NOVEL BIS-AMIDE CONTAINING COMPOUNDS EXHIBITING ANTIFUNGAL ACTIVITY

AND THEIR METHOD OF USE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application NoR 63221425 filed July 13 ^th , 2021, which is herein incorporated by reference in its entirety.

STATEMENT OF FEDERALLY FUNDED RESEARCH [0002] This invention was made with Government support under grant number R44AI 106270 awarded by the National Institutes of Health, and grant number W81XWH1810638 awarded by the U.S. Department of Defense. The government has certain rights in the invention.

FIELD OF INVENTION

[0003] The present invention describes compounds that are antifungal agents, useful for the treatment of fungal infections and related conditions. The present invention further describes a novel chemotype useful for the treatment of fungal infections and other diseases that involve fungal infection.

BACKGROUND OF THE INVENTION

[0004] Fungal infections are a growing problem in numerous medical settings. Modem medical practices including anticancer chemotherapies, immunosuppressive drugs, broad spectrum antibiotics that disrupt the microbiome and indwelling medical devices that disrupt and breach the protective immune system. This creates an opening for infection by opportunistic fungal pathogens. Fungal infections are most common in immunocompromised patients afflicted with HIV or undergoing cancer therapies, hematological stem cell replacement, or organ transplants. Fungal infections can also occur in immunocompetent individuals and the most common cause is from skin and soft tissue wounds resulting from traumatic injury. Significant morbidity is evident with these types of injuries as the local invasive infections often require frequent and extensive surgical debridement in conjunction with systemic antifungal therapy. Nevertheless, amputations are still needed in many of the cases and mortality can be as high as 25%. In both immunosuppressed and immunocompetent patients the most common fungal pathogens are Candida, Aspergillus, Cryptococcus, Mucorales and Fusarium spp. and infections are associated with a significant incidence of treatment failure and high mortality. Invasive Candidiasis (IC) is the fourth leading healthcare associated bloodstream infection in the US and is associated with a 47% mortality rate.

Invasive Aspergillosis (IA) is becoming a dominant invasive fungal disease in hematological oncology, organ transplant and exacerbated chronic obstructive pulmonary disease. The incidence of IA in hematopoietic stem cell transplants has been reported to be as high as 15% with mortality rates ranging from 20% to 50%.

[0005] Pathogenic fungi include the genus Candida (examples include C. albicans, C. glabrata, C. krusei, C. tropicalis, C. guilliermondii, C. parapsilosis, C. dubliniensis and C. auri), the genus Cryptococcus (examples include C. neoformans and C. gatti), the genus Trichosporon (examples include T. asahii, T. asteroides, T. cutaneum, T. dermatis, T. dohaense, T. inkin, T. loubieri, T. mucoides, and T. ovoides), the genus Malassezia (examples include M. globose and M. restricta), the genus Aspergillus (examples include A. fumigatus. A. flavis, A. terreu and A. niger), the genus Fusarium (examples include F. solani, F. falciforme, F. oxysporum, F. verticillioides, and F. proliferatum) , the genus Mucor (examples include M. circinelloides, M, ramosissimus, M. indicus, M. rasemosus, and M. piriformis), the genus Blastomyces (examples include B. dermatitidis and B. brasiliensis), the genus Coccidioides (examples include C. immitis, C. and posadasii), the genus Pneumocystis (examples include P. carinii and P. jiroveci), the genus Histoplasma (examples include H. capsulatum), the genus Trichophyton (examples include T. schoenleinii, T. mentagrophytes, T. verrucosum, and T. rubrum), the genus Rhizopus (examples include R. oryzae and R stolonifera), the genus Apophysomyces (examples include A. variabilis), the genus Rhizomucor (examples include R. pusillus, R. regularior, and R. chlamydosporus), the genus Lichtheimia (examples include L. ramose and L. corymbiferd), the genus Scedosporium (examples include S. apiospermum), and the genus Lomentospora (examples include L. prolificans) .

[0006] The compounds of the disclosure have excellent activity against pathogenic fungi of the genera Candida, Aspergillus, Fusarium, Cryptococcus and Mucor. They can be used to treat fungal diseases, caused by these and other susceptible fungal pathogens, such as Candidemia, Oral Candidiasis, Vulvovaginal Candidiasis (VVC) and Recurrent VVC, Aspergillosis (including Allergic Bronchopulmonary Aspergillosis, Allergic Aspergillus Sinusitis and Invasive and Disseminated Aspergillosis), Cryptococcosis (including Pulmonary Cryptococcosis and Meningeal Cryptococcosis), Mucomycosis, Blastomycosis, Superficial infections (including Skin Keratitis, Athletes Foot, Ringworm, Ocular Keratitis and Onychomycosis) and other Invasive Infections (including Sinusitis, Endophthalmitis, Otitis, Endocarditis, Pneumonia, Osteomyelitis, Meningitis and Ventriculitis).

[0007] Compounds of the disclosure can also be used to treat fungal infections in agricultural crops including Wilt disease in tomato and cotton caused by Fusarium oxysporus, Wilt of Gram caused by Fusarium orthacereas, Downy Mildew of cereals caused by Sclerospora graminicola, Damping of Seedling caused by Phythium spp., Rot of Ginger caused by Phythium debaryaum, Late Blight of Potato caused by Phytophthora infestans, Early Blight of Potato caused by Alternaria solani, Blast Disease of Rice caused by Phyricularia oryzae, Powdery Mildews caused by Erysiphe spp., Tikka Disease of Groundnut caused by Cerecospora personata, Haemelia vastatrix and Cellectotrichum falcatum, Brown Rot in Pear, Plum and Peach caused by Sclerotinia fruiticola, Leaf Spot of Oats caused by He Iminthosporium avenae, Leaf Rust of Coffee caused by Haemelia vastatrix, Red Rot of Sugarcane caused by Collectotrichum falcatum, Black Wart Disease of Potato caused by Synchytrium endobioticum, Yellow Rust of Wheat caused by Puccinia striiformis, Maize Smut caused by Ustilago maydis, Loose Smut of Wheat caused by Ustilago tritici, Covered Smut of Oat caused by Ustilago avenae, flag Smut of Wheat caused by Urocystis tritici, Covered Smut of Barley caused by Ustilago hordei, Black Rust of Wheat caused by Puccinia graminis tritici, Bankanese Disease and Loot Rot of Rice caused by Gibberealla fujikuri, and Ergot Disease of Rye caused by Claviceps purpurea.

[0008] Compounds of the disclosure can also be used to treat or prevent fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs.

[0009] Compounds of the disclosure can also be used to treat or prevent diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions are selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax.

[0010] Compounds of the disclosure can also be used to treat or prevent aspergillosis infections in horses, cattle, sheep, goats, dogs and cats.

[0011] Compounds of the disclosure can also be used to treat or prevent diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis. [0012] Compounds of the disclosure can also be used to treat or prevent mucormycosis infections in horses, cattle, sheep, goats, dogs and cats.

[0013] Compounds of the disclosure can also be used to treat or prevent diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis.

[0014] Compounds of the disclosure can also be used to treat or prevent coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii.

[0015] Compounds of the disclosure can also be used to treat or prevent blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis .

[0016] Compounds of the disclosure can also be used to treat or prevent Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis .

[0017] Compounds of the disclosure can also be used to treat or prevent dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis,Microsporum gypseum, and Trichophyton mentagrophytes .

[0018] Compounds of the disclosure can also be used to treat or prevent cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii.

[0019] Compounds of the disclosure can also be used to treat or prevent histoplasmosis in dogs caused by infection with Histoplasma capsulatum.

BRIEF SUMMARY OF THE INVENTION

[0020] The present invention is directed toward novel compounds of formula (I): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

A ¹ is selected from the group consisting of

A ² is at each occurrence independently selected from the group consisting of

A ³ is at each occurrence independently selected from the group consisting of

q is at each occurrence independently 0, 1, 2, or 3; t is at each occurrence independently 1, 2, or 3;

R ¹ is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^1a is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ² is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^2a is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2b is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2C is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2d is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2e is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2f is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

R ^2g is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2h is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ²¹ is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ² ' is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2k is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ²¹ is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ³ is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^3a is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^3C is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^3d is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^3y is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^3Z is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

In some embodiments, R ^2e and R ^3z are joined to form a heterocyclic ring consisting of five or six members;

In some embodiments, R ²ⁱ and R ^3y are joined to form a heterocyclic ring consisting of five or six members;

In some embodiments, R ³ and R ^{3 c} are joined to form a heterocyclic ring consisting of five members; R ^4a is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4b is at each occurrence independently selected from t he group consisting of H and C _1-4 alkyl;

R ^4C is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4d is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4e is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4f is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl.

[0021] The compounds of the present invention include compounds having formula (la): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof.

[0022] The compounds of the present invention include compounds having formula (lb): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof.

[0023] The compounds of the present invention include compounds having formula (II): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0024] The compounds of the present invention include compounds having formula (III): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0025] The compounds of the present invention include compounds having formula (IV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0026] The compounds of the present invention include compounds having formula (V): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0027] The compounds of the present invention include compounds having formula (VI): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0028] The compounds of the present invention include compounds having formula (VII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0029] The compounds of the present invention include compounds having formula (VIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0030] The compounds of the present invention include compounds having formula (IX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0031] The compounds of the present invention include compounds having formula (X): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0032] The compounds of the present invention include compounds having formula (XI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0033] The compounds of the present invention include compounds having formula (XII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0034] The compounds of the present invention include compounds having formula (XIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0035] The compounds of the present invention include compounds having formula (XIV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0036] The compounds of the present invention include compounds having formula (XV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0037] The compounds of the present invention include compounds having formula (XVI): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0038] The compounds of the present invention include compounds having formula (XVII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0039] The compounds of the present invention include compounds having formula (XVIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0040] The compounds of the present invention include compounds having formula (XIX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0041] The compounds of the present invention include compounds having formula (XX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0042] The compounds of the present invention include compounds having formula (XXVI): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0043] The compounds of the present invention include compounds having formula (XXVIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0044] The compounds of the present invention include compounds having formula

(XXVIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0045] The compounds of the invention also include various synthetic intermediate compounds as described below. [0046] The present invention further relates to compositions comprising: an effective amount of one or more compounds according to the present invention and an excipient.

[0047] The present invention also relates to a method for treating or preventing disease or conditions associated with fungal infection. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

[0048] The present invention yet further relates to a method for treating or preventing disease or conditions associated with fungal infection, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0049] The present invention also relates to a method for treating or preventing fungal infection, including, for example, infection with an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0050] The present invention yet further relates to a method for treating or preventing fungal infection, including, for example, infection with an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, e.g. selected from the group consisting of Candida, Cryptococcus, Aspergillus, Fusarium, Mucor, and Scedosporium, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0051] The present invention also relates to a method for treating or preventing fungal infection, including, for example, infection with an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0052] The present invention yet further relates to a method for treating or preventing fungal infection, including, for example, infection with an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0053] The present invention also relates to a method for treating or preventing disease or conditions associated with fungal infection, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, ventriculitis, COVID-19 Associated Pulmonary Aspergillosis (CAPA) and Influenza Associated Pulmonary Aspergillosis (IAPA). Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.

[0054] The present invention yet further relates to a method for treating or preventing disease or conditions associated with fungal infection, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, ventriculitis, COVID-19 Associated Pulmonary Aspergillosis (CAPA) and Influenza Associated Pulmonary Aspergillosis (IAPA), wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0055] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism from a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusariurm, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma,

Trichophyton, Rhizopus , Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, e.g. selected from the group consisting of Candida, Cryptococcus, Aspergillus, Fusariurm, Mucor, and Scedosporium. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention

[0056] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism from a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusariurm, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma,

Trichophyton, Rhizopus , Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, e.g. selected from the group consisting of Candida, Cryptococcus, Aspergillus, Fusariurm, Mucor, and Scedosporium, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0057] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism selected from the groups consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0058] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism selected from the groups consisting Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0059] The present invention also relates to a method for treating or preventing fungal infection in plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bankanese disease foot rot of rice, and ergot disease of rye. Said methods comprise administering to a plant an effective amount of a compound or composition according to the present invention.

[0060] The present invention also relates to a method for treating or preventing fungal infection in plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bankanese disease, foot rot of rice, and ergot disease of rye, wherein said method comprises administering to a plant a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0061] The present invention also relates to a method for treating or preventing fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0062] The present invention also relates to a method for treating or preventing fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0063] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa, keratitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax, wherein said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0064] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa, keratitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0065] The present invention also relates to a method for treating or preventing aspergillosis infections in horses, cattle, sheep, goats, dogs and cats said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0066] The present invention also relates to a method for treating or preventing aspergillosis infections in horses, cattle, sheep, goats, dogs and cats, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0067] The present invention also relates to a method for treating or preventing diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats. including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0068] The present invention also relates to a method for treating or preventing diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0069] The present invention also relates to a method for treating or preventing mucormycosis infections in horses, cattle, sheep, goats, dogs and cats said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0070] The present invention also relates to a method for treating or preventing mucormycosis infections in horses, cattle, sheep, goats, dogs and cats, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0071] The present invention also relates to a method for treating or preventing diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0072] The present invention also relates to a method for treating or preventing diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0073] The present invention also relates to a method for treating or preventing coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0074] The present invention also relates to a method for treating or preventing coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0075] The present invention also relates to a method for treating or preventing blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0076] The present invention also relates to a method for treating or preventing blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0077] The present invention also relates to a method for treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0078] The present invention also relates to a method for treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0079] The present invention also relates to a method for treating or preventing dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0080] The present invention also relates to a method for treating or preventing dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0081] The present invention also relates to a method for treating or preventing cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0082] The present invention also relates to a method for treating or preventing cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0083] The present invention also relates to a method for treating or preventing histoplasmosis in dogs caused by infection with Histoplasma capsulatum, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

[0084] The present invention also relates to a method for treating or preventing histoplasmosis in dogs caused by infection with Histoplasma capsulatum, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0085] The present invention also provides the compounds of the invention for use in the treatment or prevention of diseases or conditions associated with fungal infection as described herein.

[0086] The present invention also provides use of the compounds of the invention in the manufacture of a medicament for the treatment or prevention of diseases or conditions associated with fungal infection as described herein.

[0087] The present invention further relates to a process for preparing the antifungal agents of the present invention.

[0088] These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. BRIEF DESCRIPTION OF THE FIGURES

[0089] In the figures “CFU” refers to the count of colony forming units, “D” refers to the number of days after the day of inoculation (defined as Day 0), “SC” refers to subcutaneous administration, “BID” refers to a twice daily treatment, “QD” refers to a single daily dose treatment.

[0090] Figure 1 shows the activity of Example 15 in the disseminated aspergillosis model in liver (1A) and kidney (IB).

[0091] Figure 2 shows the activity of Example 25 in the disseminated aspergillosis model in liver (2A) and kidney (2B).

[0092] Figure 3 shows the activities of Examples 26 and 27 in the disseminated aspergillosis model in liver (3A) and kidney (3B).

[0093] Figure 4 shows the activities of Examples 26 and 27 in the disseminated aspergillosis model (low dose study) in liver (4 A) and kidney (4B).

[0094] Figure 5 shows the activities of Example 75 in the disseminated aspergillosis model in liver (5 A) and kidney (5B).

[0095] Figure 6 shows the activities of Examples 75 and 74 in the disseminated aspergillosis model (low dose study) in liver (6A) and kidney (6B).

[0096] Figure 7 shows the activity of Example 26 in the disseminated Fusarium solani infection model in liver (7A) and kidney (7B).

[0097] Figure 8 shows the activities of Examples 25 and 27 in the disseminated Fusarium solani infection model in liver (8A) and kidney (8B).

DETAILED DESCRIPTION OF THE INVENTION

[0098] The compounds of the disclosure act on pathogenic fungi to suppress their growth. The compounds of the disclosure can also kill fungi. As antifungal agents, the compounds of the disclosure can be used to treat local, topical and disseminated infections in animals including humans and can be used to prevent disseminated fungal infections developing from local or topical fungal infections. In another aspect of this invention, the compounds can be applied to agricultural plants, shrubs and trees to cure and prevent fungal infections and fungal diseases.

[0099] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings may also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

[0100] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

[0101] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

[0102] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0103] As used herein, the term "halogen" shall mean chlorine, bromine, fluorine and iodine.

[0104] As used herein, unless otherwise noted, “alkyl” and/or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C _1-6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, and the like. Alkyl groups can be optionally substituted. In some embodiments alkyl groups are unsubstituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3- carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as ( C _1-6 alkyl)2amino, the alkyl groups may be the same or different.

[0105] As used herein, the terms “alkenyl” and “alkynyl” groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. In some embodiments alkenyl groups are unsubstituted. In some embodiments alkynyl groups are unsubstituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1- propenyl ( also 2-methylethenyl), isopropenyl ( also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl ( also 2-chlorovinyl), 4- hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2 -ynyl ( also propargyl), propyn- 1-yl, and 2-methyl-hex-4-yn-l-yl. Nonlimiting examples of substituted alkynyl groups include, 5- hydroxy-5 -methylhex-3 -ynyl, 6-hydroxy-6-methylhept-3 -yn-2-yl, 5-hydroxy-5 -ethylhept-3 -ynyl, and the like.

[0106] As used herein, “cycloalkyl,” whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. In some embodiments cycloakyl rings are unsubstituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl- cyclopropyl, cyclopropenyl, cyclobutyl, 2,3 -dihydroxy cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-l- yl, octahydropentalenyl, octahydro- 1H -indenyl. 3a.4.5.6.7.7a-hexahydro-3H -inden-4-yl. decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro- 1H -fluorenyl. The term “cycloalkyl” also includes carbocyclic rings which are bicyclic hydrocarbon rings, non- limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo [3.3.3 ]undecanyl .

[0107] “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF ₃ , -CF ₂ CF ₃ ). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. In some embodiments haloaklyl groups are not substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0108] The term “alkoxy” refers to the group -O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted. In some embodiments alkoxy groups are unsubstituted. The term C ₃ -C ₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C ₃ -C ₆ cyclic alkoxy groups optionally may be substituted. In some embodiments C ₃ -C ₆ cyclic alkoxy groups are unsubstituted.

[0109] The term “aryl” when used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. In some embodiments aryl rings are unsubstituted. Non-limiting examples of aryl groups include: phenyl, naphthylen-l-yl, naphthylen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2- amino-4-fluorophenyl, 2-(N,N -diethylamino)phenyl. 2-cyanophenyl, 2.6-di- tert-butylphenyl. 3- methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-l-yl, and 6-cyano-naphthylen- 1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.

[0110] The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein. Aralkyl groups of the present invention are optionally substituted. In some embodiments arylalkyl groups are unsubstituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

[0111] The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted. In some embodiments heterocycle groups are unsubstituted.

[0112] Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2.3.4.5-tetrahydro- 1H -azepinyl. 2.3-dihydro- 1H - indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro- 1H -pyrrolizinyl, 3a.4.5.6.7.7a-hexahydro- 1H -bcnzo|d|imidazolyl. 3 a.4.5.6.7.7a-hexahydro- 1 H -indolyl. 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro- 1H -cycloocta|b|pyrrolyl.

[0113] The term “heteroaryl,” whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6.7-Dihydro-5H - cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. In some embodiments heteroaryl groups are unsubstituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1, 2,3,4- tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H -imidazolyl. oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4- dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H -purinyl. 9H -purinyl. 6-ami no- 9H -purinyl. 5H -pyrrolo|3.2- d\ pyrimidinyl, 7H -pyrrolo|2.3-ri|pyrimidinyl. pyndo|2.3-ri| pyrimidinyl. 2-phenylbenzo[d]thiazolyl, 1H -indolyl. 4,5,6,7-tetrahydro-1-H -indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl. [0114] One non-limiting example of a heteroaryl group as described above is C ₁ -C ₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C ₁ -C ₅ heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-l-yl, 1H -imidazol-2-yl. 1H -imidazol-4-yl. isoxazolin-5- yl, furan-2-yl, furan -3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5- yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0115] Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms, the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

[0116] For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1, 2,3,4- tetrahydroquinoline having the formula: is, for the purposes of the present invention, considered a heterocyclic unit. 6.7-Dihydro-5H - cyclopentapyrimidine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro- [1,8]naphthyridine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.

[0117] Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl”.

[0118] The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below. The substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term “substituted” is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted C ₁ alkyl; trifluoromethyl is a substituted C ₁ alkyl; 4- hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octanyl is a substituted C ₈ alkyl; 3-guanidinopropyl is a substituted C ₃ alkyl; and 2-carboxypyridinyl is a substituted heteroaryl. In some embodiments when a moiety is described as “substituted” 1 to 3 hydrogen atoms may be replaced. In some embodiments when a moiety is described as “substituted” 1 hydrogen atom may be replaced. In some embodiments where a moiety is described as “optionally substituted” the moiety is unsubstituted.

[0119] The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated. In some embodiments all variable groups are unsubstituted. For the avoidance of doubt, where a moiety is not a variable group (e.g. methyl, OCF ₃ , ethylene, etc.) the moiety is not optionally substituted unless otherwise stated.

[0120] The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine(I)), -CN, - NO ₂ , oxo (=O), -OR ⁵ , -SR ⁵ , -N(R ⁵ ) ₂ , -NR ⁵ C(O)R ⁵ , -SO ₂ R ⁵ , -SO ₂ OR ⁵ , -SO ₂ N(R ⁵ ) ₂ , -C(O)R ⁵ , -

C(O)OR ⁵ , -C(O)N(R ⁵ ) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{3- 14} cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selected independently from halogen, -CN, -NO ₂ , oxo, and R ⁵ ; wherein R ⁵ , at each occurrence, independently is hydrogen, -OR ⁶ , -SR ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)N(R ⁶ ) ₂ , - SO ₂ R ⁶ , -S(O) ₂ 0R ⁶ , -N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, cycloalkyl (e.g., C ₃ -6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R ⁵ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R ⁶ , at each occurrence, independently is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, cycloalkyl (e.g., C _3-6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R ⁶ units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

[0121] In some embodiments, the substituents are selected from i) -OR ⁷ ; for example, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ ; ii) -C(O)R ⁷ ; for example, -COCH ₃ , -COCH ₂ CH ₃ , -COCH ₂ CH ₂ CH ₃ ; iii) -C(O)OR ⁷ ; for example, -CO ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ , -CO ₂ CH ₂ CH ₂ CH ₃ ; iv) -C(O)N(R ⁷ ) ₂ ; for example, -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ ; v) -N(R ⁷ ) ₂ ; for example, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₂ CH ₃ ); vi) halogen: -F, -Cl, -Br, and -I; vii) -CH _e X _g ; wherein X is halogen, e+g =3; for example, -CH ₂ F, -CHF ₂ , -CF ₃ , - CCI3, or -CBr ₃ ; viii) -SO ₂ R ⁷ ; for example, -SO ₂ H; -SO ₂ CH ₃ ; -SO ₂ C ₆ H ₅ ; ix) C ₁ -C ₆ linear, branched, or cyclic alkyl; x) Cyano xi) Nitro; xii) N(R ⁷ )C(O)R ⁷ ; xiii) Oxo (=0); xiv) Heterocycle; and xv) Heteroaryl. wherein each R ⁷ is independently hydrogen, optionally substituted C ₁ -C ₆ , linear or branched alkyl

(e.g., optionally substituted C ₁ -C ₄ linear or branched alkyl), or optionally substituted C ₃ -C ₆ cycloalkyl (e.g optionally substituted C ₃ -C ₄ cycloalkyl), or optionally substituted phenyl; or two R ⁷ units can be taken together to form a ring comprising 3-7 ring atoms. In certain aspects, each R ⁷ is independently hydrogen, C ₁ -C ₆ linear or branched alkyl optionally substituted with halogen or C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ cycloalkyl.

[0122] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C _1-6 alkyl” is specifically intended to individually disclose C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ - C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ - C ₅ , C ₂ -C ₄ , C ₂ - C ₃ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ - C ₄ , C ₄ -C ₆ , C ₄ -C ₅ , and C ₅ -C ₆ , alkyl.

[0123] For the purposes of the present invention the terms “compound,” “analog,” and “composition of matter” stand equally well for the antifungal agent described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog”, and “composition of matter” are used interchangeably throughout the present specification.

[0124] Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

[0125] Pharmaceutically acceptable salts of compounds of the present teachings, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non- limiting examples of inorganic bases include NaHCO ₃ , Na ₂ CO ₃ , KHCO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , LiOH, NaOH, KOH, NaH ₂ PO ₄ , Na ₂ HPO ₄ , and Na ₃ PO ₄ . Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, lactic, benzene sulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methane sulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

[0126] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R ⁹ ) ₂ , each R ⁹ may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds

[0127] The terms “treat” and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.

[0128] As used herein, “therapeutically effective” and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.

[0129] Except when noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered, e.g. and who is in need of treatment. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.

The antifungal agents

[0130] The antifungal agents of the present invention include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I): including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:

A ³ is at each occurrence independently selected from the group consisting of

A ⁴ is at each occurrence independently selected from the group consisting of

q is at each occurrence independently 0, 1, 2, or 3; t is at each occurrence independently 1, 2, or 3;

R ¹ is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^1a is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ² is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^2a is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _1-4 - alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2b is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2c is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ; R ^2d is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2e is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2f is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C _3-5 -branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ . R ^2g is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C ₃ -5-branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2h is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C ₃ -5-branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ²ⁱ is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C ₃ -5-branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ² ' is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C ₃ -5-branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ^2k is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C ₃ -5-branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ²¹ is at each occurrence independently selected from the group consisting of H, C _1-4 alkyl, C _{1-4 -} alkoxy, C ₃ -5-branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

In some embodiments, R ^2e and R ^3z are joined to form a heterocyclic ring consisting of five or six members;

In some embodiments, R ²¹ and R ^3y are joined to form a heterocyclic ring consisting of five or six members;

In some embodiments, R ³ and R ^3c are joined to form a heterocyclic ring consisting of five members; R ³ is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^3a is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^3c is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^3d is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^3y is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^3z is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4a is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4b is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4c is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4d is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl;

R ^4e is at each occurrence independently selected from the group consisting of H and C _1-4 alkyl.

[0131] For the avoidance of doubt, the orientation of A ¹ , A ² and A ³ in the compound of formula (I) is as follows: the connecting bond on the left hand side of A ¹ as depicted is connected via the amide moiety to A ³ and the connecting bond on the right hand side of A ¹ as depicted is connected via the amide moiety to A ² ; the connecting bond on the left hand side of A ² as depicted is connected to A ⁴ and the connecting bond on the right hand side of A ² as depicted is connected via the amide moiety to A ¹ ; and the connecting bond on the left hand side of A ³ as depicted is connected to A ⁵ and the connecting bond on the right hand side of A ³ as depicted is connected to A ¹ via the amide moiety [0132] In some embodiments of the compounds of formula (I) A ¹ , A ² and A ³ are as defined by embodiments D1 to D25 in Table A below.

[0133] Table A: Embodiments D1 to D25

[0134] The compounds of the present invention include compounds having formula (la): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0135] The compounds of the present invention include compounds having formula (lb): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0136] The compounds of the present invention include compounds having formula (II): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0137] The compounds of the present invention include compounds having formula (III): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0138] The compounds of the present invention include compounds having formula (IV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0139] The compounds of the present invention include compounds having formula (V): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0140] The compounds of the present invention include compounds having formula (VI):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0141] The compounds of the present invention include compounds having formula (VII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0142] The compounds of the present invention include compounds having formula (VIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0143] The compounds of the present invention include compounds having formula (IX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0144] The compounds of the present invention include compounds having formula (X):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0145] The compounds of the present invention include compounds having formula (XI): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0146] The compounds of the present invention include compounds having formula (XII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0147] The compounds of the present invention include compounds having formula (XIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0148] The compounds of the present invention include compounds having formula (XIV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0149] The compounds of the present invention include compounds having formula (XV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0150] The compounds of the present invention include compounds having formula (XVI): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0151] The compounds of the present invention include compounds having formula (XVII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0152] The compounds of the present invention include compounds having formula (XVIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0153] The compounds of the present invention include compounds having formula (XIX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0154] The compounds of the present invention include compounds having formula (XX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0155] The compounds of the present invention include compounds having formula (XXVI): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0156] The compounds of the present invention include compounds having formula (XXVII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0157] The compounds of the present invention include compounds having formula (XXVIII):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0158] The following compound is excluded from the scope of compounds as claimed in claim 1: pyrimidine-4, 6-dicarboxylic acid bis-{[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl] -amide} (CAS registry number 1453839-10-5, see WO2013/130738).

[0159] In some embodiments of the compound of formula (I) when A ¹ is the pyrimidine moiety then A ² and A ³ are different moieties and/or A ⁴ and A ⁵ are different moieties. [0160] In some embodiments of the compound of formula (I) when A ¹ is the pyrimidine moiety then A ² and A ³ are different moieties.

[0161] In some embodiments of the compound of formula (I) when A ¹ is the pyrimidine moiety then A ⁴ and A ⁵ are different moieties.

[0162] In some embodiments of the compound of formula (I) when A ¹ is the pyrimidine moiety [0163] In some embodiments of the compound of formula (I) when A ¹ is the pyrimidine moiety

[0164] In some embodiments of the compound of formula (I) A ¹ is not the pyrimidine moiety

[0165] In some embodiments A ¹ is selected from the group consisting of

[0166] In some embodiments A ¹ is selected from the group consisting of

[0167] In some embodiments A ¹ is selected from the group consisting of

[0170] In some embodiments A ¹ is

[0171] In some embodiments A ¹ is

[0172] In some embodiments A ¹ is

[0173] In some embodiments A ¹ is

[0174] In some embodiments A ¹ is

[0175] In some embodiments A ¹ is [0176] In some embodiments A ¹ is

[0177] In some embodiments A ¹ is

[0178] In some embodiments A ¹ is

[0179] In some embodiments A ¹ is

[0180] In some embodiments A ¹ is

[0181] In some embodiments A ¹ is

[0182] In some embodiments A ¹ is

[0183] In some embodiments A ¹ is

[0184] In some embodiments A ¹ is

[0185] In some embodiments A ¹ is [0186] In some embodiments A ¹ is

[0187] In some embodiments A

[0188] In some embodiments A ¹ is A

[0189] In some embodiments A ² is selected from the group consisting of

[0190] In some embodiments A is selected from the group consisting of

[0191] In some embodiments A ² is selected from the group consisting of

[0192] In some embodiments A ² is selected from the group consisting of [0193] In some embodiments A ² is

[0194] In some embodiments A ² is

[0195] In some embodiments A ² is

,

[0196] In some embodiments A is

[0197] In some embodiments A ² is

[0198] In some embodiments A ² is

[0199] In some embodiments A ² is

[0200] In some embodiments A ² is

[0201] In some embodiments A is [0202] In some embodiments [0203] In some embodiments A ³ is selected from the group consisting of

[0204] In some embodiments A ³ is selected from the group consisting of

[0205] In some embodiments A ³ is selected from the group consisting of

[0206] In some embodiments A ³ is

[0207] In some embodiments A ³ is

[0208] In some embodiments A ³ is ,

[0209] In some embodiments A ³ is

[0210] In some embodiments A ³ is

[0211] In some embodiments A ³ is

[0212] In some embodiments A ³ is

[0213] In some embodiments A ³ is

,

[0214] In some embodiments A ³ is

[0215] In some embodiments A ³ is

[0216] In some embodiments A ⁴ is selected from the group consisting of

[0217] In some embodiments A ⁴ is selected from the group consisting of

[0218] In some embodiments A ⁴ is selected from the group consisting of

[0219] In some embodiments A ⁴ is selected from the group consisting of [0220] In some embodiments A ⁴ is

[0221] In some embodiments A ^4' IS

[0222] In some embodiments A ⁴ is

[0223] In some embodiments A ⁴ is

[0224] In some embodiments A ⁴ is

[0225] In some embodiments A ⁴ is

[0226] In some embodiments A ⁴ is

[0227] In some embodiments A ⁴ is

[0228] In some embodiments A ⁴ is

[0229] In some embodiments A ⁴ is

[0230] In some embodiments A ⁴ is [0231] In some embodiments A ⁴ is

[0232] In some embodiments A ⁴ i iss

[0233] In some embodiments A ⁴ is

[0234] In some embodiments A ⁴ is

[0237] In some embodiments A ⁴ is

[0238] In some embodiments A ⁴ is

[0239] In some embodiments A ⁴ is [0240] In some embodiments A ⁴ i

[0241] In some embodiments A ⁴ i

[0242] In some embodiments A ⁴ i

[0243] In some embodiments A ⁴ i

[0244] In some embodiments A ⁴ i [0245] In some embodiments A ⁵ i selected from the group consisting of

[0246] In some embodiments A ⁵ is selected from the group consisting of

[0247] In some embodiments A ⁵ is selected from the group consisting of

[0249] In some embodiments A ⁵ is

[0250] In some embodiments A ⁵ is [0251] In some embodiments A ⁵ is

[0252] In some embodiments A ⁵ is

[0253] In some embodiments A ⁵ is

[0254] In some embodiments A ⁵ is

[0255] In some embodiments A ⁵ is

[0256] In some embodiments A ⁵ is

[0257] In some embodiments A ⁵ is

[0258] In some embodiments A ⁵ is

[0259] In some embodiments A ⁵ is

[0260] In some embodiments A ⁵ is

[0261] In some embodiments A ⁵ is [0262] In some embodiments A ⁵ is

[0263] In some embodiments A ⁵ is

[0264] In some embodiments A ⁵ is

[0265] In some embodiments A ⁵ is

[0266] In some embodiments A ⁵ is

[0267] In some embodiments A ⁵ is

[0268] In some embodiments A ⁵ is [0273] In some embodiments q is at each occurrence independently 0, 1 or 2.

[0274] In some embodiments when the compound of the invention has two q, each q has the same value.

[0275] In some embodiments when the compound of the invention has two q, each q has a different value. [0276] In some embodiments q is 0, 1, 2, or 3.

[0277] In some embodiments q is 0.

[0278] In some embodiments q is 1.

[0279] In some embodiments q is 2.

[0280] In some embodiments q is 3. [0281] In some embodiments when the compound of the invention has two t, each t has the same value. [0282] In some embodiments when the compound of the invention has two t, each t has a different value.

[0283] In some embodiments t is 0, 1, 2, or 3.

[0284] In some embodiments t is 1. [0285] In some embodiments t is 2.

[0286] In some embodiments t is 3.

[0287] In some embodiments, R ^2e and R ^3z are joined to form a heterocyclic ring consisting of five members.

[0288] In some embodiments R ¹ is at each occurrence independently selected from the group consisting of H and methyl.

[0289] In some embodiments R ¹ is H.

[0290] In some embodiments R ¹ is C _1-4 alkyl.

[0291] In some embodiments R ^1a is at each occurrence independently selected from the group consisting of H and methyl. [0292] In some embodiments R ^1a is H.

[0293] In some embodiments R ^1a is C _1-4 alkyl.

[0294] In some embodiments R ² is at each occurrence independently selected from the group consisting of H and methyl.

[0295] In some embodiments R ² is H. [0296] In some embodiments R ² is C _1-4 alkyl.

[0297] In some embodiments R ^2a is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0298] In some embodiments R ^2a is at each occurrence independently selected from the group consisting of H, methyl, F, and Cl. [0299] In some embodiments R ^2a is H.

[0300] In some embodiments R ^2a is C _1-4 alkyl.

[0301] In some embodiments R ^2a is C ₁ -4-alkoxy.

[0302] In some embodiments R ^2a is C _3-5 -branched alkoxy.

[0303] In some embodiments R ^2a is F. [0304] In some embodiments R ^2a is Cl.

[0305] In some embodiments R ^2a is CN. [0306] In some embodiments R ^2a is OCF ₃ .

[0307] In some embodiments R ^2a is CF ₃ .

[0308] In some embodiments R2 ^b is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ . [0309] In some embodiments R ^2b is at each occurrence independently selected from the group consisting of H, methyl, F, and Cl.

[0310] In some embodiments R ^2b is at each occurrence independently selected from the group consisting of H or methyl.

[0311] In some embodiments R ^2b is H. [0312] In some embodiments R ^2b is C _1-4 alkyl.

[0313] In some embodiments R ^2b is C ₁ - ₄ -alkoxy.

[0314] In some embodiments R ^2b is C _3-5 -branched alkoxy.

[0315] In some embodiments R ^2b is F.

[0316] In some embodiments R ^2b is Cl. [0317] In some embodiments R ^2b is CN.

[0318] In some embodiments R ^2b is OCF ₃ .

[0319] In some embodiments R ^2b is CF ₃ .

[0320] In some embodiments R ^2c is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ . [0321] In some embodiments R ^2c is at each occurrence independently selected from the group consisting of H, methyl, F, and Cl.

[0322] In some embodiments R ^2c is H.

[0323] In some embodiments R ^2c is C _1-4 alkyl.

[0324] In some embodiments R ^2c is C ₁ -4-alkoxy. [0325] In some embodiments R ^2c is C _3-5 -branched alkoxy.

[0326] In some embodiments R ^2c is F.

[0327] In some embodiments R ^2c is Cl.

[0328] In some embodiments R ^2c is CN.

[0329] In some embodiments R ^2c is OCF ₃ . [0330] In some embodiments R ^2c is CF ₃ . [0331] In some embodiments R ^2d is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0332] In some embodiments R ^2d is at each occurrence independently selected from the group consisting of H, methyl, F, and Cl. [0333] In some embodiments R ^2d is at each occurrence independently selected from the group consisting of H or methyl.

[0334] In some embodiments R ^2d is H.

[0335] In some embodiments R ^2d is C _1-4 alkyl.

[0336] In some embodiments R ^2d is C ₁ -4-alkoxy. [0337] In some embodiments R ^2d is C _3-5 -branched alkoxy.

[0338] In some embodiments R ^2d is F.

[0339] In some embodiments R ^2d is Cl.

[0340] In some embodiments R ^2d is CN.

[0341] In some embodiments R ^2d is OCF ₃ . [0342] In some embodiments R ^2d is CF ₃ .

[0343] In some embodiments, when present, no more than two of R ^2a , R ^2b , R ^2c and R ^2d are other than H.

[0344] In some embodiments, when present, no more than one of R ^2a , R ^2b , R ^2c and R ^2d are other than H. [0345] In some embodiments, when present, R ^2a , R ^2b , R ^2c and R ^2d are H.

[0346] In some embodiments R ^2e is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0347] In some embodiments R ^2e is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl. [0348] In some embodiments R ^2e is at each occurrence independently selected from the group consisting of H, and methoxy.

[0349] In some embodiments R ^2e is H.

[0350] In some embodiments R ^2e is C _1-4 alkyl.

[0351] In some embodiments R ^2e is C ₁ - ₄ -alkoxy. [0352] In some embodiments R ^2e is C _3-5 -branched alkoxy.

[0353] In some embodiments R ^2e is F. [0354] In some embodiments R ^2e is Cl.

[0355] In some embodiments R ^2e is CN.

[0356] In some embodiments R ^2e is OCF ₃ .

[0357] In some embodiments R ^2e is CF ₃ . [0358] In some embodiments R ^2f is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0359] In some embodiments R ^2f is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

[0360] In some embodiments R ^2f is at each occurrence independently selected from the group consisting of H, methoxy, and F.

[0361] In some embodiments R ^2f is H.

[0362] In some embodiments R ^2f is C _1-4 alkyl.

[0363] In some embodiments R ^2f is C ₁ - ₄ -alkoxy.

[0364] In some embodiments R ^2f is C _3-5 -branched alkoxy. [0365] In some embodiments R ^2f is F.

[0366] In some embodiments R ^2f is Cl.

[0367] In some embodiments R ^2f is CN.

[0368] In some embodiments R ^2f is OCF ₃ .

[0369] In some embodiments R ^2f is CF ₃ . [0370] In some embodiments R ^2g is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0371] In some embodiments R ^2g is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

[0372] In some embodiments R ^2g is at each occurrence independently selected from the group consisting of H, and methoxy.

[0373] In some embodiments R ^2g is H.

[0374] In some embodiments R ^2g is C _1-4 alkyl.

[0375] In some embodiments R ^2g is C ₁ -4-alkoxy.

[0376] In some embodiments R ^2g is C _3-5 -branched alkoxy. [0377] In some embodiments R ^2g is F.

[0378] In some embodiments R ^2g is Cl. [0379] In some embodiments R ^2g is CN.

[0380] In some embodiments R ^2g is OCF ₃ .

[0381] In some embodiments R ^2g is CF ₃ .

[0382] In some embodiments R ^2h is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0383] In some embodiments R ^2h is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

[0384] In some embodiments R ^2h is at each occurrence independently selected from the group consisting of H, methoxy, and F. [0385] In some embodiments R ^2h is H.

[0386] In some embodiments R ^2h is C _1-4 alkyl.

[0387] In some embodiments R ^2h is C ₁ - ₄ -alkoxy.

[0388] In some embodiments R ^2h is C _3-5 -branched alkoxy.

[0389] In some embodiments R ^2h is F. [0390] In some embodiments R ^2h is Cl.

[0391] In some embodiments R ^2h is CN.

[0392] In some embodiments R ^2h is OCF ₃ .

[0393] In some embodiments R ^2h is CF ₃ .

[0394] In some embodiments, when present, no more than two of R ^2e R ^2f , R ^2g and R ^2h are other than H.

[0395] In some embodiments, when present, no more than one of R ^2e R ^2f , R ^2g and R ^2h are other than H.

[0396] In some embodiments, when present, R ^2e R ^2f , R ^2g and R ^2h are H.

[0397] In some embodiments R ²¹ is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0398] In some embodiments R ²¹ is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

[0399] In some embodiments R ²¹ is H.

[0400] In some embodiments R ²¹ is C _1-4 alkyl. [0401] In some embodiments R ²¹ is C ₁ - ₄ -alkoxy.

[0402] In some embodiments R ²¹ is C _3-5 -branched alkoxy. [0403] In some embodiments R ²¹ is F.

[0404] In some embodiments R ²¹ is Cl.

[0405] In some embodiments R ²¹ is CN.

[0406] In some embodiments R ²¹ is OCF ₃ . [0407] In some embodiments R ²¹ is CF ₃ .

[0408] In some embodiments R ² ' is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0409] In some embodiments R ² ' is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl. [0410] In some embodiments R ² ' is H.

[0411] In some embodiments R ² ' is C _1-4 alkyl.

[0412] In some embodiments R ² ' is C ₁ - ₄ -alkoxy.

[0413] In some embodiments R ² ' is C _3-5 -branched alkoxy.

[0414] In some embodiments R ² ' is F. [0415] In some embodiments R ² ' is Cl.

[0416] In some embodiments R ² ' is CN.

[0417] In some embodiments R ² ' is OCF ₃ .

[0418] In some embodiments R ² ' is CF ₃ .

[0419] In some embodiments R ^2k is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0420] In some embodiments R ^2k is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

[0421] In some embodiments R ^2k is H.

[0422] In some embodiments R ^2k is C _1-4 alkyl. [0423] In some embodiments R ^2k is C ₁ -4-alkoxy.

[0424] In some embodiments R ^2h is C _3-5 -branched alkoxy.

[0425] In some embodiments R ^2k is F.

[0426] In some embodiments R ^2k is Cl.

[0427] In some embodiments R ^2k is CN. [0428] In some embodiments R ^2k is OCF ₃ .

[0429] In some embodiments R ^2k is CF ₃ . [0430] In some embodiments R ²¹ is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ .

[0431] In some embodiments R ²¹ is at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl. [0432] In some embodiments R ²¹ is H.

[0433] In some embodiments R ²¹ is C _1-4 alkyl.

[0434] In some embodiments R ²¹ is C ₁ -4-alkoxy.

[0435] In some embodiments R ²¹ is C _3-5 -branched alkoxy.

[0436] In some embodiments R ²¹ is F. [0437] In some embodiments R ²¹ is Cl.

[0438] In some embodiments R ²¹ is CN.

[0439] In some embodiments R ²¹ is OCF ₃ .

[0440] In some embodiments R ²¹ is CF ₃ .

[0441] In some embodiments, when present, no more than two of R ²¹ R ² '. R ^2k and R ²¹ are other than H.

[0442] In some embodiments, when present, no more than one of R ²¹ R ² '. R ^2k and R ²¹ are other than H.

[0443] In some embodiments, when present, R ²¹ R ² '. R ^2k and R ²¹ are H.

[0444] In some embodiments R ³ is at each occurrence independently selected from the group consisting of H and methyl.

[0445] In some embodiments R ³ is H.

[0446] In some embodiments R ³ is C _1-4 alkyl.

[0447] In some embodiments R ^3a is at each occurrence independently selected from the group consisting of H and methyl. [0448] In some embodiments R ^3a is H.

[0449] In some embodiments R ^3a is C _1-4 alkyl.

[0450] In some embodiments R ^3c is at each occurrence independently selected from the group consisting of H and methyl.

[0451] In some embodiments R ^3c is H. [0452] In some embodiments R ^3c is C _1-4 alkyl. [0453] In some embodiments R ^3d is at each occurrence independently selected from the group consisting of H and methyl.

[0454] In some embodiments R ^3d is H.

[0455] In some embodiments R ^3d is C _1-4 alkyl. [0456] In some embodiments R ^3y is at each occurrence independently selected from the group consisting of H and methyl.

[0457] In some embodiments R ^3y is H.

[0458] In some embodiments R ^3y is C _1-4 alkyl.

[0459] In some embodiments R ^3z is at each occurrence independently selected from the group consisting of H and methyl.

[0460] In some embodiments R ^3z is H.

[0461] In some embodiments R ^3z is C _1-4 alkyl.

[0462] In some embodiments, R ^2e and R ^3z are joined to form a heterocyclic ring consisting of six members. [0463] In some embodiments, R ²¹ and R ^3y are joined to form a heterocyclic ring consisting of five members.

[0464] In some embodiments, R ²¹ and R ^3y are joined to form a heterocyclic ring consisting of six members.

[0465] In some embodiments, R ³ and R ^3c are joined to form a heterocyclic ring consisting of five members.

[0447] In some embodiments, R ^2e and R ^3z are joined and together with the phenyl moiety to which R ^2e is attached form an isoindoline, tetrahydroquinoline, or tetrahydroisoquinoline ring.

[0466] In some embodiments R ^2e and R ^3z together form a methylene or an ethylene bridging moiety. [0447] In some embodiments, R ²¹ and R ^3y are joined and together with the phenyl moiety to which R ²¹ is attached form an isoindoline, tetrahydroquinoline, or tetrahydroisoquinoline ring.

[0467] In some embodiments R ²¹ and R ^3y together form a methylene or an ethylene bridging moiety.

[0468] In some embodiments R ³ and R ^3c are joined and form a 4,5-dihydro- lH-imidazole ring.

