment of mammalian syncytial virus infections. 25. Savienojuma pēc 1. punkta pielietojums tāda medikamenta ražošanai, kas izmantojams immūnoloģiski izsauktas zīdītāju elpošanas ceļu iekaisuma slimības ārstēšanai.Use of a compound of claim 1 for the manufacture of a medicament for use in the treatment of an inflammatory disease of the respiratory tract of an immunologically excited mammal. 26. Paņēmiens savienojuma ar formulu (I):26. A method for a compound of formula (I): 10 kurā: n1 ir 0 vai 1; n2 ir 0, 1, 2, 3 vai 4; n3 ir 0, 1, 2, 3 vai 4; A kopā ar B veido kondensētu heterobiciklisku grupu, kurā ir 8 -12 cikla atomi, pie tam katrā no cikliem ir 5 - 7 cikla atomi un katrs no cikla atomiem var būt heteroatoms; X1 un X2 ir blakusesošie cikla atomi aromātiskā ciklā un X1 ir heteroatomu ietverošs cikla loceklis no rindas: -N=, -NR5-, -0- un -S-, kur R5 ir ūdeņraža atoms, Ci^alkilgrupa vai hetero-C2-6alkilgrupa; C ir kondensēta heteropolicikliska grupa, kas saur 8-18 cikla atomus, pie tam katrā no cikliem ir 5 - 7 cikla atomi un katrs no cikla atomiem var būt heteroatoms; X4 un X5 ir blakusesošie cikla atomi aromātiskā ciklā un X5 ir heteroatomu ietverošs cikla loceklis no rindas: -N=, -NR6-, -0- un -S-, kur R6 ir ūdeņraža atoms, Ci.8alkilgrupa vai hetero-C2-i2alkilgrupa, pie tam minētās grupas neobligāti aizvietotas ar 1 - 2 aizvietotājiem, kas neatkarīgi viens no otra, ir ņemti no rindas: Ci-6alkanoiloksigrupa, Ci-6alkilaminogrupa, di-iCļ^alkiljaminogrupa, tri-(Ci^alkil)amonija grupa, Ci^alkilkarbamoilgrupa, di-(Ci_6alkii)-karbamoilgrupa, Ci^alkoksigrupa, Ci^alkoksikarbonilgrupa, Ci^alk-oksisulfonilgrupa, aminogrupa, karboksilgrupa, karbamoilgrupa, C6-i4arilgrupa, halogēna atoms, hetero-C5.uarilgrupa, hidroksilgrupa un sulfogrupa, vai arī R6 ir tāds, kā aprakstīts zemāk; kā arī jebkādi grupas C karbocikliskie ketona, tioketona vai iminoketona atvasinājumi; X3 jr -o-, -S-, -SO-, -S02-, -CO-, -NR7- vai -CR7R8-, kur R7 ir ūdeņraža atoms, Cļ^alkilgrupa, hetero-C2-i2alkilgrupa, vai kopā ar R6 veido C2-4alkilēngrupu; R8 ir ūdeņraža atoms, Ci^alkilgrupa vai hidroksilgrupa, vai kopā ar R7 veido C2-6alkilēngrupu vai Ci^alkil-idēngrupu, pie tam jebkura no alifātiskajām vai alicikliskajām R7 un/vai R8 grupām ir neobligāti aizvietota ar 1 - 3 aizvietotājiem no rindas: C-t-ealkilaminogrupa, di-(Ci^alkil)aminogrupa, tri-(Ci^alkil)amonija grupa, Ci^alkoksigrupa, Ci^alkoksikarbonilgrupa, Ci-ealkanoiloksi-grupa, aminogrupa, karboksilgrupa, karbamoilgrupa, Ci^alkilkarbamoil-grupa, di-(Ci^alkil)karbamoilgrupa, halogēna atoms un hidroksilgrupa; R1 ir amino(Ni^)azolidinilgrupa, aminoļNļ-^azolilgrupa, (N-Mjazo-lidinilgrupa, (N^jazolilgrupa, karbamoilgrupa, ciāngrupa, -(CH2)xNH-C(NFr)R9, -(CH2)xNHC(NH)NR9R9, -C(NR9)R9, -C(NH)NHRlb, -C(NH)-NR10R10 vai -(CR11R11)yNH2 un ir pievienots