[0469] In some embodiments R ³ and R ^3c together form an ethylene bringing moiety. [0470] In some embodiments, when present, R ^3y , R ^3z , R ³ , R ^3a , R ^3c and R ^3d are H, and additionally wherein R ³ and R ^3c may together form an ethylene bringing moiety, wherein R ^2e and R ^3z may together form a methylene or an ethylene bridging moiety and wherein R ²¹ and R ^3y may together form a methylene or an ethylene bridging moiety. [0471] In some embodiments R ^4a is at each occurrence independently selected from the group consisting of H and methyl.

[0472] In some embodiments R ^4a is H.

[0473] In some embodiments R ^4a is C _1-4 alkyl.

[0474] In some embodiments R ^4b is at each occurrence independently selected from the group consisting of H and methyl.

[0475] In some embodiments R ^4b is H.

[0476] In some embodiments R ^4b is C _1-4 alkyl.

[0477] In some embodiments R ^4c is at each occurrence independently selected from the group consisting of H and methyl. [0478] In some embodiments R ^4c is H.

[0479] In some embodiments R ^4c is C _1-4 alkyl.

[0480] In some embodiments R ^4d is at each occurrence independently selected from the group consisting of H and methyl.

[0481] In some embodiments R ^4d is H. [0482] In some embodiments R ^4d is C _1-4 alkyl.

[0483] In some embodiments R ^4e is at each occurrence independently selected from the group consisting of H and methyl.

[0484] In some embodiments R ^4e is H.

[0485] In some embodiments R ^4e is C _1-4 alkyl. [0486] In some embodiments, when present, no more than two of R ^4a , R ^4b , R ^4c , and R ^4d , and

R ^4e are other than H.

[0487] In some embodiments, when present, no more than one of R ^4a , R ^4b , R ^4c , and R ^4d , and R ^4e are other than H.

[0488] In some embodiments, when present, R ^4a , R ^4b , R ^4c , R ^4d , and R ^4e are H. [0489] In some embodiments R ^4f is at each occurrence independently selected from the group consisting of H and methyl. [0490] In some embodiments R ^4f is H.

[0491] In some embodiments R ^4f is C _1-4 alkyl.

[0492] In some embodiments (Embodiment El) A ² is selected from the group consisting of

A ³ is selected from the group consisting of

A ⁵ is selected from the group consisting of

q is at each occurrence independently 0, 1, 2, or 3;

R ¹ , R ^1a and R ² are at each occurrence independently selected from the group consisting of H and unsubstituted C _1-4 alkyl;

R ^2a . R ^2b , R ^2c , R ^2d , R ^2e R ^2f , R ^2g , R ^2h , R ²¹ R ² '. R ^2k , R ²¹ are at each occurrence independently selected from the group consisting of H, unsubstituted C _1-4 alkyl, unsubstituted C ₁ -4-alkoxy, unsubstituted C _3-5 - branched alkoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ³ , R ^3a , R ^3c , R ^3d , R ^3y and R ^3z are at each occurrence independently selected from the group consisting of H and unsubstituted C _1-4 alkyl; or R ^2e and R ^3z together form a methylene or an ethylene bridging moiety; or R ²¹ and R ^3y together form a methylene or an ethylene bridging moiety; or R ³ and R ^3c together form an ethylene bringing moiety; and

R ^4a , R ^4b , R ^4c , and R ^4d are at each occurrence independently selected from the group consisting of H and unsubstituted C _1-4 alkyl.

[0493] In some embodiments (Embodiment E2) A ² is selected from the group consisting of

A ³ is selected from the group consisting of

A ⁴ is selected from the group consisting of

A ⁵ is selected from the group consisting of q is at each occurrence independently 0, 1, 2 or 3;

R ¹ , R ^1a and R ² are at each occurrence independently selected from the group consisting of H and methyl;

R ^2a . R ^2b , R ^2c , R ^2d , R ^2e R ^2f , R ^2g , R ^2h , R ²¹ R ² '. R ^2k , R ²¹ are at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, Cl, CN, OCF ₃ , and CF ₃ ;

R ³ , R ^3y and R ^3z are at each occurrence independently selected from the group consisting of H and methyl; or R ^2e and R ^3z together form a methylene or an ethylene bridging moiety; or R ²¹ and R ^3y together form a methylene or an ethylene bridging moiety; and R ^4a , R ^4b , R ^4c , and R ^4d are at each occurrence independently selected from the group consisting of H and methyl; and wherein when present, no more than two of R ^2a , R ^2b , R ^2c , and R ^2d are other than H; when present, no more than two of R ^2e R ^2f , R ^2g and R ^2h are other than H; when present, no more than two of R ²¹ R ² '. R ^2k , and R ²¹ are other than H; and when present, no more than two of R ^4a , R ^4b , R ^4c , and R ^4d are other than H.

[0494] In some embodiments (Embodiment FI) A ¹ is selected from the group consisting of

and q, A ² , A ³ , A ⁴ , A ⁵ , R ¹ , R ^1a , R ² , R ^2a , R ^2b , R ^2c , and R ^2d are as defined in Embodiment E1. [0495] In some embodiments (F2) A ¹ is selected from the group consisting of and q, A ² , A ³ , A ⁴ , A ⁵ , R ¹ , R ^1a , R ² , R ^2a , R ^2b , R ^2c , and R ^2d are as defined in Embodiment E2. [0496] The following table describes further embodiments of the invention. [0497] Table B: Embodiments Gto W

[0498] In some embodiments (Embodiment X) A ¹ is selected from the group consisting of A ² is selected from the group consisting of

A ³ is selected from the group consisting of

A ⁴ is selected from the group consisting of q is at each occurrence independently 0, 1, or 2;

R ¹ , R ^1a and R ² are at each occurrence independently selected from the group consisting of H and methyl;

R ^2a . R ^2b , R ^2c , R ^2d , are at each occurrence independently selected from the group consisting of H, methyl, F, and Cl;

R ^2e R ^2f , R ^2g , R ^2h , R ²¹ R ² '. R ^2k , R ²¹ are at each occurrence independently selected from the group consisting of H, methyl, methoxy, F, and Cl;

R ³ , R ^3a , R ^3c , R ^3d , R ^3y and R ^3z are at each occurrence independently selected from the group consisting of H and methyl; or R ^2e and R ^3z together form a methylene or an ethylene bridging moiety; or R ²¹ and R ^3y together form a methylene or an ethylene bridging moiety; or R ³ and R ^3c together form an ethylene bringing moiety; and

R ^4a , R ^4b , R ^4c , and R ^4d are at each occurrence independently selected from the group consisting of H and methyl. [0499] Compounds of the present invention include compounds having the formula (XXI) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R ^2e , R ^2f , and R ^2h are defined herein below in Table 1. Table 1 : Exemplary compounds of the formula (XXI) [0500] Compounds of the present invention include compounds having the formula (XXII) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R ^2e , R ^2f , and R ^2h are defined herein below in Table 2.

Table 2: Exemplary compounds of the formula (XXII)

[0501] Compounds of the present invention include compounds having the formula (XXIII) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R ^2e , R ^2f , and R ^2h are defined herein below in Table 3. Table 3 : Exemplary compounds of the formula (XXIII)

[0502] Compounds of the present invention include compounds having the formula (XXIV) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R ^2e , R ^2f , and R ^2h are defined herein below in Table 4. Table 4: Exemplary compounds of the formula (XXIV)

[0503] Compounds of the present invention include compounds having the formula (XXV) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R ^2f , R ^2g and R ^2h are defined herein below in Table 5. Table 5 : Exemplary compounds of the formula (XXV)

[0504] Novel synthetic intermediate compounds are also included within the scope of the invention.

[0505] Accordingly the invention provides compounds of formula (Int-I): including enantiomers, diastereomers, hydrates, solvates, and salts thereof, wherein A ¹ , A ² , A ³ , A ⁴ , A ⁵ , R ¹ and R ² are as defined for compounds of formula (I) and wherein at least one guanidine nitrogen atom in A ⁴ and/or A ⁵ is protected by a suitable protecting group, e.g. tert-butoxy carbonyl (Boc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), or benzyloxycarbonyl (Cbz).

[0506] In another embodiment of compounds of formula (Int-I) the two primary nitrogen atoms within the each guanidine moiety on A ⁴ and A ⁵ are protected by a suitable protecting group, e.g. tert-butoxycarbonyl (Boc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), or benzyloxycarbonyl (Cbz).

[0507] The embodiments described above in respect of compounds of formulae (I) to (XX) and (XXVI) to (XXVIII) also apply to compounds of formula (Int-I) where possible.

[0508] The invention also provides compounds of formula (Int-II): including enantiomers, diastereomers, hydrates, solvates, and salts thereof, wherein q, A ¹ , A ² , A ³ , R ¹ and R ² are as defined for compounds of formula (I) and R ¹⁰ is selected from the group consisting of -NH ₂ and -NH ₂ protected with a suitable protecting group, e.g. tert-butoxy carbonyl (Boc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), or benzyloxycarbonyl (Cbz) and R ¹¹ is selected from the group consisting of a suitable protecting group (e.g. tert-butoxycarbonyl (Boc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), or benzyloxycarbonyl (Cbz)) H, -C(=N)NH and -C(=N)NH protected with a suitable protecting group, e.g. te-brtutoxycarbonyl (Boc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), or benzyloxycarbonyl (Cbz).

[0509] The embodiments described above in respect of compounds of formulae (I) to (XX) and (XXVI) to (XXVIII) also apply to compounds of formula (Int-II) where possible.

[0510] The invention also provides compounds of formula (Int-III): including enantiomers, diastereomers, hydrates, solvates, and salts thereof, wherein q, A ¹ , A ² , R ¹ and R ² are as defined for compounds of formula (I) and R ¹⁰ is selected from the group consisting of -NFh and -NFh protected with a suitable protecting group, e.g. tert-butoxycarbonyl (Boc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), or benzyloxycarbonyl (Cbz), and R ¹² is halogen, e.g. chloro orbromo.

[0511] The embodiments described above in respect of compounds of formulae (I) to (XX) and (XXVI) to (XXVIII) also apply to compounds of formula (Int-III) where possible.

[0512] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

[0513] has the chemical name N ² ,N ⁵ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl ) phenyl] pyridine-2, 5 -dicarboxamide . [0514] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

[0515] has the chemical name N ² ,N ⁴ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl ) phenyl] pyridine -2,4-dicarboxamide.

[0516] For the purposes of the present invention, a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.

[0517] In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein.

PROCESS

[0518] The present invention further relates to a process for preparing the antifungal effect agents of the present invention.

[0519] Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

[0520] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

[0521] Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al, Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

[0522] The reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

[0523] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes.

GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS.

[0524] The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes. [0525] Compounds of formula (I) may be prepared according to the process outlined in schemes 1-120.

[0526] A compounds of the formula (1), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (2), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1 -ethyl-3 -(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). Alternatively, a compound of the formula (4), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (2), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). A compound of the formula (3) is reacted with a compound of the formula (5), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (6).

[0527] A compound of the formula (6) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (7). A compounds of the formula (7) is reacted with a compound of the formula (8) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9). A compound of the formula (9) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (10).

[0528] ). A compound of the formula (11) is reacted with a compound of the formula (12), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-1,1'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (13). A compound of the formula (13) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (14).

[0529] A compounds of the formula (14) is reacted with a compound of the formula (15) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16). A compound of the formula (16) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (17).

[0530] A compound of the formula (18) is reacted with a compound of the formula (19), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (20). A compound of the formula (20) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (21).

[0531] A compounds of the formula (21) is reacted with a compound of the formula (22) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (23). A compound of the formula (23) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24). [0532] A compound of the formula (25) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (26). Alternatively, a compound of the formula (25) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (26). A compounds of the formula (26) is reacted with a compound of the formula (27) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28). A compound of the formula (28) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (29).

[0533] A compound of the formula (30) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (31). Alternatively, a compound of the formula (30) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (31). A compounds of the formula (31) is reacted with a compound of the formula (32) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (33). A compound of the formula (33) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (34).

[0534] A compound of the formula (35) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36). Alternatively, a compound of the formula (35) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36). A compounds of the formula (36) is reacted with a compound of the formula (37) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (38). A compound of the formula (38) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (39).

[0535] A compound of the formula (40), a known compound or a compound prepared by known methods wherein Q ¹ is a C _{1 -6} alkyl, is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4- dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (41). A compounds of the formula (41) is reacted with a compound of the formula (42), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1 -[Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (43). A compound of the formula (43) is reacted with a compound of the formula (44), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso propyl-1,1'- biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfo nate, 2-di- tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-( 1,1'- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (45). A compound of the formula (45) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (46).

[0536] A compounds of the formula (46) is reacted with a compound of the formula (47) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (48). A compound of the formula (48) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (49). [0537] A compound of the formula (50) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51). Alternatively, a compound of the formula (50) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51). A compounds of the formula (51) is reacted with a compound of the formula (52) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (53). A compound of the formula (53) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (54). [0538] A compound of the formula (55) is reacted with a compound of the formula (56), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (57). A compound of the formula (57) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (58). A compounds of the formula (58) is reacted with a compound of the formula (59) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60).

[0539] A compound of the formula (60) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (61).

[0540] A compound of the formula (62) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (63). Alternatively, a compound of the formula (62) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran,

1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula

(63). A compounds of the formula (63) is reacted with a compound of the formula (64) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (65). A compound of the formula (65) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (66).

[0541] A compound of the formula (67) is reacted with a compound of the formula (68), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri( 1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-1,1'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (69). A compound of the formula (69) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (70). A compounds of the formula (70) is reacted with a compound of the formula (71) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (72).

[0542] A compound of the formula (72) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (73).

[0543] A compound of the formula (74) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (75). Alternatively, a compound of the formula (74) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (75). A compounds of the formula (75) is reacted with a compound of the formula (76) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (77). A compound of the formula (77) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (78).

[0544] A compound of the formula (79), a known compound or a compound prepared by known methods wherein Q ² is a Cl -6 alkyl, is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4- dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (80). A compounds of the formula (80) is reacted with a compound of the formula (81), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1 -[Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (82). A compound of the formula (82) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (83).

[0545] A compounds of the formula (83) is reacted with a compound of the formula (84) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (85). A compound of the formula (85) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86).

[0546] A compound of the formula (87), a known compound or a compound prepared by known methods wherein Q ³ is a C _1-6 alkyl, is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4- dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (88). A compounds of the formula (88) is reacted with a compound of the formula (89), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1 -[Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (90). A compound of the formula (90) is reacted with a compound of the formula (91), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso propyl-1,1'- biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfo nate, 2-di- tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-( 1,1'- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (92). A compound of the formula (92) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (93).

[0547] A compounds of the formula (93) is reacted with a compound of the formula (94) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (95). A compound of the formula (95) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (96). [0548] A compound of the formula (97) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (98). Alternatively, a compound of the formula (97) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (98). A compounds of the formula (98) is reacted with a compound of the formula (99) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (100). A compound of the formula (100) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (101). [0549] A compound of the formula (102) is reacted with a compound of the formula (103), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2', 4', 6 '-triisopropyl- 1 , 1 '-biphenyl, Sodium 2 '-dicyclohexylphosphino-2,6-dimethoxy- 1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(l,l'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (104). A compound of the formula (104) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (105). A compounds of the formula (105) is reacted with a compound of the formula (106) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (107).

[0550] A compound of the formula (107) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (108).

[0551] A compound of the formula (109) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (110). Alternatively, a compound of the formula (109) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (110). A compounds of the formula (110) is reacted with a compound of the formula (111) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (112). A compound of the formula (112) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (113).

[0552] A compound of the formula (114) is reacted with a compound of the formula (115), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-

2',4',6'-triisopropyl-1,1'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (116). A compound of the formula (116) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (117). A compounds of the formula (117) is reacted with a compound of the formula (118) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (119).

[0553] A compound of the formula (119) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (120).

[0554] A compound of the formula (121) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri( 1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (122). Alternatively, a compound of the formula (121) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (122). A compounds of the formula (122) is reacted with a compound of the formula (123) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (124). A compound of the formula (124) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (125).

[0555] A compound of the formula (126) is reacted with a compound of the formula (127) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (128). A compound of the formula (128) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (129). A compounds of the formula (129) is reacted with a compound of the formula (130) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (131). [0556] A compound of the formula (131) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).

[0557] A compound of the formula (133) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (134). A compound of the formula (134) is reacted with a compound of the formula (135), a known compound of a compound prepared by known methods, in the presence of a solvent such as a methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (136). A compound of the formula (136) is reacted with iodomethane in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (137). A compound of the formula (137) is reacted with a compound of the formula (138), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (139).

[0558] A compound of the formula (140), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (141) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (142). A compound of the formula (142) is reacted with a compound of the formula (139) in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium (II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (143). A compound of the formula (143) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (144).

[0559] A compound of the formula (145), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (146) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (147). A compound of the formula (147) is reacted with a compound of the formula (148) in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium (II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (149). A compound of the formula (149) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (150).

[0560] A compound of the formula (151), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (152) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (153). A compound of the formula (153) is reacted with a compound of the formula (154) in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium (II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (155). A compound of the formula (155) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (156).

[0561] A compound of the formula (157), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (158) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (159). A compound of the formula (159) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (160).

[0562] A compounds of the formula (161) is reacted with a compound of the formula (162), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'- dicyclohexylcarbodiimide, 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide, 1-

[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyr idinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N- dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (163). A compound of the formula (163) is reacted with a compound of the formula (164), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium (II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso propyl-1,1'- biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfo nate, 2-di- tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-( 1,1'- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (165). A compound of the formula (165) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (166).

[0563] A compounds of the formula (166) is reacted with a compound of the formula (167) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (168). A compound of the formula (168) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (169).

[0564] A compound of the formula (170) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (171). Alternatively, a compound of the formula (170) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (171). A compounds of the formula (171) is reacted with a compound of the formula (172) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (173). A compound of the formula (173) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (174).

[0565] A compound of the formula (175) is reacted with a compound of the formula (176), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (177). A compound of the formula (177) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (178). A compounds of the formula (178) is reacted with a compound of the formula (179) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (180).

[0566] A compound of the formula (180) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (181).

[0567] A compound of the formula (182) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (183). Alternatively, a compound of the formula (182) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (183). A compounds of the formula (183) is reacted with a compound of the formula (184) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (185). A compound of the formula (185) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (186).

[0568] A compound of the formula (187) is reacted with a compound of the formula (188), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(l,l'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (189). A compound of the formula (189) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (190). A compounds of the formula (190) is reacted with a compound of the formula (191) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (192).

[0569] A compound of the formula (192) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (193).

[0570] A compound of the formula (194) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (195). Alternatively, a compound of the formula (194) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (195). A compounds of the formula (195) is reacted with a compound of the formula (196) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (197). A compound of the formula (197) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (198).

[0571] A compound of the formula (199) is reacted with a compound of the formula (200) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (201). A compound of the formula (201) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (202). A compounds of the formula (202) is reacted with a compound of the formula (203) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (204).

[0572] A compound of the formula (204) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (205).

[0573] A compound of the formula (206) is reacted with a compounds of the formula (207) in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (208). A compound of the formula (208) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (209).

[0574] A compounds of the formula (210) is reacted with a compound of the formula (211), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'- dicyclohexylcarbodiimide, 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide, 1-

[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyr idinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N- dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (212). A compound of the formula (212) is reacted with a compound of the formula (213), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium (II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso propyl-1,1'- biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfo nate, 2-di- tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-( 1,1'- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (214). A compound of the formula (214) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (215).

[0575] A compounds of the formula (215) is reacted with a compound of the formula (216) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (217). A compound of the formula (217) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (218).

[0576] A compound of the formula (219) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri( 1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (220). Alternatively, a compound of the formula (219) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (220). A compounds of the formula (220) is reacted with a compound of the formula (221) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (222). A compound of the formula (222) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (223).

[0577] A compound of the formula (224) is reacted with a compound of the formula (225), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-1,1'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (226). A compound of the formula (226) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (227). A compounds of the formula (227) is reacted with a compound of the formula (228) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (229).

[0578] A compound of the formula (229) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (230).

[0579] A compound of the formula (231) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (232). Alternatively, a compound of the formula (231) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (232). A compounds of the formula (232) is reacted with a compound of the formula (233) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (234). A compound of the formula (234) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (235).

[0580] A compound of the formula (236) is reacted with a compound of the formula (237), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (238). A compound of the formula (238) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (239). A compounds of the formula (239) is reacted with a compound of the formula (240) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (241). [0581] A compound of the formula (241) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (242).

[0582] A compound of the formula (243) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (244). Alternatively, a compound of the formula (243) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (244). A compounds of the formula (244) is reacted with a compound of the formula (245) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (246). A compound of the formula (246) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (247).

[0583] A compound of the formula (248) is reacted with a compound of the formula (249) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (250). A compound of the formula (250) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (251). A compounds of the formula (251) is reacted with a compound of the formula (252) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (253).

[0584] A compound of the formula (253) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (254).

[0585] A compounds of the formula (255), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (256), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (257). Alternatively, a compound of the formula (258), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (256), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (257). A compound of the formula (257) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (259).

[0586] A compounds of the formula (259) is reacted with a compound of the formula (260) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (261). A compound of the formula (261) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (262).

[0587] A compounds of the formula (263) is reacted with a compound of the formula (264), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'- dicyclohexylcarbodiimide, 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide, 1-

[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyr idinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N- dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (265). A compound of the formula (265) is reacted with a compound of the formula (266), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium (II), palladium on carbon, bis(acetonitrile)dichloro palladium (II), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'-dimethoxybiphenyl, 2- dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso propyl-1,1'- biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-l,l'-biphenyl-3-sulfo nate, 2-di- tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-( 1,1'- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (267). A compound of the formula (267) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (268).

[0588] A compounds of the formula (268) is reacted with a compound of the formula (269) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (270). A compound of the formula (270) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (271).

[0589] A compound of the formula (272) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (273). Alternatively, a compound of the formula (272) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (273). A compounds of the formula (273) is reacted with a compound of the formula (274) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (275). A compound of the formula (275) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (276).

[0590] A compound of the formula (277) is reacted with a compound of the formula (278), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-1,1'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (279). A compound of the formula (279) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (280). A compounds of the formula (280) is reacted with a compound of the formula (281) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (282).

[0591] A compound of the formula (282) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (283). [0592] A compound of the formula (284) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (285). Alternatively, a compound of the formula (284) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (285). A compounds of the formula (285) is reacted with a compound of the formula (286) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (287). A compound of the formula (287) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (288).

[0593] A compound of the formula (289) is reacted with a compound of the formula (290), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2', 4', 6 '-triisopropyl- 1 , 1 '-biphenyl, Sodium 2 '-dicyclohexylphosphino-2,6-dimethoxy- 1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)-

N,N'-dimethyl-(l,l'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (291). A compound of the formula (291) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (292). A compounds of the formula (292) is reacted with a compound of the formula (293) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofiiran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (294).

[0594] A compound of the formula (294) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofiiran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (295). [0595] A compound of the formula (296) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (297). Alternatively, a compound of the formula (296) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (297). A compounds of the formula (297) is reacted with a compound of the formula (298) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (299). A compound of the formula (299) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (300). [0596] A compound of the formula (301) is reacted with a compound of the formula (302) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (303). A compound of the formula (303) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (304). A compounds of the formula (304) is reacted with a compound of the formula (305) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (306).

[0597] A compound of the formula (306) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (307).

[0598] A compound of the formula (308) is reacted with a compound of the formula (309), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)-

N,N'-dimethyl-(l,l'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (310). A compound of the formula (310) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (311). Alternatively, a compound of the formula (310) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation .to provide a compound of the formula (311). [0599] A compound of the formula (312) is reacted with a compound of the formula (313), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-l,T- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (314). A compound of the formula (314) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (315). Alternatively, a compound of the formula (314) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (315). A compound of the formula (315) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (316).

[0600] A compounds of the formula (316) is reacted with a compound of the formula (317) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (318). A compound of the formula (318) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (319).

[0601] A compound of the formula (320) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (321). Alternatively, a compound of the formula (320) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (321). A compounds of the formula (321) is reacted with a compound of the formula (322) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (323). A compound of the formula (323) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (324).

[0602] A compound of the formula (325) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (326). A compound of the formula (326) is reacted with a compound of the formula (327), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (328). A compound of the formula (328) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (328a). Alternatively, a compound of the formula (328) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (328a).

[0603] A compound of the formula (329) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (330). A compound of the formula (330) is reacted with a compound of the formula (331), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (332). A compound of the formula (332) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (333).

[0604] A compounds of the formula (334) is reacted with a compound of the formula (335) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (336). A compound of the formula (336) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (337).

[0605] A compound of the formula (338) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (339). Alternatively, a compound of the formula (338) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (339). A compounds of the formula (339) is reacted with a compound of the formula (340) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (341). A compound of the formula (341) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (342). [0606] A compound of the formula (343) is reacted with a compound of the formula (344) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (345). A compound of the formula (345) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (346). Alternatively, a compound of the formula (345) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation .to provide a compound of the formula (346).

[0607] A compound of the formula (347) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (348). A compound of the formula (348) is reacted with a compound of the formula (349), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (350).

[0608] A compound of the formula (351), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (352), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (353). A compound of the formula (353) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (354). A compounds of the formula (354) is reacted with a compound of the formula (355), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (356).

[0609] A compound of the formula (356) is reacted with a compound of the formula (357), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-l,T- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (358). A compound of the formula (358) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (359). Alternatively, a compound of the formula (358) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (359). A compound of the formula (359) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (360). [0610] A compounds of the formula (361) is reacted with a compound of the formula (362) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (363). A compound of the formula (363) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (364). [0611] A compound of the formula (365) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (366). A compound of the formula (366) is reacted with a compound of the formula (367), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (368). A compound of the formula (368) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (369).

[0612] A compounds of the formula (369) is reacted with a compound of the formula (370) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (371). A compound of the formula (371) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (372).

[0613] A compound of the formula (373) is reacted with a compound of the formula (374), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2', 4', 6 '-triisopropyl- 1 , 1 '-biphenyl, Sodium 2 '-dicyclohexylphosphino-2,6-dimethoxy- 1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(l,l'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (375). A compound of the formula (375) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (376). Alternatively, a compound of the formula (375) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (376). A compound of the formula (376) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (377).

[0614] A compounds of the formula (377) is reacted with a compound of the formula (378) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (379). A compound of the formula (379) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (380).

[0615] A compound of the formula (380) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (381). A compound of the formula (381) is reacted with a compound of the formula (382), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (383). A compound of the formula (383) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (384).

[0616] A compounds of the formula (385) is reacted with a compound of the formula (386) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (387). A compound of the formula (387) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (388).

[0617] A compound of the formula (389) is reacted with a compound of the formula (390) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (391). A compound of the formula (391) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (392). Alternatively, a compound of the formula (391) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (392). A compound of the formula (392) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (393).

[0618] A compounds of the formula (393) is reacted with a compound of the formula (394) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (395). A compound of the formula (395) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (397).

[0619] A compound of the formula (397) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (398). A compound of the formula (398) is reacted with a compound of the formula (399), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (400). A compound of the formula (400) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (401).

[0620] A compounds of the formula (401) is reacted with a compound of the formula (402) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (403). A compound of the formula (403) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (404).

[0621] A compound of the formula (405), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (406), a known compound or a compound prepared by known methods, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (407). A compound of the formula (407) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (408). A compounds of the formula (408) is reacted with a compound of the formula (409), a known compound or a compound made by known methods, in the presence of a coupling agent such as 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (410).

[0622] A compound of the formula (410) is reacted with a compound of the formula (411), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-l,T- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(1,1'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (412). A compound of the formula (412) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (413). Alternatively, a compound of the formula (412) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (413). A compound of the formula (413) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (414).

[0623] A compounds of the formula (415) is reacted with a compound of the formula (416) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (417). A compound of the formula (417) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (418). [0624] A compound of the formula (419) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (420). A compound of the formula (420) is reacted with a compound of the formula (421), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (422). A compound of the formula (422) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (423).

[0625] A compounds of the formula (424) is reacted with a compound of the formula (425) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (426). A compound of the formula (426) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (427).

[0626] A compound of the formula (428) is reacted with a compound of the formula (429), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(l,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl (2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2',6'- dimethoxybiphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-di-tert-butylphosphino-2',4',6'- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl- 2',4',6'-triisopropyl-l,l'-biphenyl, Sodium 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'- biphenyl-3 -sulfonate, 2-di-tert-butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'- methylbiphenyl, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2 -amine, 2'-(diphenylphosphino)- N,N'-dimethyl-(l,l'-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (430). A compound of the formula (430) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (431). Alternatively, a compound of the formula (430) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (431). A compound of the formula (431) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (432).

[0627] A compounds of the formula (433) is reacted with a compound of the formula (434) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (435). A compound of the formula (435) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran,

1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (436).

[0628] A compound of the formula (437) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (438). A compound of the formula (438) is reacted with a compound of the formula (439), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (440). A compound of the formula (440) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (441).

[0629] A compounds of the formula (442) is reacted with a compound of the formula (443) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (444). A compound of the formula (444) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (445).

[0630] A compound of the formula (446) is reacted with a compound of the formula (447) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (448). A compound of the formula (448) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (449). Alternatively, a compound of the formula (448) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (449). A compound of the formula (449) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (450).

[0631] A compounds of the formula (451) is reacted with a compound of the formula (452) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (453). A compound of the formula (453) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (454).

[0632] A compound of the formula (455) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (456). A compound of the formula (456) is reacted with a compound of the formula (457), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (458). A compound of the formula (458) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (459).

[0633] A compounds of the formula (460) is reacted with a compound of the formula (461) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (462). A compound of the formula (462) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (463). [0634] A compound of the formula (464) is reacted with a compound of the formula (465) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (466). A compound of the formula (466) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (467).

[0635] A compounds of the formula (468) is reacted with a compound of the formula (468) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (470). A compound of the formula (470) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (471).

[0636] A compound of the formula (472) is reacted with a compound of the formula (473) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (474). A compound of the formula (474) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (475). A compounds of the formula (476) is reacted with a compound of the formula (477) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (478).

[0637] A compound of the formula (479) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (480).

[0638] A compound of the formula (481) is reacted with a compound of the formula (482) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (483). A compound of the formula (483) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (484). Alternatively, a compound of the formula (483) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation .to provide a compound of the formula (484).

[0639] A compound of the formula (485) is reacted with a compound of the formula (486) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (487). A compound of the formula (487) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (488). A compound of the formula (488) is reacted with a compound of the formula (489), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (490).

[0640] A compound of the formula (491) is reacted with a compound of the formula (492) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (493). A compound of the formula (493) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (494). Alternatively, a compound of the formula (493) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. to provide a compound of the formula (494). A compound of the formula (494) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (495).

[0641] A compounds of the formula (496) is reacted with a compound of the formula (497) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (498). A compound of the formula (498) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (499).

[0642] A compound of the formula (500) is reacted with a compound of the formula (501) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (502). A compound of the formula (502) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (503). A compound of the formula (503) is reacted with a compound of the formula (504), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (505).

[0643] ). A compound of the formula (506) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (507). A compounds of the formula (507) is reacted with a compound of the formula (508) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (509). A compound of the formula (509) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (510). [0644] A compound of the formula (511), a known compound or a comopound prepared by known methods, is reacted with a compound of the formula (512), a known compound or a compound prepared by known methods, in the presence of a solvent such as methanol, ethanol, isopropanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (513). A compound of the formula (513) is reacted with di-tert-butyl decarbonate in the presence of a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, optionally in the presence of water, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (514). A compound of the formula (514) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), l,l'-bis(diphenylphosphino)ferrocene]dichloro palladium(II), bispalladium-tri(l,3-dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (515).

[0645] A compounds of the formula (515), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (516), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (517). A compound of the formula (517) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (518).

[0646] A compound of the formula (519), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (520), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (521).

[0647] The Examples provided below provide representative methods for preparing exemplary compounds of the present invention. The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds of the present invention.

[0648] The following LC/MS procedure was used for the analysis of the examples described herein. LC/MS data were determined with a Waters Alliance 2695 HPLC/MS (Waters Symmetry C18, 4.6 x 75 mm, 3.5 pm) with a 2996 diode array detector from 210-400 nm; the solvent system is 5-95% acetonitrile in water (with 0.1% trifluoroacetic acid) over nine minutes using a linear gradient, and retention times are in minutes. Mass spectrometry was performed on a Waters ZQ using electrospray in positive mode.

[0649] Preparative reverse phase HPLC was performed on a Phenomenex LUNA column (19 x 100 mm, Cl 8, 5 pm) with a 10 minute mobile phase gradient of 10% acetonitrile/water to 90% acetonitrile/ water with 0.1% trifluoroacetic acid as buffer using 214 and 254 nm as detection wavelengths. Injection and fraction collection were performed with a Gilson 215 liquid handling apparatus using Trilution LC software.

[0650] 'H-NMR ^' s were taken on a Varian 300 MHz NMR using tetramethylsilane (TMS) as internal standard (d = 0.00) with peaks reported downfield from TMS.

[0651] The examples provides methods for preparing representative compounds of formulas (I) through (XXVIII). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention.

[0652] General experimental procedures: The general experimental procedures described herein can be used by one skilled in the art to prepare the compounds of the disclosure and the intermediates necessary for preparation of the compounds of the disclosure.

[0653] Example 1: Sythensis of N ² ,N ⁵ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)phenyl]pyridine-2, 5 -dicarboxamide

[0654] Synthesis of Pyridine-2, 5-dicarbonyl dichloride: Pyridine-2,5 -dicarboxylic acid (0.50 g, 3.2 mmol) was suspended in thionyl chloride (5 ml) in a pressure vessel and heated to 100 °C for 48 hours. The solvent was evaporated to leave a solid (0.63 g, 97%).

[0655] Synthesis of N ² ,N ⁵ -bis(4-bromophenyl)pyridine-2, 5 -dicarboxamide: To a solution of Pyridine-2,5 -dicarbonyl dichloride (100 mg, 0.49 mmol) in N,N-dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.32 g, 2.5 mmol, 0.44 ml) followed by the addition of 4- bromoaniline (0.21 g, 1.2 mmol). The mixture stirred for 18 hours then water (3 ml) was added and the mixture stirred for 30 minutes. The resulting precipitate was filtered, washed with water and methanol and dried to leave the product as a solid (135 mg, 58%). [0656] Synthesis of N ² ,N ⁵ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine -2,5- dicarboxamide: A mixture of N ² ,N ⁵ -bis(4-bromophenyl)pyridine-2, 5 -dicarboxamide (50 mg, 0.11 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetr ahydropyridine -1-carboxylate (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) was diluted with water (0.4 ml) and 1,4-dioxane (1 ml). The mixture was purged with nitrogen, stirred and heated to 90 °C for 18 hours. After cooling to 20 °C the mixture was treated with water (20 ml) and dichloromethane (20 ml). The layers were separated and the organic layer was dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by reversed phase chromatography. The product fractions were neutralized with saturated NaHCO ₃ and extracted with dichloromethane. The organic extracts were dried (Na ₂ SO ₄ ) and evaporated. The pure product was dissolved in trifluoroacetic acid and dichloromethane (1:1, 2 ml) and stirred for 2 hours. The solvent was evaporated and the residue was dissolved in water and lyophilized. The product was a light yellow powder (17 mg, 22%).

[0657] Synthesis of: N ² ,N ⁵ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl )phenyl] pyridine-2,5 -dicarboxamide: A solution of N ² ,N ⁵ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl]pyridine-2, 5 -dicarboxamide (15 mg, 21 μmol), tert-butyl N-[(E)-{[(tert-butoxy) carbonyl]imino}(lH-pyrazol-1-yl)methyl]carbamate (20 mg, 63 μmol), N,N-diisopropylethylamine (27 mg, 0.21 mmol, 38 μl) in methanol (2 ml) was stirred for 24 hours followed by purification by reversed phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with dichloromethane (2 X 25 ml). The extracts were dried (Na ₂ SO ₄ ) and evaporated and the product was dissolved in trifluoroacetic acid-dichloromethane (1:1, 2 ml) for 2 h. The solvent was evaporated and the product was suspended in water (1 ml) and sonicated to give a white milky suspension. The suspension was lyophilized to leave the bis trifluoroacetic acid salt as a white powder (16 mg, 96%). ¾-NMR (DMSO-d ₆ ) d 10.82 (s, 1H), 10.70 (s, 1H), 9.19 (s, 1H), 8.55 (dd, 1H, J = 8.3 Hz, J = 2.4 Hz), 8.27 (d, 1H, J = 8.3 Hz), 7.94 (d, 2H, J = 8.9 Hz), 7.78 (d, 1H, J = 8.9 Hz), 7.51 (d, 2H, J = 8.7 Hz), 7.49 (d, 2H, J = 8.7 Hz), 7.40 (bs, 8H), 6.2 (s, 2H), 4.06 (m, 4H), 3.60 (m, 4H), 2.60 (m, 4H). LCMS (M+H ⁺ ) = 564, R _t = 3.16 mins., purity > 95%.

[0658] Example 2: Synthesis of N ² ,N ⁴ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin -4-yl)phenyl] pyridine-2, 4-dicarboxamide

[0659] Synthesis of pyridine-2, 4-dicarbonyl dichloride: Pyridine-2, 4-dicarboxylic acid (0.50 g, 3.2 mmol) was suspended in thionyl chloride (5 ml) in a pressure vessel and heated to 100 °C for 48 hours. The solvent was evaporated to leave a solid (0.60 g, 92%).

[0660] Synthesis of N ² ,N ⁴ -bis(4-bromophenyl)pyridine-2, 4-dicarboxamide: To a solution of Pyridine-2, 4-dicarbonyl dichloride (100 mg, 0.49 mmol) in N,N-dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.32 g, 2.5 mmol, 0.44 ml) followed by the addition of 4- bromoaniline (0.21 g, 1.2 mmol). The mixture stirred for 18 hours then water (3 ml) was added and the mixture stirred for 30 minutes. The resulting precipitate was filtered , washed with water and a small amount of methanol and dried to leave the product as a solid (70 mg, 30%). [0661] Synthesis of N ² ,N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine -2,4- dicarboxamide: A mixture of N ² ,N ⁴ -bis(4-bromophenyl)pyridine-2, 4-dicarboxamide, 50 mg, 0.11 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetr ahydropyridine -1-carboxylate (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) was diluted with water (0.4 ml) and 1,4-dioxane (1 ml). The mixture was purged with nitrogen, stirred and heated to 90 °C for 18 hours. After cooling to 20 °C the mixture was treated with water (20 ml) and dichloromethane (20 ml). The layers were separated and the organic layer was dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by reversed phase chromatography. The product fractions were neutralized with saturated NaHCO ₃ and extracted with dichloromethane. The organic extracts were dried (Na ₂ SO ₄ ) and evaporated. The pure product was dissolved in trifluoroacetic acid and dichloromethane (1:1, 2 ml) and stirred for 2 hours. The solvent was evaporated and the residue was dissolved in water and lyophilized. The product was a light yellow powder (25 mg, 32%).

[0662] Synthesis of N ² ,N ⁴ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl )phenyl] pyridine -2,4-dicarboxamide: A solution of N ² ,N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl]pyridine-2, 4-dicarboxamide (25 mg, 35 μmol), tert-butyl N-[(E)-{[(tert-butoxy)carbonyl] imino}(lH- pyrazol-1-yl)methyl]carbamate (33 mg, 105 μmol), N,N-diisopropylethylamine (45 mg, 0.35 mmol, 63 μl) in methanol (2 ml) was stirred for 24 hours followed by purification by reversed phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with dichloromethane (2 X 25 ml). The extracts were dried (Na ₂ SO ₄ ) and evaporated and the product was dissolved in trifluoroacetic acid-dichloromethane (1:1, 2 ml) for 2 hours. The solvent was evaporated and the product was suspended in water (1 ml) and sonicated to give a white milky suspension. The suspension was lyophilized to leave the bis trifluoroacetic acid salt as a white powder (15 mg, 54%). ¹ H-NMR (DMSO-d ₆ ) 10.82 (d, 1H, J=4.5 Hz), 8.95 (d, 1H, J=5.2 Hz), 8.63 (s, 1H), 8.15 (dd, 1H, J = 5.0 Hz, J = 1.7 Hz), 7.94 (d, 2H, J = 8.8 Hz), 7.81 (d, 2H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.49 (d, 2H, J = 8.8 Hz), 7.43 (bs, 8H), 6.2 (s, 2H), 4.06 (m, 4H), 3.62 (m, 4H), 2.58 (m, 4H). LCMS (M+H ⁺ ) = 564, R, = 3. 18 mins., purity > 95%. [0663] Example 3: Synthesis of N ² ,N ⁴ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin -4-yl)phenyl] pyridine-3 ,5 -dicarboxamide

[0664] Synthesis of pyridine-3, 5-dicarbonyl dichloride: Pyridine-3, 5-dicarboxylic acid (0.50 g, 3.2 mmol) was suspended in thionyl chloride (5 ml) in a pressure vessel and heated to 100 °C for 48 hours. The solvent was evaporated to leave a solid (0.60 g, 92%).

[0665] Synthesis of N ² ,N ⁴ -bis(4-bromophenyl)pyridine-3, 5 -dicarboxamide: To a solution of pyridine-3, 5-dicarbonyl dichloride (100 mg, 0.49 mmol) in N,N-dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.32 g, 2.5 mmol, 0.44 ml) followed by the addition of 4- bromoaniline (0.21 g, 1.2 mmol). The mixture stirred for 18 hours then water (3 ml) was added and the mixture stirred for 30 minutes. The resulting precipitate was filtered, washed with water and a small amount of methanol and dried to leave the product as a solid (138 mg, 59%). [0666] Synthesis of N ² ,N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine -3,5- dicarboxamide: A mixture of N ² ,N ⁴ -bis(4-bromophenyl)pyridine-3, 5 -dicarboxamide, 50 mg, 0.11 mmol), tert-butyl

4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-t etrahydropyridine-1-carboxylate (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) was diluted with water (0.4 ml) and

1,4-dioxane (1 ml). The mixture was purged with nitrogen, stirred and heated to 90 °C for 18 hours. After cooling to 20 °C the mixture was treated with water (20 ml) and dichloromethane (20 ml). The layers were separated and the organic layer was dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by reversed phase chromatography. The product fractions were neutralized with saturated NaHCO ₃ and extracted with dichloromethane. The organic extracts were dried (Na ₂ SO ₄ ) and evaporated. The pure product was dissolved in trifluoroacetic acid and dichloromethane (1:1, 2 ml) and stirred for 2 hours. The solvent was evaporated and the residue was dissolved in water and lyophilized. The product was a light yellow powder (29 mg, 37%).

[0667] Synthesis of N ² ,N ⁴ -bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl )phenyl] pyridine-3, 5-dicarboxamide: A solution of N ² ,N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl]pyridine-3, 5 -dicarboxamide (25 mg, 35 μmol), tert-butyl N-[(E)-{[(tert-butoxy)carbonyl] imino}(lH-pyrazol-1-yl)methyl] carbamate (33 mg, 105 μmol), N,N-diisopropylethylamine (45 mg, 0.35 mmol, 63 μl) in methanol (2 ml) was stirred for 24 hours followed by purification by reversed phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with dichloromethane (2 X 25 ml). The extracts were dried (Na ₂ SO ₄ ) and evaporated and the product was dissolved in trifluoroacetic acid-dichloromethane (1:1, 2 ml) for 2 hours. The solvent was evaporated and the product was suspended in water (1 ml) and sonicated to give a white milky suspension. The suspension was lyophilized to leave the bis trifluoroacetic acid salt as a white powder (5 mg, 19%). ¹ H-NMR (DMSO-d ₆ ) 10.67 (bs, 2H), 9.25 (d, 1H, J=2.0 Hz), 8.81 (t, 1H, J=2.0 Hz), 7.79 (d, 4H, J=8.8 Hz), 7.71 (s, 1H), 7.50 (d, 2H, J = 8.8 Hz), 7.40 (bs, 8H), 6.20 (m, 2H), 4.06 (m, 4H), 3.60 (m, 4H), 2.55 (m, 4H). LCMS (M+H ⁺ ) = 564, R 2.93 mins., purity > 95%.

[0668] Example 4: Synthesis of N ² ,N6-bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin -4-yl)phenyl] pyrazine-2, 6-dicarboxamide [0669] Synthesis of N ² ,N ⁶ -bis(4-bromophenyl)pyrazine-2, 6-dicarboxamide: To a solution of pyridine-2, 6-dicarboxylic acid (500 mg, 3.0 mmol), N,N-dimethylformamide (25 μl) and N,N- diisopropylethylamine (1.8 g, 14 mmol, 2.5 ml) in chloroform (25 ml) to 0 °C was added oxalyl chloride (0.84 g, 6.6 mmol, 0.57 ml) over 10 minutes. After stirring for 30 minutes, the ice bath was removed and 4-bromoaniline (1.3 g, 7.5 mmol) was added to the mixture. Stirred for 18 hours then filtered to remove N,N-diisopropylethylamine HC1 salt. The filtrate was washed with water (25 ml), dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by RPHPLC to leave a major product (0.65 g, mono substituted pyrazine) and a minor product (desired bis substituted pyrazine, 70 mg, 5%).

[0670] Synthesis of N ² ,N ⁶ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyrazine -2,6 -dicarboxamide: A mixture of N ² ,N ⁶ -bis(4-bromophenyl)pyrazine-2, 6-dicarboxamide (50 mg, 0.10 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetr ahydropyridine -1-carboxylate (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) was diluted with water (0.4 ml) and 1,4-dioxane (1 ml). The mixture was purged with nitrogen, stirred and heated to 90 °C for 18 hours. After cooling to 20 °C the mixture was treated with water (8 ml) and N,N- dimethylformamide (8 ml). The resulting precipitate was filtered, washed with water and methanol and dried to leave a grayish green solid (56 mg, 82%). The product was dissolved in trifluoroacetic acid and dichloromethane (1:1, 2 ml) and stirred for 2 hours. The solvent was evaporated and the residue was suspended in water, sonicated to form a fine emulsion and lyophilized. The product was a powder (53 mg, 75%).

[0671] Synthesis of N ² ,N6-bis[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4 -yl)phenyl] pyrazine-2, 6-dicarboxamide: A suspension of N ² ,N ⁶ -bis[4-(1,2,3,6-tetrahydropyridin

-4-yl)phenyl]pyridine-2, 6-dicarboxamide (49 mg, 69 μmol), tert-butyl N-[(E)-{[(tert-butoxy) carbonyl]imino}(lH-pyrazol-1-yl)methyl]carbamate (64 mg, 208 μmol) and N,N- diisopropylethylamine (89 mg, 0.69 mmol, 124 μl) in methanol (2 ml) was stirred for 24 hours. To the suspension was added DMSO (3 ml) to solubilize and the product was purified by reversed phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with ethyl acetate (2 X 50 ml). The extracts were dried (MgSO ₄ ) and evaporated and the product was dissolved in trifluoroacetic acid-dichloromethane (1:1, 2 ml) for 2 hours. The solvent was evaporated and the product was suspended in water (1 ml) and sonicated to give a white milky suspension. The suspension was lyophilized to leave the bis trifluoroacetic acid salt as a white powder (38 mg, 70%). ¹ H-NMR (DMSO-d ₆ ) 11.03 (bs, 2H), 9.50 (s, 2H), 7.90 (d, 4H, J=8.8 Hz), 7.56 (d, 4H, J=8.8 Hz), 7.45 (bs, 8H), 6.22 (m, 2H), 4.07 (m, 4H), 3.62 (m, 4H), 2.60 (m, 4H). LCMS (M+H ⁺ ) = 565, R, = 3.22 mins., purity > 95%.

[0672] Example 5: Synthesis of N ⁴ ,N ⁶ -bis(4- {2-[(4, 5-dihydro- lH-imidazol-2-yl)amino]ethyl} phenyl) pyrimidine-4, 6-dicarboxamide

[0673] Synthesis of pyrimidine-4, 6-dicarbonyl dichloride: Pyrimidine-4, 6-dicarboxylic acid (0.50 g, 3.0 mmol) was suspended in thionyl chloride (5 ml) and refluxed for 3 h. The solvent was evaporated, the crude product was dissolved in dichloromethane, filtered through a pad of celite and the solvent evaporated to leave a solid (0.47 g, 77%). [0674] Synthesis of tert-butyl 2-{[2-(4-nitrophenyl)ethyl]amino}-4,5-dihydro-lH-imidazole- 1-carboxylate: A solution of 2-(4-nitrophenyl)-1-aminoethane (0.50 g, 3.0 mmol) and 2-methylthio- 4, 5 -dihydroimidazole hydroiodide (0.66 g, 2.7 mmol) in ethanol (5 ml) was refluxed for 5 hours and the solvents were evaporated to leave a thick oil which was dissolved in dichloromethane (10 ml) and IN NaOH (4.5 ml) followed by the addition of Boc anhydride (0.74 g, 3.5 mmol). The mixture stirred for 2 hours, the organic layer was separated, dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by reversed phase HPLC and the product fractions were combined, treated with saturated NaHCO ₃ solution and extracted with ethyl acetate (2 X 50 ml). The extracts were washed with brine (50 ml), dried (MgSO ₄ ) and evaporated to a thick oil (455 mg, 50%).

[0675] Synthesis of tert-butyl 2-{[2-(4-aminophenyl)ethyl]amino}-4,5-dihydro-lH- imidazole-1-carboxylate: A solution of tert-butyl 2-{[2-(4-nitrophenyl)ethyl]amino}-4, 5-dihydro- 1H- imidazole-1-carboxylate (0.30 g, 0.90 mmol) in methanol (5 ml) was hydrogenated at 45 psi initial pressure over 10% Pd/C (45 mg) for 2 hours. The catalyst was filtered, washed with methanol and the filtrate was evaporated to leave the product as clear gum (245 mg, 90%).

[0676] Synthesis of N ⁴ ,N ⁶ -bis(4-{2-[(4,5-dihydro-lH-imidazol-2-yl)amino]ethyl}p henyl) pyrimidine-4, 6-dicarboxamide: A solution of tert-butyl 2-{[2-(4-aminophenyl)ethyl]amino}-4,5- dihydro-lH-imidazole-1-carboxylate (59 mg, 176 μmol) and N,N-diisopropylethylamine (28 mg, 219 μmol, 39 μl) in N,N-dimethylformamide (0.5 ml) was treated with pyrimidine-4, 6-dicarbonyl dichloride (15 mg, 73 μmol) and stirred 18 hours. The mixture was diluted with ethyl acetate (50 ml) and saturated NaHCO ₃ (50 ml), separated, and the organic layer was washed with water (50 ml), dried (MgSO ₄ ) and evaporated. The product was purified by reversed phase HPLC. The product fractions were combined and evaporated. The Boc protecting groups were removed during evaporation to leave a gum (13 mg, 23%). ¹ H-NMR (DMSO-d ₆ ) 10.92 (s, 2H), 9.57 (s, 1H), 8.61 (s, 1H), 8.30 (t, 2H, J=5.9 Hz), 8.0 (bs, 4H), 7.85 (d, 4H, J=8.5 Hz), 7.27 (d, 4H, J=8.5 Hz), 3.37 (dt, 4H, J=5.9 Hz, J=6.7

Hz), 2.78 (t, 4H, J=6.7 Hz). LCMS (M+H ⁺ ) = 541, R, = 1.08 mins., purity > 95%.

[0677] Example 6: Synthesis of N ⁴ ,N ⁶ -bis({4-[2-(N-methylcarbamimidamido)ethyl]phenyl}) pyrimidine-4, 6-dicarboxamide

[0678] Synthesis of tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}({methyl[2-(4- nitrophenyl)ethyl] amino })methyl] carbamate: A solution of 2-(4-nitrophenyl)-1-(methylamino)ethane (0.50 g, 2.3 mmol) and N,N-diisopropylethylamine (0.59 g, 4.6 mmol, 0.82 ml) in N,N- dimethylformamide (5 ml) was treated with tert-butyl N-[(E)-{[(tert-butoxy) carbonyl]imino}(lH-pyrazol-1-yl)methyl]carbamate (0.86 g, 2.8 mmol) and the solution stirred for 2 hours. The mixture was diluted with ethyl acetate (100 ml), washed with water (50 ml), IN HC1 (50 ml) and brine (25 ml). The solution was dried (MgSCE) and evaporated. The crude product was purified by chromatography on silica gel (ethyl acetate -hexane gradient 10-60%) to leave the desired product (242 mg, 25%).

[0679] Synthesis of tert-butyl N-[(E)-{[2-(4-aminophenyl)ethyl](methyl)amino}({[(tert- butoxy)carbonyl]imino})methyl] carbamate: A solution of tert-butyl N-[(E)-{[(tert-butoxy)carbonyl] imino}({methyl[2-(4-nitrophenyl)ethyl]amino})methyl]carbamat e (0.24 g, 0.57 mmol) in methanol (5 ml) was hydrogenated at 45 psi initial pressure over 10% Pd/C (40 mg) for 2hours. The catalyst was removed by filtration, washed with methanol and the filtrate was evaporated to leave the product as clear gum (201 mg, 90%).

[0680] Synthesis of N ⁴ ,N ⁶ -bis({4-[2-(N-methylcarbamimidamido)ethyl]phenyl})pyri midine- 4,6-dicarboxamide: A solution of tert-butyl N-[(E)-{[2-(4-aminophenyl)ethyl](methyl) amino}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (115 mg, 0.29 mmol) and N,N- diisopropylethylamine (39 mg, 0.30 mmol, 54 mΐ) in N,N-dimethylformamide (2 ml) was treated with pyrimidine-4, 6-dicarbonyl dichloride (25 mg, 0.12 mmol) and stirred for 2 hours. The mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml), IN HC1 (25 ml) and brine (25 ml). The solution was dried (MgSO ₄ ) and evaporated. The crude product was purified on silica gel eluted with a gradient of ethyl acetate in hexanes (30-100%) to leave 71 mg (65%) of light yellow gum. This was dissolved in a 1:1 mix of trifluoroacetic acid-dichloromethane and stirred for 2 hours. The solvents were evaporated to leave a light tam powder (64 mg, 94%). ¹ H-NMR (DMSO-d ₆ ) 10.91 (s, 2H), 9.57 (s, 1H), 8.60 (s, 1H), 7.86 (d, 4H, J=8.5 Hz), 7.30 (d, 4H, J=8.5 Hz), 7.25 (bs, 8H), 3.54 (t, 4H, J=7.6 Hz), 2.81 (t, 4H, J=7.6 Hz). LCMS (M+H ⁺ ) = 517. R, = 1.08 mins., purity > 95%.

[0681] Example 7: Synthesis ofN,N'-bis-(4-guanidino-phenyl)-terephthalamide

[0682] Synthesis of tert-butyl N-(4-{4-[(4-{[(tert-butoxy)carbonyl]amino}phenyl) carbamoyl]benzamido}phenyl)carbamate: To a mixture of (4-amino-phenyl)-carbamic acid tert-butyl ester (916 mg, 4.40 mmol), and diisopropylethylamine (892 mg, 1200 μL, 6.92 mmol) in CHCl ₃ (6 mL) was added a mixture of terephthaloyl dichloride (447 mg, 2.20 mmol) in CHCI ₃ (6 mL). The reaction was stirred for 16 hours, then was treated with additional CHCI ₃ (20 mL), then was sonicated for 2 minutes, and was filtered. The solid was washed with water (20 mL), isopropanol (20 mL), and hexanes (20 mL), to give tert-butyl N-(4-{4-[(4-{[(tert-butoxy)carbonyl]amino}phenyl)carbamoyl] benzamido}phenyl)carbamate (1.06 g, 88%) as a white solid.

[0683] Synthesis of N,N'-bis-(4-amino-phenyl)-terephthalamide: A mixture of tert-butyl N- (4-{4-[(4-{ [(tert-butoxy)carbonyl]amino}phenyl)carbamoyl]benzamido}phen yl)carbamate ( 1.06 g, 1.94 mmol) in CH ₂ CI ₂ (13 mL) and methanol (7 mL) was treated with a 4N solution of HC1 in 1,4- dioxane (5 mL). The reaction was stirred for 4 days, then was concentrated. The residue was treated with N,N-dimethylformamide (15 mL), and a 4N solution of HC1 in 1,4-dioxane (5 mL). The reaction was stirred for 16 hours, then was treated with water (50 mL), and was filtered. The solid was washed with isopropanol (30 mL), and then hexanes (30 mL). The solid was treated with DMSO (15 mL), followed by a 4N solution of HC1 in 1,4-dioxane (5 mL). The reaction was stirred for 4 days, then was treated with water (70 mL), and was filtered. The solid was washed with isopropanol (20 mL), and then hexanes (20 mL). The solid was slurried in CH ₂ Cl ₂ (10 mL), then was treated with trifluoroacetic acid (6 mL). The reaction was stirred for 16 hours, then was concentrated, to give N,N'-bis-(4-amino-phenyl)-terephthalamide as the bis- trifluoroacetic acid salt (604 mg, 54%) as a white solid.

[0684] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}[(4-{4-[(4-{[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino }phenyl)carbamoyl] benzamido}phenyl)amino]methylidene]carbamate (SB-10-126): A mixture of N,N'-bis-(4-amino- phenyl)-terephthalamide. 2 trifluoroacetic acid (230 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-1-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was concentrated, then the residue was treated with water (20 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), then was treated with 10% aqueous citric acid (20 mL) and was filtered through Celite. The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}[(4- {4-[(4-{[(lZ)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy) carbonyl]imino})methyl]amino}phenyl) carbamoyl]benzamido}phenyl)amino]methylidene]carbamate (110 mg, 33%) as a beige solid. [0685] Synthesis of N,N'-bis-(4-guanidino-phenyl)-terephthalamide: A mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}[(4-{4-[(4-{[(lZ)-{[(t ert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } phenyl)carbamoyl] benzamido } phenyl) amino] methylidene] carbamate (110 mg, 0.13 mmol) in CH ₂ CI ₂ (1.3 mL) was treated with trifluoroacetic acid (1.3 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative -HPLC, to give N,N'-bis-(4-guanidino-phenyl)-terephthalamide as the bis- trifluoroacetic acid salt (64 mg, 75%) as a white solid. MS: 431 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.53 (s, 1 H) 9.72 (s, 1 H) 8.09 (s, 2 H) 7.86 (d, J=8.79 Hz, 2 H) 7.40 (s, 4 H) 7.24 (d, J=8.79 Hz, 2 H).

[0686] Example 8: Synthesis of 2-fluoro-N1,N4-bis(4-(guanidinomethyl)phenyl) terephthalamide

[0687] Synthesis of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2-fluoro- benzoylamino} -benzyl) -carbamic acid tert-butyl ester. To a mixture of 2-fluoro-terephthabc acid (368 mg, 2.00 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (987 mg, 4.44 mmol), and triethylamine (947 mg, 1120 μL, 8.00 mmol) in N,N-dimethylformamide (6 mL) was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (2272 mg, 6.00 mmol). The reaction was stirred for 4 days, then was treated with water (90 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with water (30 mL), isopropanol (30 mL), and hexanes (30 mL), to give (4-{4-[4-(tert-butoxycarbonylamino- methyl)-phenylcarbamoyl]-2-fluoro-benzoylamino}-benzyl)-carb amic acid tert-butyl ester (1.00 g, 84%) as a white solid.

[0688] Synthesis of N ¹ N ⁴ -bis-(arninornethylphenyl)-fluoroterephthalarnide: A mixture of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2-fluoro-benzoylamino}-benzyl)- carbamic acid tert-butyl ester (0.99 g, 1.67 mmol) in CH ₂ CL ₂ (15 mL) was treated with trifluoroacetic acid (6 mL). The reaction was stirred for 16 hours, then was treated with methanol (10 mL), and was concentrated. The residue was treated with ethyl acetate (50 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with hexanes (20 mL), to give xxx as the bis- trifluoroacetic acid salt (0.98 g, 95%) as a white solid.

[0689] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }-2-fluorobenzamido)phenyl]methyl}amino)methylidene] carbamate. A mixture of N'.N ⁴ - bis(4-(aminomethyl)phenyl)-2-fluoroterephthalamide 2 trifluoroacetic acid (248 mg, 0.40 mmol) in N,N-dimethylformamide 3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-1- guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was concentrated, then the residue was treated with water (20 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-({[(lE)-{[ (tert- butoxy)carbonyl] amino } ( { [(tert-butoxy) carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } -

2-fluorobenzamido)phenyl]methyl} amino)methylidene] carbamate (299 mg, 85%) as a white solid. [0690] Synthesis of 2-fluoro-Nl,N4-bis(4-(guanidinomethyl)phenyl)terephthalamide : A mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-({[(lE)-{[ (tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } - 2-fluorobenzamido)phenyl]methyl}amino)methylidene]carbamate (299 mg, 0.34 mmol) in CH ₂ CL ₂ (3.4 mL) was treated with trifluoroacetic acid (3.4 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 2-fluoro-Nl,N4- bis(4-(guanidinomethyl)phenyl)terephthalamide as the bis- trifluoroacetic acid salt (198 mg, 83%) as a white solid. MS: 477 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.59 (s, 1 H) 10.46 (s, 1 H) 7.91 (d, J= 9.37 Hz, 5 H) 7.67 - 7.86 (m, 6 H) 7.22 - 7.35 (m, 7 H) 4.34 (d, 7=5.27 Hz, 4 H). [0691] Example 9: Synthesis of trans-cyclohexane- 1,4-dicarboxylic acid bis-[(4- guanidinomethy1-phenyl)-amide]

[0692] Synthesis of [4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -trans- cyclohexanecarbonyl}-amino)-benzyl]-carbamic acid tert-butyl ester. The title compound was prepared according the procedure of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2-fluoro-benzoylamino}-benzyl)-carbamic acid tert-butyl ester except that 2-fluoro-terephthalic acid was replaced with trans-yclohexane- 1,4-dicarboxylic acid (344 mg, 2.00 mmol), and using (4-amino- benzyl)-carbamic acid tert-butyl ester (987 mg, 4.44 mmol), to give [4-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-trans-cyclohexa necarbonyl}-amino)-benzyl]- carbamic acid tert-butyl ester (1.09 g, 94%) as a white solid.

[0693] Synthesis of trans-cyclohexane- 1,4-dicarboxylic acid bis-[(4-aminomethyl -phenyl- amide]. To a mixture of [4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -trans- cyclohexanecarbonyl} -amino) -benzyl] -carbamic acid tert-butyl ester (1.09 g, 1.88 mmol) in CH ₂ CI ₂ (10 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with diethylether (25 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethylether (30 mL), to give trans- cyclohexane- 1,4-dicarboxylic acid bis-[(4-aminomethy1-phenyl)-amide] as the bis- trifluoroacetic acid salt (1.02 g, 89%) as a white solid.

[0694] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}[({4-[(lr,4r)-4-{[4- ( { [( 1 E) - { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl]carbamoyl}cyclohexaneamido]phenyl}methyl)amino]methyl idene]carbamate. A mixture of trans-cyclohexane- 1,4-dicarboxylic acid bis-[(4-aminomethy1-phenyl)-amide] 2 trifluoroacetic acid (243 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-1- guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was concentrated, then the residue was treated with water (30 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-60% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}[({4-[(lr,4r)-4-{[4-({ [(lE)- { [(tert-butoxy) carbonyl] amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } cyclohexaneamido]phenyl}methyl)amino]methylidene]carbamate (156 mg, 45%) as a white solid.

[0695] Synthesis of trans-cyclohexane- 1,4-dicarboxylic acid bis-[(4-guanidinomethyl- phenyl)-amide]: To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}[({4-[(lr,4r)-4- { [4-({ [( lE)-{ [(tert-butoxy)carbonyl]amino}({ [(tert-butoxy)carbonyl]imino})methyl] amino}methyl)phenyl]carbamoyl}cyclohexaneamido]phenyl}methyl )amino]methylidene]carbamate (187 mg, 0.22 mmol) in CH ₂ CL ₂ (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 4 days, then was concentrated. The crude material was purified by preparative-HPLC to give trans-cyclohexane- 1,4-dicarboxylic acid bis-[(4-guanidinomethyl-phenyl)-amide] as the bis- trifluoroacetic acid salt (122 mg, 80%) as a white solid. MS: 465 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.88 - 10.01 (m, 2 H) 7.94 (t, J=5.86 Hz, 2 H) 7.58 (d, J=8.79 Hz, 5 H) 7.20 (d, J=8.79 Hz, 7 H) 4.27 (d, J=5.86 Hz, 4 H) 3.04 - 3.21 (m, 2 H) 2.33 (br. s., 2 H) 1.88 (d, J=7.62 Hz, 4

H) 1.37 - 1.53 (m, 4 H) 1.15 - 1.28 (m, 3 H).

[0696] Example 10: Synthesis of cis-cyclohexane- 1,4-dicarboxylic acid bis-[(4- guanidinomethyl-phenyl)-amide] [0697] Synthesis of [4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -cis- cyclohexanecarbonyl}-amino)-benzyl]-carbamic acid tert-butyl ester. The title compound was prepared according to the procedure of (4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-2-fluoro-benzoylamino}-benzyl)-carbamic acid tert-butyl ester except that 2- fluoro-terephthalic acid was replaced with trans-yclohexane- 1,4-dicarboxylic acid (344 mg, 2.00 mmol), and using (4-amino-benzyl)-carbamic acid tert-butyl ester (987 mg, 4.44 mmol), to give [4- ({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-ci s-cyclohexanecarbonyl}-amino)- benzyl]-carbamic acid tert-butyl ester (0.69 g, 60%) as a white solid.

[0698] Synthesis of cis-cyclohexane- 1,4-dicarboxylic acid bis-[(4-aminomethyl-phenyl)- amide]. To a mixture of [4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -cis- cyclohexanecarbonyl} -amino) -benzyl] -carbamic acid tert-butyl ester (0.69 g, 1.19 mmol) in CH ₂ CI ₂ (10 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethylether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, to give cis-cyclohexane- 1,4-dicarboxylic acid bis-[(4-aminomethyl-phenyl)- amide] as the bis- trifluoroacetic acid salt (717 mg, 99%) as a light brown solid.

[0699] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}[({4-[(ls,4s)-4-{[4- ( { [( 1 E) - { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } cyclohexaneamido] phenyl } methyl)amino] methylidene] carbamate . The title compound was prepared according to the procedure of tert-butyl N-[(lE)-{[(tert- butoxy)carbonyl] amino} [({4-[( lr,4r)-4-{ [4-({ [( lE)-{ [(tert-butoxy)carbonyl]amino}({ [(tert-butoxy) carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } cyclohexaneamido]phenyl } methyl) amino]methylidene]carbamate except that trans-cyclohexane- 1,4-dicarboxybc acid bis-[(4- aminomethyl-phenyl)-amide] 2 trifluoroacetic acid was replaced with cis-cyclohexane-1,4- dicarboxylic acid bis-[(4-aminomethyl-phenyl)-amide]. 2 trifluoroacetic acid (243 mg, 0.40 mmol), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}[({4-[(ls,4s)-4-{[4-({ [(lE)-{[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } cyclohexaneamido]phenyl}methyl)amino]methylidene]carbamate (156 mg, 45%) as a white solid. [0700] Synthesis of cis-cyclohexane-l,4-dicarboxylic acid bis-| (4-guanidinomethyl-phenyl)- amide]: To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}[({4-[(ls,4s)-4-{[4-

( { [( 1 E) - { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl]carbamoyl}cyclohexaneamido]phenyl}methyl)amino]methyl idene]carbamate (156 mg, 0.18 mmol) in CH ₂ CL ₂ (1.8 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC to give cis- cyclohexane- 1,4-dicarboxybc acid bis-[(4-guanidinomethyl-phenyl)-amide] as the bis- trifluoroacetic acid salt (98 mg, 79%) as a white solid. MS: 465 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.82 (s, 2 H) 7.95 (t, J=5.57 Hz, 2 H) 7.58 (d, J=8.79 Hz, 4 H) 7.20 (d, J=8.20 Hz, 7 H) 4.27 (d,

J=5.86 Hz, 4 H) 1.83 - 2.07 (m, 4 H) 1.59 (br. s., 3 H). [0701] Example 11: Synthesis ofN,N'-bis-(4-guanidinomethyl-cyclohexyl)-terephthalamide

[0702] Synthesis of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylcarbamo yl]- benzoylamino}-cyclohexylmethyl)-carbamic acid tert-butyl ester. To a mixture of (4-amino- cyclohexylmethyl)-carbamic acid tert-butyl ester (799 mg, 3.50 mmol), and diisopropylethylamine (710 mg, 955 μL, 5.50 mmol) in N,N-dimethylformamide (4.8 mL) was added dropwise a solution of terephthaloyl dichloride (356 mg, 1.75 mmol) in N,N-dimethylformamide (4.8 mL). The reaction was stirred for 16 hours, then was filtered. The solid was washed with N,N-dimethylformamide (10 mL), water (20 mL), isopropanol (20 mL), and hexanes (20 mL), to give (4-{4-[4-(tert- butoxycarbonylamino-methyl)-cyclohexylcarbamoyl] -benzoylamino } -cyclohexylmethyl)-carbamic acid tert-butyl ester (660 mg, 64%) as a white solid.

[0703] Synthesis of N,N'-bis-(4-aminomethyl-cyclohexyl)-terephthalamide. To a mixture of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylcarbamo yl]-benzoylamino}- cyclohexylmethyl)-carbamic acid tert-butyl ester (660 mg, 1.13 mmol) in CH ₂ CL ₂ (6 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 5 hours, then was concentrated. The residue was treated with diethylether (30 mL), then was sonicated for 5 minutes, and was filtered. The solid was washed with diethylether (20 mL), to give N,N'-bis-(4-aminomethyl-cyclohexyl)- terephthalamide. 2 trifluoroacetic acid (669 mg, 96%) as a white solid.

[0704] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[(lr,4r)-4-(4- { [( 1 r,4r)-4-( { [( 1 E)- { [(tert-butoxy)carbonyl]amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)cyclohexyl] carbamoyl } benzamido)cyclohexyl] methyl } amino)methylidene] carbamate . A mixture of N,N'-bis-(4-aminomethyl-cyclohexyl)-terephthalamide. 2 trifluoroacetic acid (246 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-1-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was concentrated, then the residue was treated with water (25 mL), and was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[(lr,4r)-4-(4-{[(lr, 4r)- 4-({ [( lE)-{ [(tert-butoxy)carbonyl]amino}({ [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)cyclohexyl] carbamoyl } benzamido) cyclohexyl]methyl}amino)methylidene] carbamate (96 mg, 28%) as a white solid.

[0705] Synthesis of N,N'-bis-(4-guanidinomethyl-cyclohexyl)-terephthalamide: To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[(lr,4r)-4-(4-{[(lr, 4r)-4-({[(lE)-{[(tert- butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)cyclohexyl] carbamoyl}benzamido)cyclohexyl]methyl}amino)methylidene]carb amate (96 mg, 0.11 mmol) in CH ₂ CI ₂ (1.1 mL) was added trifluoroacetic acid (1.1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N,N'-bis-(4- guanidinomethyl-cyclohexyl)-terephthalamide. 2 trifluoroacetic acid (50 mg, 65%) as a white solid. MS: 471 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.33 (d, 7=7.62 Hz, 1 H) 7.88 (s, 2 H) 7.62 (br. s., 1 H) 3.62 - 3.85 (m, 1 H) 2.97 (t, 7=6.15 Hz, 2 H) 1.87 (d, J =10.54 Hz, 2 H) 1.76 (d, 7=11.72 Hz, 2 H) 1.22 - 1.52 (m, 3 H) 0.95 - 1.17 (m, 2 H).

[0706] Example 12: Synthesis of N ¹ ,N ⁴ -bis(4-(guanidinomethyl)phenyl)-2- methylterephthalamide

[0707] Synthesis of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2- methyl-benzoylamino}-benzyl)-carbamic acid tert-butyl ester. The title compound was prepared according to the procedure of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2- fluoro-benzoylamino}-benzyl)-carbamic acid tert-butyl ester except that 2-fluoro-terephthalic acid was replaced with 2-methyl-terephthalic acid (288 mg, 1.60 mmol) using (4-amino-benzyl)-carbamic acid tert-butyl ester (790 mg, 3.55 mmol), triethylamine (758 mg, 896 μL, 6.40 mmol), and 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1818 mg, 4.80 mmol), to give (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2- methyl-benzoylamino}-benzyl)-carbamic acid tert-butyl ester (696 mg, 74%) as a white solid.

[0708] Synthesis of N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl)-2-methylterephthalamide. To a mixture of (4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- 2-methyl-benzoylamino}- benzyl)-carbamic acid tert-butyl ester (696 mg, 1.18 mmol) in CH ₂ CI ₂ (6 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 5 hours, then was concentrated. The residue was treated with diethylether (30 mL), and was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethylether (20 mL), to give N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl)-2- methylterephthalamide (748 mg, >100%) as a white solid, that was used without further purification.

[0709] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl}-2-methylbenzamido)phenyl]methyl}amino)methylidene ]carbamate. The title compound was prepared according to the procedure of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4- (4- { [4-( { [( 1 E)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl]amino } methyl)phenyl] carbamoyl } -2-fluorobenzamido)phenyl] methyl } amino)methylidene] carbamate except that N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl)-2-fluoro terephthalamide 2 trifluoroacetic acid was replaced with N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl)-2-methylterephthalamide (247 mg, 0.40 mmol), to give tert- butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-({[(lE)-{[ (tert- butoxy)carbonyl] amino } ( { [(tert-butoxy) carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } - 2-methylbenzamido)phenyl]methyl} amino)methylidene] carbamate (219 mg, 63%) as a white solid.

[0710] Synthesis of N ¹ ,N ⁴ -bis(4-(guanidinomethyl)phenyl)-2-methylterephthalamid e: To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-({[(lE)-{[ (tert- butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl ] carbamoyl } - 2-methylbenzamido)phenyl]methyl}amino)methylidene]carbamate (219 mg, 0.25 mmol) in CH ₂ CI ₂ (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N ¹ ,N ⁴ -bis(4- (guanidinomethyl)phenyl)-2-methylterephthalamide. 2 trifluoroacetic acid (45 mg, 26%) as a white solid. MS: 473 M+H+; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.46 (s, 1 H) 10.37 (s, 1 H) 8.03 (t, J=5.86 Hz, 2 H) 7.84 - 7.98 (m, 2 H) 7.76 (dd, J=17.28, 8.49 Hz, 4 H) 7.58 (d, J=7.62 Hz, 1 H) 7.25 - 7.38 (m, 7 H) 4.33 (dd, 7=5.57, 2.64 Hz, 4 H) 2.45 (s, 3 H).

[0711] Example 13: Synthesis of N,N'-bis-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]- terephthalamide

[0712] Synthesis of di-tert-butyl 4,4'-((terephthaloylbis(azanediyl))bis(4,1- phenylene))bis(piperazine-1-carboxylate). General Procedure D was followed, using of terephthaloyl dichloride (356 mg, 1.75 mmol), and 4-(4-amino-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (971 mg, 3.50 mmol), to give di-tert-butyl 4,4'-((terephthaloylbis(azanediyl))bis(4,1- phenylene))bis(piperazine-l -carboxylate) (743 mg, 62%) as a pale yellow solid.

[0713] Synthesis of N,N'-bis-(4-piperazin-1-yl-phenyl)-terephthalamide: To a mixture of di- tert-butyl 4,4'-((terephthaloylbis(azanediyl))bis(4, 1 -phenylene))bis(piperazine- 1 -carboxylate) (743 mg, 1.09 mmol) in CH ₂ CI ₂ (6 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with diethylether (20 mL), then was sonicated for 5 minutes, and was filtered. The solid was washed with diethylether (20 mL), to give N,N'-bis-(4-piperazin-1-yl-phenyl)-terephthalamide. 4 trifluoroacetic acid (878 mg, 86%) as a pale green solid. [0714] Synthesis of ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -benzoylamino) -phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester. A mixture of N.N'-bis-(4-pipcrazin-l- yl-phenyl)-terephthalamide 4 trifluoroacetic acid salt (376 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was treated with triethylamine (409 mg, 561 μL, 4.00 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-1-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (50 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The fdtrate was separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -benzoylamino) -phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (178 mg, 46%) as a pale yellow solid.

[0715] Synthesis of N,N'-bis-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]-terepht halamide: To a mixture of ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino-methyl)- piperazin- 1 -yl] -phenylcarbamoyl } -benzoylamino) -phenyl] -piperazin- 1 -yl } -tert-butoxycarbonylimino- methyl)-carbamic acid tert-butyl ester (178 mg, 0.18 mmol) in CH ₂ CI ₂ (1.8 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (1.6 mL), followed by 0.1% trifluoroacetic acid in water (1.6 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give N,N'-bis-[4-(4-carbamimidoyl- piperazin-1-yl)-phenyl]-terephthalamide. 4 trifluoroacetic acid (135 mg, 73%) as a yellow solid. MS:

569 M+H+; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.22 (br. s., 1 H) 8.05 (br. s., 2 H) 7.64 (br. s., 2 H) 7.49 (br. s., 5 H) 6.99 (d, J=7.03 Hz, 2 H) 3.53 - 3.67 (m, 7 H) 3.50 - 3.66 (m, 8 H) 3.48 - 3.64 (m, 8 H) 3.57 (br. s., 11 H) 3.17 - 3.25 (m, 8 H).

[0716] Example 14: Synthesis of N,N'-bis-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]- isophthalamide

[0717] Synthesis of di-tert-butyl 4,4'-((isophthaloylbis(azanediyl))bis(4,1- phenylene))bis(piperazine-1-carboxylate). To a mixture of 4-(4-amino-phenyl)-piperazine-1- carboxylic acid tert-butyl ester (971 mg, 3.50 mmol), and diisopropylethylamine (710 mg, 955 μL, 5.50 mmol) in N,N-dimethylformamide (4.8 mL) was added a solution of terephthaloyl dichloride (356 mg, 1.75 mmol) in N,N-dimethylformamide (4.8 mL). The reaction was stirred for 16 hours, then was treated with water (150 mL) and ethyl acetate (60 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give di-tert-butyl 4,4'-((isophthaloylbis(azanediyl))bis(4, 1 -phenylene))bis(piperazine- 1 -carboxylate) . The original ethyl acetate/ water fdtrate was allowed to stand for 10 minutes, then the layers were separated. The organic layer was treated with ethyl acetate (20 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL). Both solids were di-tert-butyl 4,4'-((isophthaloylbis(azanediyl))bis(4, 1 -phenylene))bis(piperazine- 1 -carboxylate) (595 mg, 50%) as grey solids.

[0718] Synthesis of N,N'-bis-(4-piperazin-1-yl-phenyl)-isophthalamide. To a mixture of di- tert-butyl 4,4'-((isophthaloylbis(azanediyl))bis(4, 1 -phenylene))bis(piperazine- 1 -carboxylate) (590 mg, 0.87 mmol) in CH ₂ CI ₂ (5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethylether (25 mL), then the mixture was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethylether (2 x 10 mL), to give N,N'-bis-(4-piperazin-1-yl-phenyl)-isophthalamide. 4 trifluoroacetic acid (609 mg, 74%) as a purple solid.

[0719] Synthesis of ({4-[4-(3-{4-[4-(tert-Butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -benzoylamino) -phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester. A mixture of N,N'-bis-(4-piperazin-1- yl-phenyl)-isophthalamide. 4 trifluoroacetic acid (376 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated with triethylamine (409 mg, 561 μL, 4.00 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-1-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The reaction was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-6% methanol: CH ₂ CI ₂ ), to give ({4-[4-(3-{4- [4-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino-methyl )-piperazin- 1 -yl] -phenylcarbamoyl } - benzoylamino)-phenyl]-piperazin-1-yl}-tert-butoxycarbonylimi no-methyl)-carbamic acid tert-butyl ester (271 mg, 70%) as a pale green solid.

[0720] Synthesis of N,N'-bis-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]-isophth alamide: To a mixture of ({4-[4-(3-{4-[4-(tert-Butoxycarbonylamino-tert-butoxycarbony limino-methyl)- piperazin- 1 -yl] -phenylcarbamoyl } -benzoylamino) -phenyl] -piperazin- 1 -yl } -tert-butoxycarbonylimino- methyl)-carbamic acid tert-butyl ester (271 mg, 0.28 mmol) in CH ₂ CI ₂ (2.8 mL) was added trifluoroacetic acid (2.8 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N,N'-bis-[4-(4-carbamimidoyl-piperazin-1-yl)- phenyl]-isophthalamide. 4 trifluoroacetic acid (204 mg, 71%) as a pale yellow solid. MS: 569 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) d ppm 10.19 - 10.37 (m, 1 H) 8.49 (s, 1 H) 8.10 (dd, J=7.91, 1.46 Hz, 1 H) 7.59 - 7.76 (m, 3 H) 7.52 (s, 4 H) 6.99 (d, J=8.79 Hz, 2 H) 3.57 (d, J=4.69 Hz, 4 H) 3.20 (d, J =4.10 Hz, 4 H).

[0721] Example 15: Synthesis of N-[4-(1-Carbamimidoyl-l,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide

[0722] Synthesis of N-(4-bromo-phenyl)-terephthalamic acid methyl ester. To a mixture of 4- bromo-aniline (516 mg, 3.00 mmol) and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in CHCI ₃ (8 mL) was added a mixture of 4-chlorocarbonyl -benzoic acid methyl ester (687 mg, 3.46 mmol) in CHCI ₃ (8 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (75 mL) and water (25 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with IN HC1 (20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated to give N- (4-bromo-phenyl)-terephthalamic acid methyl ester (860 mg, 86%) as a beige solid.

[0723] Synthesis of N-(4-bromo-phenyl)-terephthalamic acid. To a mixture of N-(4-bromo- phenyl)-terephthalamic acid methyl ester (860 mg, 2.57 mmol) in 1,4-dioxane (12 mL) was added a 10N aqueous sodium hydroxide solution (2.6 mL). The reaction was stirred for 16 hours, then was treated with further 10N aqueous sodium hydroxide solution (2.6 mL). The reaction was stirred for 3 hours, then was heated at 40 °C for 16 hours. The reaction was concentrated, then the residue was treated with ethyl acetate (30 mL) and water (40 mL). The organic layer was removed by pipette, then the aqueous layer was adjusted to pH 1 using concentrated HC1. The mixture was treated with ethyl acetate (50 mL), then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give N-(4-bromo-phenyl)-terephthalamic acid (505 mg, 61%) as a white solid. The ethyl acetate/ acidic water filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated to give N-(4-bromo-phenyl)-terephthalamic acid (267 mg, 33%) as a white solid.

[0724] Synthesis of {4-[4-(4-bromo-phenylcarbamoyl)-benzoylamino]-benzyl}-carbam ic acid tert-butyl ester. To a mixture of N-(4-bromo-phenyl)-terephthalamic acid (772 mg, 2.41 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (595 mg, 2.67 mmol), and triethylamine (571 mg, 675 μL, 4.82 mmol) in N,N-dimethylformamide (7 mL) was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1369 mg, 3.62 mmol). The reaction was stirred for 1 hour, then further N,N-dimethylformamide (3 mL) was added, and the reaction was stirred for 16 hours. The reaction was treated with water (150 mL), and ethyl acetate (80 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give {4-[4-(4-bromo-phenylcarbamoyl)- benzoylamino] -benzyl }-carbamic acid tert-butyl ester (1.00 g, 79%) as a white solid.

[0725] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. A mixture of {4- [4-(4-bromo-phenylcarbamoyl)-benzoylamino]-benzyl}-carbamic acid tert-butyl ester (1.00 g, 1.91 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-1-carboxylic acid tert-butyl ester (701 mg, 2.24 mmol), Pd(OAc)2 (21 mg, 0.091 mmol), and 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (83 mg, 0.21 mmol) in 1,4-dioxane (13.7 mL) and 2M K ₂ CO ₃ (4.8 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]-benzoylamino}- phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (898 mg, 75%) as a grey solid.

[0726] Synthesis of N-(4-aminomethyl-phenyl)-N'-[4-(1,2,3,6-tetrahydro-pyridin-4 -yl)- phenyl]-terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridi ne-l -carboxylic acid tert-butyl ester (898 mg, 1.43 mmol) in CH ₂ CI ₂ (8 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with ethyl acetate (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethylether (2 x 15 mL), to give N-(4-aminomethyl-phenyl)-N'-[4-(1,2,3,6-tetrahydro-pyridin-4 -yl)-phenyl]- terephthalamide. 2 trifluoroacetic acid (848 mg, 91%) as a grey solid.

[0727] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino (methyl) phenyl] carbamoyl } benzamido)phenyl] -1,2,3, 6-tetrahydropyridin- 1 -yl } )methylidene] carbamate . A mixture of N-(4-aminomethyl-phenyl)-N'-[4-( 1 ,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] - terephthalamide. 2 trifluoroacetic acid (262 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-1-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The reaction was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }benzamido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (228 mg,

63%) as a pale yellow solid.

[0728] Synthesis of N-[4-(1-Carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pheny l]-N'-(4- guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)phenyl] - 1 ,2, 3 ,6- tetrahydropyridin- 1-yl})methylidene]carbamate (228 mg, 0.25 mmol) in CH ₂ CI ₂ (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 2 days, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(1-Carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephth alamide. 2 trifluoroacetic acid (70 mg, 38%) as a pale yellow solid. MS: 511 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.45 (d, J=2.34 Hz, 2 H) 8.09 (s, 5 H) 7.96 (t, J=5.86 Hz, 1 H) 7.78 - 7.87 (m, 4 H) 7.44 - 7.56 (m, 7 H) 7.30 (d, J=8.79 Hz, 3 H) 6.19 (br. s., 1 H) 4.34 (d, J=5.86 Hz, 2 H) 4.07 (br. s., 2 H) 3.62 (t, J=5.27 Hz, 2 H) 2.59 (br. s., 2 H).

[0729] Example 16: Synthesis of N ¹ ,N ⁴ -bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-2- chloroterephthalamide

[0730] Synthesis of 2-chloro-terephthalic acid. A mixture of 2-chloro-terephthalic acid dimethyl ester (1.00 g, 4.37 mmol) in tetrahydrofuran (22 mL) was treated with a 10 N aqueous NaOH solution (8.5 mL). The reaction was heated in a sealed vessel at 70 °C for 16 hours. The reaction was concentrated to remove the tetrahydrofuran, then the mixture was adjusted to pH 1 using 1 N HC1. The mixture was maintained at 4°C for 3 hours, then was filtered, and the solid was washed with water (20 mL), to give 2-chloro-terephthalic acid (324 mg, 37%) as a white solid.

[0731] Synthesis of di-tert-butyl 4,4'-(((2-chloroterephthaloyl)bis(azanediyl))bis(4,1- phenylene))bis(piperazine-1-carboxylate): To a mixture of 2-chloro-terephthalic acid (315 mg, 1.57 mmol), piperazine- 1 -carboxylic acid tert-butyl ester (967 mg, 3.48 mmol), and triethylamine (744 mg, 880 μL, 6.28 mmol) in N,N-dimethylformamide (4.8 mL) was added 1-

[bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate

(1784 mg, 4.71 mmol). The reaction was stirred for 16 hours, then was treated with water (75 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give di-tert-butyl 4,4'-(((2- chloroterephthaloyl)bis(azanediyl))bis(4,1-phenylene))bis(pi perazine-1-carboxylate) (740 mg, 66%) as a white solid.

[0732] Synthesis of 2-chloro-Nl,N4-bis(4-(piperazin-1-yl)phenyl)terephthalamide: To a mixture of di-tert-butyl 4,4'-(((2-chloroterephthaloyl)bis(azanediyl))bis(4, 1 - phenylene))bis(piperazine-1-carboxylate) (740 mg, 1.03 mmol) in CH ₂ CI ₂ (6 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (20 mL), to give 2-chloro-Nl,N4-bis(4-(piperazin-1- yl)phenyl)terephthalamide as the tetra- trifluoroacetic acid salt (945 mg, 94%) as a pale green solid.

[0733] Synthesis of ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -2-chloro-benzoylamino)-phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester. A mixture of 2-chloro-Nl,N4-bis(4- (piperazin- 1-yl)phenyl)terephthalamide. 4 trifluoroacetic acid (390 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was treated with triethylamine (409 mg, 561 μL, 4.00 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-7% methanol: CH ₂ CI ₂ ), to give ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -2-chloro-benzoylamino)-phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (262 mg, 65%) as a yellow solid.

[0734] Synthesis of N ¹ ,N ⁴ -bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-2- chloroterephthalamide: To a mixture of ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -2-chloro-benzoylamino)-phenyl] - piperazin- 1-yl}-tert-butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (262 mg, 0.26 mmol) in CH ₂ CI ₂ (2.6 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 5 days, then was concentrated. The residue was treated with N,N-dimethylformamide (2 mL), followed by 0.1% trifluoroacetic acid in water (2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give N'.N ⁴ - bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-2-chloroterepht halamide as the tetra- trifluoroacetic acid salt (183 mg, 67%) as a pale yellow solid. MS: 604 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.41 (s, 1 H) 10.27 (s, 1 H) 8.10 (s, 1 H) 7.89 - 8.04 (m, 1 H) 7.54 - 7.76 (m, 6 H) 7.48 (br. s., 8 H) 6.99 (d, J= 7.62 Hz, 4 H) 3.57 (br. s., 8 H) 3.18 (br. s., 8 H).

[0735] Example 17: Synthesis of N ¹ ,N ⁴ -bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-2- methylterephthalamide

[0736] Synthesis of di-tert-butyl 4,4'-(((2-methylterephthaloyl)bis(azanediyl))bis(4,1- phenylene))bis(piperazine-1-carboxylate): To a mixture of 2-methyl-terephthalic acid (288 mg, 1.60 mmol), piperazine- 1 -carboxylic acid tert-butyl ester (985 mg, 3.55 mmol), and triethylamine (758 mg, 896 μL, 6.40 mmol) in N,N-dimethylformamide (4.8 mL) was added 1-

[bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1818 mg, 4.80 mmol). The reaction was stirred for 16 hours, then was treated with water (75 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give di-tert-butyl 4,4'-(((2- methylterephthaloyl)bis(azanediyl))bis(4, 1 -phenylene))bis(piperazine- 1 -carboxylate) (791 mg, 71%) as a white solid.

[0737] Synthesis of 2-methyl-N ¹ ,N ⁴ -bis(4-(piperazin-1-yl)phenyl)terephthalamide: To a mixture of di-tert-butyl 4,4'-(((2-methylterephthaloyl)bis(azanediyl))bis(4,1- phenylene))bis(piperazine-l -carboxylate) (791 mg, 1.13 mmol) in CH ₂ CI ₂ (6.7 mL) was added trifluoroacetic acid (3.4 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give 2-methyl-N ¹ ,N ⁴ -bis(4- (piperazin-1-yl)phenyl)terephthalamide as the tetra- trifluoroacetic acid salt (964 mg, 89%) as a pale green solid.

[0738] Synthesis of ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -2 -methyl -benzoylamino)-phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester. A mixture of 2-methyl-N ¹ ,N ⁴ -bis(4- (piperazin-1-yl)phenyl)terephthalamide. 4 trifluoroacetic acid (382 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was treated with triethylamine (409 mg, 561 μL, 4.00 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-7% methanol: CH ₂ CI ₂ ), to give ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbony limino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -2 -methyl -benzoylamino)-phenyl] -piperazin- 1 -yl } -tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (284 mg, 72%) as a yellow solid.

[0739] Synthesis of N ^l .N ⁴ -bis(4-(4-carbamimidoyl piperazin- 1 -yl)phcnyl)-2- methylterephthalamide : To a mixture of ({4-[4-(4-{4-[4-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -2-methyl-benzoylamino)-phenyl] - piperazin- 1-yl}-tert-butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (284 mg, 0.29 mmol) in CH ₂ CI ₂ (2.9 mL) was added trifluoroacetic acid (2.9 mL). The reaction was stirred for 2 days, then was concentrated. The residue was treated with N,N-dimethylformamide (2 mL), followed by 0.1% trifluoroacetic acid in water (2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give N'.N ⁴ - bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-2-methylterepht halamide as the tetra- trifluoroacetic acid salt (188 mg, 62%) as a beige solid. MS: 583 M+H+;

[0740] Example 18: Synthesis of N ² ,N ⁵ -bis(4-(4-carbamimidoylpiperazin-1- yl)phenyl)pyridine-2, 5 -dicarboxamide

[0741] Synthesis of di-tert-butyl 4,4'-(((pyridine-2,5-dicarbonyl)bis(azanediyl))bis(4,1- phenylene))bis(piperazine-1-carboxylate). To a mixture of pyridine-2, 5-dicarboxylic acid (267 mg, 1.60 mmol), piperazine- 1 -carboxylic acid tert-butyl ester (985 mg, 3.55 mmol), and triethylamine (758 mg, 896 μL, 6.40 mmol) in N,N-dimethylformamide (4.8 mL) was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1818 mg, 4.80 mmol). The reaction was stirred for 16 hours, then was treated with dilute aqueous NaHCO ₃ (100 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give di-tert-butyl 4,4'-(((pyridine-2,5- dicarbonyl)bis(azanediyl))bis(4,1-phenylene))bis(piperazine- 1-carboxylate) (854 mg, 78%) as a yellow solid.

[0742] Synthesis of N ² ,N ⁵ -bis(4-(piperazin-1-yl)phenyl)pyridine-2, 5 -dicarboxamide: To a mixture of di-tert-butyl 4,4'-(((pyridine-2,5-dicarbonyl)bis(azanediyl))bis(4,1- phenylene))bis(piperazine-1-carboxylate) (854 mg, 1.25 mmol) in CH ₂ CI ₂ (7 mL) was added trifluoroacetic acid (3.5 mL). The reaction was stirred for 5 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N ² ,N ⁵ -bis(4-(piperazin-1- yl)phenyl)pyridine-2, 5 -dicarboxamide as the penta- trifluoroacetic acid salt (1.14 g, 86%) as a red solid.