jebkuram no cikla B atomiem, kuram ir brīva valence, pie kam X ir 0 vai 1, y ir 0, 1,2 vai 3, katrs R9, neatkarīgi viens no otra, ir ūdeņraža atoms vai Ci^alkilgrupa, katrs R10, neatkarīgi viens no otra, ir Ci^alkilgrupa un katrs R11, neatkarīgi viens no otra, ir ūdeņraža atoms, Ci.3alkilgrupa vai arī kopā ar otru R11 un oglekļa atomu, kam tie ir pievienoti, veido ciklopropilgrupu, pie tam jebkura no R1 ietilpstošām alifātiskajām vai 11 LV 12495 alicikliskajām grupām grupām ir neobligāti aizvietota ar 1 - 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkoksikarbonilgrupa, Ci-ealkanoiloksigrupa, karboksilgrupa, karb-amoilgrupa, Cļ^alkilkarbarnoilgrupa, di-(Ci^alkil)karbamoilgrupa, C-i^alkilsulfonilgrupa un hidroksilgrupa; katrs R2, neatkarīgi viens no otra, ir Ci^alkilgrupa, Ci^alkoksikarbonil-grupa, Ci-ealkanoiloksigrupa, Ci^alkoksigrupa, karboksilgrupa, karbamoilgrupa, Ci^alkilkarbamoilgrupa, di-(Ci^alkil)karbamoilgrupa, Ci.6alkilsulfiniigrupa, Ci^alkilsulfonilgrupa, C-i-ealkiltiogrupa, halogēna atoms vai hidroksilgrupa, un ir pievienots pie jebkura no cikla B atomiem, kuram ir brīva valence, pie tam jebkura no alifātiskajām grupām, kas ietilpst R2 ir neobligāti aizvietota ar 1 - 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci^alkoksi-karbonilgrupa, Ci^alkanoiloksigrupa, karboksilgrupa, karbamoilgrupa, C^alkilkarbamoilgrupa, dKC^alkiOkarbamoilgrupa, Ci^alkilsulfonil-grupa un hidroksilgrupa; katrs R3, neatkarīgi viens no otra, ir Ci-ealkilgrupa, Ci^alkoksigrupa, Ci^alkiltiogrupa, ciāngrupa, halogēna atoma, perhalogenēta C^alkil-grupa vai hidroksilgrupa, un ir pievienota pie jebkura no cikla C atomiem, kam ir brīva valence; R4 ir -R12, -OR12, -N(R13)R12, -SR12, -SOR12, -S02R12, -S020R12, -S02-N(R13)R12, -N(R13)S02R12, -CO-R12, -COOR12, -CON(R13)R12, -N(R13)-CO-R12, -0C(0)N(R13JR12, -N(R13)COOR12, -(CH2)2N(R13)CO- N(R13)R12, -0P(0)(0R13)0R12 vai -CON(R14)CH(COOH)R12, un ir •pievienots pie jebkura no cikla C atomiem, kuram ir brīva valence, z ir 0, 1 vai 2, R12 ir R15 vai -X6-(R15)nis. kur n15 ir 1 vai 2, X6 ir Ci-ioalkilēngrupa, ciklo-C3-ioalkilēngrupa, hetero-C2-ioalkilēngrupa vai heterociklo-C3.ioalkilēngrupa un katrs no R15, neatkarīgi viens no otra, ir ūdeņraža atoms, Ce-uarilgrupa, C3-uCikloalkilgrupa, Ce-upolicikloarilgrupa, hetero-Ce-upolicikloarilgrupa, hetero-Cs-udkloalkilgrupa, hetero-Ce-uarilgrupa, vai arī kāda tā ir aprakstīta zemāk; R13 ir ūdeņraža atoms, Ci^alkilgrupa vai hetero-C2-6alkilgrupa; R14 ir ūdeņraža atoms, Ci^alkilgrupa, vai arī kopā ar X6 un R15 veido C3_4alkilēngrupu; jebkura alifātiskā vai alicikliskā grupa, kas ietilpst R4 ir neobligāti aizvietota ar 1 - 5 