[0743] Synthesis of [(4-{4-[(5-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbon ylimino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -pyridine-2-carbonyl)-amino] -phenyl } -piperazin- 1 -yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester. A mixture of N ² ,N ⁵ -bis(4-(piperazin-1- yl)phenyl)pyridine-2, 5 -dicarboxamide 4 trifluoroacetic acid (422 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was treated with triethylamine (450 mg, 617 μL, 4.40 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-7% methanol: CH ₂ CI ₂ ), to give [(4-{4-[(5-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbon ylimino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -pyridine-2-carbonyl)-amino] -phenyl } -piperazin- 1 -yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (417 mg, >100%) as a yellow solid, that was used without further purification.

[0744] Synthesis of N ² ,N ⁵ -bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)pyridine- 2,5- dicarboxamide: To a mixture of [(4-{4-[(5-{4-[4-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-piperazin-1-yl]-phenylcarbamoyl} -pyridine-2-carbonyl)-amino]- phenyl}-piperazin-1-yl)-tert-butoxycarbonylimino-methyl]-car bamic acid tert-butyl ester (417 mg,

0.43 mmol) in CH ₂ CI ₂ (4.3 mL) was added trifluoroacetic acid (4.3 mL). The reaction was stirred for

2 days, then was concentrated. The residue was treated with N,N-dimethylformamide (2 mL), followed by 0.1% trifluoroacetic acid in water (2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (5 mL), and hexanes (5 mL), to give N ² ,N ⁵ -bis(4-(4-carbamimidoylpiperazin-1-yl)phenyl)pyridine- 2, 5 -dicarboxamide as the penta- trifluoroacetic acid salt (280 mg, 57%) as an orange solid. MS: 570 M+H+; 'H NMR (3006 MHz, DMSO-d ₆ ) δ ppm 10.61 (s, 1 H) 10.48 (br. s., 1 H) 9.16 (br. s., 1 H) 8.52 (d, 7= 7.62 Hz, 1 H) 8.24 (d, J=8.20 Hz, 1 H) 7.93 (br. s., 1 H) 7.80 (d, 7=8.20 Hz, 3 H) 7.65 (d, 7=8.20 Hz, 3 H) 7.54 (br. s., 10 H) 7.00 (d, 7=7.03 Hz, 5 H) 3.57 (br. s., 4 H) 3.21 - 3.27 (m, 4 H).

[0745] Example 19: Synthesis of furan-2,5-dicarboxylic acid bis-{[4-(4-carbamimidoyl- piperazin- 1 -yl)-phenyl] -amide }

[0746] Synthesis of tert-butyl 4-(4-{5-[(4-{4-[(tert-butoxy)carbonyl]piperazin-1- yl}phenyl)carbamoyl]furan-2-amido}phenyl)piperazine-1-carbox ylate. To a mixture of furan-2,5- dicarboxylic acid (250 mg, 1.60 mmol), 4-(4-amino-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (985 mg, 3.55 mmol), and triethylamine (758 mg, 896 μL, 6.40 mmol) in N,N- dimethylformamide (4.8 mL) was added 1-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1818 mg, 4.80 mmol). The reaction was stirred for 5 days, then was treated with water (75 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give tert-butyl 4- (4-{5-[(4-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}phenyl)ca rbamoyl]furan-2- amido}phenyl)piperazine-1-carboxylate (834 mg, 77%) as a yellow solid.

[0747] Synthesis of furan-2,5-dicarboxylic acid bis-[(4-piperazin-1-yl-phenyl)-amide]. To a mixture of tert-butyl 4-(4-{5-[(4-{4-[(tert-butoxy)carbonyl]piperazin-l-yl}phenyl) carbamoyl]furan-2- amido}phenyl)piperazine-l-carboxylate (830 mg, 1.23 mmol) in CH ₂ CI ₂ (7 mL) was added trifluoroacetic acid (3.5 mL). The reaction was stirred for 5 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give furan-2,5-dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide] as the tetra- trifluoroacetic acid salt (959 mg, 84%) as a pale green solid.

[0748] Synthesis of [(4-{4-[(5-{4-[4-(tert-Butoxycarbonylamino-tert-butoxycarbon ylimino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -furan-2 -carbonyl) -amino] -phenyl } -piperazin- 1 -yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester. To a mixture of furan-2, 5 -dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide]. 2 trifluoroacetic acid (372 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was added triethylamine (409 mg, 561 μL, 4.00 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-7% methanol: CH ₂ CI ₂ ), to give [(4-{4-[(5-{4-[4-(tert-Butoxycarbonylamino-tert-butoxycarbon ylimino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -furan-2 -carbonyl) -amino] -phenyl } -piperazin- 1 -yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (316 mg, 82%) as a yellow solid.

[0749] Synthesis of furan-2, 5 -dicarboxylic acid bis-{[4-(4-carbamimidoyl-piperazin-l-yl)- phenyl] -amide}: To a mixture of [(4-{4-[(5-{4-[4-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -furan-2 -carbonyl)-amino] -phenyl } - piperazin- l-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (316 mg, 0.33 mmol) in CH ₂ CI ₂ (3.3 mL) was added trifluoroacetic acid (3.3 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give furan-2, 5- dicarboxylic acid bis-{[4-(4-carbamimidoyl-piperazin-l-yl)-phenyl]-amide}as the tetra- trifluoroacetic acid salt (174 mg, 52%) as a yellow solid. MS: 559 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.16 (s, 1 H) 7.61 (d, J= 8.79 Hz, 2 H) 7.45 (s, 4 H) 7.35 (s, 1 H) 7.01 (d, J= 8.79 Hz, 2 H) 3.57 (br. s., 4 H) 3.20 (br. s., 4 H).

[0750] Example 20: Synthesis of N-[4-(4-carbamimidoyl-piperazin-l-yl)-phenyl]-N'-(4- guanidinomethyl-phenyl)-terephthalamide

[0751] Synthesis of 4- [4-(4-methoxy carbonyl -benzoylamino)-phenyl] -piperazine- 1- carboxylic acid tert-butyl ester. To a mixture of 4-(4-amino-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester (832 mg, 3.00 mmol), and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in CHCI ₃ (8 mL) was added a solution of 4-chlorocarbonyl -benzoic acid methyl ester (687 mg, 3.46 mmol) in CHCI ₃ (8 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (20 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-70% ethyl acetate: hexanes), to give 4- [4-(4-methoxy carbonyl -benzoylamino)-phenyl] -piperazine- 1 -carboxylic acid tert-butyl ester (697 mg, 53%) as a pale yellow solid.

[0752] Synthesis of 4-[4-(4-carboxy-benzoylamino)-phenyl]-piperazine-l-carboxyli c acid tert-butyl ester. To a mixture of 4- [4-(4-methoxy carbonyl -benzoylamino)-phenyl] -piperazine- 1- carboxylic acid tert-butyl ester (697 mg, 1.59 mmol) in 1,4-dioxane (7.5 mL) was added a 10N aqueous NaOH solution (1.6 mL). The reaction was heated at 60 °C for 24 hours. The mixture was treated with further 1,4-dioxane (3 mL), and 10N aqueous NaOH solution (1 mL). The reaction was heated at 60°C for 18 hours, then was concentrated to remove the 1,4-dioxane. The residue was treated with water (20 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give 4-[4-(4-carboxy-benzoylamino)-phenyl]-piperazine-l-carboxyli c acid tert-butyl ester (499 mg, 74%) as a pale green solid.

[0753] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-phenyl)-piperazine-l-carboxylic acid tert-butyl ester. To a mixture of 4-[4-(4- carboxy-benzoylamino)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester (499 mg, 1.17 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (289 mg, 1.30 mmol), and triethylamine (277 mg, 328 μL, 2.34 mmol) in N,N-dimethylformamide (3.4 mL) was added 1- [bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (665 mg, 1.76 mmol). The reaction was treated with further N,N-dimethylformamide (2 mL), then was stirred for 16 hours. The reaction was treated with further triethylamine (422 mg, 500 μL, 3.57 mmol), and l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate (1100 mg, 2.91 mmol). The reaction was stirred for 24 hours. The reaction was treated with water (90 mL), and ethyl acetate (50 mL), then was shaken, and filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), then dried under high-vacuum, to give 4-(4- {4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-ben zoylamino}-phenyl)-piperazine-l- carboxylic acid tert-butyl ester (583 mg, 79%) as a white solid. terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (583 mg, 0.93 mmol) in CH ₂ CI ₂ (5.3 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with ethyl acetate (25 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with ethyl acetate (10 mL), to give N-(4- aminomethyl-phenyl)-N'-(4-piperazin-l-yl-phenyl)-terephthala mide as the tris- trifluoroacetic acid salt (519 mg, 72%) as a grey solid.

[0755] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl}benzamido)phenyl]piperazin-l-yl})methylidene]carba mate. To a mixture of N-(4- aminomethyl-phenyl)-N'-(4-piperazin-l-yl-phenyl)-terephthala mide. 3 trifluoroacetic acid (309 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (409 mg, 561 μL, 4.00 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL), dried (NarSOr). and concentrated. The crude material was purified by column on silica (0-5% methanol: CH ₂ CI ₂ ), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- {[(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido) phenyl]piperazin-l-yl})methylidene]carbamate (155 mg, 42%) as a yellow solid.

[0756] Synthesis of N-[4-(4-carbamimidoyl-piperazin-l-yl)-phenyl]-N'-(4-guanidin omethyl- phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4- (4- { [4-( { [( 1 E)- { [(tert-butoxy)carbonyl]amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)phenyl]piperazin- 1 - yl})methylidene] carbamate (155 mg, 0.17 mmol) in CH ₂ CI ₂ (1.7 mL) was added trifluoroacetic acid (1.7 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(4-carbamimidoyl-piperazin-l-yl)-phenyl]-N'-(4- guanidinomethyl-phenyl)-terephthalamide as the tris- trifluoroacetic acid salt (84 mg, 58%) as a yellow solid. MS: 514 MH+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.43 (s, 1 H) 10.24 (s, 1 H) 8.07 (s, 4 H) 7.97 (t, 7=6.15 Hz, 1 H) 7.78 (d, 7=8.79 Hz, 2 H) 7.65 (d, 7=8.79 Hz, 2 H) 7.49 (s, 4 H) 7.30 (d, J=8.79 Hz, 3 H) 6.99 (d, 7=9.37 Hz, 2 H) 4.34 (d, 7=5.86 Hz, 2 H) 3.57 (br. s., 4 H) 3.19 (br. s , 4 H).

[0757] Example 21: Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methoxy-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamid e

[0758] Synthesis of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-terephthalami c acid methyl ester. To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (1.33 g, 6.00 mmol), and diisopropylethylamine (1210 mg, 1630 μL, 9.42 mmol) in CHCI ₃ (16 mL) was added dropwise a solution of 4-chlorocarbonyl-benzoic acid methyl ester (1.37 mmol) in CHCI ₃ (16 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with ethyl acetate (60 mL) and water (60 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]- terephthalamic acid methyl ester (1.62 g, 70%) as a white solid.

[0759] Synthesis of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-terephthalami c acid. A mixture of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-terephthalami c acid methyl ester (1.62 g, 4.21 mmol) in 1,4-dioxane (25 mL) was treated with a 10N aqueous NaOH solution (4.2 mL). The reaction was heated at 60 °C for 24 hours. The mixture was treated with further 10N aqueous NaOH solution (2 mL), then was heated at 60°C for 24 hours. The reaction was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]- terephthalamic acid (1.48 g, 95%) as a white solid.

[0760] Synthesis of {4-[4-(4-bromo-3-methoxy-phenylcarbamoyl)-benzoylamino]-benz yl}- carbamic acid tert-butyl ester. To a mixture of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]- terephthalamic acid (0.74 g, 2.00 mmol), 4-bromo-3-methoxy-phenylamine (444 mg, 2.20 mmol), and triethylamine (379 mg, 448 μL, 3.19 mmol) in N,N-dimethylformamide (6 mL) was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1135 mg, 3.00 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give {4-[4-(4-bromo-3-methoxy-phenylcarbamoyl)- benzoylamino] -benzyl }-carbamic acid tert-butyl ester (936 mg, 84%) as a white solid.

[0761] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-2-methoxy-phenyl)-3,6-dihydro-2H-pyridine-l-ca rboxylic acid tert-butyl ester. A mixture of {4-[4-(4-bromo-3-methoxy-phenylcarbamoyl)-benzoylamino]-benz yl}-carbamic acid tert- butyl ester (936 mg, 1.69 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H- pyridine-1 -carboxylic acid tert-butyl ester (620 mg, 1.98 mmol), Pd(OAc) ₂ (19 mg, 0.080 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (73 mg, 0.19 mmol) in 1,4-dioxane (12 mL) and 2M K ₂ CO ₃ (4.2 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -2-methoxy-phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (935 mg, 84%) as a grey solid.

[0762] Synthesis of N-(4-aminomethyl-phenyl)-N'-[3-methoxy-4-(1,2,3,6-tetrahydro -pyridin- 4-yl) -phenyl] -terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -2-methoxy-phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (935 mg, 1.42 mmol) in CH ₂ CI ₂ (8 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N-(4-aminomethyl-phenyl)-N'-[3-methoxy-4-( 1,2,3, 6-tetrahydro- pyridin-4-yl)-phenyl] -terephthalamide as the bis- trifluoroacetic acid salt (977 mg, >100%) as a grey solid, that was used without further purification.

[0763] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino (methyl) phenyl] carbamoyl }benzamido)-2-methoxyphenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl} )methylidene] carbamate. To a mixture of N-(4-aminomethyl-phenyl)-N'-[3-methoxy-4-(1,2,3,6-tetrahydro -pyridin- 4-yl) -phenyl] -terephthalamide 2 trifluoroacetic acid (274 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aquoues citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-2-methoxy phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamat e (244 mg, 65%) as an off-white solid.

[0764] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-met hoxy- phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lE)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{ [4-({ [(lZ)-{ [(tert-butoxy)carbonyl]amino} ({ [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-2-methoxy phenyl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (244 mg, 0.26 mmol) in CH ₂ CI ₂ (2.6 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-N'-(4-guanidinome thyl-phenyl)-terephthalamide as the bis- trifluoroacetic acid salt (122 mg, 61%) as a white solid. MS: 541 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.45 (d, 7=4.69 Hz, 2 H) 8.09 (s, 4 H) 7.91 - 8.04 (m, 1 H) 7.79 (d, 7=8.79 Hz, 2 H) 7.55 (d, J=1.76 Hz, 1 H) 7.42 (br. s., 6 H) 7.30 (d, 7=8.79 Hz, 3 H) 7.16 (d, 7=8.20 Hz, 2 H) 5.85 (s, 1 H) 4.34 (d, 7=5.86 Hz, 2 H) 4.02 (br. s., 2 H) 3.78 (s, 3 H) 3.56 (t, 7=5.57 Hz, 2 H) 2.50 - 2.56 (m, 2 H).

[0765] Example 22: Synthesis of N-[4-(l -carbamimidoyl- 1,2,3, 6-tetrahydro-pyridin-4-yl)-2- methoxy-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamid e

[0766] Synthesis of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-terephthalami c acid methyl ester. To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (1.33 g, 6.00 mmol), and diisopropylethylamine (1210 mg, 1630 μL, 9.42 mmol) in CHCI ₃ (16 mL) was added a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1.37 g, 6.92 mmol) in CHCI ₃ (16 mL) dropwise. The reaction was stirred forl6 hours, then was concentrated. The residue was treated with ethyl acetate (60 mL), and water (60 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL) and hexanes (20 mL), to give N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]- terephthalamic acid methyl ester (1.62 g, 70%) as a white solid.

[0767] Synthesis of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-terephthalami c acid. A mixture of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-terephthalami c acid methyl ester (1.62 g, 4.21 mmol) in 1,4-dioxane (25 mL) was treated with a ION aqueous NaOH solution (4.2 mL). The reaction was heated at 60 °C for 24 hours, then was concentrated. The reaction was treated with further ION aqueous NaOH solution (2 mL), then was heated at 60 °C for 24 hours. The reaction was concentrated, and then the residue was treated with water (50 mL). The mixture was adjusted to pHl using IN HC1, then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with isopropanol (20 mL), and hexanes (20 mL) to give N-[4-(tert-butoxycarbonylamino-methyl)- phenyl]-terephthalamic acid (1.48 g, 95%) as a white solid.

[0768] Synthesis of {4-[4-(4-bromo-2-methoxy-phenylcarbamoyl)-benzoylamino]-benz yl}- carbamic acid tert-butyl ester. To a mixture of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]- terephthalamic acid (740 mg, 2.00 mmol), 4-bromo-2-methoxy-phenylamine (444 mg, 2.20 mmol), and triethylamine (379 mg, 448 μL, 3.19 mmol) in N,N-dimethylformamide (6 mL) was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1135 mg, 3.00 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give {4-[4-(4-bromo-2-methoxy-phenylcarbamoyl)- benzoylamino] -benzyl (-carbamic acid tert-butyl ester (892 mg, 80%) as a white solid. [0769] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-3-methoxy-phenyl)-3,6-dihydro-2H-pyridine-l-ca rboxylic acid tert-butyl ester. A mixture of {4-[4-(4-bromo-2-methoxy-phenylcarbamoyl)-benzoylamino]-benz yl}-carbamic acid tert- butyl ester (892 mg, 1.61 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H- pyridine- 1 -carboxylic acid tert-butyl ester (591 mg, 1.89 mmol), Pd(OAc)2 (18 mg, 0.076 mmol), and

2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (70 mg, 0.18 mmol) in 1,4-dioxane (11.5 mL) and 2M K ₂ CO ₃ (4 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 °C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -3 -methoxy-phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (615 mg, 58%) as a grey solid.

[0770] Synthesis of N-(4-aminomethyl-phenyl)-N'-[2-methoxy-4-( 1,2,3, 6-tetrahydro-pyridin- 4-yl) -phenyl] -terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -3 -methoxy-phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (615 mg, 0.94 mmol) in CH ₂ CI ₂ (5.3 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 5 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N-(4-aminomethyl-phenyl)-N'-[2-methoxy-4-(1,2,3,6-tetrahydro - pyridin-4-yl)-phenyl] -terephthalamide as the bis- trifluoroacetic acid salt (638 mg, 99%) as a grey solid. [0771] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino }methyl) phenyl] carbamoyl }benzamido)-3 -methoxyphenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl} )methylidene] carbamate. To a mixture of N-(4-aminomethyl-phenyl)-N'-[2-methoxy-4-(1,2,3,6-tetrahydro -pyridin- 4-yl) -phenyl] -terephthalamide 2 trifluoroacetic acid (274 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aquoues citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- {[(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-3 - methoxyphenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]c arbamate (237 mg, 63%) as a pale yellow solid.

[0772] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-met hoxy- phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lE)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{ [4-({ [(lZ)-{ [(tert-butoxy)carbonyl]amino} ({ [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-3 -methoxy phenyl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (237 mg, 0.25 mmol) in CH ₂ CI ₂ (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (3 mL), followed by 0.1% trifluoroacetic acid in water (3 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give N-[4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-2-methoxy-phenyl]-N'-(4-guanidinome thyl-phenyl)-terephthalamide as the bis- trifluoroacetic acid salt (92 mg, 48%) as a light red solid. MS: 541 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.44 (br. s., 1 H) 9.61 (br. s., 1 H) 8.07 (br. s., 5 H) 7.92 (br. s., 1 H) 7.77 (br. s., 4 H) 7.55 (br. s., 5 H) 7.01 - 7.43 (m, 8 H) 6.25 (br. s., 1 H) 4.32 (br. s., 2 H) 4.08 (br. s., 2 H) 3.87 (br. s., 3 H) 3.62 (br. s., 2 H) 2.61 (br. s., 2 H).

[0773] Example 23: Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl] -N'-(4-guanidinomethyl-3 -methyl -phenyl)-terephthalamide

[0774] Synthesis of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2-methyl-4-nitrophenyl)methyl] carbamate. To a mixture of di-tert-butyl iminodicarboxylate (1.04 g, 4.80 mmol) in N,N- dimethylformamide (6 mL) was added a 60% dispersion of NaH in mineral oil (261 mg, 6.53 mmol). The reaction was stirred for 15 minutes, then was treated with a solution of 1-bromomethyl -2 -methyl - 4-nitro-benzenemethane (1.00 g, 4.35 mmol) in N,N-dimethylformamide (2 mL). The reaction was stirred for 2 days, then was treated with water (120 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 25 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0- 20% ethyl acetate: hexanes), to give tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2-methyl-4- nitrophenyl)methyl] carbamate (815 mg, 51%) as a viscous yellow gum.

[0775] Synthesis of tert-butyl N-[(4-amino-2-methylphenyl)methyl]-N-[(tert- butoxy)carbonyl] carbamate. A mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2-methyl-4- nitrophenyl)methyl] carbamate (815 mg, 2.22 mmol) and 5% Pd/C (200 mg) in methanol (12 mL) was hydrogenated at 40 psi for 16 hours. The reaction was filtered through Celite, and the Celite was washed with methanol (2 x 10 mL). The combined fdtrates were concentrated, to give tert-butyl N- [(4-amino-2-methylphenyl)methyl]-N-[(tert-butoxy)carbonyl]ca rbamate (722 mg, 97%) as a white solid.

[0776] Synthesis of tert-butyl N-[(4-{4-[(4-bromophenyl)carbamoyl]benzamido}-2- methylphenyl)methyl]-N-[(tert-butoxy)carbonyl]carbamate. A mixture of tert-butyl N-[(4-amino-2- methylphenyl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (717 mg, 2.13 mmol), N-(4-bromo- phenyl) -terephthalamic acid (616 mg, 1.92 mmol), and triethylamine (454 mg, 537 μL, 3.85 mmol) in

N,N-dimethylformamide (5.7 mL) was treated with l-[bis(dimethylamino)methylene]-lH-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1091 mg, 2.88 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 25 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-

50% ethyl acetate: hexanes), to give tert-butyl N-[(4-{4-[(4-bromophenyl)carbamoyl]benzamido}-2- methylphenyl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (1.15 g, 94%) as a beige solid.

[0777] Synthesis of tert-butyl 4-[4-(4-{[4-({bis[(tert-butoxy)carbonyl]amino}methyl)-3- methylphenyl]carbamoyl}benzamido)phenyl]-1,2,3,6-tetrahydrop yridine-l-carboxylate. A mixture of tert-butyl N-[(4-{4-[(4-bromophenyl)carbamoyl]benzamido}-2-methylphenyl )methyl]-N-[(tert- butoxy)carbonyl] carbamate (1150 mg, 1.80 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (661 mg, 2.11 mmol), Pd(OAc)2 (20 mg, 0.085 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (78 mg, 0.20 mmol) in 1,4- dioxane (13 mL) and 2M K ₂ CO ₃ (4.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried (Na2SC>4), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl 4-[4-(4-{[4-({bis[(tert-butoxy)carbonyl]amino}methyl)-3- methylphenyl]carbamoyl}benzamido)phenyl]-1,2,3,6-tetrahydrop yridine-l-carboxylate (1.02 g, 77%) as an off-white solid. [0778] Synthesis of N-(4-aminomethyl-3-methyl-phenyl)-N'-[4-(1,2,3,6-tetrahydro- pyridin-4- yl)-phenyl]-terephthalamide. To a mixture of tert-butyl 4-[4-(4-{[4-({bis[(tert- butoxy)carbonyl] amino }methyl)-3 -methylphenyl] carbamoyl }benzamido)phenyl] - 1 ,2,3 ,6- tetrahydropyridine-l-carboxylate (1.02 g, 1.38 mmol) in CH ₂ CI ₂ (8 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N-(4-aminomethyl-3-methyl-phenyl)-N'-[4-(l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-terephthalamide as the bis- trifluoroacetic acid salt (1.01 g, >100%) as a pale yellow solid, that was used without further purification. [0779] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)-

{ [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) -3 - methylphenyl] carbamoyl }benzamido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of N-(4-aminomethyl-3-methyl-phenyl)-N'-[4-(1,2,3,6-tetrahydro- pyridin-4- yl)-phenyl]-terephthalamide. 2 trifluoroacetic acid (267 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- {[(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) -3 -methylphenyl] carbamoyl } benzamido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methyliden e]carbamate (291 mg, 79%) as a pale yellow solid.

[0780] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pheny l]-N'-(4- guanidinomethyl-3 -methyl -phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( {4-[4-(4- { [4-( { [( 1 E)- { [(tert-butoxy) carbonyl] amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)-3 -methylphenyl] carbamoyl } benzamido)phenyl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (291 mg, 0.32 mmol) in CH ₂ CI ₂ (3.2 mL) was added trifluoroacetic acid (3.2 mL). The reaction was stirred for 2 days, then was concentrated. The residue was treated with N,N-dimethylformamide (2 mL), followed by 0.1% trifluoroacetic acid in water (2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give N-[4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-3 -methyl -phenyl)-terephthalamide as the bis- trifluoroacetic acid salt (107 mg, 44%) as a pale orange solid. MS: 525 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.44 (s, 1 H) 10.37 (s, 1 H) 8.08 (s, 5 H) 7.93 (s, 1 H) 7.80 (d, J=8.20 Hz, 3 H) 7.58 - 7.71 (m, 2 H) 7.41 - 7.54 (m, 6 H) 7.20 (d, J=8.20 Hz, 2 H) 6.19 (br. s., 1 H) 4.30 (d, J=4.69 Hz, 2 H) 4.07 (br. s., 2 H) 3.62 (br. s., 2 H) 2.59 (br. s., 2 H) 2.27 (s, 3 H).

[0781] Example 24: Synthesis of N-(2 -carbamimidoyl-2, 3-dihydro- lH-isoindol-5-yl)-N'-[4- ( 1 -carbamimidoyl- 1 ,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-terephthalamide [0782] Synthesis of 5-[4-(4-bromo-phenylcarbamoyl)-benzoylamino]-l, 3-dihydro-isoindole- 2-carboxylic acid tert-butyl ester. To a mixture of N-(4-bromo-phenyl)-terephthalamic acid (616 mg, 1.92 mmol), 5-amino-l,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (500 mg, 2.13 mmol), and triethylamine (454 mg, 537 μL, 3.85 mmol) in N,N-dimethylformamide (5.7 mL) was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (1091 mg, 2.88 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 5-[4-(4-bromo-phenylcarbamoyl)-benzoylamino]- l,3-dihydro-isoindole-2-carboxybc acid tert-butyl ester (743 mg, 72%) as a white solid.

[0783] Synthesis of 5-{4-[4-(l-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4- yl)- phenylcarbamoyl]-benzoylamino}-l,3-dihydro-isoindole-2 -carboxylic acid tert-butyl ester. A mixture of 5-[4-(4-bromo-phenylcarbamoyl)-benzoylamino]-l,3-dihydro-iso indole-2-carboxylic acid tert- butyl ester (743 mg, 1.39 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H- pyridine-1 -carboxylic acid tert-butyl ester (508 mg, 1.63 mmol), Pd(OAc)2 (16 mg, 0.065 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (60 mg, 0.16 mmol) in 1,4-dioxane (10 mL) and 2M K ₂ CO ₃ (3.4 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The mixture was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 5-{4-[4-(l-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4- yl)-phenylcarbamoyl]-benzoylamino}-l,3-dihydro-isoindole-2 -carboxylic acid tert-butyl ester (731 mg, 82%) as a grey solid.

[0784] Synthesis of N-(2, 3-dihydro-lH-isoindol-5-yl)-N'-[4-( 1,2,3, 6-tetrahydro-pyridin-4-yl)- phenyl]-terephthalamide. To a mixture of 5-{4-[4-(l-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-phenylcarbamoyl]-benzoylamino}-l,3-dihydro-isoindole-2 -carboxylic acid tert-butyl ester (731 mg, 1.14 mmol) in CH ₂ CI ₂ (6.5 mL) was added trifluoroacetic acid (3.3 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N-(2,3-dihydro-lH-isoindol-5-yl)-N'-[4-(1,2,3,6-tetrahydro-p yridin-4-yl)-phenyl]- terephthalamide as the bis- trifluoroacetic acid salt (879 mg, >100%) as a grey solid, which was used without further purification.

[0785] Synthesis of {[5-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylim ino- methyl)- 1 ,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl} -benzoylamino)- 1 ,3-dihydro-isoindol-2- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester. To a mixture of N-(2,3-dihydro- lH-isoindol-5-yl)-N'-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-ph enyl]-terephthalamide. 2 trifluoroacetic acid (267 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give {[5-(4-{4-[1-(tert-butoxycarbonylamino- tert-butoxycarbonylimino-methyl)- 1 ,2,3 ,6-tetrahydro-pyridin-4-yl] -phenylcarbamoyl } - benzoylamino)-l,3-dihydro-isoindol-2-yl]-tert-butoxycarbonyl imino-methyl}-carbamic acid tert- butyl ester (175 mg, 47%) as an off-white solid.

[0786] Synthesis of N-(2-carbamimidoyl-2, 3-dihydro- lH-isoindol-5-yl)-N'-[4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-terep hthalamide: To a mixture of { [5-(4-{4- [ 1 -(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- 1 ,2,3 ,6-tetrahydro-pyridin-4-yl] - phenylcarbamoyl } -benzoylamino)- 1 ,3 -dihydro-isoindol-2-yl] -tert-butoxycarbonylimino-methyl } - carbamic acid tert-butyl ester (175 mg, 0.19 mmol) in CH ₂ CI ₂ (1.9 mL) was added trifluoroacetic acid (1.9 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (1.2 mL), followed by 0.1% trifluoroacetic acid in water (1.2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give N-(2-carbamimidoyl-2,3-dihydro-lH-isoindol-5-yl)-N'-[4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-terep hthalamide as the bis- trifluoroacetic acid salt (131 mg, 92%) as pale red solid. MS: 523 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.48 (d, J=14.65 Hz, 2 H) 8.08 (br. s., 5 H) 7.84 - 8.02 (m, 7 H) 7.79 (d, 7=8.20 Hz, 3 H) 7.69 (d, 7=7.62 Hz, 2 H) 7.31 - 7.61 (m, 15 H) 6.18 (br. s., 1 H) 4.73 (d, 7=13.47 Hz, 4 H) 4.06 (br. s., 2 H) 2.58 (br. s., 2 H).

[0787] Example 25: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide

[0788] Synthesis of 3 -(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid methyl ester. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid monomethyl ester (500 mg, 2.94 mmol), 4-bromo-phenylamine (557 mg, 3.23 mmol), and triethylamine (557 mg, 659 DL, 4.70 mmol) in N,N-dimethylformamide (9 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1670 mg, 4.41 mmol). The reaction was stirred for 3 days, then was treated with water (135 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 25 mL), IN HC1 (25 mL), saturated aqueous NaHCO ₃ (25 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 3-(4-bromo- phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxylic acid methyl ester (909 mg, 95%) as a white solid. [0789] Synthesis of 3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxyl ic acid. To a mixture of 3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxyl ic acid methyl ester (909 mg, 2.80 mmol) in 1,4-dioxane (13 mL) was added a 10N aqueous NaOH solution (2.8 mL). The reaction was heated at 60°C for 18 hours, then was treated with further 10N aqueous NaOH solution (2.8 mL). The reaction was heated at 80°C for 18 hours. The reaction was concentrated, then the residue was treated with water (20 mL), and was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxyl ic acid (385 mg, 44%) as a white solid. The isopropanol and hexanes filtrates were concentrated, then the residue was treated with ethyl acetate (100 mL), and was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated, to give 3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxyl ic acid (194 mg, 22%) as a white solid.

[0790] Synthesis of (4-{[3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-car bonyl]- amino} -benzyl) -carbamic acid tert-butyl ester. To a mixture of 3-(4-bromo-phenylcarbamoyl)- bicyclo[1.1.1]pentane-l -carboxylic acid (579 mg, 1.87 mmol), (4-amino-benzyl)-carbamic acid tert- butyl ester (459 mg, 2.07 mmol), and triethylamine (441 mg, 522 μL, 3.73 mmol) in N,N- dimethylformamide (5.5 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1060 mg, 2.80 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give (4-{[3- (4-bromo-phenylcarbamoyl)-bicyclo[1.1. l]pentane-l -carbonyl] -amino }-benzyl)-carbamic acid tert- butyl ester (786 mg, 82%) as a white solid.

[0791] Synthesis of 4-[4-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo[1.1. l]pentane-l-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine -l-carboxylic acid tert- butyl ester. A mixture of (4-{[3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-car bonyl]- amino}-benzyl)-carbamic acid tert-butyl ester (786 mg, 1.53 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyl ic acid tert-butyl ester (558 mg, 1.79 mmol), Pd(OAc)2 (18 mg, 0.071 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (66 mg, 0.18 mmol) in 1,4-dioxane (11 mL) and 2M K ₂ CO ₃ (3.7 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered through Celite. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give, 4-[4-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclofl .1. l]pentane-l-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine -l-carboxylic acid tert- butyl ester (460 mg, 49%) as a white solid.

[0792] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({3-[4-(tert-butoxy carbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)-phenyl]-3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (460 mg, 0.75 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give bicyclo[1.1.1]pentane-l,3- dicarboxylic acid (4-aminomethyl-phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis- trifluoroacetic acid salt (489 mg, >100%) as a yellow solid, which was used without further purification.

[0793] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino }methyl) phenyl] carbamoyl }bicyclo[1.1. l]pentane-l-amido)phenyl] -1,2,3, 6-tetrahydropyridin-l- yl})methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4- aminomethyl-phenyl) -amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 trifluoroacetic acid (258 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N-[(1Z)- { [(tert-butoxy)carbonyl] amino } ( { 4- [4-(3 - { [4-( { [( 1 Z) - { [(tert-butoxy)carbonyl] amino }( { [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [1.1.1 ]pentane- 1 - amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]ca rbamate (276 mg, 77%) as pale yellow solid. [0794] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- {[(tert-butoxy)carbonyl] amino}({ [(tert-butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]car bamoyl} bicyclo[ 1.1.1] pentane-l-amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})meth ylidene]carbamate (276 mg, 0.31 mmol) in CH ₂ CI ₂ (3.1 mL) was added trifluoroacetic acid (3.1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (2 mL), followed by 0.1% trifluoroacetic acid in water (2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis- trifluoroacetic acid salt (162 mg, 72%) as a pale orange solid. MS: 501 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.70 (s, 2 H) 7.94 (d, J=6.44 Hz, 2 H) 7.64 (dd, 7=8.20, 3.52 Hz, 5 H) 7.40 - 7.54 (m, 7 H) 7.22 (d, 7=8.79 Hz, 4 H) 6.15 (br. s., 1 H) 4.29 (d, 7=5.86 Hz, 2 H) 4.05 (br. s., 2 H) 3.60 (br. s., 2 H) 2.55 (br. s., 2 H) 2.31 (s, 6 H).

[0795] Example 26: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide

[0796] Synthesis of 4-(4-bromo-phenylcarbamoyl)-bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (500 mg, 2.36 mmol), 4-bromo-phenylamine (447 mg, 2.59 mmol), and triethylamine (447 mg, 529 μL, 3.77 mmol) in N,N-dimethylformamide (7 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1341 mg, 3.54 mmol). The reaction was stirred for 16 hours, then was treated with water (105 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 25 mL), IN HC1 (25 mL), saturated aqueous NaHCO ₃ (25 mL), and brine (15 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give 4-(4- bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (738 mg, 85%) as a white solid. [0797] Synthesis of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxyli c acid. To a mixture of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxyli c acid methyl ester (738 mg, 2.02 mmol) in 1,4-dioxane (9 mL) was added a ION aqueous NaOH solution (2 mL). The reaction was heated at 80 °C for 20 hours. The reaction was treated with further 10N aqueous NaOH solution (2 mL). The reaction was heated at 80°C for 20 hours. The reaction was concentrated, then the residue was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.2]octane-l-carboxylic acid (237 mg, 33%) as a white solid. The combined isopropanol/hexanes filtrate was concentrated. The residue was treated with ethyl acetate (80 mL), then was washed with water (10 mL), and brine (10 mL), dried (Na SCL). and concentrated, to give 4- (4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxylic acid (408 mg, 57%) as a white solid.

[0798] Synthesis of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]- amino} -benzyl) -carbamic acid tert-butyl ester. To a mixture of 4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.2]octane-l-carboxylic acid (640 mg, 1.82 mmol), (4-amino-benzyl)-carbamic acid tert- butyl ester (446 mg, 2.01 mmol), and triethylamine (429 mg, 507 μL, 3.62 mmol) in N,N- dimethylformamide (5.3 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1030 mg, 2.72 mmol). The reaction was stirred for 16 hours, then was treated with water (75 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 25 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0-70% ethyl acetate: hexanes), to give (4-{[4-(4-bromo- phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carbonyl]-amino}-ben zyl)-carbamic acid tert-butyl ester (534 mg, 53%) as a white solid. [0799] Synthesis of 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester. A mixture of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]- amino}-benzyl)-carbamic acid tert-butyl ester (534 mg, 0.96 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyb c acid tert-butyl ester (350 mg, 1.12 mmol), Pd(OAc)2 (11 mg, 0.046 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (41 mg, 0.11 mmol) in 1,4-dioxane (7 mL) and 2M K ₂ CO ₃ (2.3 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). The mixture was filtered through Celite, then the organic layer was washed with brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give 4-[4-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane- 1 -carbonyl } -amino)-phenyl] - 3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (212 mg, 34%) as a pale yellow solid. [0800] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxybc acid (4-aminomethyl-phenyl)- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane- 1 -carbonyl } -amino)-phenyl] - 3,6-dihydro-2H-pyridine-l-carboxybc acid tert-butyl ester (212 mg, 0.32 mmol) in CH ₂ CI ₂ (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (10 mL), to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid (4-aminomethyl-phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis- trifluoroacetic acid salt (204 mg, 93%) as a light orange solid. [0801] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)phenyl] - 1 ,2, 3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. A mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 trifluoroacetic acid (202 mg, 0.29 mmol) in N,N-dimethylformamide (2.8 mL) was treated slowly with triethylamine (206 mg, 282 μL, 2.02 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l- guanylpyrazole (288 mg, 0.93 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (45 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N- [(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)-{[ (tert-butoxy)carbonyl] amino} ({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 - amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]ca rbamate (125 mg, 46%) as a white solid.

[0802] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- {[(tert-butoxy)carbonyl]amino}({[(tert -butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 - amido)phenyl]- 1,2, 3, 6-tetrahydropyridin-l-yl})methylidene] carbamate (125 mg, 0.13 mmol) in CH ₂ CI ₂ (1.3 mL) was added trifluoroacetic acid (1.3 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3, 6-tetrahydro-pyridin-4-yl)- phenyl]-amide (4-guanidinomethyl-phenyl)-amide as the bis- trifluoroacetic acid salt (30 mg, 30%) as a white solid. MS: 543 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.21 (s, 2 H) 7.83 (s, 2 H) 7.63 (dd, J=8.49, 5.57 Hz, 4 H) 7.31 - 7.46 (m, 7 H) 7.20 (d, 7=8.20 Hz, 3 H) 6.13 (br. s., 1 H) 4.28 (d, 7=6.44 Hz, 2 H) 4.04 (br. s., 2 H) 3.60 (s, 2 H) 2.54 (br. s., 2 H) 1.83 (s, 12 H).

[0803] Example 27: Synthesis of pyridine-2,5 -dicarboxylic acid 5-{[4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide} 2-[(4-guanidinomethyl-phenyl)-amide]

[0804] Synthesis of 5-(4-bromo-phenylcarbamoyl)-pyridine-2-carboxylic acid methyl ester. To a mixture of pyridine-2, 5-dicarboxylic acid 2-methyl ester (500 mg, 2.76 mmol), 4-bromo- phenylamine (523 mg, 3.03 mmol), and triethylamine (523 mg, 619 μL, 4.41 mmol) in N,N- dimethylformamide (8.5 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1568 mg, 4.14 mmol). The reaction was stirred for 1 day, then was treated with water (130 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate: hexanes), to give 5-(4-bromo-phenylcarbamoyl)-pyridine-2- carboxylic acid methyl ester (511 mg, 55%) as a white solid.

[0805] Synthesis of 5-(4-bromo-phenylcarbamoyl)-pyridine-2-carboxylic acid. To a mixture of 5-(4-bromo-phenylcarbamoyl)-pyridine-2-carboxylic acid methyl ester (506 mg, 1.51 mmol) in 1,4-dioxane (6.7 mL) was added a 10N aqueous NaOH solution (1.5 mL). The reaction was heated at 80°C for 20 hours. The reaction was concentrated, then the residue was adjusted to pHl using IN

HC1. The mixture was filtered, then the solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give 5-(4-bromo-phenylcarbamoyl)-pyridine-2 -carboxylic acid (381 mg, 79%) as a white solid. The isopropanol/ hexanes filtrate was concentrated. The residue was treated with ethyl acetate (30 mL), then was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated, to give 5-(4-bromo- phenylcarbamoyl)-pyridine-2 -carboxylic acid (56 mg, 12%) as a white solid.

[0806] Synthesis of (4-{[5-(4-bromo-phenylcarbamoyl)-pyridine-2-carbonyl]-amino} - benzyl)-carbamic acid tert-butyl ester. To a mixture of 5-(4-bromo-phenylcarbamoyl)-pyridine-2- carboxylic acid (437 mg, 1.36 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (334 mg, 1.50 mmol), and triethylamine (321 mg, 379 μL, 2.71 mmol) in N,N-dimethylformamide (4 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate (770 mg, 2.03 mmol). The reaction was stirred for 16 hours, then was treated with water (60 mL) and ethyl acetate (40 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give (4-{[5-(4-bromo- phenylcarbamoyl)-pyridine-2-carbonyl]-amino}-benzyl)-carbami c acid tert-butyl ester (552 mg, 77%) as a white solid.

[0807] Synthesis of 4-[4-({6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- pyridine-3 -carbonyl }-amino)-phenyl] -3, 6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester. A mixture of (4-{[5-(4-bromo-phenylcarbamoyl)-pyridine-2-carbonyl]-amino} -benzyl)-carbamic acid tert-butyl ester (550 mg, 1.05 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro - 2H-pyridine-l -carboxylic acid tert-butyl ester (383 mg, 1.23 mmol), Pd(OAc)2 (12 mg, 0.050 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (45 mg, 0.12 mmol) in 1,4-dioxane (7.7 mL) and 2M K ₂ CO ₃ (2.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give 4-[4-({6-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -pyridine-3 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (557 mg, 85%) as a pale yellow solid.

[0808] Synthesis of pyridine-2, 5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide] 5-{[4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide}. To a mixture of 4-[4-({6-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -pyridine-3 -carbonyl } -amino)-phenyl] -3 ,6-dihydro- 2H-pyridine-l -carboxylic acid tert-butyl ester (557 mg, 0.89 mmol) in CH ₂ CI ₂ (4.7 mL) was added trifluoroacetic acid (2.4 mL). The reaction was stirred for 20 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (10 mL), to give pyridine-2, 5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide] 5-{[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide} as the tris- trifluoroacetic acid salt (712 mg, >100%) as a pale green solid, that was used without further purification.

[0809] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino (methyl) phenyl] carbamoyl }pyridine-3 -amido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl} )methylidene] carbamate. A mixture of pyridine-2, 5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide] 5-{[4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide}. 3 trifluoroacetic acid (308 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was concentrated, then the residue was treated with water (25 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(lE)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl} pyridine-3-amido)phenyl]-1,2,3,6- tetrahydropyridin-l-yl})methylidene] carbamate (242 mg, 66%)( as a pale yellow solid.

[0810] Synthesis of pyridine-2,5 -dicarboxylic acid 5-{[4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide} 2-[(4-guanidinomethyl-phenyl)-amide]: To a mixture of tert- butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(lE)- {[(tert-butoxy)carbonyl]amino} ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } pyridine -3 -amido)phenyl] -1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (242 mg, 0.27 mmol) in CH ₂ CI ₂ (2.7 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (1.7 mL), followed by 0.1% trifluoroacetic acid in water (1.7 mL) dropwise. The mixture was filtered, then the solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give pyridine-2, 5 -dicarboxylic acid 5-{[4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide } 2-[(4-guanidinomethyl-phenyl)- amide] as the tris- trifluoroacetic acid salt (94 mg, 41%) as a beige solid. MS: 512 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.81 (s, 1 H) 10.68 (s, 1 H) 9.18 (br. s., 1 H) 8.55 (d, 7=8.20 Hz, 1 H) 8.28 (d, J=8.20 Hz, 1 H) 7.94 (d, 7=7.62 Hz, 5 H) 7.77 (d, 7=8.20 Hz, 3 H) 7.39 - 7.60 (m, 8 H) 7.31 (d, 7=8.20 Hz, 3 H) 6.20 (br. s., 1 H) 4.34 (d, 7=5.27 Hz, 2 H) 4.07 (br. s., 2 H) 3.62 (br. s., 2 H) 2.59 (br. s., 2 H).

[0811] Example 28: Synthesis of pyridine-2, 5 -dicarboxylic acid 2-{[4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide} 5-[(4-guanidinomethyl-phenyl)-amide]

[0812] Synthesis of 6-(4-bromo-phenylcarbamoyl)-nicotinic acid methyl ester. To a mixture of pyridine-2, 5 -dicarboxylic acid 2-methyl ester (500 mg, 2.76 mmol), 4-bromo-phenylamine (523 mg, 3.03 mmol), and triethylamine (523 mg, 619 μL, 4.41 mmol) in N,N-dimethylformamide (8.5 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate (1568 mg, 4.14 mmol). The reaction was stirred for 1 day, then was treated with water (130 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (20 mL), dried (Na ₂ SO ₄ ). and concentrated, to give 6-(4-bromo-phenylcarbamoyl)-nicotinic acid methyl ester (620 mg, 67%) as an off-white solid.

[0813] Synthesis of 6-(4-bromo-phenylcarbamoyl)-nicotinic acid. To a mixture of 6-(4- bromo-phenylcarbamoyl)-nicotinic acid methyl ester (620 mg, 1.85 mmol) in 1,4-dioxane (8.2 mL) was added a ION aqueous NaOH solution (1.85 mL). The reaction was heated at 80°C for 20 hours. The reaction was concentrated, then the residue was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give 6-(4- bromo-phenylcarbamoyl)-nicotinic acid (318 mg, 54%) as a white solid. The isopropanol/ hexanes filtrate was concentrated. The residue was treated with ethyl acetate (40 mL) and water (10 mL). The organic layem was washed with brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated, to give 6-(4- bromo-phenylcarbamoyl)-nicotinic acid (48 mg, 8%) as a white solid.