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Ci-ealkilgrupa, Ci^alkilaminogrupa, di-iCļ^alkiljaminogrupa, Ci-ealkilkarbamoilgrupa, di-(Ci^alkil)karbamoilgrupa, Ci^alkoksigrupa, Ci^alkoksikarbonilgrupa, Ci^alkilsulfinilgrupa, C^alkilsulfonilgrupa, Ci-ealkiltiogrupa, aminogrupa, C6.ioarilsulfonilgrupa, karbamoilgrupa, karboksilgrupa, ciāngrupa, guanidīngrupa, halogēna atoms, hidroksilgrupa, merkaptogrupa un ureīdgrupa; 12 jebkura aromātiskā grupa, kas ietilpst R15, ir neobligāti aizvietota ar 1 -3 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: ciāngrupa, guanidīngrupa, halogēna atoms, halogēnaizvietota Ci.ealkilgrupa, -R16, -OR16, -SR16, -SOR16, -S02R16, -S020R16, -S02-N(R13)R , -CO-R16, -COOR16 un -CON(R13)R16, kur R13 nozīmes ir jau minētās un R16 ir ūdeņraža atoms, ar aizvietotāju, kas ņemts no rindas: Ci^alkilaminogrupa, di-(Ci^alkil)aminogrupa, tri-(Ci^alkil)amonija grupa, Ci-ealkilkarbamoilgrupa, di-(Ci-6alkil)karbamoilgrupa, Ci^alk-oksikarbonilgrupa, Ci^alkoksisulfonilgrupa, aminogrupa, karboksil-grupa, karbamoilgrupa, hidroksilgrupa vai sulfogrupa, neobligāti monoaizvietota Ci-galkilgrupa, C3^cikloalkilgrupa, hetero-Ci^alkilgrupa, hetero-Cs^arilgrupa, hetero-C^cikloalkilgrupa vai fenilgrupa, ar tādu noteikumu, ka n1 nav 0, kad n2 ir 0 vai R2 ir Ci-ealkilgrupa vai Ci.6alkoksigrupa, n3 ir 0 vai R3 ir Ci-ealkilgrupa vai Ci-ealkoksigrupa un R4 ir ūdeņraža atoms, Ci-ioalkilgrupa vai C-M0alkoksigrupa, kā arī šī savienojuma N-oksīdu, zāļu priekštečvielu, aizsargāto atvasinājumu, individuālu izomēru, izomēru maisījumu un farmaceitiski pieņemamu sāļu iegūšanai, kas ietver: (a) savienojuma ar formulu (I):Wherein: n1 is 0 or 1; n2 is 0, 1, 2, 3 or 4; n3 is 0, 1, 2, 3 or 4; A together with B forms a fused heterobicyclic group having 8 to 12 ring atoms, each having 5 to 7 ring atoms and each of the ring atoms may be a heteroatom; X1 and X2 are adjacent ring atoms in the aromatic ring and X1 is a heteroatom-containing member of the ring: -N =, -NR5-, -O-, and -S-, where R5 is hydrogen, C1-4alkyl or hetero-C2-6alkyl ; C is a fused heteropolicyclic group that holds 8-18 ring atoms, each having 5 to 7 ring atoms in each ring and each of the ring atoms may be a heteroatom; X4 and X5 are adjacent ring atoms in the aromatic ring and X5 is a heteroatom-containing member of the ring: -N =, -NR6-, -O-, and -S-, wherein R6 is hydrogen, C1-8 alkyl, or hetero-C2-2alkyl furthermore, said groups are optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-6alkanoyloxy, C1-6alkylamino, di-C1-4alkylamino, tri- (C1-4alkyl) ammonium, C1-6alkyl; alkylcarbamoyl, di- (C1-6alkyl) carbamoyl, C1-4alkoxy, C1-6alkoxycarbonyl, C1-6alkoxysulfonyl, amino, carboxyl, carbamoyl, C6-4aryl, halogen, hetero-C5aryl, hydroxyl, and sulfo, or R6 is as described below; as well as any carbocyclic ketone, thioketone or iminocetone derivatives of Group C; X3 jr -o-, -S-, -SO-, -SO2-, -CO-, -NR7-, or -CR7R8-, wherein R7 is hydrogen, C1-4alkyl, hetero-C2-12alkyl, or