[0814] Synthesis of (4-{[6-(4-Bromo-phenylcarbamoyl)-pyridine-3-carbonyl]-amino} - benzyl)-carbamic acid tert-butyl ester. To a mixture of 6-(4-bromo-phenylcarbamoyl)-nicotinic acid (361 mg, 1.12 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (276 mg, 1.24 mmol), and triethylamine (265 mg, 313 μL, 2.24 mmol) in N,N-dimethylformamide (3.3 mL) was added 1- [bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (636 mg, 1.68 mmol). The reaction was stirred for 16 hours, then was treated with water (60 mL) and ethyl acetate (40 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give (4-{[6-(4-Bromo-phenylcarbamoyl)-pyridine-3- carbonyl] -amino} -benzyl) -carbamic acid tert-butyl ester (486 mg, 83%) as a white solid.

[0815] Synthesis of 4-[4-({5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- pyridine-2-carbonyl}-amino)-phenyl] -3, 6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester. A mixture of (4-{[6-(4-Bromo-phenylcarbamoyl)-pyridine-3-carbonyl]-amino} -benzyl)-carbamic acid tert-butyl ester (484 mg, 0.92 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro - 2H-pyridine-1 -carboxylic acid tert-butyl ester (336 mg, 1.08 mmol), Pd(OAc)2 (11 mg, 0.044 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (40 mg, 0.11 mmol) in 1,4-dioxane (7 mL) and 2M K ₂ CO ₃ (2.2 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give 4-[4-({6-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -pyridine-3 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (468 mg, 81%) as a pale yellow solid. [0816] Synthesis of pyridine-2, 5-dicarboxylic acid 5-[(4-aminomethyl-phenyl)-amide] 2-{[4-

(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide}. To a mixture of 4-[4-({6-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -pyridine-3 -carbonyl } -amino)-phenyl] -3 ,6-dihydro- 2H-pyridine-l -carboxylic acid tert-butyl ester (466 mg, 0.75 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with ethyl acetate (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with ethyl acetate (15 mL), to give pyridine-2, 5-dicarboxylic acid 5-[(4-aminomethyl-phenyl)-amide] 2-{[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide}as the tris- trifluoroacetic acid salt (495 mg, 86%) as a pale green solid.

[0817] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(5-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino (methyl) phenyl] carbamoyl }pyridine-2-amido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl} )methylidene] carbamate. A mixture of pyridine-2, 5 -dicarboxylic acid 5-[(4-aminomethyl-phenyl)-amide] 2-{[4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide}. 3 trifluoroacetic acid (308 mg, 0.40 mmol) in N,N- dimethylformamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was concentrated, then the residue was treated with water (25 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( {4- [4-(5 - { [4-( { [( 1 E)- { [(tert-butoxy)carbonyl]amino } ( { [(tert-butoxy) carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl}pyridin e-2-amido)phenyl]-1,2,3,6- tetrahydropyridin-l-yl})methylidene] carbamate (241 mg, 66%) as a pale yellow solid.

[0818] Synthesis of pyridine-2,5 -dicarboxylic acid 2-{[4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide} 5-[(4-guanidinomethyl-phenyl)-amide]: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(5-{[4-({[(lE)- {[(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } pyridine -2-amido) phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamat e (241 mg, 0.26 mmol) in CH ₂ CI ₂ (2.6 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (1.7 mL), followed by 0.1% trifluoroacetic acid in water (1.7 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (6 mL), and hexanes (6 mL), to give pyridine-2, 5- dicarboxylic acid 2-{[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phen yl]-amide} 5-[(4- guanidinomethyl-phenyl)-amide] as the tris- trifluoroacetic acid salt (47 mg, 21%) as a beige solid. MS: 512 M+H+; ¹ H NMR(300 MHz, DMSO-d ₆ ) δ ppm 10.80 (br. s., 1 H) 10.66 (br. s., 1 H) 9.17 (br. s., 1 H) 8.56 (br. s., 1 H) 8.30 (br. s., 1 H) 7.92 (br. s., 4 H) 7.77 (br. s., 3 H) 7.22 - 7.59 (m, 12 H) 6.19 (br. s., 1 H) 4.34 (br. s., 2 H) 4.06 (br. s., 2 H) 3.61 (br. s., 2 H) 2.58 - 2.64 (m, 2 H).

[0819] Example 29: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl - 6-yl)-N'-(4-guanidinomethyl-phenyl)-terephthalamide

[0820] Synthesis of N-(5-bromo-pyridin-2-yl)-terephthalamic acid methyl ester. To a mixture of terephthalic acid monomethyl ester (541 mg, 3.00 mmol), 5-bromo-pyridin-2-ylamine (575 mg, 3.32 mmol), and triethylamine (710 mg, 838 μL, 6.00 mmol) in N,N-dimethylformamide (9 mL) was added l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate (1704 mg, 4.50 mmol). The reaction was stirred for 16 hours, then was treated with water (135 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (25 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0- 30% ethyl acetate: hexanes), to give N-(5-bromo-pyridin-2-yl)-terephthalamic acid methyl ester (138 mg, 14%) as a white solid.

[0821] Synthesis of N-(5-bromo-pyridin-2-yl)-terephthalamic acid. To a mixture of N-(5- bromo-pyridin-2-yl)-terephthalamic acid methyl ester (464 mg, 1.38 mmol) in 1,4-dioxane (6.1 mL) was added a 10N aqueous NaOH solution (1.4 mL). The reaction was heated at 80°C for 16 hours, then was concentrated. The residue was treated with water (30 mL), then was adjusted to pH 1 using IN HC1. The mixture was filtered, then the solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give N-(5-bromo-pyridin-2-yl)-terephthalamic acid (384 mg, 87%) as a white solid. The isopropanol/ hexanes filtrate was concentrated, to give N-(5-bromo-pyridin-2-yl)-terephthalamic acid (25 mg, 6%) as a white solid.

[0822] Synthesis of {4-[4-(5-bromo-pyridin-2-ylcarbamoyl)-benzoylamino]-benzyl}- carbamic acid tert-butyl ester. To a mixture of N-(5-bromo-pyridin-2-yl)-terephthalamic acid (409 mg, 1.27 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (313 mg, 1.40 mmol), and triethylamine (300 mg, 355 μL, 2.54 mmol) in N,N-dimethylformamide (3.7 mL) was added 1- [bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (721 mg, 1.90 mmol). The reaction was treated with further N,N-dimethylformamide (2 mL), then was stirred for 3 days. The reaction was treated with water (90 mL), and ethyl acetate (50 mL), then was shaken, and filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give {4-[4-(5-bromo-pyridin-2-ylcarbamoyl)-benzoylamino]-benzyl}- carbamic acid tert-butyl ester (422 mg, 66%) as a light grey solid.

[0823] Synthesis of 6-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- benzoylamino}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxy lic acid tert-butyl ester. A mixture of {4-[4-(5-bromo-pyridin-2-ylcarbamoyl)-benzoylamino]-benzyl}- carbamic acid tert-butyl ester (422 mg, 0.80 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-l- carboxylic acid tert-butyl ester (293 mg, 0.94 mmol), Pd(OAc)2 (9 mg, 0.040 mmol), and 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (35 mg, 0.09 mmol) in 1,4-dioxane (6 mL) and 2M K ₂ CO ₃ (1.9 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 6-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- benzoylamino}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxy lic acid tert-butyl ester (233 mg, 46%) as a beige solid. The ethyl acetate/ water fdtrate was separated, then the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 6-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-benzoylamino}-3',6'-dihydro-2'H-[3,4']bipyr idinyl-1'-carboxylic acid tert-butyl ester (203 mg, 40%) as a white solid.

[0824] Synthesis of N-(4-aminomethyl-phenyl)-N'-(1',2',3',6'-tetrahydro-[3,4']bi pyridinyl-6- yl)-terephthalamide. To a mixture of 6-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- benzoylamino}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxy lic acid tert-butyl ester (436 mg, 0.70 mmol) in CH ₂ CI ₂ (3.7 mL) was added trifluoroacetic acid (1.9 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N-(4-aminomethyl-phenyl)-N'-1',2', 3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-terephthalamide as the tris- trifluoroacetic acid salt (497 mg, 92%) as a light brown solid.

[0825] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl }benzamido)pyridin-3 -yl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene]carbamate . To a mixture of N-(4-aminomethyl-phenyl)-N'-(1',2',3',6'-tetrahydro-[3,4']bi pyridinyl-6-yl)- terephthalamide. 3 trifluoroacetic acid (308 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(1Z)- { [(tert-butoxy)carbonyl] amino } ( {4- [6-(4- { [4-( { [( 1 E)- { [(tert-butoxy)carbonyl]amino } ( { [(tert-butoxy) carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)pyridin-3 -yl] - 1 ,2, 3 ,6- tetrahydropyridin-l-yl})methylidene] carbamate (164 mg, 45%) as a white solid.

[0826] Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl -6-yl)-N'-(4- guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(lE)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)pyridin-3 -yl] - 1 ,2, 3 ,6- tetrahydropyridin-l-yl})methylidene]carbamate (164 mg, 0.18 mmol) in CH ₂ CI ₂ (1.8 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-N'-(4-guanidinomethyl-phenyl)-tereph thalamide as the tris- trifluoroacetic acid salt (110 mg, 72%) as a white solid. MS: 512 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.06

(s, 1 H) 10.45 (s, 1 H) 8.53 (s, 1 H) 8.11 - 8.28 (m, 4 H) 7.95 - 8.11 (m, 3 H) 7.87 (br. s., 1 H) 7.78 (d,

J=8.20 Hz, 2 H) 7.41 (br. s., 4 H) 7.29 (d, J=8.79 Hz, 3 H) 6.31 (br. s., 1 H) 4.32 (d, J=5.27 Hz, 2 H)

4.08 (br. s., 2 H) 3.63 - 3.69 (m, 1 H) 2.62 (br. s., 2 H).

[0827] Example 30: Synthesis of N-[4-(l-carbamimidoyl-2,5-dihydro-lH-pyrrol-3-yl)- phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide

[0828] Synthesis of 3-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-phenyl)-2, 5 -dihydro-pyrrole- 1-carboxylic acid tert-butyl ester. A mixture of {4-[4-(4- bromo-phenylcarbamoyl)-benzoylamino]-benzyl}-carbamic acid tert-butyl ester (702 mg, 1.34 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,5-dihydro -pyrrole-l-carboxylic acid tert- butyl ester (467 mg, 1.58 mmol), Pd(0Ac) ₂ (15 mg, 0.068 mmol), and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (59 mg, 0.15 mmol) in 1,4-dioxane (10.2 mL) and 2M K ₂ CO ₃ (3.2 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 3-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]-benzoylamino}- phenyl)-2,5-dihydro-pyrrole-l-carboxylic acid tert-butyl ester (597 mg, 73%) as a grey solid.

[0829] Synthesis of N-(4-aminomethyl-phenyl)-N'-[4-(2,5-dihydro-lH-pyrrol-3-yl)- phenyl]- terephthalamide. To a mixture of 3-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-phenyl)-2, 5 -dihydro-pyrrole- 1-carboxylic acid tert-butyl ester (597 mg, 0.97 mmol) in CH ₂ CI ₂ (5.1 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethylether (20 mL), to give N- (4-aminomethyl-phenyl)-N'-[4-(2,5-dihydro-lH-pyrrol-3-yl)-ph enyl]-terephthalamide. 2 trifluoroacetic acid (641 mg, >100%) as a grey solid, that was used without further purification. [0830] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({3-[4-(4-{[4-({[(lE)-

{ [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl}benzamido)phenyl]-2,5-dihydro-lH-pyrrol-l-yl})meth ylidene]carbamate. A mixture of N-(4-aminomethyl-phenyl)-N'-[4-(2,5-dihydro-lH-pyrrol-3-yl)- phenyl]-terephthalamide. 2 trifluoroacetic acid (641 mg, 1.00 mmol) in N,N-dimethylformamide (9.5 mL) was treated with triethylamine (700 mg, 960 μL, 6.85 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (980 mg, 3.15 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (150 mL), then was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), 10% aqueous citric acid (30 mL), and brine (20 mL). The combined organic layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({3-[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl}benzamido)phenyl]-2,5-dihydro-lH-pyrrol-l-yl})meth ylidene]carbamate (395 mg, 44%) as a beige solid.

[0831] Synthesis of N-[4-(l-carbamimidoyl-2,5-dihydro-lH-pyrrol-3-yl)-phenyl]-N' -(4- guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino }({3-[4-(4-{[4-({[(lE)-{ [(tert-butoxy)carbonyl] amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)phenyl] -2,5 -dihydro- lH-pyrrol-l-yl})methybdene]carbamate (395 mg, 0.44 mmol) in CH ₂ CI ₂ (4.4 mL) was added trifluoroacetic acid (4.4 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(l-carbamimidoyl-2,5-dihydro-lH- pyrrol-3-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephtha lamide as the bis- trifluoroacetic acid salt (125 mg, 39%) as a white solid. MS: 497 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.54 (br. s., 1 H) 10.47 (br. s., 1 H) 8.09 (br. s., 5 H) 7.74 - 7.93 (m, 4 H) 7.21 - 7.64 (m, 13 H) 6.42 (br. s., 1 H) 4.56 (br. s., 2 H) 4.34 (br. s., 4 H).

[0832] Example 31: Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-N'-(4-guanidinomethyl-phenyl)-N-methyl-terephthalami de

[0833] Synthesis of N-(4-bromo-phenyl)-N-methyl-terephthalamic acid methyl ester. To a mixture of (4-bromo-phenyl)-methyl-amine (558 mg, 3.00 mmol) and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in CHCI ₃ (8 mL) was added a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (687 mg, 3.46 mmol) in CHCI ₃ (8 mL). The reaction was stirred for 3 days, then was concentrated. The residue was treated with ethyl acetate (100 mL), and was washed with water (30 mL), IN HC1 (30 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give N-(4-bromo-phenyl)-N-methyl-terephthalamic acid methyl ester (746 mg, 71%) as a white solid.

[0834] Synthesis of N-(4-bromo-phenyl)-N-methyl-terephthalamic acid. To a mixture of N- (4-bromo-phenyl)-N-methyl-terephthalamic acid methyl ester (746 mg, 2.14 mmol) in 1,4-dioxane (10 mL) was added a 10N aqueous sodium hydroxide solution (2.1 mL). The reaction was heated at 80°C for 16 hours. The reaction was concentrated, then the residue was treated water (50 mL), then was adjusted to pH 1 using concentrated HC1. The solid was treated with 1,4-dioxane (10 mL), and 10N aqueous sodium hydroxide solution (3 mL). The reaction was heated at 90°C for 24 hours. The reaction was treated with further 10N aqueous sodium hydroxide solution (3 mL), then was heated at 90°C for 48 hours. The reaction was concentrated, then the residue was treated with water (30 mL), and was adjusted to pH 1 using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (10 mL), to give N-(4-bromo-phenyl)-N-methyl-terephthalamic acid (462 mg, 65%) as a white solid.

[0835] Synthesis of (4-{4-[(4-bromo-phenyl)-methyl-carbamoyl]-benzoylamino}-benz yl)- carbamic acid tert-butyl ester. To a mixture of N-(4-bromo-phenyl)-N-methyl-terephthalamic acid (462 mg, 1.38 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (343 mg, 1.55 mmol), and triethylamine (280 mg, 378 μL, 2.77 mmol) in N,N-dimethylformamide 4.1 mL) was added 1- [bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (792 mg, 2.08 mmol). The reaction was stirred for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give (4-{4-[(4-bromo-phenyl)-methyl-carbamoyl]-benzoylamino}-benz yl)-carbamic acid tert-butyl ester (635 mg, 86%) as a white solid.

[0836] Synthesis of 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- benzoyl}-methyl-amino)-phenyl]-3,6-dihydro-2H-pyridine-l-car boxylic acid tert-butyl ester. A mixture of (4-{4-[(4-bromo-phenyl)-methyl-carbamoyl]-benzoylamino}-benz yl)-carbamic acid tert- butyl ester (635 mg, 1.18 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H- pyridine-1 -carboxylic acid tert-butyl ester (432 mg, 1.39 mmol), Pd(OAc)2 (13 mg, 0.059 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (52 mg, 0.13 mmol) in 1,4-dioxane (9 mL) and 2M K ₂ CO ₃ (2.8 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL), then was washed with water (20 mL), and brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-benzoyl}-methyl -amino)-phenyl]-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (655 mg, 87%) as a pale yellow solid.

[0837] Synthesis of N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydro -pyridin- 4-yl) -phenyl] -terephthalamide. To a mixture of 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-benzoyl}-methyl-amino)-phenyl]-3,6-dihydro- 2H-pyridine-l-carboxylic acid tert- butyl ester (655 mg, 1.02 mmol) in CH ₂ CI ₂ (5.1 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-( 1,2,3, 6-tetrahydro- pyridin-4-yl)-phenyl]-terephthalamide. 2 trifluoroacetic acid (724 mg, >100%) as a pale orange solid, that was used without further purification.

[0838] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(N-methyl4- {[4-({[(lZ)-{ [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } benzamido)phenyl] -1,2,3, 6-tetrahydropyridin- 1 -yl } )methylidene] carbamate . A mixture of N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydro -pyridin-4-yl)-phenyl]- terephthalamide 2 trifluoroacetic acid (267 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (15 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(N-methyl4-{[4- ({[(lZ)-{[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methyliden e]carbamate (207 mg, 56%) as a pale yellow solid. [0839] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pheny l]-N'-(4- guanidinomethyl-phenyl)-N-methyl-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(N-methyl4-{[4-({[(lZ)-{[(tert- butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)phenyl] - 1 ,2, 3 ,6- tetrahydropyridin-l-yl})methylidene]carbamate (207 mg, 0.22 mmol) in CH ₂ CI ₂ (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative -HPLC, to give N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-N-methyl -terephthalamide as the bis- trifluoroacetic acid salt (91 mg, 55%) as a white solid. MS: 525 M+H+; 'H NMR (300 MHz, DMSO- d ₆ ) δ ppm 10.27 (s, 1 H) 7.98 (t, J= 5.57 Hz, 1 H) 7.77 (d, J=8.20 Hz, 2 H) 7.70 (d, J=8.20 Hz, 2 H) 7.35 - 7.55 (m, 9 H) 7.21 (dd, J=19.33, 8.20 Hz, 7 H) 6.18 (br. s., 1 H) 4.30 (d, J=5.86 Hz, 2 H) 4.01 (br. s., 2 H) 3.55 - 3.61 (m, 2 H) 3.37 (s, 3 H).

[0840] Example 32: Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-N'-(4-guanidinomethyl-phenyl)-2,5-dimethyl-terephtha lamide

[0841] Synthesis of 2,5-dimethyl-terephthalic acid dimethyl ester. A mixture of 2,5-dimethyl- terephthalic acid (1.21 g, 6.23 mmol) in methanol (50 mL) wasw heated at reflux for 30 minutes. To the mixture was added thionyl chloride (16.6 mL, 124.6 mmol). The reaction was heated at reflux for 12 hours, then was concentrated. The residue was treated with ethyl acetate (80 mL), and was washed with 2N NaOH (25 mL), and brine (10 mL), dried (NarSOr). and concentrated, to give 2,5-dimethyl- terephthalic acid dimethyl ester (1.16 g, 84%) as an off-white solid.

[0842] Synthesis of 2,5-dimethyl-terephthalic acid monomethyl ester. To a mixture of 2,5- dimethyl-terephthalic acid dimethyl ester (1.16 g, 5.22 mmol) in methanol (16 mL) was heated at reflux for 15 minutes, then crushed KOH (293 mg, 5.22 mmol) was added. The reaction was heated at reflux for 3.5 hours, then was concentrated. The residue was partitioned between ethyl acetate (25 mL) and water (50 mL). The aquoues layer was adjusted to pHl using IN HC1, then the mixture was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 2,5-dimethyl- terephthalic acid monomethyl ester (149 mg, 14%) as a white solid. The isopropanol/ hexanes filtrate was concentrated, to give 2,5-dimethyl-terephthalic acid monomethyl ester (453 mg, 42%) as a white solid.

[0843] Synthesis of N-(4-bromo-phenyl)-2,5-dimethyl-terephthalamic acid methyl ester. To a mixture of 2,5 -dimethyl -terephthalic acid monomethyl ester (602 mg, 2.89 mmol), 4-bromo- phenylamine (548 mg, 3.17 mmol), and triethylamine (548 mg, 649 μL, 4.62 mmol) in N,N-dimethyl formamide (9 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridini um 3- oxid hexafluorophosphate (1643 mg, 4.34 mmol). The reaction was stirred for 16 hours, then was treated with water (135 mL), and was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), IN HC1 (30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give N-(4-bromo-phenyl)-2,5-dimethyl- terephthalamic acid methyl ester (540 mg, 52%) as a white solid.

[0844] Synthesis of N-(4-bromo-phenyl)-2,5-dimethyl-terephthalamic acid. To a mixture of N-(4-bromo-phenyl)-2,5-dimethyl-terephthalamic acid methyl ester (540 mg, 1.49 mmol) in 1,4- dioxane (7 mL) was added a 10N aqueous NaOH solution (1.5 mL). The reaction was heated at 90°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (10 mL), and was dried under high vacuum, to give N-(4-bromo-phenyl)-2,5- dimethyl-terephthalamic acid (499 mg, 95%) as a white solid.

[0845] Synthesis of {4-[4-(4-bromo-phenylcarbamoyl)-2,5-dimethyl-benzoylamino]-b enzyl}- carbamic acid tert-butyl ester. To a mixture of N-(4-bromo-phenyl)-2,5-dimethyl-terephthalamic acid (499 mg, 1.43 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (356 mg, 1.61 mmol), and triethylamine (291 mg, 393 μL, 2.88 mmol) in N,N-dimethylformamide (4.3 mL) was added 1- [bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (823 mg, 2.16 mmol). The reaction was stirred for 16 hours, then was treated with water (60 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give {4-[4-(4-bromo-phenylcarbamoyl)-2,5-dimethyl- benzoylamino] -benzyl }-carbamic acid tert-butyl ester (511 mg, 65%) as a white solid.

[0846] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]-2,5- dimethyl-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-l-car boxylic acid tert-butyl ester. A mixture of {4-[4-(4-bromo-phenylcarbamoyl)-2,5-dimethyl-benzoylamino]-b enzyl}-carbamic acid tert-butyl ester (511 mg, 0.93 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro - 2H-pyridine-l -carboxylic acid tert-butyl ester (339 mg, 1.09 mmol), Pd(OAc)2 (10 mg, 0.046 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (41 mg, 0.10 mmol) in 1,4-dioxane (7 mL) and 2M K ₂ CO ₃ (2.2 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The organic layer was washed with brine (10 mL), then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-(4-{4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-2,5-dimethyl-be nzoylamino}-phenyl)-3, 6-dihydro- 2H-pyridine-l -carboxylic acid tert-butyl ester (192 mg, 32%) as a white solid. The ethyl acetate filtrate was dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -2,5 -dimethyl -benzoylamino } -phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (65 mg, 11%) as a white solid.

[0847] Synthesis of N-(4-aminomethyl-phenyl)-2,5-dimethyl-N'-[4-(1,2,3,6-tetrahy dro- pyridin-4-yl)-phenyl]-terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino- methyl)-phenylcarbamoyl]-2,5-dimethyl-benzoylamino}-phenyl)- 3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (257 mg, 0.39 mmol) in CH ₂ CI ₂ (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (10 mL), to give N-(4-aminomethyl-phenyl)-2,5-dimethyl-N'-[4-(l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-terephthalamide as the bis- trifluoroacetic acid salt (264 mg, 99%) as a light brown solid.

[0848] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino (methyl) phenyl] carbamoyl } -2, 5 -dimethylbenzamido)phenyl] -1,2,3, 6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of N-(4-aminomethyl-phenyl)-2,5-dimethyl-N'-[4-(1,2,3,6-tetrahy dro- pyridin-4-yl)-phenyl]-terephthalamide. 2 trifluoroacetic acid (262 mg, 0.38 mmol) in N,N- dimethylformamide (3.8 mL) was added triethylamine (266 mg, 365 μL, 2.60 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (372 mg, 1.20 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4- ( { [( 1 E) - { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } -2, 5 -dimethylbenzamido)phenyl] -1,2,3, 6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (108 mg, 30%) as a white solid.

[0849] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pheny l]-N'-(4- guanidinomethyl -phenyl)-2, 5 -dimethyl -terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( {4- [4-(4- { [4-( { [( 1 E)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy) carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl}-2, 5-dimethyl benzamido)phenyl]-1,2,3,6- tetrahydropyridin-l-yl})methylidene]carbamate (108 mg, 0.12 mmol) in CH ₂ CI ₂ (1.2 mL) was added trifluoroacetic acid (1.2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative -HPLC, to give N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-2, 5 -dimethyl -terephthalamide as the bis- trifluoroacetic acid salt (59 mg, 64%) as a white solid. MS: 539 M+H+; 'H NMR (300 MHz, DMSO- d ₆ ) δ ppm 10.38 (d, J=4.10 Hz, 2 H) 7.91 (t, J=5.86 Hz, 2 H) 7.68 - 7.80 (m, 5 H) 7.35 - 7.53 (m, 9 H) 7.27 (d, J= 8.79 Hz, 3 H) 6.16 (br. s., 1 H) 4.31 (d, J= 5.86 Hz, 2 H) 4.06 (br. s., 2 H) 3.61 (s, 3 H) 2.57

(br. s., 2 H) 2.37 (s, 7 H).

[0850] Example 33: Synthesis of pyridine-2,5 -dicarboxylic acid 5-{[4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-amide} 2-[(4-guanidinomethyl-phenyl)-amide] [0851] Synthesis of 6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -nicotinic acid methyl ester. To a mixture of pyridine-2, 5-dicarboxylic acid 5-methyl ester (500 mg, 2.76 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (674 mg, 3.03 mmol), and triethylamine (523 mg, 619 μL, 4.41 mmol) in N,N-dimethylformamide (8.5 mL) was added 1- [bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate (1568 mg, 4.15 mmol). The reaction was stirred for 16 hours, then water (130 mL) was added, and the mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -nicotinic acid methyl ester (907 mg, 85%) as a pale yellow solid.

[0852] Synthesis of 6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -nicotinic acid. To a mixture of 6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-nico tinic acid methyl ester (907 mg, 2.35 mmol) in 1,4-dioxane (11 mL) was added a ION aqueous NaOH solution (2.35 mL). The reaction was heated at 80°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (15 mL), then was dried under high vacuum, to give 6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-nico tinic acid (739 mg, 85%) as a pale yellow solid.

[0853] Synthesis of (4-{[5-(4-bromo-3-fluoro-phenylcarbamoyl)-pyridine-2-carbony l]- amino}-benzyl)-carbamic acid tert-butyl ester. The title compound was prepared according to the procedure for (4-{4-[(4-bromo-phenyl)-methyl-carbamoyl]-benzoylamino}-benz yl)-carbamic acid tert-butyl ester except that 6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl] -nicotinic acid was substituted for N-(4-bromo-phenyl)-N-methyl-terephthalamic acid and 4-bromo-3-fluoroaniline was substituted for (4-amino-benzyl)-carbamic acid tert-butyl ester.

[0854] Synthesis of 4-[4-({6-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- pyridine-3 -carbonyl } -amino)-2-fluoro-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester. The title compound was prepared according to the procedure for 4-[4-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-benzoyl}-methyl -amino)-phenyl]-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester except that (4-{[5-(4-bromo-3-fluoro-phenylcarbamoyl)- pyridine-2-carbonyl] -amino }-benzyl)-carbamic acid tert-butyl ester was substituted for (4-{4-[(4- bromo-phenyl)-methyl -carbamoyl] -benzoylamino } -benzyl)-carbamic acid tert-butyl ester.

[0855] Synthesis of pyridine-2, 5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide] 5-{ [3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide}. The title compound was prepared according to the procedure of N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydro - pyridin-4-yl)-phenyl]-terephthalamide except that 4-[4-({6-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -pyridine-3 -carbonyl } -amino)-2-fluoro-phenyl] -3 ,6-dihydro-2H-pyridine- 1 - carboxylic acid tert-butyl ester was substituted for 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-benzoyl}-methyl-amino)-phenyl]-3,6-dihydro- 2H-pyridine-l-carboxylic acid tert- butyl ester.

[0856] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } pyridine -3 -amido)-2 -fluorophenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. The title compound was prepared according to the procedure for tert-butyl N-[(1Z)- { [(tert-butoxy)carbonyl] amino } ( {4- [4-(N-methyl4- { [4-( { [( 1Z)- { [(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl }benzamido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl} )methylidene] carbamate except that pyridine-2, 5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide] 5-{[3-fluoro-4-(l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide}was substituted for N-(4-aminomethyl-phenyl)-N'-methyl-N'- [4-( 1 ,2,3 ,6-tetrahydro-pyridin-4-yl)-phenyl] -terephthalamide .

[0857] Synthesis of pyridine-2,5 -dicarboxylic acid 5-{[4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-fluoro-phenyl] -amide} 2-[(4-guanidinomethyl-phenyl)-amide]: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } pyridine -3 -amido)-2 -fluorophenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (142 mg, 0.15 mmol) in CH ₂ CI ₂ (1.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction was stirred for 3 days, then was concentrated. The residue was treated with N,N-dimethyl formamide (1.3 mL), followed by 0.1% trifluoroacetic acid in water (1.3 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give pyridine-2, 5-dicarboxylic acid 5-{[4-(l-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl] -amide} 2-[(4-guanidinomethyl-phenyl)-amide] as the tris- trifluoroacetic acid salt (64 mg, 49%) as a beige solid. MS: 530 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.85 (br. s., 1 H) 10.79 (s, 1 H) 9.18 (br. s., 1 H) 8.55 (d, 7=6.44 Hz, 1 H) 8.28 (d, 7= 7.62 Hz, 1 H) 7.87 - 8.06 (m, 4 H) 7.76 (d, J=14.06 Hz, 1 H) 7.18 - 7.65 (m, 13 H) 5.98 - 6.11 (m, 1 H) 4.33 (d, 7=5.27 Hz, 2 H) 4.07 (br. s., 2 H) 3.60 (br. s., 2 H) 2.56 (br. s., 2 H).

[0858] Example 34: Synthesis of N ¹ -[4-(l-carbamimidoyl- 1,2,3, 6-tetrahydro-pyridin-4-yl)- phenyl]-N4-(4-guanidinomethyl-phenyl)-2-methyl-terephthalami de

[0859] Synthesis of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl] -2 -methyl - terephthalamic acid methyl ester. To a mixture of 2-methyl-terephthalic acid 1 -methyl ester (492 mg, 2.53 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (618 mg, 2.78 mmol), and triethylamine (480 mg, 647 μL, 4.05 mmol) in N,N-dimethyl formamide (8 mL) was added l-bis(dimethylamino) methylene-lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1441 mg, 3.80 mmol).

The reaction was stirred for 16 hours, then was treated with water (120 mL), and was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give N-[4-(tert- butoxycarbonylamino-methyl)-phenyl]-2-methyl-terephthalamic acid methyl ester (839 mg, 83%) as a white solid.

[0860] Synthesis of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-2-methyl- terephthalamic acid. To a mixture of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-2-methyl- terephthalamic acid methyl ester (839 mg, 2.11 mmol) in 1,3-dioxane (10 mL) was added a ION aqueous NaOH solution (2.1 mL). The reaction was heated at 80°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with water (15 mL), and was dried under high vacuum, to give N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-2-methyl-tere phthalamic acid (685 mg, 84%) as a white solid.

[0861] Synthesis of {4-[4-(4-bromo-phenylcarbamoyl)-3-methyl-benzoylamino]-benzy l}- carbamic acid tert-butyl ester. To a mixture of N-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-2- methyl-terephthalamic acid (685 mg, 1.78 mmol), 4-bromo-phenylamine (340 mg, 1.98 mmol), and triethylamine (337 mg, 455 μL,.85 mmol) in N,N-dimethyl formamide (5.5 mL) was added 1- bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1012 mg, 2.67 mmol). The reaction was stirred for 3 days, then was treated with water (80 mL), and was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (25 mL), and brine (15 mL), dried (Na ₂ SO ₄ ), and concentrated.

The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give {4-[4-(4- bromo-phenylcarbamoyl)-3 -methyl -benzoylamino] -benzyl }-carbamic acid tert-butyl ester (675 mg, 70%) as a white solid. [0862] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]-2- methyl-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-l-carbo xylic acid tert-butyl ester. A mixture of {4-[4-(4-bromo-phenylcarbamoyl)-3-methyl-benzoylamino]-benzy l}-carbamic acid tert- butyl ester (675 mg, 1.25 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H- pyridine- 1 -carboxylic acid tert-butyl ester (456 mg, 1.47 mmol), Pd(OAc)2 (13 mg, 0.062 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (55 mg, 0.13 mmol) in 1,4-dioxane (9.5 mL) and 2M K ₂ CO ₃ (3 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (60 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -2 -methyl -benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert- butyl ester (498 mg, 62%) as a grey solid.

[0863] Synthesis of N4-(4-aminomethyl-phenyl)-2-methyl-Nl-[4-(1,2,3,6-tetrahydro -pyridin-

4-yl) -phenyl] -terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -2 -methyl -benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert- butyl ester (498 mg, 0.78 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (25 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (2 x 15 mL), to give N4-(4-aminomethyl-phenyl)-2-methyl-Nl-[4-( 1,2,3, 6-tetrahydro- pyridin-4-yl)-phenyl]-terephthalamide as the bis-trifluoroacetic acid salt (568 mg, >100%) as a light grey solid, that was used without further purification.

[0864] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino }methyl) phenyl] carbamoyl } -2-methylbenzamido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl} )methylidene] carbamate . A mixture of N ⁴ -(4-aminomethyl-phenyl)-2-methyl-N 1 -[4-( 1 ,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-terephthalamide. 2 trifluoroacetic acid (267 mg, 0.40 mmol) in N,N-dimethyl formamide 3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (15 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4- ({[(lZ)-{ [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } -2-methylbenzamido)phenyl] - 1 ,2,3,6-tetrahydropyridin- 1 -yl}) methylidene] carbamate (200 mg, 54%) as a white solid.

[0865] Synthesis of N ¹ -| 4-( 1 -carbarn imidoyl- 1 ,2.3.6-tetrahydro-pyridin-4-yl)-phcnyl |-N4-(4- guanidinomethyl-phenyl)-2-methyl-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( {4- [4-(4- { [4-( { [( 1Z)- { [(tert-butoxy)carbonyl]amino } ( { [(tert-butoxy) carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } -2-methylbenzamido)phenyl] - 1 ,2, 3 ,6- tetrahydropyridin-l-yl})methybdene]carbamate (200 mg, 0.22 mmol) in CH ₂ CI ₂ (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give Nl-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-N4-(4-guanidinomethyl-phenyl)-2 -methyl -terephthalamide as the bis- trifluoroacetic acid salt (109 mg, 66%) as a white solid. MS: 525 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.47 (s, 1 H) 10.35 (s, 1 H) 7.89 (br. s., 3 H) 7.69 - 7.86 (m, 4 H) 7.59 (d, J=7.62 Hz, 1 H) 7.36 - 7.53 (m, 6 H) 7.30 (s, 2 H) 6.16 (br. s., 1 H) 4.32 (d, J=5.86 Hz, 2 H) 4.06 (br. s., 2 H) 3.57 - 3.68 (m, 2 H) 2.57 (br. s., 2 H) 2.44 (s, 3 H). [0866] Example 35: Synthesis of N-[6-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- pyridazin-3 -yl] -N'-(4-guanidinomethyl-phenyl)-terephthalamide

[0867] Synthesis of N-(6-bromo-pyridazin-3-yl)-terephthalamic acid methyl ester. To a mixture of 6-bromo-pyridazin-3-ylamine (783 mg, 4.50 mmol), 4-dimethylaminopyridine (45 mg), and diisopropylethylamine (912 mg, 1227 μL, 7.08 mmol) in CHCI ₃ (12 mL) was added dropwise a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1032 mg, 5.19 mmol) in CHCI ₃ (12 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (NaiSCL). and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give N-(6-bromo-pyridazin-3-yl)-terephthalamic acid methyl ester (740 mg, 49%) as a pale yellow solid.

[0868] Synthesis of 4-[6-(4-methoxycarbonyl-benzoylamino)-pyridazin-3-yl]-3,6-di hydro-

2H-pyridine-l -carboxylic acid tert-butyl ester. To a mixture of N-(6-bromo-pyridazin-3-yl)- terephthalamic acid methyl ester (977 mg, 2.91 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1060 mg, 3.42 mmol), Pd(OAc)2 (30 mg, 0.14 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (128 mg, 0.30 mmol) in 1,4- dioxane (22 mL) and 2M K ₂ CO ₃ (7 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered, and the fdtrate layers were separated. The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give 4-[6-(4- methoxycarbonyl-benzoylamino)-pyridazin-3 -yl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester (470 mg, 37%) as a pale yellow solid.

[0869] Synthesis of 4-[6-(4-carboxy-benzoylamino)-pyridazin-3-yl]-3,6-dihydro-2H - pyridine- 1 -carboxylic acid tert-butyl ester. To a mixture of 4-[6-(4-methoxycarbonyl-benzoylamino)- pyridazin-3-yl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (470 mg, 1.07 mmol) in 1,4-dioxane (5 mL) was added a 10N aqueous NaOH solution (1.1 mL). The reaction was heated at 80°C for 18 hours, then was concentrated. The residues was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), and concentrated, to give 4-[6-(4-carboxy- benzoylamino)-pyridazin-3-yl]-3,6-dihydro-2H-pyridine-l-carb oxylic acid tert-butyl ester (286 mg, 63%) as a pale yellow solid.

[0870] Synthesis of 4-(6-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-l-carb oxylic acid tert-butyl ester. A mixture of 4-[6-(4-carboxy-benzoylamino)-pyridazin-3-yl]-3,6-dihydro-2H -pyridine-l-carboxylic acid tert- butyl ester (286 mg, 0.67 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (168 mg, 0.76 mmol), and triethylamine (137 mg, 184 μL, 1.35 mmol) in N,N-dimethyl formamide (3 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridini um 3-oxid hexafluorophosphate (387 mg, 1.02 mmol). The reaction was stirred for 16 hours, then was treated with water (45 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give 4-(6-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -pyridazin-3 -yl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester (236 mg, 56%) as a white solid.

[0871] Synthesis of N-(4-aminomethyl-phenyl)-N'-[6-(1,2,3,6-tetrahydro-pyridin-4 -yl)- pyridazin-3-yl]-terephthalamide. To a mixture of 4-(6-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -pyridazin-3 -yl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester (236 mg, 0.38 mmol) in CH ₂ CI ₂ (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (5 x 5 mL), to give N-(4-aminomethyl-phenyl)-N'-[6-(1,2,3,6-tetrahydro-pyridin-4 -yl)- pyridazin-3-yl]-terephthalamide as the tris-trifluoroacetic acid salt (266 mg, 91%) as a beige solid.

[0872] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino (methyl) phenyl] carbamoyl }benzamido)pyridazin-3 -yl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of N-(4-aminomethyl-phenyl)-N'-[6-(1,2,3,6-tetrahydro-pyridin-4 -yl)- pyridazin-3 -yl]-terephthalamide. 3 trifluoroacetic acid (264 mg, 0.34 mmol) in N,N-dimethyl formamide (3.3 mL) was adde triethylamine (240 mg, 329 μL, 2.35 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (336 mg, 1.08 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (45 mL) and was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N- [(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(lZ)-{[ (tert-butoxy)carbonyl] amino} ({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido) pyridazin-3 -yl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (191 mg, 62%) as a white solid.

[0873] Synthesis of N-[6-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrid azin-3-yl]- N'-(4-guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[6-(4-{ [4-({ [(lZ)-{ [(tert-butoxy)carbonyl]amino} ({ [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)pyridazin-3 -yl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (191 mg, 0.21 mmol) in CH ₂ CI ₂ (2.1 mL) was added trifluoroacetic acid (2.1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[6-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-N'-(4-guanidinometh yl-phenyl)-terephthalamide as the tris- trifluoroacetic acid salt (114 mg, 64%) as a white solid. MS: 513 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.65 (s, 1 H) 10.46 (s, 1 H) 8.39 (d, J=9.37 Hz, 1 H) 8.19 (d, J=8.20 Hz, 3 H) 8.03 - 8.16 (m, 4 H) 7.98 (t, J=5.57 Hz, 1 H) 7.78 (d, J=8.79 Hz, 2 H) 7.51 (br. s., 5 H) 7.29 (d, J=8.20 Hz, 4 H) 6.75 (br. s., 1 H) 5.73 (s, 1 H) 4.33 (d, J=5.86 Hz, 2 H) 4.17 (br. s., 2 H) 3.65 - 3.73 (m, 2 H) 2.81 (br. s., 2 H).

[0874] Example 36: Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-N'-(4-guanidinomethyl-phenyl)-N'-methyl-terephthalam ide

[0875] Synthesis of (4-methylamino-benzyl)-carbamic acid tert-butyl ester. To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (1.50 g, 6.84 mmol) and benzotriazole (814 mg, 6.84 mmol) in ethanol (6.5 mL) was added a 37% aqueous formaldehyde solution (0.49 mL, 6.51 mmol). The reaction was stirred for 3 days, then was concentrated. The residue was treated with tetrahydrofuran (6.5 mL), followed by sodium borohydride (293 mg, 7.65 mmol). The reaction was stirred for 4 hours, then further sodium borohydride (105 mg, 2.93 mmol) was added. The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (90 mL) and saturated aqueous NaHCO ₃ (25 mL). The organic layer was washed with brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give (4-methylamino-benzyl)-carbamic acid tert-butyl ester (1.01 g, 63%) as a clear viscous liquid.

[0876] Synthesis of (4-{[4-(4-bromo-phenylcarbamoyl)-benzoyl]-methyl-amino}-benz yl)- carbamic acid tert-butyl ester. To a mixture of N-(4-bromo-phenyl)-terephthalamic (614 mg, 1.92 mmol), acid (4-methylamino-benzyl)-carbamic acid tert-butyl ester (504 mg, 2.13 mmol), and triethylamine (331 mg, 446 μL, 2.79 mmol) in N,N-dimethyl formamide (5.4 mL) was added 1- bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1091 mg, 2.88 mmol). The reaction was stirred for 16 hours, then was treated with water (80 mL), and was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), IN HC1 (20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (15 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give (4- {[4-(4-bromo-phenylcarbamoyl)-benzoyl] -methyl-amino }-benzyl)-carbamic acid tert-butyl ester (1.01 g, 98%) as a white solid.

[0877] Synthesis of 4-[4-(4-{[4-(tert-butoxycarbonylamino-methyl)-phenyl]-methyl - carbamoyl}-benzoylamino)-phenyl]-3,6-dihydro-2H-pyridine-l-c arboxylic acid tert-butyl ester. A mixture of (4- {[4-(4-bromo-phenylcarbamoyl)-benzoyl] -methyl -amino }-benzyl)-carbamic acid tert- butyl ester (1010 mg, 1.88 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H- pyridine-1 -carboxylic acid tert-butyl ester (683 mg, 2.20 mmol), Pd(OAc) ₂ (19 mg, 0.090 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (83 mg, 0.19 mmol) in 1,4-dioxane (14 mL) and 2M K ₂ CO ₃ (4.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (75 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-(4- { [4-(tert-butoxycarbonylamino-methyl)-phenyl] -methyl-carbamoyl } -benzoylamino)-phenyl] -3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (1180 mg, 98%) as a white solid.

[0878] Synthesis of N-(4-aminomethyl-phenyl)-N-methyl-N'-[4-( 1,2,3, 6-tetrahydro-pyridin- 4-yl) -phenyl] -terephthalamide. To a mixture of 4-[4-(4-{[4-(tert-butoxycarbonylamino-methyl)- phenyl]-methyl-carbamoyl}-benzoylamino)-phenyl]-3,6-dihydro- 2H-pyridine-l-carboxylic acid tert- butyl ester (1180 mg, 1.84 mmol) in CH ₂ CI ₂ (9.2 mL) was added trifluoroacetic acid (4.6 mL). The reaction was stirred for 3 hours, then was concentrated. The residue was treated with diethyl ether (40 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (3 x 10 mL), to give N-(4-aminomethyl-phenyl)-N-methyl-N'-[4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl] -terephthalamide as the bis-trifluoroacetic acid salt (1.33 g, >100%) as a yellow solid, that was used without further purification.

[0879] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino }methyl)phenyl]

(methyl)carbamoyl }benzamido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate . To a mixture of N-(4-aminomethyl-phenyl)-N-methyl-N'-[4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]- terephthalamide. 2 trifluoroacetic acid (267 mg, 0.40 mmol) in N,N-dimethyl formamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL) and was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- {[(tert-butoxy) carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] (methyl)carbamoyl } benzamido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methyliden e]carbamate (131 mg, 35%) as a pale yellow solid.

[0880] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pheny l]-N'-(4- guanidinomethyl-phenyl)-N'-methyl-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] (methyl)carbamoyl } benzamido)phenyl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (131 mg, 0.14 mmol) in CH ₂ CI ₂ (1.4 mL) was added trifluoroacetic acid (1.4 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -N'-(4-guanidinomethyl-phenyl)-N'-methyl-terephthalamide as the bis-trifluoroacetic acid salt (73 mg, 69%) as a white solid. MS: 525 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.28 (s, 1 H) 7.88 (s, 2 H) 7.74 (dd, J=16.40, 8.20 Hz, 5 H) 7.38 - 7.51 (m, 10 H) 7.13 - 7.27 (m, 7 H) 6.16 (br. s., 1 H) 4.27 (d, J=5.86 Hz, 2 H) 4.05 (br. s., 2 H) 3.56 - 3.67 (m, 2 H) 2.55 (br. s., 2 H).

[0881] Example 37: Synthesis of N-[5-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- pyrazin-2-yl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide

[0882] Synthesis of N-(5-bromo-pyrazin-2-yl)-terephthalamic acid methyl ester. To a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1147 mg, 5.77 mmol) in pyridine (5 mL) was added a solution of 5-bromo-pyrazin-2-ylamine (870 mg, 5.00 mmol) in pyridine (5 mL). The reaction was stirred for 2 hours, then was heated at 60°C for 24 hours, and then was concentrated. The residue was treated with ethyl acetate (100 mL), and IN HC1 (50 mL), then was shaken, and was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give N-(5-bromo- pyrazin-2-yl)-terephthalamic acid methyl ester (601 mg, 36%) as a white solid. The ethyl acetate/ IN HC1 fdtrate was separated, then the aqueous layer was extracted with ethyl acetate (60 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give N-(5-bromo-pyrazin-2-yl)-terephthalamic acid methyl ester (85 mg, 5%) as a white solid.