together with R6 forms a C 2-4 alkylene group; R 8 is hydrogen, C 1-6 alkyl or hydroxy, or together with R 7 forms a C 2-6 alkylene group or a C 1-6 alkylidene group, furthermore any of the aliphatic or alicyclic R 7 and / or R 8 groups is optionally substituted with 1 to 3 substituents from the row: C 1-6 alkylamino, di- (C 1-4 alkyl) amino, tri- (C 1-6 alkyl) ammonium, C 1-6 alkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkanoyloxy, amino, carboxyl, carbamoyl, C 1-6 alkylcarbamoyl, di - (C 1-6 alkyl) carbamoyl, halogen and hydroxy; R 1 is amino (N 1 -) azolidinyl, amino-N-n-azolyl, (N-Meso-lidinyl, (N 4 -Solzolyl, carbamoyl, cyano, - (CH 2) x NH-C (NFr) R 9, - (CH 2) x NHC (NH) NR9R9, -C (NR9) R9, -C (NH) NHR1b, -C (NH) -NR10R10, or - (CR11R11) yNH2 and attached to any of the ring B atoms having free valence, wherein X is 0 or 1 , y is 0, 1, 2 or 3, each R 9, independently of one another, is hydrogen or C 1-4 alkyl, each R 10, independently of one another, is C 1-6 alkyl, and each R 11 is independently hydrogen atom, C 1-3 alkyl or together with the other R 11 and the carbon atom to which they are attached form a cyclopropyl group, and any of the aliphatic or R 1 alcyclic groups of R 1 is optionally substituted with 1 to 2 substituents independently of one another. from each other, taken from the group consisting of C 1-6 alkoxycarbonyl, C 1-6 alkanoyloxy, carboxyl, carbamoyl, C 1-4 alkylcarbarnoyl, di- (C 1-4 alkyl) carbamoyl, C 1-4 alkylsulfonyl each R2 independently of one another is C1-6alkyl, C1-6alkoxycarbonyl, C1-6alkanoyloxy, C1-4alkoxy, carboxyl, carbamoyl, C1-4alkylcarbamoyl, di- (C1-4alkyl) carbamoyl, C1-6alkyl; 6alkylsulfinyl, C1-4alkylsulfonyl, C1-6alkylthio, halogen or hydroxyl, and attached to any of the B-atoms in the ring having free valence, any of the aliphatic groups included in R2 being optionally substituted with 1 to 2 substituents , independently of one another, are taken from the group consisting of C 1-6 alkoxy-carbonyl, C 1-4 alkanoyloxy, carboxyl, carbamoyl, C 1-6 alkylcarbamoyl, dCC 1-6 alkylOcarbamoyl, C 1-6 alkylsulfonyl and hydroxy; each R 3, independently of one another, is C 1 -C 6 alkyl, C 1-4 alkoxy, C 1-6 alkylthio, cyano, halogen, perhalogenated C 1-4 alkyl, or hydroxyl, and is attached to any of the C atoms in the ring having free valence; R4 is -R12, -OR12, -N (R13) R12, -SR12, -SOR12, -SO2R12, -SO2R12, -SO2-N (R13) R12, -N (R13) SO2R12, -CO-R12, -COOR12 , -CON (R13) R12, -N (R13) -CO-R12, -OC (O) N (R13JR12, -N (R13) COOR12, - (CH2) 2N (R13) CO-N (R13) R12, -0P (O) (OR13) R12 or -CON (R14) CH (COOH) R12, and • is attached to any of the C atoms in the ring having free valence, z is 0, 1 or 2, R12 is R15 or - X 6 - (R 15) n n is 1 or 2, X 6 is C 1-10 alkylene, cyclo-C 3 -C 10 alkylene, hetero-C 2-10 