[0883] Synthesis of 4-[5-(4-methoxycarbonyl-benzoylamino)-pyrazin-2-yl]-3,6-dihy dro-2H- pyridine-1 -carboxylic acid tert-butyl ester. A mixture of N-(5-bromo-pyrazin-2-yl)-terephthalamic acid methyl ester (686 mg, 2.04 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro - 2H-pyridine-l -carboxylic acid tert-butyl ester (744 mg, 2.40 mmol), Pd(OAc)2 (21 mg, 0.098 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (90 mg, 0.21 mmol) in 1,4-dioxane (15.5 mL) and 2M K ₂ CO ₃ (5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na2SO _t ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[5-(4-methoxycarbonyl- benzoylamino)-pyrazin-2-yl]-3,6-dihydro-2H-pyridine-l-carbox ylic acid tert-butyl ester (589 mg, 66%) as a pale yellow solid.

[0884] Synthesis of 4-[5-(4-Carboxy-benzoylamino)-pyrazin-2-yl]-3,6-dihydro-2H-p yridine-

1-carboxylic acid tert-butyl ester. To a mixture of 4-[5-(4-methoxycarbonyl-benzoylamino)-pyrazin-

2-yl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (589 mg, 1.34 mmol) in 1,4-dioxane (6.3 mL) was added a 10N aqueous NaOH solution (1.4 mL). The reaction was heated at 80°C for 4 hours, then was treated wth further 10N aqueous NaOH solution (5 mL). The reaction was heated at 80°C for 16 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with water (10 mL), and dried under high vacuum, to give 4-[5-(4-Carboxy-benzoylamino)-pyrazin-2-yl]-3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (510 mg, 90%) as a white solid.

[0885] Synthesis of 4-(5-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-l-carbox ylic acid tert-butyl ester. A mixture of 4-[5-(4-carboxy-benzoylamino)-pyrazin-2-yl]-3,6-dihydro-2H-p yridine-l-carboxylic acid tert- butyl ester 505 mg, 1.19 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (296 mg, 1.34 mmol), and triethylamine (242 mg, 327 μL, 2.40 mmol) in N,N-dimethyl formamide (3.6 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridini um 3-oxid hexafluorophosphate (685 mg, 1.80 mmol). The reaction was stirred for 16 hours, then was treated with water (55 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give 4-(5-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-benzoylamino}-pyrazin-2-yl)-3,6-dihydro-2H- pyridine-l-carboxylic acid tert-butyl ester (540 mg, 72%) as a grey solid.

[0886] Synthesis of N-(4-aminomethyl-phenyl)-N'-[5-(1,2,3,6-tetrahydro-pyridin-4 -yl)- pyrazin-2-yl]-terephthalamide. To a mixture of 4-(5-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-benzoylamino}-pyrazin-2-yl)-3,6-dihydro-2H- pyridine-l-carboxylic acid tert-butyl ester (540 mg, 0.87 mmol) in CH ₂ CI ₂ (4.6 mL) was added trifluoroacetic acid (2.3 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (20 mL), to give N-(4-aminomethyl-phenyl)-N'-[5-(1,2,3,6-tetrahydro-pyridin-4 -yl)-pyrazin-2- yl]-terephthalamide as the tris-trifluoroacetic acid salt (607 mg, 91%) as a grey solid.

[0887] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl}benzamido)pyrazin-2-yl]-1,2,3,6-tetrahydropyridin- l-yl})methylidene]carbamate. To a mixture of N-(4-aminomethyl-phenyl)-N'-[5-(1,2,3,6-tetrahydro-pyridin-4 -yl)-pyrazin-2-yl]- terephthalamide. 3 trifluoroacetic acid (308 mg, 0.40 mmol) in N,N-dimethyl formamide (3.8 mL) was treated slowly with triethylamine (282 mg, 387 μL, 2.77 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lZ)- {[(tert-butoxy) carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)pyrazin-2-yl]-1,2,3,6-tetrahydropyridin-l-yl})meth ylidene]carbamate (259 mg, 71%) as a pale yellow solid.

[0888] Synthesis of N-[5-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyraz in-2-yl]- N'-(4-guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lZ)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)pyrazin-2-yl] - 1 ,2,3 , 6- tetrahydropyridin-l-yl})methylidene]carbamate (259 mg, 0.28 mmol) in CH ₂ CI ₂ (2.8 mL) was added trifluoroacetic acid (2.8 mL). The reaction was stirred for 2 days, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[5-(l-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-pyrazin-2-yl]-N'-(4-guanidinomethyl-phenyl)-te rephthalamide as the tris-trifluoroacetic acid salt (110 mg, 46%) as a white solid. MS: 513 MH+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.34 (s, 1 H) 10.47 (s, 1 H) 9.38 (d, J=1.17 Hz, 1 H) 8.75 (d, 7=1.17 Hz, 1 H) 8.14 - 8.23 (m, 2 H) 8.08 (d, 7=8.20 Hz, 3 H) 7.78 (d, 7=8.20 Hz, 2 H) 7.58 (br. s., 4 H) 7.29 (d, 7=8.79 Hz, 4 H) 6.80 (br. s., 1 H) 4.33 (d, 7=5.86 Hz, 2 H) 4.16 (br. s., 2 H) 3.64 (t, 7=5.57 Hz, 2 H) 2.72 (br. s., 2 H).

[0889] Example 38: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide [4-(2-guanidino-ethyl)-phenyl]-amide

[0890] Synthesis of [2-(4-{[3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l- carbonyl] -amino }-phenyl)-ethyl]-carbamic acid tert-butyl ester. To a mixture of 3-(4-bromo- phenylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid (836 mg, 2.70 mmol), [2-(4-amino- phenyl) -ethyl] -carbamic acid tert-butyl ester (717 mg, 3.04 mmol), and triethylamine (549 mg, 742 □L, 5.45 mmol) in N,N-dimethyl formamide (8.2 mL) was added l-bis(dimethylamino)methylene- lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1554 mg, 4.08 mmol). The reaction was stirred for 16 hours, then was treated with water (120 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give [2-(4-{[3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l- carbonyl]-amino}- phenyl) -ethyl] -carbamic acid tert-butyl ester (840 mg, 59%) as a white solid.

[0891] Synthesis of 4-[4-({3-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamo yl]- bicyclofl .1. l]pentane-l-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine -l-carboxylic acid tert- butyl ester. A mixture of [2-(4-{[3-(4-bromo-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l- carbonyl]- amino}-phenyl)-ethyl] -carbamic acid tert-butyl ester (840 mg, 1.59 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyl ic acid tert-butyl ester (578 mg, 1.86 mmol), Pd(OAc)2 (16 mg, 0.076 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (70 mg, 0.216mmol) in 1,4-dioxane (12 mL) and 2M K ₂ CO ₃ (3.8 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (50 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-[4-({3-[4-(2-tert- butoxycarbonylamino-ethyl)-phenylcarbamoyl] -bicyclo [1.1.1 ]pentane- 1 -carbonyl } -amino)-phenyl] - 3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (500 mg, 50%) as a grey solid. [0892] Synthesis of bicyclofl .1. l]pentane-l,3-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({3-[4-(2-tert- butoxycarbonylamino-ethyl)-phenylcarbamoyl] -bicyclo [1.1.1 ]pentane- 1 -carbonyl } -amino)-phenyl] - 3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (500 mg, 0.79 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 5 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), and was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give bicyclo[1.1.1]pentane-l,3- dicarboxylic acid [4-(2-amino-ethyl)-phenyl]-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- amide (595 mg, >100%) as a grey solid, that was used without further purification. [0893] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-(2-

{ [( 1 E)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl [bicyclo [1.1.1 ]pentane- 1 -amido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 trifluoroacetic acid (263 mg, 0.40 mmol) in N,N-dimethyl formamide (3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l- guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(3-{ [4-(2-{ [( lE)-{ [(tert-butoxy)carbonyl]amino}({ [(tert- butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl } bicyclo [1.1.1 ]pentane - 1 - amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]ca rbamate (197 mg, 54%) as a pale yellow solid.

[0894] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide [4-(2-guanidino-ethyl)-phenyl]-amide; To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-(2-{[(lE )-{[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl } bicyclofl .1.1] pentane-l-amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})meth ylidene]carbamate (197 mg, 0.22 mmol) in CH ₂ CI ₂ (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethyl formamide (1.5 mL), followed by 0.1% trifluoroacetic acid in water (1.5 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide [4-(2-guanidino-ethyl)-phenyl] -amide as the bis- trifluoroacetic acid salt (85 mg, 52%) as a pale orange solid. MS: 515 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.70 (br. s., 1 H) 9.62 (br. s., 1 H) 7.92 (br. s., 1 H) 7.37 - 7.69 (m, 14 H) 7.18 (d,

J=7.62 Hz, 3 H) 6.15 (br. s., 1 H) 4.04 (br. s., 2 H) 3.59 (br. s., 3 H) 2.86 (s, 2 H) 2.71 - 2.75 (m, 2 H)

2.54 (br. s., 2 H) 2.30 (br. s., 6 H). [0895] Example 39: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l- carbamimidoyl- 1 ,2,3 ,6-tetrahydro-pyridin-4-yl)-3 -fluoro-phenyl] -amide(4-guanidinomethyl -phenyl)- amide

[0896] Synthesis of 3-(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid methyl ester. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid monomethyl ester (751 mg, 4.42 mmol), 4-bromo-3-fluoro-phenylamine (922 mg, 4.85 mmol), and triethylamine (837 mg, 990 μL, 7.06 mmol) in N,N-dimethyl formamide (13.5 mL) was added 1- bis(dimethylamino) methylene-lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (2508 mg, 6.62 mmol). The reaction was stirred for 16 hours, then was treated with water (200 mL). The mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were washed with water (2 x 25 mL), IN HC1 (25 mL), saturated aqueous NaHCO ₃ (25 mL), and brine (20 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 3 -(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid methyl ester (1.42 g, 94%) as a white solid.

[0897] Synthesis of 3-(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid. To a mixture of 3-(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid methyl ester (1.42 g, 4.15 mmol) in 1,4-dioxane (19 mL) was added a ION aqueous NaOH solution (4.1 mL). The reaction was heated at 60°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (20 mL), and dried under high vacuum, to give 3-(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid (970 mg, 71%) as a white solid.

[0898] Synthesis of (4-{[3-(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pent ane-l- carbonyl] -amino }-benzyl)-carbamic acid tert-butyl ester. To a mixture of 3-(4-bromo-3-fluoro- phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxybc acid (970 mg, 2.96 mmol), (4-amino-benzyl)- carbamic acid tert-butyl ester (722 mg, 3.27 mmol), and triethylamine (696 mg, 940 μL, 5.88 mmol) in N,N-dimethyl formamide (8.8 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3- triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1676 mg, 4.43 mmol). The reaction was stirred for 16 hours, then was treated with water (130 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (30 mL), and hexanes (30 mL), to give (4-{[3-(4-bromo-3-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pent ane-l-carbonyl]-amino}-benzyl)- carbamic acid tert-butyl ester (1.23 g, 78%) as a white solid.

[0899] Synthesis of 4-[4-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclofl .1. l]pentane-l-carbonyl}-amino)-2-fluoro-phenyl]-3,6-dihydro-2H -pyridine-l-carboxylic acid tert-butyl ester. A mixture of (4-{[3-(4-bromo-3-fluoro-phenylcarbamoyl)- bicyclo[1.1.1]pentane-l-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester (1.23 g, 2.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-l-carboxylic acid tert-butyl ester (842 mg, 2.69 mmol), Pd(OAc) ₂ (27 mg, 0.11 mmol), and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (99 mg, 0.27 mmol) in 1,4-dioxane (17 mL) and 2M K ₂ CO ₃ (5.6 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)-2- fluoro-phenyl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (1.33 g, 91%) as a white solid.

[0900] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxybc acid (4-aminomethyl-phenyl)- amide [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)-2- fluoro-phenyl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (1.33 g, 2.10 mmol) in CH ₂ CI ₂ (10.6 mL) was added trifluoroacetic acid (5.3 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (25 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl- phenyl)-amide [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis-trifluoroacetic acid salt (1.60 g, >100%) as a yellow solid, that was used without further purification. [0901] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)-

{ [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }bicyclo [1.1.1 ]pentane- 1 -amido)-2 -fluorophenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } ) methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4- aminomethyl-phenyl) -amide [3-fluoro-4-( 1,2,3, 6-tetrahydro-pyridin-4-yl)-phenyl] -amide. 2 trifluoroacetic acid (265 mg, 0.40 mmol) in N,N -dimethyl formamide 3.8 mL) was treated slowly with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } bicyclo [1.1.1 ]pentane- 1 -amido)-2 -fluorophenyl] - 1 ,2,3,6-tetrahydropyridin- 1 - yl})methylidene] carbamate (153 mg, 42%) as a pale yellow solid.

[0902] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-amide(4-gu anidinomethyl-phenyl)-amide: A mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [1.1.1 ]pentane- 1 -amido)-2 -fluorophenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } ) methylidene] carbamate (153 mg, 0.17 mmol) in CH ₂ CI ₂ (1.7 mL) was treated with trifluoroacetic acid (1.7 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethyl formamide (1.5 mL), followed by 0.1% trifluoroacetic acid in water (1.5 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phen yl]-amide (4-guanidinomethyl-phenyl)- amide as the bis-trifluoroacetic acid salt (80 mg, 63%) as a light brown solid. MS: 519 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.44 (s, 1 H) 10.35 (s, 1 H) 8.08 (s, 4 H) 7.90 (s, 1 H) 7.79 (d, J=8.79 Hz, 2 H) 7.58 - 7.68 (m, 2 H) 7.41 (br. s., 5 H) 7.30 (d, J=8.21 Hz, 3 H) 7.11 (d, 7=9.38 Hz, 2 H) 5.63 (s, 1 H) 4.34 (d, 7=6.45 Hz, 2 H) 4.03 (br. s., 2 H) 3.56 - 3.70 (m, 2 H) 2.42 (br. s., 2 H) 2.26 (s, 3 H).

[0903] Example 40: Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide

[0904] Synthesis of N-(4-bromo-3-methyl-phenyl)-terephthalamic acid methyl ester. To a mixture of 4-bromo-3 -methyl -phenylamine (558 mg, 3.00 mmol) and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in CHCI ₃ (8 mL) was added a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (687 mg, 3.46 mmol) in CHCI ₃ (8 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (70 mL) and was washed with water (20 mL), IN HC1 (20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give N-(4-bromo-3-methyl-phenyl)-terephthalamic acid methyl ester (723 mg, 69%) as a white solid.

[0905] Synthesis of N-(4-bromo-3-methyl-phenyl)-terephthalamic acid. To a mixture of N- (4-bromo-3-methyl-phenyl)-terephthalamic acid methyl ester (723 mg, 2.08 mmol) in 1,4-dioxane (10 mL) was added a 10N aqueous NaOH solution (2.1 mL). The reaction was heated at 90°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with water (20 mL), and was dried under high vacuum, to give N-(4-bromo-3-methyl-phenyl)-terephthalamic acid (640 mg, 92%) as a white solid.

[0906] Synthesis of 4-[4-(4-carboxy-benzoylamino)-2-methyl-phenyl]-3,6-dihydro-2 H- pyridine- 1 -carboxylic acid tert-butyl ester. To a mixture of N-(4-bromo-3-methyl-phenyl)- terephthalamic acid (640 mg, 1.92 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (467 mg, 2.12 mmol), and triethylamine (450 mg, 608 μL, 3.81 mmol) in N,N-dimethyl formamide (5.7 mL) was added 1 -bis(dimethylamino)methylene- 1H- 1 ,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1084 mg, 2.87 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL), and ethyl acetate (60 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-[4-(4-carboxy-benzoylamino)- 2-methyl-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (783 mg, 76%) as a white solid.

[0907] Synthesis of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-l-car boxylic acid tert-butyl ester. A mixture of 4-[4-(4-carboxy-benzoylamino)-2-methyl -phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (783 mg, 1.45 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (530 mg, 1.69 mmol), Pd(OAc)2 (17 mg, 0.069 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (62 mg, 0.17 mmol) in 1,4-dioxane (11 mL) and 2M K ₂ CO ₃ (3.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). The mixture was shaken, then was filtered. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-(4-{4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-benzoylamino}-2 -methyl-phenyl)-3,6-dihydro-2H- pyridine- 1 -carboxylic acid tert-butyl ester (304 mg, 33%) as a pale yellow solid.

[0908] Synthesis of N-(4-aminomethyl-phenyl)-N'-[3-methyl-4-(1,2,3,6-tetrahydro- pyridin-4- yl)-phenyl]-terephthalamide. To a mixture of 4-(4-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -2 -methyl -phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester (299 mg, 0.47 mmol) in CH ₂ CI ₂ (2.4 mL) was added trifluoroacetic acid (1.2 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (15 mL), to give N-(4-aminomethyl-phenyl)-N'-[3-methyl-4-(1,2,3,6-tetrahydro- pyridin- 4-yl) -phenyl] -terephthalamide as the bis-trif uoroacetic acid salt (308 mg, 98%) as a pale yellow solid.

[0909] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-2-methylphenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate . A mixture of N-(4-aminomethyl-phenyl)-N'-[3-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]- terephthalamide. 2 trifluoroacetic acid (308 mg, 0.46 mmol) in N,N-dimethyl formamide (4.4 mL) was treated with triethylamine (323 mg, 442 μL, 3.16 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (452 mg, 1.45 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (65 mL) and then was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-2-methyl phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamat e (206 mg, 48%) as a pale yellow solid.

[0910] Synthesis of N-[4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-met hyl- phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lZ)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-2-methylphenyl] - 1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (206 mg, 0.22 mmol) in CH ₂ CI ₂ (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3 -methyl -phenyl] -N'-(4-guanidinomethyl-phenyl)-terephthalamide as the bis- trifluoroacetic acid salt (78 mg, 47%) as a white solid. MS: 525 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.44 (s, 1 H) 10.35 (s, 1 H) 8.08 (s, 4 H) 7.90 (s, 1 H) 7.79 (d, J= 8.79 Hz, 2 H) 7.58 - 7.68 (m, 2 H) 7.41 (br. s., 5 H) 7.30 (d, 7=8.21 Hz, 3 H) 7.11 (d, 7=9.38 Hz, 2 H) 5.63 (s, 1 H) 4.34 (d, J=6.45 Hz, 2 H) 4.03 (br. s., 2 H) 3.56 - 3.70 (m, 2 H) 2.42 (br. s., 2 H) 2.26 (s, 3 H).

[0911] Example 41: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxybc acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-phen yl]-amide (4-guanidinomethyl-phenyl)- amide

[0912] Synthesis of 3-(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid methyl ester. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxybc acid monomethyl ester (500 mg, 2.94 mmol), 4-bromo-2-fluoro-phenylamine (613 mg, 3.22 mmol), and triethylamine (557 mg, 658 μL, 4.69 mmol) in N,N-dimethyl formamide (9 mL) was added 1- bis(dimethylamino)methylene -lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1668 mg, 4.40 mmol). The reaction was stirred for 3 days, then was treated with water (135 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), IN HC1 (30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give 3 -(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid methyl ester (908 mg, 90%) as a pale yellow solid. [0913] Synthesis of 3-(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid. To a mixture of 3-(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid methyl ester (908 mg, 2.65 mmol) in 1,4-dioxane (12 mL) was added a ION aqueous NaOH solution (2.7 mL). The reaction was heated at 60°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (20 mL), and was dried under high vacuum, to give 3-(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pentane-l - carboxylic acid (505 mg, 58%) as a white solid. [0914] Synthesis of (4-{[3-(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo[1.1.1]pent ane-l- carbonyl] -amino} -benzyl) -carbamic acid tert-butyl ester. To a mixture of 3-(4-bromo-2-fluoro- phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxybc acid (505 mg, 1.54 mmol), (4-amino-benzyl)- carbamic acid tert-butyl ester (374 mg, 1.70 mmol), and triethylamine (361 mg, 487 μL, 3.05 mmol) in N,N-dimethyl formamide (4.6 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3- triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (869 mg, 2.30 mmol). The reaction was stirred for 16 hours, then was treated with water (75 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give (4- { [3 -(4-bromo-2-fluoro-phenylcarbamoyl)-bicyclo [1.1.1 ]pentane- 1 -carbonyl] -amino } -benzyl)- carbamic acid tert-butyl ester (561 mg, 68%) as a white solid.

[0915] Synthesis of 4-[4-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclol 1.1.1] pentane- 1 -carbonyl } -amino)-3 -fluoro-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester. A mixture of (4-{[3-(4-bromo-2-fluoro-phenylcarbamoyl)- bicyclo[1.1.1]pentane-l-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester (561 mg, 1.05 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-l-carboxylic acid tert-butyl ester (384 mg, 1.23 mmol), Pd(OAc)2 (12 mg, 0.050 mmol), and 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (45 mg, 0.12 mmol) in 1,4-dioxane (7.8 mL) and 2M K ₂ CO ₃ (2.6 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)-3- fluoro-phenyl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (509 mg, 76%) as a beige solid.

[0916] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)- amide [2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)-3- fluoro-phenyl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (504 mg, 0.79 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide [2- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis-trifluoroacetic acid salt (670 mg, >100%) as a beige solid, that was used without further purification. [0917] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }bicyclo [1.1.1 ]pentane- 1 -amido)-3 -fluorophenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } ) methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4- aminomethyl-phenyl) -amide [2-fluoro-4-( 1,2,3, 6-tetrahydro-pyridin-4-yl)-phenyl] -amide. 2 trifluoroacetic acid (265 mg, 0.40 mmol) in N,N-dimethyl formamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis- Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclofl .1. l]pentane-l-amido)-3-fluorophenyl]-1,2,3,6-tetrahydropyridin -l-yl})methylidene] carbamate (208 mg, 57%) as a pale yellow solid.

[0918] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-phenyl]-amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }bicyclo[1.1.1] pentane-l-amido)-3-fluorophenyl]-1,2,3,6-tetrahydropyridin-l - yl})methylidene] carbamate (203 mg, 0.22 mmol) in CH ₂ CI ₂ (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethyl formamide (1.5 mL), followed by 0.1 % trifluoroacetic acid in water (1.5 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexanes (10 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-phen yl]-amide (4-guanidinomethyl-phenyl)- amide as the bis-trifluoroacetic acid salt (87 mg, 53%) as a beige solid. MS: 519 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.71 (br. s., 1 H) 9.50 - 9.65 (m, 1 H) 7.91 (br. s., 2 H) 7.65 (br. s., 2 H) 7.52 - 7.63 (m, 3 H) 7.44 (br. s., 6 H) 7.16 - 7.36 (m, 5 H) 6.29 (br. s., 1 H) 4.31 (br. s., 2 H) 4.06 (br. s., 2 H) 3.60 (br. s., 2 H) 2.56 (br. s., 2 H) 2.32 (br. s., 6 H).

[0919] Example 42: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(4- guanidino-cyclohex- 1 -enyl)-phenyl] -amide (4-guanidinomethyl-phenyl)-amide enyl) -phenyl] -amide (4-aminomethyl-phenyl)-amide. A mixture of (4-{[3-(4-bromo-2-fluoro- phenylcarbamoyl)-bicyclo[1.1.1]pentane-l-carbonyl]-amino}-be nzyl)-carbamic acid tert-butyl ester (929 mg, 1.81 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-l- carboxylic acid tert-butyl ester (684 mg, 2.12 mmol), Pd(OAc)2 (21 mg, 0.086 mmol), and 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (77 mg, 0.21 mmol) in 1,4-dioxane (13.4 mL) and 2M K ₂ CO ₃ (4.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(4-amino- cyclohex-1 -enyl) -phenyl] -amide (4-aminomethyl-phenyl)-amide (10.5 g, 92%) as a grey solid.

[0921] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(4-amino-cyclohex-l- enyl) -phenyl] -amide (4-aminomethyl-phenyl)-amide. To a mixture of bicy clo[ 1.1.1 ]pentane- 1,3- dicarboxylic acid [4-(4-amino-cyclohex-l-enyl)-phenyl] -amide (4-aminomethyl-phenyl)-amide (1.05 g, 1.67 mmol) in CH ₂ CI ₂ (8.4 mL) was added trifluoroacetic acid (4.2 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(4- amino-cyclohex-l-enyl)-phenyl] -amide (4-aminomethyl-phenyl)-amide as the bis-trifluoroacetic acid salt (1.34 g, >100%) as a grey solid, that was used without further purification.

[0922] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }bicyclo [1.1.1 ]pentane- 1 -amido)phenyl] cyclohex-3 -en- 1 -yl } amino)methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(4-amino-cyclohex-l- enyl) -phenyl] -amide (4-aminomethyl-phenyl)-amide. 2 trifhioroacetic acid (265 mg, 0.40 mmol) in

N,N-dimethyl formamide (3.8 mL) was added triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The mixture was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( {4- [4-(3 - { [4-( { [( 1Z)- { [(tert-butoxy)carbonyl]amino } ( { [(tert-butoxy) carbonyl] imino })methyl] amino }methyl)phenyl] carbamoyl }bicyclo[1.1. l]pentane-l-amido)phenyl] cyclohex-3 -en-l-yl}amino)methylidene] carbamate (257 mg, 69%) as a pale yellow solid.

[0923] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [4-(4-guanidino-cyclohex-l- enyl) -phenyl] -amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(lZ)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [1.1.1] pentane- 1 - amido)phenyl] cyclohex-3-en-l-yl}amino)methylidene]carbamate (244 mg, 0.27 mmol) in CH ₂ CI ₂ (2.7 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[1.1.1]pentane- 1,3-dicarboxylic acid [4-(4-guanidino-cyclohex-l-enyl)-phenyl]-amide (4-guanidinomethyl-phenyl)- amide as the bis-trifluoroacetic acid salt (62 mg, 31%) as a white solid. MS: 515 MH+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.70 (s, 1 H) 9.66 (s, 1 H) 7.87 (s, 1 H) 7.62 (dd, 7=8.50, 6.74 Hz, 5 H) 7.54 (d, J=7.62 Hz, 1 H) 7.38 (d, J=8.79 Hz, 3 H) 7.23 (d, 7=8.79 Hz, 4 H) 6.07 (br. s., 1 H) 4.30 (d, J=5.86 Hz, 2 H) 3.62 - 3.81 (m, 1 H) 2.31 (s, 6 H).

[0924] Example 43: Synthesis of N-[5-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6- methyl-pyrazin-2-yl]-N'-(4-guanidinomethyl-phenyl)-terephtha lamide

[0925] Synthesis of N-(5-bromo-6-methyl-pyrazin-2-yl)-terephthalamic acid methyl ester. To a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1196 mg, 6.02 mmol) in pyridine (5.2 mL) was added a mixture of 5-bromo-6-methyl-pyrazin-2-ylamine (980 mg, 5.21 mmol) in pyridine (5.3 mL). The reaction was heated at 60°C for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (100 mL) and IN HC1 (50 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give N-(5-bromo- 6-methyl-pyrazin-2-yl)-terephthalamic acid methyl ester (1.62 g, 89%) as a pale yellow solid.

[0926] Synthesis of 4-[5-(4-methoxycarbonyl-benzoylamino)-3-methyl-pyrazin-2-yl] -3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester. A mixture of N-(5-bromo-6-methyl-pyrazin- 2-yl)-terephthalamic acid methyl ester (1.62 g, 4.63 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyb c acid tert-butyl ester (1.69 g, 5.44 mmol), Pd(OAc)2 (47 mg, 0.22 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (204 mg, 0.47 mmol) in 1,4-dioxane (35 mL) and 2M K ₂ CO ₃ (11 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (110 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 4-[5-(4-methoxycarbonyl-benzoylamino)-3-methyl-pyrazin-2-yl] -3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (906 mg, 43%) as a pale yellow solid.

[0927] Synthesis of 4-[5-(4-carboxy-benzoylamino)-3-methyl-pyrazin-2-yl]-3,6-dih ydro-2H- pyridine-1 -carboxylic acid tert-butyl ester. To a mixture of 4-[5-(4-methoxycarbonyl- benzoylamino)-3-methyl-pyrazin-2-yl]-3,6-dihydro-2H-pyridine -l-carboxylic acid tert-butyl ester (906 mg, 2.00 mmol) in 1,4-dioxane (9.4 mL) was added a 10N aqueous NaOH solution (2 mL). The reaction was heated at 90°C for 16 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered, and the solid was washed with water (20 mL). The solid was treated with isopropanol (50 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with hexanes (20 mL), The solid was dried under high vacuum, to give 4-[5-(4-carboxy-benzoylamino)-3- methyl-pyrazin-2-yl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (718 mg, 82%) as an off-white solid.

[0928] Synthesis of 4-(5-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl ]- benzoylamino}-3-methyl-pyrazin-2-yl)-3,6-dihydro-2H-pyridine -l-carboxylic acid tert-butyl ester. A mixture of 4-[5-(4-carboxy-benzoylamino)-3-methyl-pyrazin-2-yl]-3,6-dih ydro-2H-pyridine-l- carboxylic acid tert-butyl ester (718 mg, 1.64 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (403 mg, 1.82 mmol), and triethylamine (385 mg, 522 μL, 3.25 mmol) in N,N-dimethyl formamide (4.9 mL) was treated with l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridini um 3-oxid hexafluorophosphate (927 mg, 2.46 mmol). The reaction was stirred for 16 hours, then was treated with water (75 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-(5-{4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-benzoylamino}-3 -methyl-pyrazin-2-yl)-3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (841 mg, 80%) as a pale yellow solid.

[0929] Synthesis of N-(4-aminomethyl-phenyl)-N'-[6-methyl-5-(1,2,3,6-tetrahydro- pyridin-4- yl)-pyrazin-2-yl]-terephthalamide. To a mixture of 4-(5-{4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -benzoylamino } -3 -methyl -pyrazin-2 -yl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester (841 mg, 1.31 mmol) in CH ₂ CI ₂ (6.6 mL) was added trifluoroacetic acid (3.3 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give N-(4-aminomethyl-phenyl)-N'- [6-methyl-5-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]- terephthalamide as the tris-trifluoroacetic acid salt (1100 mg, >100%) as a pale yellow solid, that was used without further purification.

[0930] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }benzamido)-3 -methylpyrazin-2-yl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. A mixture of N-(4-aminomethyl-phenyl)-N'-[6-methyl-5-(1,2,3,6-tetrahydro- pyridin-4- yl)-pyrazin-2-yl]-terephthalamide. 3 trifluoroacetic acid (392 mg, 0.50 mmol) in N,N-dimethyl formamide (4.8 mL) was treated with triethylamine (350 mg, 480 μL. 3.43 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (490 mg, 1.58 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (75 mL) and was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-3-methylpyrazin-2-yl]-1,2,3,6-tetrahydropyridin-l -yl})methylidene]carbamate (227 mg, 49%) as a white solid.

[0931] Synthesis of N-[5-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-met hyl- pyrazin-2-yl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide: To a mixture of tert-butyl N-[(1Z)- { [(tert-butoxy)carbonyl]amino}({4-[5-(4-{ [4-({ [( lZ)-{ [(tert-butoxy)carbonyl] amino} ({ [(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } benzamido)-3 -methyl pyrazin-2- yl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (227 mg, 0.25 mmol) in CH ₂ CI ₂ (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[5-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-6-methyl-pyrazin-2-yl]-N'-( 4-guanidinomethyl-phenyl)- terephthalamide as the tris-trifluoroacetic acid salt (124 mg, 57%) as a white solid. MS: 527 M+H+;

¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.30 (s, 1 H) 10.47 (s, 1 H) 9.25 (s, 1 H) 8.18 (d, J=8.21 Hz, 3 H) 8.03 - 8.14 (m, 2 H) 7.92 - 8.03 (m, 1 H) 7.79 (d, J= 8.79 Hz, 2 H) 7.49 (br. s., 4 H) 7.30 (d,

J= 8.79 Hz, 3 H) 6.10 (br. s., 1 H) 4.34 (d, J=5.86 Hz, 2 H) 4.12 (br. s., 2 H) 3.64 (t, J= 5.57 Hz, 2 H) 2.63 (br. s., 2 H) 2.47 - 2.51 (m, 6 H). [0932] Example 44: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [6-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-y l]-amide (4-guanidinomethyl-phenyl)- amide

[0933] Synthesis of 4-chlorocarbonyl-bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (1.38 g, 6.50 mmol) in CHCI ₃ (36 mL) and N,N-dimethyl formamide (15 drops) was added dropwise oxalyl chloride (1.33 g, 891 μL. 10.39 mmol). The reaction was stirred for 3 hours, then was concentrated, to give 4- chlorocarbonyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, that was used without further purification.

[0934] Synthesis of 4-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester. To a mixture of 6-bromo-pyridazin-3-ylamine (981 mg, 5.63 mmol), 4- dimethylaminopyridine (56 mg), and diisopropylethylamine (1142 mg, 1537 μL, 8.87 mmol) in CHCI ₃ (15 mL was added dropwise a mixture of 4-chlorocarbonyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester in CHC13 (15 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (20 mL), and brine (20 mL). dried (NaiSCL). and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 4-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[2.2.2]octane-l-c arboxylic acid methyl ester (1.54 g, 74%) as a pale yellow solid.

[0935] Synthesis of 4-{6-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-l-carbonyl)-am ino]- pyridazin-3-yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester. A mixture of 4-(6-bromo- pyridazin-3-ylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyl ic acid tert-butyl ester (1525 mg, 4.92 mmol), Pd(OAc)2 (43 mg, 0.21 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (184 mg, 0.43 mmol) in 1,4-dioxane (32 mL) and 2M K ₂ CO ₃ (10 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (150 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0- 100% ethyl acetate: hexanes), to give 4-{6-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-l-carbonyl)- amino]-pyridazin-3-yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1.47 g, 75%) as a pale yellow solid.

[0936] Synthesis of 4-{6-[(4-carboxy-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyr idazin-3- yl}-3,6-dihydro-2H-pyridine-l-carboxybc acid tert-butyl ester. To a mixture of 4-{6-[(4- methoxycarbonyl-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyri dazin-3-yl}-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester (1.47 g, 3.12 mmol) in 1,4-dioxane (14 mL) was added a ION aqueous NaOH solution (3.1 mL). The reaction was heated at 90°C for 16 hours, then was concentrated. The residue was treated with water (100 mL), and was adjusted to pHl using IN HC1. The mixture was filtered, then the solid was washed with water (20 mL), and was dried under high vacuum, to give 4-{6-[(4-carboxy-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyr idazin-3-yl}-3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (1.04 g, 73%) as a beige solid.

[0937] Synthesis of 4-[6-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo[2.22]octane- 1 -carbonyl } -amino) -pyridazin-3 -yl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester. A mixture of 4-{6-[(4-carboxy-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyr idazin-3- yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1.04 g, 2.28 mmol), (4-amino- benzyl)-carbamic acid tert-butyl ester (559 mg, 2.51 mmol), and triethylamine (537 mg, 726 DL, 4.54 mmol) in N,N-dimethyl formamide (6.6 mL) was treated with l-bis(dimethylamino)methylene-lH- 1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (289 mg, 3.40 mmol). The reaction was stirred for 16 hours, then was treated with further (4-amino-benzyl)-carbamic acid tert-butyl ester (280 mg, 1.26 mmol), triethylamine (269 mg, 363 μL, 2.27 mmol), and 1- bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (645 mg, 1.70 mmol). The reaction was stirred for 3 days, then was treated with water (100 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL), to give 4-[6-({4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-pyridazin-3 -yl] -3 ,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (677 mg, 45%) as a beige solid. [0938] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)- amide [6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide. To a mixture of 4-[6-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane- 1 -carbonyl } -amino)- pyridazin-3-yl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (672 mg, 1.02 mmol) in CH ₂ CI ₂ (5.4 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 3 days, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl- phenyl)-amide [6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide as the tris-trifluoroacetic acid salt (1139 mg, >100%) as a light brown solid, that was used without further purification.

[0939] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(lE)-

{ [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)pyridazin-3 -yl] - 1 ,2,3 , 6-tetrahydropyridin- 1 -yl } ) methylidene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl- phenyl)-amide [6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide (321 mg, 0.40 mmol) in N,N-dimethyl formamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL) and was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL). The combined aqueous layers were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)pyridazin-3 -yl] - 1 ,2,3 , 6-tetrahydropyridin- 1 -yl } ) methylidene] carbamate (112 mg, 30%) as a white solid.

[0940] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [6-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-pyridazin-3-yl] -amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[( lZ)-{ [(tert-butoxy)carbonyl]amino}({4-[6-(4-{ [4-({ [(lE)-{ [(tert-butoxy) carbonyl] amino} ({[(tert-butoxy)carbonyl] imino })methyl] amino} methyl)phenyl] carbamoyl} bicyclo [2.2.2]octane- 1 -amido)pyridazin-3 -yl] - 1 ,2,3 , 6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (112 mg, 0.12 mmol) in CH ₂ CI ₂ (1.2 mL) was added trifluoroacetic acid (1.2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HoLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [6-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-pyridazin-3-yl] -amide (4-guanidinomethyl-phenyl)-amide as the tris-trifluoroacetic acid salt (62 mg, 58%) as a white solid. MS: 545 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.52 (s, 1 H) 9.25 (s, 1 H) 8.23 (d, J= 9.96 Hz, 1 H) 7.98 (d, J=9.38 Hz, 1 H) 7.89 (s, 1 H) 7.63 (d, J=8.79 Hz, 2 H) 7.48 (br. s., 4 H) 7.20 (d, J=8.21 Hz, 3 H) 6.70 (br. s., 1 H) 4.28 (d, J=5.86 Hz, 2 H) 4.15 (br. s., 2 H) 3.64 (br. s., 2 H) 2.78 (br. s., 2 H) 1.86 (d, J=9.38 Hz, 12 H). [0941] Example 45: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [5-( 1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl] -amide (4-guanidinomethyl-phenyl)- amide

[0942] Synthesis of 3-chlorocarbonyl-bicyclo[1.1.1]pentane-l-carboxylic acid methyl ester.

To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid monomethyl ester (981 mg, 5.77 mmol) in diethyl ether (21 mL) was added oxalyl chloride (1024 μL. 11.50 mmmol), followed by N,N- dimethyl formamide (42 mL). The reaction was stirred for 3 hours, then was concentrated. The residue was treated with CH ₂ CI ₂ (20 mL), then was concentrated, to give 3-chlorocarbonyl- bicyclo[ 1.1.1] pentane- 1 -carboxylic acid methyl ester, that was used without further purification.

[0943] Synthesis of 3-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane-l-ca rboxylic acid methyl ester. To a mixture of 3-chlorocarbonyl-bicyclo[1.1.1]pentane-l-carboxylic acid methyl ester in pyridine (5 mL) was added a mixture of 5-bromo-pyrazin-2-ylamine (870 mg, 5.00 mmol) in pyridine (5 mL). The reaction was heated at 60°C for 16 hours, then was concentrated. The residue was treated with IN HC1 (50 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL) and hexanes (20 mL), to give 3-(5-bromo- pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid methyl ester (235 mg, 14%) as a white solid. The IN HC1/ ethyl acetate filtrate was separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 3-(5-bromo-pyrazin-2- ylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxylic acid methyl ester (1.21 g, 74%) as a white solid. [0944] Synthesis of 3-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane-l-ca rboxylic acid. To a mixture of 3-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane-l-ca rboxylic acid methyl ester (1.45 g, 4.43 mmol) in 1,4-dioxane (20 mL) was added a 10N aqueous NaOH solution (4.4 mL). The reaction was stirred for 3 days, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (20 mL), and was dried under high vacuum, to give 3-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane-l-ca rboxylic acid (1.10 g, 80%) as a white solid.

[0945] Synthesis of (4-{[3-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane -l- carbonyl] -amino} -benzyl) -carbamic acid tert-butyl ester. To a mixture of 3-(5-bromo-pyrazin-2- ylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxybc acid (1.10 g, 3.52 mmol), (4-amino-benzyl)- carbamic acid tert-butyl ester (867 mg, 3.91 mmol), and triethylamine (829 mg, 1124 μL, 7.00 mmol) in N,N-dimethyl formamide (10.5 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3- triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1996 mg, 5.29 mmol). The reaction was stirred for 16 hours, then was treated with water (150 mL), and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL) and hexanes (20 mL), to give (4- { [3 -(5 -bromo-pyrazin-2-ylcarbamoyl)-bicyclo [1.1.1 ]pentane- 1 -carbonyl] -amino } -benzyl)- carbamic acid tert-butyl ester (1.19 g, 66%) as a white solid.

[0946] Synthesis of 4-[5-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo[1.1.1] pentane-l-carbonyl}-amino)-pyrazin-2-yl]-3,6-dihydro-2H-pyri dine-l-carboxylic acid tert-butyl ester. A mixture of (4-{[3-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[1.1.1]pentane -l- carbonyl] -amino} -benzyl) -carbamic acid tert-butyl ester (1.19 g, 2.30 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-l-carboxybc acid tert-butyl ester (841 mg, 2.71 mmol), Pd(OAc)2 (24 mg, 0.12 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (102 mg, 0.24 mmol) in 1,4-dioxane (18 mL) and 2M K ₂ CO ₃ (5.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (100 mL) and water (50 mL), then was shaken, and filtered. The fdtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[5-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]-bicyclo[1.1. l]pentane-l- carbonyl}-amino)-pyrazin-2-yl]-3,6-dihydro-2H-pyridine-l-car boxylic acid tert-butyl ester (910 mg, 64%) as a pale yellow solid. [0947] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)- amide [5-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-amide. To a mixture of 4-[5-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)-pyrazin- 2-yl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (910 mg, 1.47 mmol) in CH ₂ CI ₂ (7.7 mL) was added trifluoroacetic acid (3.9 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (40 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide [5-(1,2,3,6-tetrahydro- pyridin-4-yl)-pyrazin-2-yl]-amide as the tris-trifluoroacetic acid salt (1117 mg, 100%) as a yellow solid.

[0948] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(3-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl }bicyclo [ 1.1.1 ]pentane- 1 -amido)pyrazin-2-yl] - 1 ,2,3 ,6-tetrahydropyridin-l- yl})methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4- aminomethyl-phenyl) -amide [5 -( 1 ,2,3 ,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl] -amide . 3 trifluoroacetic acid (59 mg, 0.40 mmol) in N,N-dimethyl formamide (3.8 mL) was treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanyl pyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours. The reaction was treated with water (60 mL) and was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl]amino}({4-[5-(3-{[4-({[(lZ)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino})methyl] amino }methyl)phenyl] carbamoyl }bicyclo[1.1. l]pentane-l- amido)pyrazin-2-yl]-1,2,3,6-tetrahydropyridin-l-yl})methylid ene]carbamatel92 mg, 53%) as a pale yellow solid. [0949] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [5-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(3-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo[ 1.1.1] pentane- 1 -amido)pyrazin-2-yl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (192 mg, 0.21 mmol) in CH ₂ CI ₂ (2.1 mL) was added trifluoroacetic acid (2.1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [5-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-pyrazin-2-yl] -amide (4-guanidinomethyl-phenyl)-amide as the tris-trifluoroacetic acid salt (58 mg, 33%) as a white solid. MS: 503 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.81 (s, 1 H) 9.72 (s, 1 H) 9.25 (s, 1 H) 8.70 (s, 1 H) 7.91 (br. s., 1 H) 7.63 (d, J=8.21 Hz, 3 H) 7.47 (br. s., 4 H) 7.23 (d,

J=8.21 Hz, 4 H) 6.77 (br. s., 1 H) 4.30 (d, J=5.27 Hz, 2 H) 4.14 (br. s., 2 H) 3.62 (br. s., 2 H) 2.69 (br. s., 2 H) 2.37 (s, 6 H). [0950] Example 46: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [5-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl] -amide (4-guanidinomethyl-phenyl)- amide

[0951] Synthesis of 4-chlorocarbonyl-bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (1.40 g, 6.60 mmol) in CHCI ₃ (37 mL) and N,N-dimethyl formamide (15 drops) was added dropwise oxalyl chloride (1.35 g, 904 μL. 10.54 mmol). The reaction was stirred for 3 hours, then was concentrated, to give 4- chlorocarbonyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, that was used without further purification.

[0952] Synthesis of 4-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester. To a mixture of 4-chlorocarbonyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester in pyridine (5.7 mL) was added a mixture of 5-bromo-pyrazin-2-ylamine (995 mg, 6.72 mmol). The reaction was heated at 60°C for 18 hours, then was concentrated. The residue was treated with IN HC1 (50 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 4-(5-bromo-pyrazin-2-ylcarbamoyl)-bicyclo[2.2.2]octane-l-car boxylic acid methyl ester (1.72 g, 82%) as a white solid.

[0953] Synthesis of 4-{5-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-l-carbonyl)-am ino]- pyrazin-2-yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester. A mixture of 4-(5-bromo- pyrazin-2-ylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (1.72 g, 4.67 mmol), 4- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2 H-pyridine-l-carboxylic acid tert-butyl ester (1704 mg, 5.50 mmol), Pd(OAc)2 (48 mg, 0.24 mmol), and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (206 mg, 0.48 mmol) in 1,4-dioxane (36 mL) and 2M K ₂ CO ₃ (11 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (200 mL) and water (50 mL). The mixture was shaken, then was filtered. The fdtrate was separated. The organic layer was washed with brine (20 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0- 75% ethyl acetate: hexanes), to give 4-{5-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-l-carbonyl)- amino]-pyrazin-2-yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1.70 g, 77%) as a pale yellow solid.

[0954] Synthesis of 4-{5-[(4-carboxy-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyr azin-2- yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester. To a mixture of 4-{5-[(4- methoxycarbonyl-bicyclo[2.22]octane- 1 -carbonyl)-amino] -pyrazin-2-yl } -3 ,6-dihydro-2H-pyridine- 1 - carboxylic acid tert-butyl ester (1.70 g, 3.61 mmol) in 1,4-dioxane (16 mL) was added a 10N aqueous NaOH solution (3.6 mL). The reaction was heated at 90°C for 16 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with IN HC1 (4 x 20 mL), and water (20 mL), to give 4-{5-[(4-carboxy-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyr azin-2-yl}-3,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (1.08 g, 66%) as a white solid.

[0955] Synthesis of 4-[5-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo[2.22]octane- 1 -carbonyl } -amino)-pyrazin-2-yl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester. A mixture of 4-{5-[(4-carboxy-bicyclo[2.2.2]octane-l-carbonyl)-amino]-pyr azin-2- yl}-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1.08 g, 2.37 mmol), (4-amino- benzyl)-carbamic acid tert-butyl ester (584 mg, 2.63 mmol), and triethylamine (558 mg, 757 μL, 4.71 mmol) in N,N-dimethyl formamide (7 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3- triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1343 mg, 3.56 mmol). The reaction was stirred for 16 hours, then was treated with water (100 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), and saturated aqueous NaHCO ₃ (30 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[5-({4-[4-(tert-butoxycarbonylamino- methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane - 1 -carbonyl } -amino) -pyrazin-2-yl] -3 , 6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (845 mg, 54%) as a white solid.