alkylene or heterocyclo-C 3 alkylalkylene, and each of R 15, independently of one another, is hydrogen. , Cuaryl, C3-Cycloalkyl, Ce-upolcycloalkyl, hetero-Ce-upolecycloalkyl, hetero-C8-cycloalkyl, hetero-Ce-uaryl, or as described below; R13 is hydrogen, C1-6alkyl or hetero- C2-6alkyl; R14 is hydrogen, C1-6alkyl, or together with X6 and R15 form C3-4alkylene; any aliphatic or alicyclic group included in R4 is optionally closed; ethoxy with 1 to 5 substituents independently selected from the group consisting of C1-6alkyl, C1-4alkylamino, di-C1-4alkylamino, C1-6alkylcarbamoyl, di- (C1-4alkyl) carbamoyl, C1-4alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, amino, C 6-10 arylsulfonyl, carbamoyl, carboxyl, cyano, guanidine, halogen, hydroxy, mercapto and uride; 12 any aromatic group of R15 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, guanidine, halogen, halogen substituted C1-4alkyl, -R16, -OR16, -SR16 , -SOR16, -SO2R16, -SO2R16, -SO2-N (R13) R, -CO-R16, -COOR16, and -CON (R13) R16, where R13 has the meanings already mentioned and R16 is hydrogen with a substituent taken from the group consisting of C 1-6 alkylamino, di- (C 1-4 alkyl) amino, tri- (C 1-6 alkyl) ammonium, C 1-6 alkylcarbamoyl, di- (C 1-6 alkyl) carbamoyl, C 1-6 alkyloxycarbonyl, C 1-4 alkoxysulfonyl, amino group, carboxyl group, carbamoyl, hydroxyl or sulpho group, optionally mono-substituted C 1-8 alkyl, C 3-6 cycloalkyl, hetero-C 1-6 alkyl, hetero-C 1-4 aryl, hetero-C 1-4 cycloalkyl or phenyl, provided that n 1 is not 0 when n2 is 0 or R2 is C1-6alkyl or C1-6alkoxy, n3 is 0 or R3 is C1-6alkyl or C1-4alkoxy and R4 is hydrogen for the production of N-oxides, prodrugs of the compound, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof, comprising: (a) a compound of formula (I): vai tā aizsargātā atvasinājuma iedarbību ar savienojumu (II):or exposure to a protected derivative by compound (II): vai tā aizsargātu atvasinājumu, kurā L ir atšķeļamā grupa, D kopā ar vinilēngrupu, pie kuras tas kondensēts, veido monociklisku vai kondensētu biciklisku divvērtīgu grupu, kas satur 5-15 cikla atomus, pie kam katrs cikls satur 5-7 cikla atomus un katrs no cikla atomiem var būt heteroatoms, R29 ir -OH, -NHR6 vai -SH, kur R6 ir ūdeņraža atoms vai grupa no rindas: Ci.ealkilgrupa un C2.i2heteroalkilgrupa, pie kam šīs grupas var būt aizvietotas 13 LV 12495 ar 1- 2 aizvietotājiem, kas, neatkarīgi viens no otra, ir ņemti no rindas: Cļ-ealkanoiloksigrupa, Ci^alkilaminogrupa, di(Ci^alkil)aminogrupa, tri(Ci. 6alkil)amonija grupa, Ci^alkilkarbamoilgrupa, di(Ci^alkil)karbamoilgrupa, Ci^alkoksigrupa, Ci^alkoksikarboniigrupa, Ci^alkoksisuifonilgrupa, aminogrupa, karboksilgrupa, karbamoiigrupa, Ce-uarilgrupa, halogēna atoms, Cs-uheteroarilgrupa, hidroksilgrupa un sulfogrupa, un n1, n2, n3, A, B, X1, X2, X3, R1, R2, R3, R4 un R6 nozīmes ir jau minētās, pēc tam, ja nepieciešams, aizsarggrupu atšķelšanu; vai arī: (b) savienojuma ar formulu (3):or a protected derivative thereof in which L is a cleavable group, D together with the vinyl group to which it is fused forms a monocyclic or fused bicyclic bivalent radical containing from 5 to 15 ring atoms, each ring containing 5-7 ring atoms and each of each ring ring atoms may be heteroatoms, R29 is -OH, -NHR6 or -SH, wherein R6 is hydrogen or a group consisting of C1-6alkyl and C2-2 heteroalkyl, wherein these groups may be substituted with 13U12495 with 1 to 2 substituents which, independently of one another, are taken from the group consisting of C 1-6 alkanoyloxy, C 1-6 alkylamino, di (C 1-6 alkyl) amino, tri (C 1-6 alkyl) ammonium, C 1-6 alkylcarbamoyl, di (C 1-6 alkyl) carbamoyl, C1-4alkoxy, C1-4alkoxycarbonyl, C1-4alkoxyphonyl, amino, carboxyl, carbamoyl, Cuaryl, halogen, C3-6 heteroaryl, hydroxyl and sulfo, and n1, n2, n3, A, B, X1, X2, X3, R 1, R 2, R 3, R 4 and R 6 have the meanings already mentioned, then, if not desirable, protecting groups; or: (b) a compound of formula (3): 4 vai tā aizsargātu atvasinājumu, kur L ir atšķeļamā grupa, R30 ir -OH, -NHR5 vai -SH un n1, n2, n3, B, C, X3, X4, X5, R1, R2, R3, R4 un R5 nozīmes ir jau minētās, pēc tam, ja nepieciešamas, aizsarggrupu atšķelšanu; (c) neobligātu tālāku savienojuma ar formulu (I) pārvēršanu par tā farmaceitiski pieņemamu sāli; (d) neobligātu tālāku savienojuma ar formulu (I) sāls formas pārvēršanu par pamatsavienojumu; (e) neobligātu tālāku savienojuma ar formulu (I) neoksidētās formas pārvēršanu par tā farmaceitiski pieņemamu N-oksīdu; (f) neobligātu tālāku savienojuma ar formulu (I) N-oksīda formas pārvēršanu par tā neoksidēto formu; 14 (g) neobligātu savienojuma ar formulu (I) pamatformas pārvēršanu par ta atvasinājumu - zāļu priekštečvielu; (h) neobligātu savienojuma ar formulu (I) zāļu priekštečvielas formas pārvēršanu par savienojuma pamatformu.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 of the already mentioned, then, if necessary, separation of the protecting groups; (c) optionally converting a compound of formula (I) into a pharmaceutically acceptable salt thereof; (d) optionally converting the salt form of the compound of formula (I) into a parent compound; (e) optionally converting the non-oxidized form of the compound of formula (I) into a pharmaceutically acceptable N-oxide thereof; (f) optionally converting the N-oxide form of the compound of formula (I) into its non-oxidized form; 14 (g) converting an optional base form of formula (I) into a derivative of a drug precursor; (h) converting an optional precursor form of the compound of formula (I) into a basic form of the compound.
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