[0956] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)- amide [5-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-amide. To a mixture of 4-[5-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane- 1 -carbonyl } -amino)-pyrazin- 2-yl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid (4-aminomethyl-phenyl)-amide [5-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]- amide (845 mg, 1.28 mmol) in CH ₂ CI ₂ (6.8 mL) was added trifluoroacetic acid (3.4 mL). The reaction was stirred for 16 hours, then was treated with water (90 mL), and was washed with ethyl acetate (2 x 50 mL). The aqueous layer was concentrated, then was adjusted to pH7 using saturated aqueous NaHCO ₃ . The mixture was allowed to stand for 10 minutes, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), then was dried under high vacuum, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)-amide [5-(1,2,3,6-tetrahydro- pyridin-4-yl)-pyrazin-2-yl]-amide (246 mg, 42%) as a beige solid. [0957] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl}bicyclo[2.2.2]octane-l-amido)pyrazin-2-yl]-1,2,3,6 -tetrahydropyridin-l-yl})methylidene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)- amide [5-(1,2,3,6 -tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-amide (246 mg, 0.53 mmo) in N,N-dimethyl formamide (5 mL) was added triethylamine (153 mg, 210 μL, 1.50 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (519 mg, 1.67 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours, then was treated with water (75 mL), and was extracted with ethyl acetate (4 x 40 mL). The combined organic extracts were washed with water (2 x 30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(1Z)- { [(tert-butoxy)carbonyl] amino } ( { 4- [5 -(4- { [4-( { [( 1 E) - { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy) carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)pyrazin-2- yl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]carbamate (191 mg, 38%) as a pale yellow solid.

[0958] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [5-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-pyrazin-2-yl] -amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(lE)- {[(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane-l-amido)pyrazin-2-yl]-1,2,3,6-tetrahydropyridin-l-yl} )methylidene]carbamate (191 mg, 0.20 mmol) in CH ₂ CI ₂ (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative -HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [5-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- pyrazin-2-yl] -amide (4-guanidinomethyl-phenyl)-amide as the tris-trifluoroacetic acid salt (95 mg, 54%) as a white solid.. MS: 545 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.20 (s, 1 H) 9.15 - 9.30 (m, 2 H) 8.67 (d, 7=1.76 Hz, 1 H) 7.95 (t, 7=5.57 Hz, 1 H) 7.62 (d, 7=8.79 Hz, 2 H) 7.52 (br. s., 4 H) 7.20 (d, J=8.21 Hz, 4 H) 6.74 (br. s., 1 H) 4.28 (d, 7=5.86 Hz, 2 H) 4.13 (br. s., 2 H) 3.62 (t, 7=5.57 Hz, 2 H) 2.67 (br. s., 2 H) 1.85 (d, 7=7.03 Hz, 12 H). [0959] Example 47: Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [6-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-y l]-amide (4-guanidinomethyl-phenyl)- amide [0960] Synthesis of 3-chlorocarbonyl-bicyclo[1.1.1]pentane-l-carboxylic acid methyl ester.

To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxybc acid monomethyl ester (981 mg, 5.77 mmol) in diethyl ether (21 mL) was added oxalyl chloride (1024 μL. 11.50 mmol) followed by N,N-dimethyl formamide (42 μL). The reaction was stirred for 3 hours, then was concentrated. The material was used without further purification.

[0961] Synthesis of 3-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]pentane-l- carboxylic acid methyl ester. To a mixture of 6-bromo-pyridazin-3-ylamine (871 mg, 5.00 mmol), 4- dimethylaminopyridine (50 mg), and diisopropylethylamine (1014 mg, 1364 μL, 7.87 mmol) in CHCI ₃ (13.3 mL) was added dropwise a mixture of 3-chlorocarbonyl-bicyclo[1.1.1]pentane-l- carboxylic acid methyl ester in CHCI ₃ (13.3 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 3-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]pentane-l- carboxylic acid methyl ester (1.41 g, 87%) as a pale yellow solid.

[0962] Synthesis of 3-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]pentane-l- carboxylic acid. To a mixture of 3-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]pentane-l- carboxylic acid methyl ester (1.39 g, 4.26 mmol) in 1,4-dioxane (19 mL) was treated with a 10N aqueous NaOH solution (4.3 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (20 mL), and was dried under high vacuum, to give 3 -(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]pentane-l -carboxylic acid (848 mg, 64%) as a beige solid.

[0963] Synthesis of (4-{[3-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]penta ne-l-carbonyl]- amino}-benzyl)-carbamic acid tert-butyl ester. To a mixture of 3-(6-bromo-pyridazin-3- ylcarbamoyl)-bicyclo[1.1.1]pentane-l-carboxylic acid (844 g, 2.70 mmol), (4-amino-benzyl)- carbamic acid tert-butyl ester (666 mg, 3.00 mmol), and triethylamine (637 mg, 864 μL, 5.38 mmol) in N,N-dimethyl formamide (8 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5- bpyridinium 3-oxid hexafluorophosphate (1533 mg, 4.06 mmol). The reaction was stirred for 16 hours, then was treated with water (120 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were filtered through Celite, and the filtrate was separated. The organic layer was washed with water (2 x 30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give (4- { [3-(6-bromo-pyridazin-3 -ylcarbamoyl)-bicyclo [1.1.1 ]pentane- 1 -carbonyl] -amino } - benzyl)-carbamic acid tert-butyl ester (1.02 g, 873%) as a tacky white solid.

[0964] Synthesis of 4-[6-({3-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclofl .1. l]pentane-l -carbonyl }-amino)-pyridazin-3-yl] -3, 6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester. A mixture of (4-{[3-(6-bromo-pyridazin-3-ylcarbamoyl)-bicyclo[1.1.1]penta ne- 1 -carbonyl] -amino }-benzyl)-carbamic acid tert-butyl ester (1.02 g, 1.97 mmol), 4-(4, 4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin e-l-carboxylic acid tert-butyl ester (721 mg, 2.32 mmol), Pd(OAc)2 (21 mg, 0.10 mmol), and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (87 mg, 0.21 mmol) in 1,4-dioxane (15 mL) and 2M K ₂ CO ₃ (4.7 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (75 mL). The mixture was washed with water (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-5% methanol: dichloromethane), to give 4-[6-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)- pyridazin-3-yl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (323 mg, 27%) as a pale yellow solid.

[0965] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)- amide [6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide. To a mixture of 4-[6-({3-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[1.1. l]pentane-l-carbonyl}-amino)- pyridazin-3-yl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (321 mg, 0.51 mmol) in CH ₂ CI ₂ (2.8 mL) was added trifluoroacetic acid (1.4 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (20 mL), to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide [6-(1,2,3,6-tetrahydro- pyridin-4-yl)-pyridazin-3-yl] -amide as the tris-trifluoroacetic acid salt (162 mg, 42%) as a pale orange solid. The filter was washed with methanol (2 x 10 mL), and the methanol filtrates were combined and concentrated, to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide [6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide as the tris-trifluoroacetic acid salt (192 mg, 50%) as a clear film.

[0966] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(3-{[4-({[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [1.1.1 ]pentane- 1 -amido)pyridazin-3 -yl] - 1 ,2,3 , 6-tetrahydropyridin- 1 - yl})methylidene] carbamate. To a mixture of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid (4- aminomethyl-phenyl) -amide [6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide. 3 trifluoroacetic acid (352 mg, 0.46 mmol) in N,N-dimethyl formamide (4.4 mL) was added triethylamine (324 mg, 444 μL, 3.17 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (454 mg, 1.46 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours, then was treated with water (65 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 25 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( {4- [6-(3 - { [4-( { [( 1Z)- { [(tert-butoxy)carbonyl]amino } ( { [(tert-butoxy) carbonyl] imino })methyl] amino }methyl)phenyl] carbamoyl} bicyclo [1.1. l]pentane-l-amido)pyridazin- 3-yl]-1,2,3,6-tetrahydropyridin-l-yl}) methylidene] carbamate (152 mg, 37%) as an off-white solid.

[0967] Synthesis of bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [6-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[6-(3-{[4-({[(lZ)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [1.1.1] pentane - 1 -amido)pyridazin-3 -yl] - 1 ,2,3 , 6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (152 mg, 0.17 mmol) in CH ₂ CI ₂ (1.7 mL) was added trifluoroacetic acid (1.7 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative -HPLC, to give bicyclo[1.1.1]pentane-l,3-dicarboxylic acid [6-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-pyridazin-3-yl] -amide (4-guanidinomethyl-phenyl)-amide as the tris- trifluoroacetic acid salt (88 mg, 61%) as a white solid. MS: 503 M+H+; 'H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.05 - 11.19 (m, 1 H) 9.74 (s, 1 H) 9.69 (s, 1 H) 8.87 (br. s, 2 H) 8.16 - 8.31 (m, 2 H) 7.93 - 8.07 (m, 4 H) 7.50 - 7.70 (m, 12 H) 7.14 - 7.27 (m, 7 H) 6.65 - 6.83 (m, 2 H) 4.30 (d, J=5.86 Hz, 6 H) 4.15 (br. s., 5 H) 3.54 - 3.69 (m, 4 H) 2.78 (br. s., 2 H) 2.54 - 2.60 (m, 1 H) 2.38 (s, 6 H). [0968] Example 48: Synthesis of bicyclo[2.2.1]heptane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide

[0969] Synthesis of 4-(4-bromo-phenylcarbamoyl)-bicyclo [2.2. l]heptane-l -carboxylic acid methyl ester. To a mixture of bicyclo[2.2.1]heptane-l,4-dicarboxybc acid monomethyl ester (500 mg, 2.52 mmol), 4-bromo-phenylamine (478 mg, 2.77 mmol), and triethylamine (478 mg, 646 μL, 4.03 mmol) in N,N-dimethyl formamide (7.5 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3- triazolo4,5-bpyridinium 3-oxid hexafluorophosphate (1433 mg, 3.78 mmol). The reaction was stirred for 16 hours, then was treated with water (100 mL), and was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 30 mL), IN HC1 (25 mL), and saturated aqueous NaHCO ₃ (25 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.1]heptane-l-carboxylic acid methyl ester (856 mg, 96%) as a white solid. [0970] Synthesis of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.1]heptane-l-carboxyl ic acid.

To a mixture of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.1]heptane-l-carboxyl ic acid methyl ester (856 mg, 2.43 mmol) in 1,4-dioxane (11 mL) was added a 10N aqueous NaOH solution (2.4 mL). The reaction was heated at 90°C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (20 mL), then was dried under high vacuum, to give 4-(4-bromo-phenylcarbamoyl)-bicyclo [2.2. l]heptane-l -carboxylic acid (662 mg, 81%) as a white solid. [0971] Synthesis of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.1]heptane-l-car bonyl]- amino} -benzyl) -carbamic acid tert-butyl ester. To a mixture of 4-(4-bromo-phenylcarbamoyl)- bicyclo [2.2. l]heptane-l -carboxylic acid (662 mg, 1.96 mmol), (4-amino-benzyl)-carbamic acid tert- butyl ester (482 mg, 2.17 mmol), and triethylamine (461 mg, 625 μL, 3.89 mmol) in N,N-dimethyl formamide (5.8 mL) was added l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5-bpyridini um 3- oxid hexafluorophosphate (1109 mg, 2.94 mmol). The reaction was stirred for 16 hours, then was treated with water (90 mL) and ethyl acetate (50 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), then was dried under high vacuum, to give (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.1]heptane-l-car bonyl]-amino}- benzyl)-carbamic acid tert-butyl ester (532 mg, 50%) as a white solid.

[0972] Synthesis of 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo[2.2.1] heptane-l-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-l -carboxylic acid tert- butyl ester. A mixture of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.1]heptane-l-car bonyl]- amino}-benzyl)-carbamic acid tert-butyl ester (532 mg, 0.98 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyl ic acid tert-butyl ester (359 mg, 1.16 mmol), Pd(OAc)2 (11 mg, 0.050 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (43 mg, 0.11 mmol) in 1,4-dioxane (7.5 mL) and 2M K ₂ CO ₃ (2.3 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered through Celite. The filtrate was separated. The organic layer was washed with brine (10 mL), dried (Na2SC>4), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo[2.2. l]heptane-l-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine -l-carboxylic acid tert- butyl ester (89 mg, 14%) as a white solid. [0973] Synthesis of bicyclo[2.2.1]heptane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[4-(tert- butoxy carbonyl amino-methyl)-phenylcarbamoyl] -bicyclo [2.2.1 ]heptane- 1 -carbonyl } -amino)- phenyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (87 mg, 0.14 mmol) in CH ₂ CI ₂ (1 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (15 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (10 mL), to give bicyclo[2.2.1]heptane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)-amide [4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl] -amide as the bis-trifluoroacetic acid salt (126 mg, >100%) as a pale yellow solid, that was used without further purification.

[0974] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.1 ]heptane- 1 -amido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of bicyclo[2.2.1]heptane-l,4-dicarboxybc acid (4-aminomethyl-phenyl)- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 trifluoroacetic acid ( to give tert-butyl N- [(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)-{[ (tert-butoxy)carbonyl]amino} ({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.1] heptane- 1 - amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]ca rbamate (126 mg, 0.19 mmol) in N,N- dimethyl formamide (1.8 mL) was added triethylamine (131 mg, 180 μL, 1.28 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (184 mg, 0.59 mmol). The reaction was stirred for 15 minutes, then was heated at 35°C for 16 hours, then was treated with water (40 mL), and was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert- butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- {[(tert-butoxy)carbonyl]amino} ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.1 ]heptane- 1 - amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]ca rbamate (40 mg, 23%) as a clear fdm.

[0975] Synthesis of bicyclo[2.2.1]heptane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-

1.2.3.6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide: To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- {[(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.1] heptane-l-amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})meth ylidene]carbamate (40 mg, 0.043 mmol) in CH ₂ CI ₂ (0.43 mL) was added trifluoroacetic acid (0.43 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.1 ]heptane- 1 ,4-dicarboxylic acid [4-( 1 -carbamimidoyl- 1.2.3.6-tetrahydro-pyridin-4-yl)- phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis-trifluoroacetic acid salt (14 mg, 43%) as a beige solid. MS: 529 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.35 (s, 2 H) 7.88 (br. s., 1 H) 7.65 (dd, J=8.50, 4.98 Hz, 5 H) 7.40 (d, 7=4.69 Hz, 7 H) 7.21 (d, 7=8.79 Hz, 4 H) 6.14 (s, 1 H) 4.29 (d, J=5.86 Hz, 2 H) 4.05 (br. s., 2 H) 2.55 (br. s., 2 H) 1.94 - 2.07 (m, 6 H) 1.79 (d, 7=6.45 Hz, 4 H).

[0976] Example 49: Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(l-carbamimidoyl-

1.2.3.6-tetrahydro-pyridin-4-yl)-phenyl]-amide} hydrochloride

[0977] Synthesis of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester: A mixture of 4-bromo-phenylamine (0.850 g, 4.95 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-l(2H)-carboxyla te (1.76 g, 5.69 mmol), and 2 M Na ₂ CO ₃ solution (7.4 mL, 14.85 mmol) in 1,4-dioxane (19 mL) was degassed by bubbling nitrogen through the mixture for five minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.350 g, 0.495 mmol) was added, and the reaction was heated at 85 °C for 18 hours. The mixture was partitioned between ethyl acetate and water, filtered through Celite, then separated, dried (Na2S04), filtered, and concentrated. Silica gel chromatography (0 to 100% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the desired compound (0.83 g, 61%) as a white, waxy solid.

[0978] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl] -amide} trifluoroacetate. To a mixture of pyrimidine-4, 6-dicarboxylic acid (0.120 g, 0.714 mmol), 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (0.450 g, 1.64 mmol), 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (0.471 g, 2.46 mmol), and hydroxybenzotriazole (0.332 g, 2.46 mmol) was added N,N-dimethylacetamide (1.5 mL). The yellow slurry was stirred at 23 °C for 72 hours. The mixture was partitioned between dichloromethane and saturated NaHCO ₃ solution and separated. The organic layer was washed with 0.1 N HC1 solution, then dried (MgSO ₄ ). filtered, and concentrated. The residue was suspended in ethyl acetate (12 mL), stirred for 90 minutes, then filtered and rinsed with additional ethyl acetate to yield a yellow solid. This material was dissolved in dichloromethane (23 mL) to which trifluoroacetic acid (8 mL) was then added. After stirring at 23 °C for three hours, the reaction was concentrated. The residue was triturated with ethyl acetate, filtered, and dried under vacuum to yield the desired compound (0.420 g, 83%).

[0979] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide} hydrochloride: To a suspension of pyrimidine-4, 6- dicarboxylic acid bis-{[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide} trifluoroacetate (0.400 g, 0.564 mmol) and N, N-diisopropylethylamine (0.251 g, 0.338 mL, 1.94 mmol) in N,N- dimethylacetamide (6 mL) at 23 °C under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbamate (0.385 g, 1.24 mmol). The reaction was stirred at 23 °C for 18 hours. The mixture was partitioned between dichloromethane and water and separated. The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded a yellow solid (0.255 g). This material was dissolved 4 N HCl-l,4-dioxane (8 mL), sonicated briefly to aid dissolution, then stirred at 23 °C. After six hours, the reaction was concentrated. The residue was triturated with ethyl acetate, filtered, and dried under vacuum to yield the desired compound as a yellow solid (0.190 g, 53%).

[0980] Example 50: Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(l,l-difluoro-2- guanidino-ethyl)-phenyl] -amide } trifluoroacetate

[0981] Synthesis of difluoro-(4-nitro-phenyl)-acetic acid ethyl ester: To a solution of 1-iodo- 4-nitro-benzene (6.65 g, 26.7 mmol) and bromo-difluoro-acetic acid ethyl ester (5.97 g, 29.4 mmol) in N,N-dimethyl formamide (100 mL) was added Cu powder (4.24 g, 66.8 mmol). The mixture was heated at 100 °C for 18 hours. The reaction was cooled to 23 °C and 1 N Na ₂ HPO ₄ solution (67 mL, 67 mmol) was added. After stirring for 30 minutes, the mixture was filtered through Celite, and the filtered solids were rinsed with ethyl acetate (250 mL). The filtrate was washed with water (2 x 50 mL); the organic layer was then dried (Na ₂ SO ₄ ), filtered, and concentrated. Silica gel chromatography (0 to 20% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the desired compound (1.1 g, 17%).

[0982] Synthesis of 2,2-difluoro-2-(4-nitro-phenyl)-ethanol: To a solution of difluoro-(4- nitro-phenyl)-acetic acid ethyl ester (0.674 g, 2.75 mmol) in EtOH (9 mL) at 0 °C was added NaBH ₄ (0.157 g, 4.15 mmol). The ice bath was removed, and the reaction was stirred at 23 °C for two hours before quenching with 1 N HC1 solution (2 mL) and concentrating. The residue was partitioned between ethyl acetate and water and separated. The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated, Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the desired compound (0.650 g) as a yellow solid.

[0983] Synthesis of 2,2-difluoro-2-(4-nitro-phenyl)-ethylamine: To a solution of 2,2-difluoro- 2-(4-nitro-phenyl)-ethanol (0.650 g, 3.20 mmol) and pyridine (0.405 g, 0.414 mL, 5.12 mmol) in acetonitrile (6 mL) at 0 °C was added trifluoromethanesulfonic anhydride (0.978 g, 0.583 mL, 3.47 mmol) dropwise. After five minutes, concentrated ammonium hydroxide solution (5 mL) was added, and the reaction was stirred at 23 °C for 18 hours. The mixture was extracted with dichloromethane (3x). The organic layers were combined, dried, filtered, and concentrated. Silica gel chromatography (10 to 100% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the desired compound (0.320 g, 49%).

[0984] Synthesis of [2,2-difluoro-2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester: To a solution of 2,2-difluoro-2-(4-nitro-phenyl)-ethylamine (0.320 g, 1.58 mmol) in tetrahydrofuran (5 mL) at 23 °C was added di-tert-butyl dicarbonate (0.518 g, 2.37 mmol) and triethylamine (0.239 g, 0.330 mL, 2.37 mmol). The reaction was stirred at 23 °C for 18 hours. The mixture was partitioned between ethyl acetate and water and separated. The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated. Silica gel chromatography (0 to 25% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the desired compound (0.280 g, 59%).

[0985] Synthesis of [2-(4-amino-phenyl)-2,2-difluoro-ethyl]-carbamic acid tert-butyl ester: A mixture of [2,2-difluoro-2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.280 g, 0.926 mmol) in tetrahydrofuran (15 mL) was degassed by bubbling nitrogen through for 10 minutes, then stirred under hydrogen for 16 hours. The reaction was purged with nitrogen, filtered through Celite, then concentrated to yield the desired compound (0.223 g, 86%).

[0986] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(2-amino-l,l-difluoro-ethyl)- phenyl] -amide} trifluoroacetate. To a mixture of pyrimidine-4, 6-dicarboxylic acid (0.067 g, 0.400 mmol), [2-(4-amino-phenyl)-2,2-difluoro-ethyl]-carbamic acid tert-butyl ester (0.223 g, 0.800 mmol), 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (0.192 g, 1.00 mmol), and hydroxybenzotriazole (0.135 g, 1.00 mmol) was added N,N-dimethyl formamide (0.5 mL). The suspension was sonicated until homogeneous, then stirred at 23 °C for 72 hours. The mixture was partitioned between dichloromethane and 0.5 N HC1 solution and separated. The organic layer was washed with saturated NaHCO ₃ solution, then dried (Na ₂ SO ₄ ). filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {2-[4-({6- [4-(2-tert-butoxycarbonylamino- 1 , 1 -difluoro-ethyl)-phenylcarbamoyl]-pyrimidine-4-carbonyl} - amino)-phenyl]-2,2-difluoro-ethyl}-carbamic acid tert-butyl ester as a light yellow solid. This compound was dissolved in methylene chloride (4 mL), and trifluoroacetic acid was (2 mL) was added. After stirring at 23 °C for four hours, the reaction was concentrated to yield the desired compound, which was used without further purification in the next reaction.

[0987] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(l,l-difluoro-2-guanidino- ethyl)-phenyl] -amide} trifluoroacetate: A mixture of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(2- amino-l,l-difluoro-ethyl)-phenyl]-amide} trifluoroacetate (0.180 g, 0.256 mmol), tert-butyl N-[(Z)- {[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl] carbamate (0.222 g, 0.715 mmol), and N, N- diisopropylethylamine (0.185 g, 0.250 mL, 1.43 mmol) in N,N-dimethyl formamide (2 mL) was stirred at 23 °C for 40 hours. The solution was partitioned between ethyl acetate and water and separated. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, dried (Na SCL). filtered, and concentrated. Silica gel chromatography (20 to 100% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded an off-white foam. This material was dissolved in methylene chloride (8 mL), to which trifluoroacetic acid (5 mL) was added. After stirring at 23 °C for 18 hours, the reaction was concentrated, then diluted with ethyl acetate and concentrated again (2x). The residue was triturated with ethyl acetate, then filtered and dried under vacuum to yield the desired compound (0.124 g, 61%).

[0988] Example 51: Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(4-carbamimidoyl- piperazin- 1 -yl)-phenyl] -amide }trifluoroacetate

[0989] Synthesis of 4-(4-amino-phenyl)-piperazine-l -carboxylic acid tert-butyl ester: To a solution of 4-(4-nitro-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (1.200 g, 3.90 mmol) in a mixture of MeOH (30 mL)and tetrahydrofuran (15 mL) was added NH4CI (2.500 g, 46.80 mmol) and zinc dust (1.500 g, 23.40 mmol). The reaction was warmed to 37 °C for one hour, then the temperature was increased to 55 °C. After cooling to 23 °C, acetic acid (3 mL) was added, and the mixture was heated at 55 °C for 18 hours. The reaction was filtered and concentrated. The residue was partitioned between ethyl acetate and water (basified with 1 N NaOH solution) and separated. The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated to yield the desired compound as a black oil (0.840 g, 78%), which was used without further purification in the next reaction.

[0990] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide] trifluoroacetate: A mixture of pyrimidine-4, 6-dicarboxylic acid (0.0300 g, 0.181 mmol), N, N- diisopropylethylamine (1.00 mL), and l-Bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5- bpyridinium 3-oxid hexafluorophosphate (0.185 g, 0.486 mmol) in methylene chloride (1.2 mL) at 23 °C under N2 was stirred for 30 minutes, before adding a solution of 4-(4-amino-phenyl)-piperazine-l- carboxylic acid tert-butyl ester (0.125 g, 0.450 mmol) in methylene chloride (0.400 mL) and stirring at 23 °C for 18 hours. Ethyl acetate (3 mL) was added, and the suspension was concentrated. Water (5 mL) and ethyl acetate (10 mL) were added to the residue; the resulting solid was sonicated briefly, then collected by filtration and air-dried. This material was slurried in methylene chloride (1 mL), to which trifluoroacetic acid (3 mL) was then added. After stirring for two hours, the reaction was concentrated. The residue was triturated with ether (15 mL); the ether was then decanted to yield the desired compound as a soft solid, which was used without further purification.

[0991] Synthesis of [(4-{4-[(6-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbon ylimino- methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -pyrimidine-4-carbonyl)-amino] -phenyl} -piperazin- 1 -yl)- tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: To a slurry of pyrimidine-4, 6- dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide] trifluoroacetate (-0.0700 g, -0.250 mmol) and triethylamine (0.3152 g, 2.17 mL, 1.50 mmol) in methylene chloride (3 mL) at 23 °C was added water (0.200 mL), followed by N,N-dimethyl formamide (2 mL). Additional triethylamine (0.108 mL, 0.750 mmol) was added, followed by tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH- pyrazol-l-yl)methyl]carbamate (0.194 g, 0.625 mmol), and the reaction was stirred at 23 °C for 72 hours. The solution was diluted with ethyl acetate (30 mL) and water (20 mL) and separated. The organic layer was then dried (Na ₂ SO ₄ ), filtered, and concentrated. Silica gel chromatography (0 to 45% ethyl acetate - methylene chloride), followed by concentration and drying under vacuum, yielded the desired compound (0.0500 g, 21%) as a soft solid.

[0992] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(4-carbamimidoyl-piperazin-l- yl)-phenyl] -amide }trifluoroacetate: To a solution of [(4-{4-[(6-{4-[4-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-piperazin- 1 -yl] -phenylcarbamoyl } -pyrimidine-4-carbonyl)-amino] - phenyl} -piperazin-l-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (0.0500 g, 0.0515 mmol) in dichloromethane (2 mL) at was added trifluoroacetic acid (3 mL) dropwise over one minute. The reaction was stirred at 23 °C for two hours, then concentrated. The residue was suspended in water (10 mL). After 60 minutes, the solid was collected by filtration, washed slowly with a 1 : 1 mixture of MeOH : tetrahydrofuran (4 mL), and dried in a vacuum oven for 18 hours to yield the desired compound (0.0450 g, quantitative).

[0993] Example 52: Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(2-guanidino- ethyl)-phenyl] -amide } [0994] Synthesis of pyrimidine-4, 6-dicarbonyl dichloride: To a mixture of pyrimidine-4, 6- dicarboxylic acid (0.200 g, 11.9 mmol) and N,N-dimethyl formamide (0.109 g, 0.116 mL, 1.49 mmol) in anhydrous methylene chloride at 23 °C under N2 was added oxalyl chloride (0.453 g, 0.306 mL, 3.57 mmol) dropwise over 30 minutes. After 30 minutes, additional oxalyl chloride (0.045 mL in 0.500 mL of anhydrous methylene chloride) was added dropwise, and the reaction was stirred for 72 hours. The nearly homogeneous mixture was used as a solution in the next reaction.

[0995] Synthesis of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester: To a solution of 4-(2-amino-ethyl)-phenylamine (3.300 g, 24.3 mmol) in a mixture of tetrahydrofuran (20 mL) and ethyl acetate (30 mL) at 23 °C was added a solution of di-tert-butyl dicarbonate (5.460 g, 25.0 mmol) in ethyl acetate (10 mL) dropwise over 30 minutes. After four hours, the mixture was concentrated and dried under vacuum for 72 hours to yield the desired compound as a white solid (5.40 g, 94%). amide} trifluoroacetate: A mixture of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.331 g, 1.40 mmol) and N, N-diisopropylethylamine (0.426 g, 0.574 mL, 3.30 mmol) in anhydrous methylene chloride (4 mL) at 23 °C under N2 was sonicated briefly until homogeneous, then cooled to 0 °C. A solution of pyrimidine-4, 6-dicarbonyl dichloride (0.126 g, 0.540 mmol) in methylene chloride (2 mL) was added dropwise over two minutes. The ice bath was removed, and the reaction was stirred at 23 °C for 18 hours. The mixture was concentrated, and the residue was partitioned between ethyl acetate (20 mL) and water (10 mL) and separated. The organic layer was dried (Na SCL). filtered, and concentrated. The residue was triturated with methylene chloride to form a solid, which was collected by filtration, suspended in methylene chloride (2 mL), then treated with trifluoroacetic acid (4 mL). The reaction was complete within four hours, then concentrated. This material was triturated with ether (2 x 20 mL), then dried under vacuum to yield 0.170 mg. The mother liquor from the first methylene chloride trituration / filtration was separately treated with trifluoroacetic acid in a similar manner as the filtered solid, then purified by reverse-phase HPLC (5 to 37% MeCN - water (both with 0.1% trifluoroacetic acid) over 11 min.). The fractions containing the title compounds were lyophilized to yield 50 mg. This material was combined with the product from the ether trituration to yield the desired product (0.220 g, 64%).

[0997] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(2-guanidino-ethyl)-phenyl]- amide}: To a slurry of pyrimidine-4, 6-dicarboxylic acid bis- { [4-(2-amino-ethyl)-phenyl] -amide} trifluoroacetate (0.220 g, 0.350 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (3 mL) was added triethylamine (0.636 g, 900 mL, 6.30 mmol) dropwise over one minute. After ten minutes, the reaction was cooled to 0 °C with an ice bath, and tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbamate (0.520 g, 1.68 mmol) was added. The ice bath was removed after five minutes, and the mixture was stirred at 23 °C for 48 hours. The reaction was concentrated. The residue was dissolved in ethyl acetate (30 mL) and washed with water (3 x 20 mL). The organic layer was then dried (Na ₂ SO ₄ ), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - methylene chloride), followed by concentration and drying under vacuum, yielded the desired guanylated intermediate. This compound was deprotected by dissolving in methylene chloride (2 mL) and treating with trifluoroacetic acid (3 mL). Concentration, followed by lyophilization from 1,4-dioxane / water, yield the desired compound (0.102 g, 41%). [0998] Example 53: Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(l-carbamimidoyl- azetidin-3 -yloxy) -phenyl] -amide } trifluoroacetate

[0999] Synthesis of 3-(4-nitro-phenoxy)-azetidine-l-carboxylic acid tert-butyl ester: To a mixture of 3 -hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (1.580 g, 9.13 mmol) in anhydrous tetrahydrofuran (12 mL) at 23 °C under N was added potassium tert-butoxide (1.155 g, 10.3 mmol). After 30 minutes, l-fluoro-4-nitro-benzene (1.260 g, 8.95 mmol) was added, and the mixture was stirred at 23 °C for 18 hours. The reaction was concentrated. The residue was partitioned between ethyl acetate (60 mL) and water (30 mL) and separated. The organic layer was then dried (Na ₂ SO ₄ ). filtered, concentrated, and dried under vacuum to yield the desired compound (1.7 g, 64.5%) as a solid.

[1000] Synthesis of 3 -(4-amino-phenoxy)-azetidine-l -carboxylic acid tert-butyl ester: To a solution of 3 -(4-nitro-phenoxy)-azetidine-l -carboxylic acid tert-butyl ester (2.590 g, 8.80 mmol) in a mixture of tetrahydrofuran (10 mL) and MeOH (20 mL) at 23 °C under N was added ammonium chloride (4.750 g, 88.0 mmol) followed by zinc dust (2.900 g, 44.0 mmol). The reaction was heated at 75 °C for 18 hours. The mixture was cooled to 23 °C, filtered through Celite, and concentrated. The residue was partitioned between ethyl acetate (50 mL) and water (30 mL) and separated. The organic layer was then dried (Na ₂ SO ₄ ). filtered, and concentrated. Silica gel chromatography (5 to 80% ethyl acetate - methylene chloride), followed by concentration and drying under vacuum, yielded the title compound (0.710 g, quantitative).

[1001] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(azetidin-3-yloxy)-phenyl]- amide} trifluoroacetate: To a mixture of 3 -(4-amino-phenoxy)-azetidine- 1 -carboxylic acid tert-butyl ester (0.317 g, 1.20 mmol) and N, N-diisopropylethylamine (0.774 g, 1.1 mL, 6.0 mmol) in anhydrous methylene chloride (4 mL) at 23 °C under N2 was cooled to 0 °C with an ice bath. A solution of pyrimidine-4, 6-dicarbonyl dichloride (0.126 g, 0.540 mmol) in methylene chloride (2.5 mL) was added dropwise. The ice bath was removed after five minutes, and the reaction was stirred at 23 °C for three hours. The suspension was diluted with ethyl acetate (20 mL) and water (10 mL) and stirred. The solid was collected by filtration and air dried for 20 minutes to yield a yellow solid (0.390 g), which was dissolved / suspended in methylene chloride (4 mL), then treated with trifhioroacetic acid (8 mL). After stirring at 23 °C for 18 hours, the reaction was concentrated. This material was triturated with ether (2 x 15 mL), then dried under vacuum to yield the title compound.

[1002] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-{[4-(l-carbamimidoyl-azetidin-3- yloxy)-phenyl] -amide} trifluoroacetate: To a suspension of pyrimidine-4, 6-dicarboxylic acid bis-{[4- (azetidin-3-yloxy)-phenyl] -amide} trifluoroacetate (0.220 g, 0.480 mmol) and triethylamine (1.200 g, 1.70 mL) in a mixture of methylene chloride (2 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate (0.372 g, 1.20 mmol). The mixture was stirred at 23 °C for 18 hours. The reaction was partially concentrated to remove methylene chloride, then diluted with ethyl acetate (30 mL) and water (15 mL) and separated. The organic layer was washed with water (15 mL), then dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was suspended in methylene chloride (4 mL) and trifluoroacetic acid (7 mL) was added dropwise over one minute. After two hours, the reaction was concentrated; the residue was suspended in 20% MeCN - water (8 mL), sonicated, heated briefly to 50 °C, then stirred at 23 °C for 18 hours. The solid was collected by filtration, washed with ethyl acetate, then dried in a vacuum oven for 18 hours to yield the title compound (0.144 g, 85%).

[1003] Example 54: Synthesis of pyridine-2, 4-dicarboxylic acid bis-{[4-(4-carbamimidoyl- piperazin-l-yl)-phenyl] -amide} trifluoroacetate [1004] Synthesis of pyridine-2, 4-dicarbonyl dichloride: To a mixture of pyridine-2, 4- dicarboxylic acid (0.207 g, 1.24 mmol) and N,N-dimethyl formamide (0.118 g, 0.128 mL, 1.61 mmol) in anhydrous methylene chloride (4 mL) at 23 °C under N2 was added a solution of oxalyl chloride (0.456 g, 0.309 mL, 3.59 mmol) in methylene chloride (1 mL) dropwise over 20 minutes. After 30 minutes, additional oxalyl chloride (0.100 mL) was added, and the reaction was stirred for 90 minutes. Additional methylene chloride (1 mL) was added, and the soluble portion of the mixture was removed with a syringe and used without further purification.

[1005] Synthesis of pyridine-2, 4-dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide] trifluoroacetate: A mixture of 4-(4-amino-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (0.609 g, 2.20 mmol) and N, N-diisopropylethylamine (2.600 g, 3.60 mL, 20.0 mmol) in anhydrous methylene chloride (15 mL) was cooled to 0 °C. A solution of pyridine-2, 4-dicarbonyl dichloride (1.00 mmol) in methylene chloride (~4 mL) was added dropwise over five minutes. The cooling bath was removed after 10 minutes, and the reaction was stirred at 23 °C for 18 hours. The mixture was concentrated, and the residue was diluted with ethyl acetate (10 mL) and water (10 mL) and stirred for six days. The resulting solid was collected by filtration and briefly air dried to yield a light brown solid (0.454 g). This material was dissolved in methylene chloride (7 mL), and trifluoroacetic acid (10 mL) was added dropwise over ten minutes. After stirring at 23 °C for 18 hours, the reaction was concentrated. The residue was triturated with ether (2 x 20 mL), which was decanted. This material was purified by reverse-phase HPLC (5 to 45% MeCN - water (both with 0.1% trifluoroacetic acid) over 15 min.). The fractions containing the title compound were lyophilized to yield the desired product as a brown solid (0.0500 g, 6%). [1006] Synthesis of pyridine-2, 4-dicarboxylic acid bis-{[4-(4-carbamimidoyl-piperazin-l-yl)- phenyl] -amide} trifluoroacetate: To a solution of pyridine-2, 4-dicarboxylic acid bis-[(4-piperazin-l- yl-phenyl)-amide] trifluoroacetate (0.716 g, 0.660 mmol) and triethylamine (0.800 g, 1.14 mL, 7.92 mmol) in a mixture of methylene chloride (5 mL) and N,N-dimethyl formamide (5 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate (0.512 g, 1.65 mmol). The mixture was stirred at 23 °C for 72 hours. The reaction was partially concentrated to remove methylene chloride, then diluted with ethyl acetate (40 mL) and water (20 mL) and separated. The organic layer was washed with water (2 x 20 mL), then dried (Na SCL). filtered, and concentrated. Silica gel chromatography (5 to 100% ethyl acetate - methylene chloride), followed by concentration and drying under vacuum, yielded 0.440 g of the desired intermediate. This compound was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (10 mL) was added dropwise over 5 minutes. The mixture was stirred at 23 °C for 18 hours, then concentrated. The residue was purified by reverse-phase HPLC (15 to 65% MeCN - water (both with 0.1% trifluoroacetic acid)). The fractions containing the title compound were combined, concentrated, then lyophilized. Lyophillization was repeated using 1:1 1,4-dioxane : water with the same result. The residue was concentrated, then dried in a vacuum oven to yield the desired compound (0.082 g, 14%).

[1007] Example 55: Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-[(4-guanidinomethyl- phenyl)-amide] trifluoroacetate

[1008] Synthesis of (4-amino-benzyl)-carbamic acid tert-butyl ester: To a solution of 4- aminomethyl-phenylamine (2.170 g, 17.8 mmol) in ethyl acetate (30 mL) at 0 °C was added di-tert- butyl dicarbonate (4.080 g, 18.7 mmol) dropwise over 30 minutes. The ice bath was removed, and the suspension was stirred at 23 °C for 18 hours. The mixture was concentrated and dried under vacuum to yield the title compound as a white solid (5.30 g, quantitative).

[1009] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-[(4-aminomethyl-phenyl)-amide] trifluoroacetate: To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (0.400 g, 1.80 mmol) and N, N-diisopropylethylamine (0.774 g, 1.10 mL, 6.00 mmol) in anhydrous methylene chloride (6 mL) at 0 °C (cooled with an ice bath) under N2 was added a solution of pyrimidine-4, 6-dicarbonyl dichloride (0.600 mmol) in methylene chloride dropwise over two minutes. The ice bath was removed, and the reaction was stirred at 23 °C for 18 hours. The mixture was concentrated; the residue was diluted with ethyl acetate (35 mL) and water (20 mL) and stirred for 30 minutes. The resulting solid was collected by filtration and air dried, then dissolved in methylene chloride (4 mL), and treated with trifluoroacetic acid (10 mL). After stirring at 23 °C for 90 minutes, the reaction was concentrated. The residue was purified by reverse-phase HPLC to provide the title compound.

[1010] Synthesis of pyrimidine-4, 6-dicarboxylic acid bis-[(4-guanidinomethyl-phenyl)- amide] trifluoroacetate: To a solution of pyrimidine-4, 6-dicarboxylic acid bis-[(4-aminomethyl- phenyl)-amide] trifluoroacetate (0.550 mmol) and triethylamine (0.667 g, 0.952 mL, 6.60 mmol) in a mixture of methylene chloride (6 mL) and N,N-dimethyl formamide (4 mL) at 23 °C was added tert- butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate (0.426 g, 1.375 mmol). The mixture was stirred at 23 °C for 18 hours. The reaction was partially concentrated to remove methylene chloride, then diluted with ethyl acetate (50 mL) and water (20 mL) and separated. The organic layer was washed with water (2 x 20 mL), then dried (Na SCL). filtered, and concentrated. Silica gel chromatography (0 to 100% ethyl acetate - methylene chloride), followed by concentration and drying under vacuum, yielded 0.240 g of a white solid. This compound was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (7 mL) was added dropwise. The mixture was stirred at 23 °C for 18 hours, then concentrated. The residue was purified by reverse- phase HPLC (15 to 65% MeCN - water (both with 0.1% trifluoroacetic acid)). The fractions containing the title compound were combined, concentrated, then lyophilized from 1,4-dioxane - water to yield the title compound (0.110 g, 29%).

[1011] Example 56: Synthesis of pyridine-2, 4-dicarboxylic acid bis-{[4-(2-guanidino-ethyl)- phenyl] -amide} trifluoroacetate

[1012] Synthesis of pyridine-2, 4-dicarboxylic acid bis- { [4-(2-amino-ethyl)-phenyl] -amide} trifluoroacetate: To a mixture of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.179 g, 0.760 mmol) and N, N-diisopropylethylamine (0.383 g, 2.97 mmol) in anhydrous methylene chloride (4 mL) at 0 °C (cooled with an ice bath) under N2 was added a solution of pyridine-2, 4-dicarbonyl dichloride (0.067 g, 0.33 mmol) in methylene chloride was added dropwise over three minutes. The ice bath was removed, and the reaction was stirred at 23 °C for ten minutes. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water and separated. The organic layer was concentrated. Silica gel chromatography (0 to 100% ethyl acetate - methylene chloride), followed by concentration and drying under vacuum, yielded the desired intermediate as a solid. This material was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (7 mL) was added. After two hours at 23 °C, the mixture was concentrated. The residue was triturated with ether (20 mL), which was then decanted to yield the title compound.

[1013] Synthesis of pyridine-2, 4-dicarboxylic acid bis-{[4-(2-guanidino-ethyl)-phenyl]- amide} trifluoroacetate: To a solution of pyridine-2, 4-dicarboxylic acid bis-{[4-(2-amino-ethyl)- phenyl] -amide} trifluoroacetate (0.09 mmol) and triethylamine (0.091 g, 0.130 mL, 0.90 mmol) in a mixture of methylene chloride (2 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert- butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate (0.072 g, 2.30 mmol). The mixture was stirred at 23 °C for 18 hours. The reaction was concentrated, then partitioned between ethyl acetate (30 mL) and water (20 mL) and separated. The organic layer was concentrated. This compound was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (5 mL) was added dropwise. The mixture was stirred at 23 °C for 18 hours, then concentrated. The residue was triturated with ether (15 mL), which was then decanted, and the resulting material was lyophilized from MeCN - water to yield the title compound (0.055 g, 74%). [1014] Example 57: Synthesis of thiophene-2,5 -dicarboxylic acid bis-{[4-(2-guanidino- ethyl)-phenyl] -amide } trifluoroacetate

[1015] Synthesis of thiophene-2, 5-dicarbonyl dichloride: To a mixture of thiophene-2,5 - dicarboxylic acid (0.190 g, 1.10 mmol) and N,N-dimethyl formamide (0.072 g, 0.077 mL, 0.99 mmol) in anhydrous methylene chloride (4 mL) at 23 °C under N2 was added a solution of oxalyl chloride (0.421 g, 0.284 mL, 3.31 mmol) in methylene chloride (2 mL) dropwise over 60 minutes. The mixture was stirred for 30 minutes, then a portion of it was used immediately in the next reaction. [1016] Synthesis of thiophene-2,5 -dicarboxylic acid bis-{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate: To a mixture of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.270 g, 1.14 mmol) and N, N-diisopropylethylamine (0.350 g, 0.501 mL, 2.72 mmol) in anhydrous methylene chloride (5 mL) at 0 °C (cooled with an ice bath) under N2 was added a solution of thiophene-2, 5- dicarbonyl dichloride (0.114 g, 0.544 mmol) in methylene chloride was added dropwise over five minutes. The ice bath was removed after 10 minutes, and the reaction was stirred at 23 °C for three hours. The mixture was diluted with ethyl acetate (6 mL) and water (5 mL), stirred and sonicated briefly, then left standing for three hours. The solid was collected by filtration and air dried for 18 hours. This material was suspended in methylene chloride, and trifluoroacetic acid (5 mL) was added. After two hours at 23 °C, the mixture was concentrated. The residue was triturated with ether (20 mL), which was then decanted to yield the desired compound, which was used without further purification in the next reaction.

[1017] Synthesis of thiophene-2, 5 -dicarboxylic acid bis-{[4-(2-guanidino-ethyl)-phenyl]- amide} trifluoroacetate: To a solution of thiophene-2,5 -dicarboxylic acid bis-{[4-(2-amino-ethyl)- phenyl] -amide} trifluoroacetate (0.360 mmol) and NEt ₃ (0.291 g, 0.416 mL, 2.88 mmol) in a mixture of methylene chloride (7 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert-butyl N- [(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]c arbamate (0.258 g, 0.832 mmol). The mixture was stirred at 23 °C for 18 hours. The reaction was concentrated, then partitioned between ethyl acetate (30 mL) and water (20 mL) and separated. The organic layer was washed with water (2 x 20 mL), then dried (Na ₂ SO ₄ ). filtered, and concentrated. The material was suspended in methylene chloride (2 mL) and trifluoroacetic acid (4 mL) was added. The mixture was stirred at 23 °C for 18 hours, then concentrated. The residue was lyophilized from MeCN - water to yield the title compound (0.072 g, 28%) as an off-white solid.

[1018] Example 58: Synthesis of N,N'-bis-[4-(2-guanidino-ethyl)-phenyl]-terephthalamide trifluoroacetate

[1019] Synthesis of N,N'-bis-[4-(2-amino-ethyl)-phenyl]-terephthalamide trifluoroacetate: To a mixture of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.290 g, 1.23 mmol) and N, N-diisopropylethylamine (0.210 g, 0.300 mL, 1.62 mmol) in anhydrous methylene chloride (8 mL) at 23 °C was added terephthaloyl dichloride (0.120 g, 0.540 mmol). The reaction was stirred at 23 °C for 18 hours. The mixture was concentrated, then diluted with ethyl acetate (10 mL) and water (8 mL), and sonicated for five minutes. The resulting solid was collected by filtration, briefly air dried, then dissolved in methylene chloride (4 mL). Trifluoroacetic acid (6 mL) was added, and the reaction was stirred for four hours before concentrating. The residue was purified by reverse-phase HPLC (10 to 55% MeCN - water (both with 0.1% trifluoroacetic acid)). The fractions containing the title compound were combined, concentrated, then lyophilized from MeCN - water to yield the title compound.

[1020] Synthesis of N,N'-bis-[4-(2-guanidino-ethyl)-phenyl]-terephthalamide trifluoroacetate:

To a suspension of N,N'-bis-[4-(2-amino-ethyl)-phenyl]-terephthalamide trifluoroacetate (0.400 mmol) and N, N-diisopropylethylamine (0.464 g, 0.660 mL, 3.60 mmol) in a mixture of methylene chloride (5 mL) and N,N-dimethyl formamide (4 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbamate (0.285 g, 0.920 mmol). The mixture was stirred at 23 °C for 40 hours. The reaction was concentrated, then diluted with ethyl acetate (10 mL) and water (7 mL) and sonicated for four minutes. The solid was collected by filtration, then dissolved in trifluoroacetic acid (6 mL) and stirred at 23 °C for 4.5 hours. The mixture was concentrated; the residue was purified by reverse-phase HPLC (13 to 55% MeCN - water (both with 0.1% trifluoroacetic acid) over 15 minutes). The fractions containing the title compound were combined, concentrated, then lyophilized from 33% MeCN - water to yield the title compound (0.171 g, 60%) as a white solid.

[1021] Example 59: Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(4- carbamimidoyl-piperazin- 1 -yl)-phenyl] -amide } trifluoroacetate

[1022] Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide] trifluoroacetate: A mixture of lH-pyrazole-3,5-dicarboxylic acid (0.052 g, 0.371 mmol) and N, N- diisopropylethylamine (0.205 mL, 0.144 g, 1.11 mmol) in N,N-dimethyl formamide (2 mL) at 23 °C was stirred for five minutes, before adding l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5- bpyridinium 3-oxid hexafluorophosphate (0.255 g, 0.850 mmol) and stirring for 30 minutes. After adding 4-(4-amino-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (0.196 g, 0.850 mmol), the reaction was stirred at 23 °C for 18 hours. The reaction was diluted with ethyl acetate (20 mL) and water (15 mL) and left standing for 30 minutes. The resulting solid was collected by filtration and air dried to yield the desired intermediate as a grey solid. This material was suspended in methylene chloride (3 mL), and trifluoroacetic acid (5 mL) was then added. After stirring for two hours, the reaction was concentrated. The residue was triturated with ether (10 mL); the ether was then decanted to yield the title compound as a grey solid, which was used without further purification. [1023] Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(4-carbamimidoyl-piperazin- 1-yl) -phenyl] -amide} trifluoroacetate: To a suspension of lH-pyrazole-3,5-dicarboxylic acid bis-[(4- piperazin-l-yl-phenyl)-amide] trifluoroacetate (0.200 g, 0.285 mmol) and NEt3 (0.231 g, 0.330 mL, 2.29 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate (0.221 g, 0.713 mmol). The reaction was stirred at 23 °C for 18 hours and then heated at 52 °C for 18 hours. The mixture had become homogeneous. The heat was turned off and stirring was continued at 23 °C for 18 hours. The reaction was diluted with ethyl acetate (30 mL) and water (25 mL) and separated. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. Silica gel chromatography (0 to 100% (25% isopropanol - 75% methylene chloride); 100 to 0% methylene chloride), followed by concentration and drying under vacuum, yielded the desired intermediate. This compound was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (5 mL) was added. The mixture was stirred at 23 °C for three hours, then concentrated. The residue was triturated with ethyl acetate (10 mL), and the mixture was left standing for 18 hours. After a brief period on the centrifuge, the ethyl acetate was decanted, and the residue was lyophilized from 25% MeCN - water to yield the title compound (0.058 g, 26%).

[1024] Example 60: Synthesis of N,N'-bis-(4-guanidinomethyl-phenyl)-terephthalamide trifluoroacetate [1025] Synthesis of N,N'-bis-(4-aminomethyl-phenyl)-terephthalamide trifluoroacetate: To a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (0.273 g, 1.23 mmol) and N, N- diisopropylethylamine (0.202 g, 0.290 mL, 1.56 mmol) in methylene chloride (5 mL) at 23 °C was added terephthaloyl dichloride (0.113 g, 0.560 mmol). The suspension was stirred at 23 °C for 18 hours, then heated at 30 °C for an additional 18 hours. The mixture was concentrated, then diluted with ethyl acetate (20 mL) and water (15 mL), sonicated briefly, then stirred at 23 °C for 18 hours. The resulting solid was collected by filtration and air dried for 72 hours. This material was dissolved in methylene chloride (3 mL), and trifluoroacetic acid (5 mL) was added at 23 °C. After three hours, the reaction was concentrated, then twice triturated with ether (20 mL) to yield the title compound.

[1026] Synthesis of N,N'-bis-(4-guanidinomethyl-phenyl)-terephthalamide trifluoroacetate: To a solution of N,N'-bis-(4-aminomethyl-phenyl)-terephthalamide trifluoroacetate (0.260 mmol) and NEt3 (0.500 g, 5.00 mmol) in N,N-dimethyl formamide (2.4 mL) at 23 °C was added tert-butyl N- [(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]c arbamate (0.240 g, 0.770 mmol). The reaction was stirred at 23 °C for five minutes, then heated at 35 °C for 18 hours. The reaction was cooled to 23 °C, then partitioned between ethyl acetate (30 mL) and water (20 mL) and separated. The organic layer was washed with water (20 mL), then dried (Na ₂ SO ₄ ) and concentrated. The residue was suspended in methylene chloride (3 mL), then filtered. The solid and the mother liquor were separately treated with trifluoroacetic acid and stirred for 18 hours at 23 °C. The reactions were combined and purified by reverse-phase HPLC (3 to 50% MeCN - water (both with 0.1% trifluoroacetic acid) over 18 minutes). The fractions containing the title compound were combined, concentrated, then lyophilized from 20% MeCN - water to yield the desired compound (0.100 g, 56%). [1027] Example 61: Synthesis of N,N'-bis-[4-(4-carbamimidoyl-piperazin-l-yl)-phenyl]- terephthalamide trifluoroacetate

[1028] Synthesis of N,N'-bis-(4-piperazin-l-yl-phenyl)-terephthalamide trifluoroacetate: To a solution of 4-(4-amino-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (0.300 g, 1.08 mmol) and N, N-diisopropylethylamine (0.186 g, 0.270 mL, 1.44 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (3 mL) at 23 °C was added terephthaloyl dichloride (0.104 g, 0.516 mmol). The reaction was stirred at 23 °C for 18 hours; the suspension was then heated at 35 °C for an additional 18 hours. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL), then stirred for 60 minutes. The resulting solid was collected by filtration and air dried. This material was dissolved in methylene chloride (3 mL), and trifluoroacetic acid (4 mL) was added at 23 °C. After four hours, the reaction was concentrated, then twice triturated with ether (20 mL) to yield the title compound.

[1029] Synthesis of N,N'-bis-[4-(4-carbamimidoyl-piperazin-l-yl)-phenyl]-terepht halamide trifluoroacetate: To a suspension of N,N'-bis-(4-piperazin-l-yl-phenyl)-terephthalamide trifluoroacetate (0.450 mmol) and NEt3 (0.490 g, 4.85 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (3 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbamate (0.412g, 1.33 mmol). The suspension was heated at 45 °C for five days. The reaction was cooled to 23 °C, then partitioned between ethyl acetate (30 mL) and water (30 mL) and separated. The organic layer was washed with water (2 x 30 mL), then dried (Na ₂ SO ₄ ) and concentrated. The residue was suspended in ethyl acetate (5 mL), left standing for five minutes, then the solid was collected by filtration and air dried for 18 hours. This material was dissolved in methylene chloride (10 mL), treated with trifluoroacetic acid (19 mL), stirred for three hours at 23 °C, then concentrated. The residue was purified by reverse-phase HPLC (3 to 45% MeCN - water (both with 0.1% trifluoroacetic acid) over 20 minutes). The fractions containing the title compound were combined and lyophilized to yield the desired compound (0.108 g, 30%).

[1030] Example 62: Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(2-guanidino- ethyl)-phenyl] -amide } trifluoroacetate

[1031] Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(2-amino-ethyl)-phenyl]- amide} trifluoroacetate: To a mixture of lH-pyrazole-3,5-dicarboxylic acid (0.0620 g, 0.181 mmol) and N, N-diisopropylethylamine (0.164 g, 0.240 mL, 1.27 mmol) in N,N-dimethyl formamide (1.2 mL) was added (l-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyr idinium 3-oxide hexafluorophosphate (0.452 g, 1.19 mmol) and l-hydroxy-7-azabenzotriazole (0.124 g, 0.913 mmol). The reaction was stirred for 60 minutes before adding [2-(4-amino-phenyl)-ethyl]-carbamic acid tert- butyl ester (0.220 g, 0.93 mmol), stirring for an additional ten minutes, then heating at 39 °C for 18 hours. The mixture was diluted with water (10 mL), and a precipitate formed over 35 minutes. The solid was collected by filtration and air-dried briefly. This material was dissolved in methylene chloride (2 mL) and treated with trifluoroacetic acid (5 mL). After stirring for two hours, the reaction was concentrated. The residue was triturated with ether (15 mL) to yield the title compound.

[1032] Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(2-guanidino-ethyl)-phenyl]- amide} trifluoroacetate: To a suspension of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(2-amino- ethyl)-phenyl] -amide} trifluoroacetate (0.360 mmol) and NEt3 (0.350 g, 3.46 mmol) in methylene chloride (3 mL) at 23 °C was added N,N-dimethyl formamide (2 mL), followed by tert-butyl N-[(Z)- {[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbam ate (0.370 g, 1.19 mmol). The suspension was heated at 39 °C for 18 hours. The reaction was cooled to 23 °C, then concentrated. The residue was partitioned between ethyl acetate (30 mL) and a mixture of water (15 mL) and 10% citric acid (15 mL) and separated. The organic layer was washed with water (2 x 20 mL), then dried (Na ₂ SO ₄ ), concentrated, and dried under vacuum. The residue was dissolved in methylene chloride (2 mL), treated with trifluoroacetic acid (4 mL), then stirred at 23 °C for 18 hours. After concentration, the residue was purified by reverse-phase HPLC (5 to 47% MeCN - water (both with 0.1% trifluoroacetic acid) over 20 minutes). The fractions containing the title compound were combined, concentrated, and lyophilized to yield the title compound (0.177 g, 70%).

[1033] Example 63: Synthesis of l-methyl-lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(4- carbamimidoyl-piperazin- 1 -yl)-phenyl] -amide } trifluoroacetate

[1034] Synthesis of l-methyl-lH-pyrazole-3,5-dicarboxylic acid bis-[(4-piperazin-l-yl- phenyl)-amide] trifluoroacetate: To a solution of l-methyl-lH-pyrazole-3,5-dicarboxylic acid (0.098 g, 0.576 mmol) and N, N-diisopropylethylamine (0.193 g, 0.280 mL, 1.50 mmol) in N,N-dimethyl formamide (1 mL) at 23 °C was added l-bis(dimethylamino)methylene-lH-1,2,3-triazolo4,5- bpyridinium 3-oxid hexafluorophosphate (0.570 g, 1.50 mmol). After stirring for 45 minutes, 4-(4- amino-phenyl)-piperazine- 1 -carboxylic acid tert-butyl ester (0.335 g, 1.21 mmol) was added. The reaction was stirred at 23 °C for 45 minutes, then heated at 45 °C for 18 hours. The reaction was cooled to 23 °C and diluted with water (20 mL). Two hours later, the black solid was collected by fdtration, washed with ether (5 mL), and air dried to yield a brown solid. This material was suspended in methylene chloride (5 mL), and trifluoroacetic acid (7 mL) was then added. After stirring for three hours, the reaction was concentrated. The residue was triturated with ether (15 mL); the ether was then decanted. Isopropyl acetate (10 mL) was added to the residue, and the resulting solid was collected by filtration to yield the title compound as a soft solid, which was used without further purification

[1035] Synthesis of l-methyl-lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(4-carbamimidoyl- piperazin-l-yl)-phenyl] -amide} trifluoroacetate: To a solution of l-methyl-lH-pyrazole-3,5- dicarboxylic acid bis-[(4-piperazin-l-yl-phenyl)-amide] trifluoroacetate (0.480 mmol) and NEt3 (0.436 g, 0.635 mL, 4.32 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (3 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol- l-yl)methyl] carbamate (0.447 g, 1.44 mmol). After three hours, an additional portion (0.140 g, 0.452 mmol) of tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate was added, and the reaction was stirred at 23 °C for 18 hours. The mixture was concentrated, then partitioned between isopropyl acetate (30 mL) and 10% citric acid (15 mL) and separated. The organic layer was washed with water (15 mL), concentrated, and dried under vacuum. The residue was dissolved in methylene chloride (4 mL), treated with trifluoroacetic acid (6 mL), then stirred at 23 °C for 90 minutes before concentrating again. The residue was purified by reverse-phase HPLC (5 to 47% MeCN - water (both with 0.1% trifluoroacetic acid) over 18 minutes). The fractions containing the title compound were combined, concentrated, and lyophilized to yield the title compound (0.216 g, 56%).

[1036] Example 64: Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{ [4-( 1- carbamimidoyl-azetidin-3-yl)-phenyl]-amide} trifluoroacetate

[1037] Synthesis of lH-pyrazole-3, 5-dicarbonyl dichloride: To a suspension of lH-pyrazole- 3,5-dicarboxylic acid (0.240 g, 1.38 mmol) and N,N-dimethyl formamide (0.020 g, 0.022 mL, 0.276 mmol) in CHCI ₃ (6 mL) at 23 °C under N ₂ was added oxalyl chloride (0.490 g, 0.335 mL, 3.86 mmol) dropwise over 10 minutes. The reaction was heated at 37 °C for 60 minutes, then at 75 °C for 18 hours. The solution was cooled to 23 °C, then concentrated and dried under vacuum to yield a solid which was used without further purification.

[1038] Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-[(4-azetidin-3-yl-phenyl)-amide] trifluoroacetate: To a solution of 3-(4-amino-phenyl)-azetidine-l-carboxylic acid tert-butyl ester (0.230 g, 0.930 mmol) and N, N-diisopropylethylamine (0.225 g, 1.74 mmol) in CHCI ₃ (5 mL) at 23 °C was added a solution of lH-pyrazole-3, 5-dicarbonyl dichloride (0.390 mmol) in CHCI ₃ (7 mL) dropwise over five minutes. After 15 minutes, additional portions of 3-(4-amino-phenyl)-azetidine-l- carboxylic acid tert-butyl ester C0.045 g) and N, N-diisopropylethylamine (0.200 mL) was added, and the reaction continued to stir at 23 °C. The mixture was concentrated, then diluted with isopropyl acetate (5 mL) and 10% citric acid solution (5 mL). The precipitated solid was collected by filtration, rinsed with ether (5 mL), then air dried for 18 hours. Additional solids were present in the mother liquor; this was diluted with ether (5 mL), and a second crop of crystals was collected by filtration and washing with ether (5 mL). The two crops were combined and suspended in methylene chloride (3 mL), and trifluoroacetic acid (4 mL) was then added. After stirring at 23 °C for 18 hours, the reaction was concentrated. The residue was triturated with ether (2 x 15 mL) to yield the desired compound as a soft solid, which was used without further purification. [1039] Synthesis of lH-pyrazole-3,5-dicarboxylic acid bis-{[4-(l-carbamimidoyl-azetidin-3- yl)-phenyl] -amide} trifluoroacetate: To a suspension of lH-pyrazole-3,5-dicarboxylic acid bis-[(4- azetidin-3-yl-phenyl)-amide] trifluoroacetate (0.300 mmol) and NEt3 (0.600 g, 6.00 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert- butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl ]carbamate (0.450 g, 1.45 mmol). The reaction was stirred at 23 °C for 18 hours. The mixture was concentrated, then partitioned between isopropyl acetate (30 mL) and 10% citric acid (10 mL) and separated. The organic layer was washed with water (20 mL), dried (Na ₂ SO ₄ ). concentrated, and dried under vacuum. The residue was dissolved in methylene chloride (3 mL), treated with trifluoroacetic acid (4 mL), then stirred at 23 °C for 18 hours. After concentrating, the residue was purified by reverse-phase HPLC (5 to 47% MeCN - water (both with 0.1% trifluoroacetic acid) over 18 minutes). The fractions containing the title compound were combined, concentrated, and lyophilized to yield the desired compound (0.102 g, 47%).

[1040] Example 65: Synthesis of N,N'-bis-[4-(l-carbamimidoyl-azetidin-3-yl)-phenyl]- terephthalamide trifluoroacetate

[1041] Synthesis of N,N'-bis-(4-azetidin-3-yl-phenyl)-terephthalamide trifluoroacetate: To a solution of 3 -(4-amino-phenyl)-azetidine-l -carboxylic acid tert-butyl ester (0.225 g, 0.907 mmol) and N, N-diisopropylethylamine (0.156 g, 1.21 mmol) in CHCI ₃ (7 mL) at 23 °C was added terephthaloyl dichloride (0.087 g, 0.432 mmol). Over 30 minutes, the suspension became homogenous, and N,N- dimethyl formamide (2 mL) was added to improve solubility. The reaction was stirred at 23 °C for 18 hours. The mixture was diluted with water (30 mL) and sonicated for one minute. The solid was collected by filtration, then suspended in methylene chloride (2 mL). Trifluoroacetic acid (4 mL) was added, and the reaction was stirred at 23 °C for three hours then concentrated. The residue was triturated with ether (15 mL) to yield the desired compound, which was used without further purification.

[1042] Synthesis of N,N'-bis-[4-(l-carbamimidoyl-azetidin-3-yl)-phenyl]-terephth alamide trifluoroacetate: To a suspension of N,N'-bis-(4-azetidin-3-yl-phenyl)-terephthalamide trifluoroacetate (0.360 mmol) and NEt3 (0.290 g, 0.420 mL, 2.88 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbamate (0.335 g, 1.08 mmol). The reaction was stirred at 23 °C for 18 hours, then concentrated. The residue was partitioned between isopropyl acetate (25 mL) and 10% citric acid (15 mL) and separated. The organic layer was washed with water (25 mL), and a precipitate began to form in the biphasic mixture. The combined layers were concentrated, then dissolved in methylene chloride (4 mL), treated with trifluoroacetic acid (5 mL), and stirred at 23 °C for 18 hours. The reaction was concentrated. The residue was purified by reverse- phase HPLC (5 to 49% MeCN - water (both with 0.1% trifluoroacetic acid)). The fractions containing the title compound were combined, concentrated, and lyophilized to yield the title compound (0.098 g, 37%). [1043] Example 66: Synthesis of N,N'-bis-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-

7 -yl)-terephthalamide trifluoroacetate

[1044] Synthesis of N,N'-bis-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-terephthalami de trifluoroacetate: To a solution of 7-amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (0.317 g, 1.28 mmol) and N, N-diisopropylethylamine (0.207 g, 0.300 mL, 1.61 mmol) in CHCI ₃ (4 mL) at 23 °C was added terephthaloyl dichloride (0.120 g, 0.595 mmol). The reaction was stirred at 23 °C for 18 hours. The mixture was concentrated, then diluted with ethyl acetate (15 mL) and 10% citric acid solution (5 mL) and separated. The organic layer was washed with water (10 mL), then dried (Na ₂ SO ₄ ) and concentrated. The resulting solid was dissolved in methylene chloride (4 mL), treated with trifluoroacetic acid (4 mL), and stirred at 23 °C for 18 hours. The mixture was concentrated. The residue was triturated with ether (2 x 20 mL) to yield the desired compound, which was used without further purification.

[1045] Synthesis of N,N'-bis-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-y l)- terephthalamide trifluoroacetate: To a suspension of N,N'-bis-( 1,2,3, 4-tetrahydro-isoquinolin-7-yl)- terephthalamide trifluoroacetate (0.500 mmol) and NEt3 (0.455 g, 0.650 mL, 4.50 mmol) in a mixture of methylene chloride (3 mL) and N,N-dimethyl formamide (2 mL) at 23 °C was added tert-butyl N- [(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]c arbamate (0.372 g, 1.20 mmol). The reaction was stirred at 23 °C for 18 hours. The mixture was then heated at 37 °C for 18 hours and then cooled to 23 °C and concentrated. The residue was partitioned between isopropyl acetate (25 mL) and 10% citric acid (20 mL) and separated. The organic layer was washed with water (25 mL), dried (Na ₂ SO ₄ ), concentrated, and dried under vacuum to yield the desired intermediate. This material was dissolved in methylene chloride (4 mL), treated with trifluoroacetic acid (4 mL), and stirred at 23 °C for two hours. The reaction was concentrated. The residue was purified by reverse-phase HPLC (5 to 51% MeCN - water (both with 0.1% trifluoroacetic acid)). The fractions containing the title compound were combined, concentrated, and lyophilized to yield the title compound (0.105 g, 28%).

[1046] Example 67: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide

[1047] Synthesis of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester. A mixture of 4-bromo-phenylamine (3.00 g, 17.44 mmol), 4-(4, 4,5,5 -tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyl ic acid tert-butyl ester (5.93 g, 19.16 mmol), and [1,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (142 mg, 0.18 mmol) in 1,4-dioxane (40 mL) and 2M K ₂ CO ₃ (26 mL) was degassed by bubbling nitrogen through the mixture of 10 minutes. The reaction was heated at 80 °C for 18 hours. The reaction was cooled, treated with ethyl acetate (200 mL), then was washed with water (75 mL), and brine (30 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to provide 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (4.09 g, 86%) as a beige solid. [1048] Synthesis of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicy clo

[2.2.2]octane-l-carboxylic acid methyl ester. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (3.18 g, 14.91 mmol), (4-amino-benzyl)-carbamic acid tert-butyl ester (3.48 g, 15.66 mmol), and triethylamine (3.52 g, 4.75 mL, 29.73 mmol) in N,N-dimethyl formamide (40 mL) was added (l-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyr idinium 3-oxide hexafluorophosphate (8.47 g, 22.34 mmol). The reaction was treated with additional bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (1.59 g, 7.48 mmol), (4-amino-benzyl)- carbamic acid tert-butyl ester (1.74 g, 7.83 mmol), triethylamine (1.76 g, 2.38 mL, 14.87 mmol), (1- [Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridi nium 3-oxide hexafluorophosphate (4.24 g, 11.17 mmol), and N,N-dimethyl formamide (10 mL). The reaction was stirred for 16 hours, then was poured into water (750 mL). The mixture was treated with ethyl acetate (150 mL), then was shaken. The mixture was filtered, then the solid was washed with isopropanol (50 mL), and hexanes (50 mL), to give 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicy clo[2.2.2]octane-l- carboxylic acid methyl ester (4.38 g, 47%) as a white solid. The water/ethyl acetate filtrate was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined ethyl acetate layers were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), and dried (Na ₂ SO ₄ ). The isopropanol/hexanes filtrate was dried (Na ₂ SO ₄ ). The ethyl acetate and isopropanol/hexanes were combined, and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to provide 4-[4-(tert-butoxycarbonylamino- methyl)-phenylcarbamoyl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (1.31 g, 14%) as a white solid. [1049] Synthesis of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicy clo [2.2.2]octane-l-carboxylic acid. To a mixture of 4-[4-(tert-butoxycarbonylamino-methyl)-phenyl carbamoyl]-bicyclo[2.2.2]octane-l-carboxybc acid methyl ester (5.69 g, 13.66 mmol) in 1,4-dioxane (63 mL) was added a ION aqueous NaOH solution (14 mL). The reaction was heated at 90 °C for 18 hours, then cooled and concentrated. The residue was treated with water (150 mL), then was adjusted to pH=l using IN HC1. The mixture was allowed to stand for 5 minutes, then was filtered. The solid was washed with water (50 mL), then was dried under high vacuum, to provide 4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[2.2.2]o ctane-l-carboxylic acid (5.63 g, >100%) as a white solid, that was used without further purification.

[1050] Synthesis of 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoy l]- bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester. To a mixture of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- bicyclo[2.2.2]octane-l-carboxylic acid ( (5.62 g, 13.96 mmol), 4-(4-amino-phenyl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (4.02 g, 14.66 mmol), and triethylamine (3.30 g, 4.44 mL, 27.85 mmol) in N,N-dimethyl formamide (37 mL) was added (l-[bis(dimethylamino)methylene]-lH- 1,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (7.93 g, 20.91 mmol). The reaction was stirred for 18 hours, then was poured into water (590 mL) and ethyl acetate (150 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (50 mL), and hexanes (50 mL), then was dried under high vacuum, to provide 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 - carboxylic acid tert-butyl ester (5.10 g, 56%) as an off-white solid.

[1051] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxybc acid (4-aminomethyl-phenyl)- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[4-(tert- butoxycarbonylamino-methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane- 1 -carbonyl } -amino)-phenyl] - 3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (5.10 g, 7.74 mmol) in CH ₂ CI ₂ (39 mL) was added trifluoroacetic acid (20 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (70 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (50 mL), to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid (4-aminomethyl-phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis-trifluoroacetic acid salt (7.25 g, >100%) as a pale yellow solid, that was used without further purification. [1052] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)-

{ [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)phenyl] - 1 ,2, 3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-phenyl)- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 trifluoroacetic acid (7.25 g, 10.56 mmol) in N,N-dimethyl formamide (53 mL) was added triethylamine (7.27 g, 9.97 mL, 70.93 mmol). The reaction was stirred for 15 minutes, then was treated with N,N’-bis-Boc-l-guanylpyrazole (10.19 g, 32.71 mmol). The reaction was stirred for 15 minutes, then was heated at 35 °C for 20 hours. The reaction was then cooled and treated with water (750 mL). The mixture was extracted with ethyl acetate (4 x 100 mL). The combined organic extracts were washed with water (2 x 40 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to provide tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)phenyl] - 1 ,2, 3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate (4.15 g, 42%) as a white solid.

[1053] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide. To a mixture of tert- butylN-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-({[ (lE)-{[(tert-butoxy)carbonyl]amino}

({ [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)phenyl] carbamoyl } bicyclo [2.2.2] octane - 1 - amido)phenyl]- 1,2, 3, 6-tetrahydropyridin-l-yl})methylidene] carbamate (4.15 g, 4.40 mmol) in CH ₂ CI ₂ (22 mL) was added trifluoroacetic acid (22 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (50 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (30 mL), and isopropanol (30 mL). The solid was treated with ethanol (100 mL), then the mixture was heated to boiling, and was filtered hot. The solid was washed with ethanol (20 mL), and dried under high vacuum, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis-trifluoroacetic acid salt (2.40 g, 71%) as a white solid. The ethanol filtrate was concentrated to ~50 mL, then was heated to boiling, and was filtered hot. The solid was washed with hexanes (20 mL), to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3, 6-tetrahydro-pyridin-4-yl)- phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis-trifluoroacetic acid salt (246 mg, 7%) as a white solid. The filtrate was allowed to stand at 20 °C for 16 hours, then was filtered, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3, 6-tetrahydro-pyridin-4-yl)- phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis-trifluoroacetic acid salt (118 mg, 3%) as a white solid. MS: 543 M+H+; ¾ NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.24 (s, 2 H) 7.98 (t, J=5.57 Hz, 1 H) 7.63 (dd, J=8.50, 6.15 Hz, 5 H) 7.49 (br. s., 4 H) 7.39 (d, =8.79 Hz, 2 H) 7.20 (d, J=8.79 Hz, 2 H) 6.14 (br. s., 1 H) 4.28 (d, J=5.86 Hz, 2 H) 4.05 (br. s., 2 H) 3.60 (t, J=5.27 Hz, 2 H) 2.55 (br. s., 2 H) 1.83 (s, 12 H).

[1054] Example 68: Synthesis of bis-HCl bis-hydrate salt of bicyclo[2.2.2]octane-l,4- dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -amide (4- guanidinomethyl-phenyl)-amide hydrochloride salt

[1055] Synthesis of the bis-HCl bis-hydrate salt of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -amide (4-guanidinomethyl-phenyl)- amide hydrochloride salt: To methanol (27 mL) was added dropwise concentrated HC1 (3 mL), to make an HC1 in methanol solution. To a warmed mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-( 1 -carbamimidoyl- 1 ,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidinomethyl- phenyl) -amide. 2 trifluoroacetic acid (2.10 g, 2.73 mmol) in methanol (40 mL) was added the HC1 in methanol solution (10 mL). The mixture was allowed to stand at 20°C for 30 minutes, then was concentrated. The residue was treated with methanol (40 mL), was warmed, and to this was added the HC1 in methanol solution (10 mL). The mixture was allowed to stand at 20 °C for 30 minutes, then was concentrated. The residue was treated with methanol (40 mL), was warmed, and to this was added the HC1 in methanol solution (10 mL). The mixture was allowed to stand at 20 °C for 30 minutes, then was concentrated. The residue was lyophilized, to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -amide (4- guanidinomethyl-phenyl)-amide. 2 hydrochloric acid 2. LLO (1.60 g, 99%) as a white solid. MS: 543 M+H+; ‘H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.27 (s, 2 H) 8.00 (s, 1 H) 7.64 (dd, J=8.50, 6.15 Hz, 4 H) 7.50 (br. s., 3 H) 7.39 (d, J=8.21 Hz, 2 H) 7.21 (d, J=8.21 Hz, 2 H) 6.14 (br. s., 1 H) 4.29 (d, J=5.86 Hz, 2 H) 4.05 (br. s., 2 H) 3.60 (br. s., 2 H) 2.55 (br. s., 2 H) 1.84 (s, 12 H). Microanalysis: C: Expected 55.30%, Found 55.88%; H: Expected 6.81%, Found 6.34%; N: Expected 17.20%; Found 17.19%.

[1056] Example 69: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide [4-(2-guanidino-ethyl)- phenyl]-amide [1057] Synthesis of 4-(4-bromo-phenylcarbamoyl)-bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (1.00 g, 4.71 mmol), 4-bromoaniline (894 mg, 5.18 mmol), and triethylamine (894 mg, 1208 μL, 7.54 mmol) in N,N-dimethylformamide (14 mL) was added l-[Bis(dimethylamino)methylene]-lH-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (2679 mg, 7.07 mmol). The reaction was stirred for 3 days, then was diluted with water (200 mL). The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (2 x 30 mL), IN HC1 (30 mL), and saturated aqueous NaHCO ₃ (30 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give 4-(4-bromo- phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (1.51 g) as a white solid.

[1058] Synthesis of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxyli c acid. To a mixture of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxyli c acid methyl ester (1.51 g, 4.12 mmol) in 1,4-dioxane (19 mL) was added a 10N aqueous NaOH solution (4.1 mL). The reaction was heated at 90 °C for 18 hours, then cooled to 23 °C and concentrated. The residue was treated with water (50 mL), then was adjusted to pHl using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (15 mL), IN HC1 (15 mL), and water (15 mL), then was dried under high vacuum, to give 4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.2]octane-l-carboxylic acid (1.26 g) as a white solid. [1059] Synthesis of [2-(4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-c arbonyl]- amino}-phenyl)-ethyl]-carbamic acid tert-butyl ester. To a mixture of 4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.2]octane-l-carboxylic acid (630 mg, 1.79 mmol), [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (468 mg, 1.98 mmol), and triethylamine (421 mg, 571 μL, 3.55 mmol) in dimethylformamide (5.3 mL) was added l-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, (1013 mg, 2.69 mmol). The reaction was stirred for 16 hours, then was diluted with water (75 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (20-60% ethyl acetate: hexanes), to give [2-(4-{[4-(4-bromo- phenylcarbamoyl)-bicyclo [2.2.2] octane - 1 -carbonyl] -amino } -phenyl) -ethyl] -carbamic acid tert-butyl ester (696 mg) as a white solid.

[1060] Synthesis of 4-[4-({4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamo yl]- bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester. A mixture of [2-(4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-c arbonyl]- amino}-phenyl)-ethyl]-carbamic acid tert-butyl ester (694 mg, 1.22 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyb c acid tert-butyl ester (446 mg, 1.44 mmol), Pd(OAc)2 (14 mg, 0.062 mmol), and S-Phos (53 mg, 0.14 mmol) in 1,4-dioxane (9.3 mL) and 2M K ₂ CO ₃ (2.9 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 °C for 16 hours. The reaction was then cooled and diluted with ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-({4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamo yl]- bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester (480 mg) as a pale yellow solid.

[1061] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[4-(2-tert- butoxycarbonylamino-ethyl)-phenylcarbamoyl] -bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] - 3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (480 mg, 0.71 mmol) in CH ₂ CI ₂ (3.7 mL) was added trifluoroacetic acid (1.9 mL). The reaction was stirred for 3 hours, then was concentrated. The residue was treated with diethyl ether (25 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid [4-(2-amino-ethyl)-phenyl]-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- amide as the bis-trifluoroacetic acid salt (512 mg) as a yellow solid, that was used without further purification. [1062] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-(2- { [( 1 E)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 -amido)phenyl] - 1 ,2, 3 ,6-tetrahydropyridin- 1 -yl } )methylidene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]- amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 TFA (512 mg, 0.73 mmol) in dimethylformamide (5 mL) was added triethylamine (504 mg, 692 μL, 4.92 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (708 mg, 2.27 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was then cooled, diltued with water (75 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-(2-{[(lE )-{[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl } bicyclo[2.2.2]octane-l-amido)phenyl]-1,2,3,6-tetrahydropyrid in-l-yl})methylidene]carbamate (427 mg) as a white solid.

[1063] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide [4-(2-guanidino-ethyl)-phenyl]-amide. To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[4-(2-{[(lE )-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl ]amino}ethyl)phenyl] carbamoyl}bicyclo[2.2.2]octane-l-amido)phenyl]-1,2,3,6-tetra hydropyridin-l-yl}) methylidene]carbamate (427 mg, 0.45 mmol) in CH ₂ CI2 (4.5 mL) was added trifluoroacetic acid (4.5 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -amide [4-(2-guanidino- ethyl)-phenyl]-amide as the bis-trifluoroacetic acid sat (117 mg) as a white solid. MS: 557 M+H+; ¹ H NMR (300MHz, dmso) d = 9.24 (s, 1H), 9.15 (s, 1H), 7.64 (d, J=8.8 Hz, 3H), 7.56 (d, J=8.8 Hz, 2H), 7.52 - 7.34 (m, 7H), 7.15 (d, J=8.2 Hz, 2H), 6.14 (br. s., 1H), 4.05 (br. s., 2H), 3.31 (d, J=6.4 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.54 (br. s., 2H), 1.83 (s, 12H).

[1064] Example 70: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidino-phenyl)-amide.

[1065] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l -Synthesis of (4-{[4-(4- bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carbonyl]-amin o}-phenyl)-carbamic acid tert-butyl ester. To a mixture of 4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carboxyli c acid (630 mg, 1.79 mmol), (4-amino-phenyl)-carbamic acid tert-butyl ester (412 mg, 1.98 mmol), and triethylamine (421 mg, 571 μL, 3.55 mmol) in N,N-dimethylformamide (5.3 mL) was added 1- [Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate, (1013 mg, 2.69 mmol). The reaction was stirred for 16 hours, then was diluted with water (75 mL) and ethyl acetate (50 mL). The mixture was shaken and then filtered. The solid was washed with isopropanol (20 mL) and hexanes (20 mL), to give (4-{[4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.2]octane-l-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (450 mg) as a white solid.

[1066] Synthesis of 4-(4-{[4-(4-tert-butoxycarbonylamino-phenylcarbamoyl)- bicyclo [2.2.2]octane- 1 -carbonyl] -amino } -phenyl)-3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester. A mixture of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]- amino }-phenyl)-carbamic acid tert-butyl ester (450 mg, 0.83 mmol), 4-(4, 4,5,5 -tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyl ic acid tert-butyl ester (303 mg, 0.98 mmol), Pd(OAc)2 (10 mg, 0.042 mmol), and 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl, (36 mg, 0.095 mmol) in 1,4-dioxane (6.3 mL) and 2M K ₂ CO ₃ (2 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 °C for 16 hours. The reaction was then cooled and diluted with ethyl acetate (70 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give 4-(4-{[4- (4-tert-butoxycarbonylamino-phenylcarbamoyl)-bicyclo[2.2.2]o ctane-l-carbonyl]-amino}-phenyl)- 3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (413 mg) as a grey solid.

[1067] Synthesis of bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-amino-phenyl)-amide [4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-(4-{[4-(4-tert- butoxycarbonylamino-phenylcarbamoyl)-bicyclo [2.2.2] octane- 1 -carbonyl] -amino } -phenyl)-3 ,6- dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester (411 mg, 0.64 mmol) in CH ₂ CI ₂ (3.3 mL) was added trifluoroacetic acid (1.7 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (25 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (15 mL), to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid (4-amino-phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis-trifluoroacetic acid salt (476 mg) as a grey solid, that was used without further purification.

[1068] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}[4-(4-{4-[(4-{[(lZ)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] amino }phenyl)carbamoyl] bicyclo[2.2.2]octane-l-amido}phenyl)-1,2,3,6-tetrahydropyrid in-l-yl]methylidene]carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-amino-phenyl)-amide [4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl] -amide. 2 TFA (476 mg, 0.71 mmol) in N,N-dimethylformamide (4.9 mL) was added triethylamine (489 mg, 671 μL, 4.77 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (686 mg, 2.20 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (75 mL), then was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 25 mL), 10% aqueous citric acid (25 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}[4-(4-{4-[(4-{[(lZ)-{[ (tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } phenyl)carbamoyl] bicyclo [2.2.2] octane- 1 -amido } phenyl)- 1,2,3,6-tetrahydropyridin-l-yl]methylidene]carbamate (241 mg) as an off-white solid.

[1069] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidino-phenyl)-amide. To a mixture of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}[4-(4-{4-[(4-{[(lZ)-{[ (tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino} phenyl)carbamoyl]bicyclo [2.2.2]octane-l-amido}phenyl)-1,2,3,6-tetrahydropyridin-l-yl ]methylidene]carbamate (241 mg, 0.26 mmol) in CH ₂ CI2 (2.6 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (4-guanidino-phenyl)-amide as the bis- trifluoroacetic acid salt (113 mg) as a white solid. MS: 529 M+H+; ¹ HN NMR (300MHz, dm so) δ = 9.65 (s, 1H), 9.32 (s, 1H), 9.23 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.48 - 7.31 (m, 10H), 7.14 (d, J=8.8 Hz, 2H), 6.14 (br. s., 1H), 4.05 (br. s., 2H), 3.70 - 3.58 (m, 2H), 2.55 (br. s., 2H), 1.84 (s, 12H).

[1070] Example 71: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2- guanidino-ethyl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide.

[1071] Synthesis of 4-chlorocarbonyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid monomethyl ester (2.00 g, 9.40 mmol) in CHCI ₃ (50 mL) and N,N-dimethylformamide (20 drops) was added oxalyl chloride (1918 mg, 1289 μL, 15.05 mmol). The reaction was stirred for 4 hours, then was concentrated, to give 4- chlorocarbonyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, that was used without further purification.

[1072] Synthesis of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester. To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (1.81 g, 8.15 mmol), and N,N-diisopropylethylamine (1644 mg, 2214 μL, 12.80 mmol) in CHCI ₃ (2 mL) was added dropwise a mixture of 4-chlorocarbonyl-bicyclo[2.2.2]octane-l- carboxylic acid methyl ester in CHCI ₃ (22 mL). The reaction was stirred for 3 days, then was concentrated. The residue was treated with ethyl acetate (50 mL) and water (75 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (30 mL) and hexanes (30 mL), to give 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicy clo[2.2.2]octane-l-carboxylic acid methyl ester (1.91 g) as a white solid.

[1073] Synthesis of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- bicyclo[2.2.2]octane-l-carboxylic acid. To a mixture of 4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-bicyclo[2.2.2]octane-l-carboxybc acid methyl ester (1.90 g, 4.56 mmol) in 1,4- dioxane (21 mL) was added a 10N aqueous NaOH solution (4.6 mL). The reaction was heated at 90 °C for 18 hours, thn cooled and concentrated. The residue was treated with water (50 mL), then was adjusted to pH 1 using IN HC1. The mixture was filtered, then the solid was washed with water (25 mL), and dried under high vacuum, to give 4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-bicyclo[2.2.2]octane-l-carboxylic acid (1.72 g) as a white solid.

[1074] Synthesis of {2-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamo yl]- bicyclo[2.2.2]octane-l-carbonyl}-amino)-phenyl]-ethyl}-carba mic acid tert-butyl ester. To a mixture of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicy clo[2.2.2]octane-l-carboxylic acid (430 mg, 1.07 mmol), [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (270 mg, 1.14 mmol), and triethylamine (243 mg, 329 μL, 2.06 mmol) in N,N-dimethylformamide (3 mL) was added l-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate (585 mg, 1.55 mmol). The reaction was stirred for 16 hours, then was diluted with water (45 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0- 100% ethyl acetate: hexanes), to give {2-[4-({4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl] -bicyclo [2.2.2] octane - 1 -carbonyl } -amino) -phenyl] -ethyl } -carbamic acid tert-butyl ester (495 mg) as a pale yellow solid.

[1075] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]- amide (4-aminomethyl-phenyl)-amide. To a mixture of {2-[4-({4-[4-(tert-butoxycarbonylamino- methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane - 1 -carbonyl } -amino) -phenyl] -ethyl } -carbamic acid tert-butyl ester (490 mg, 0.79 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid [4-(2-amino-ethyl)-phenyl] -amide (4-aminomethyl-phenyl)-amide as the bis- tridluoroacetic acid salt (377 mg) as a beige solid.

[1076] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl}bicyclo[2.2.2]octane- l-amido)phenyl]methyl}amino)methylidene]carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]-amide (4-amino methyl -phenyl)-amide. 2 TFA (372 mg, 0.57 mmol) in dimethylformamide (5.4 mL) was added triethylamine (393 mg, 539 μL, 3.85 mmol). The reaction was stirred for 15 minutes, then N,N’-bis- Boc-guanylpyrazole (550 mg, 1.77 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was cooled and diluted with water (75 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N- [( 1Z)- { [(tert-butoxy)carbonyl] amino } ( { [4-(4- { [4-(2- { [( 1 E)- { [(tert-butoxy)carbonyl]amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl } bicyclo [2.2.2] octane - 1 - amido)phenyl]methyl}amino)methylidene]carbamate (247 mg) as a white solid.

[1077] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-guanidino-ethyl)- phenyl]-amide (4-guanidinomethyl-phenyl)-amide. To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( { [4-(4- { [4-(2- { [( 1 E)- { [(tert-butoxy)carbonyl]amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } ethyl)phenyl] carbamoyl } bicyclo [2.2.2] octane - 1 - amido)phenyl]methyl}amino)methylidene]carbamate (247 mg, 0.27 mmol) in CH ₂ CI ₂ (2.7 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-guanidino-ethyl)-phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis- trifluoroacetic acid salt (81 mg) as a white solid. MS: 505 M+H+; 'H NMR (300MHz, dmso) δ = 9.22 (s, 1H), 9.14 (s, 1H), 7.91 (t, J=6.2 Hz, 1H), 7.59 (dd, 7=8.8, 17.6 Hz, 4H), 7.48 (br. s., 1H), 7.18 (dd, J=8.8, 14.1 Hz, 8H), 4.28 (d, J= 5.9 Hz, 2H), 3.31 (d, J=5.3 Hz, 3H), 2.71 (t, 7=7.0 Hz, 2H), 1.83 (s, 12H).

[1078] Example 72: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-guanidino- ethoxy) -phenyl] -amide (4-guanidinomethyl-phenyl)-amide .

[1079] Synthesis of {2-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamo yl]- bicyclo[2.2.2]octane-l-carbonyl}-amino)-phenoxy]-ethyl}-carb amic acid tert-butyl ester. To a mixture of 4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicy clo[2.2.2]octane-l- carboxylic acid (430 mg, 1.03 mmol), [2-(4-amino-phenoxy)-ethyl]-carbamic acid tert-butyl ester (288 mg, 1.14. mmol), and triethylamine (243 mg, 329 μL, 2.06 mmol) in dimethylformamide (3 mL) was added l-[Bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate (585 mg, 1.55 mmol). The reaction was stirred for 16 hours, then was treated with water (45 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0- 100% ethyl acetate: hexanes), to give {2-[4-({4-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-bicyclo[2.2.2]octane-l-carbonyl}-amino)-phe noxy]-ethyl}-carbamic acid tert- butyl ester (505 mg) as a pale purple solid.

[1080] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxybc acid [4-(2-amino-ethoxy)-phenyl]- amide (4-aminomethyl-phenyl)-amide. To a mixture of {2-[4-({4-[4-(tert-butoxycarbonylamino- methyl)-phenylcarbamoyl] -bicyclo [2.2.2] octane - 1 -carbonyl } -amino) -phenoxy] -ethyl } -carbamic acid tert-butyl ester (500 mg, 0.77 mmol) in CH ₂ CI ₂ (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated, for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[2.2.2]octane-l,4- dicarboxylic acid [4-(2-amino-ethoxy)-phenyl]-amide (4-aminomethyl-phenyl)-amide as the bis- trifluoroacetic acid salt (480 mg) as a grey solid.

[1081] Synthesis of tert-butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(lZ)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethoxy )phenyl] carbamoyl}bicyclo[2.2.2]octane- l-amido)phenyl]methyl}amino)methylidene]carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-amino-ethoxy)-phenyl]-amide (4- aminomethyl-phenyl) -amide. 2 TFA (475 mg, 0.72 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (493 mg, 676 μL, 4.83 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (690 mg, 2.22 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (75 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert- butyl N-[(lZ)-{[(tert-butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(lZ)- {[(tert-butoxy)carbonyl]amino} ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } ethoxy )phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 - amido)phenyl]methyl}amino)methylidene]carbamate (254 mg) as a beige solid.

[1082] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-guanidino-ethoxy)- phenyl]-amide (4-guanidinomethyl-phenyl)-amide. To a mixture of tert-butyl N-[(lZ)-{[(tert- butoxy)carbonyl] amino } ( { [4-(4- { [4-(2- { [( 1Z)- { [(tert-butoxy)carbonyl] amino } ( { [(tert- butoxy)carbonyl] imino } )methyl] amino } ethoxy )phenyl] carbamoyl } bicyclo [2.2.2] octane- 1 - amido)phenyl]methyl}amino)methylidene]carbamate (254 mg, 0.28 mmol) in CH ₂ CI ₂ (2.8 mL) was added trifluoroacetic acid (2.8 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(2-guanidino-ethoxy)-phenyl] -amide (4-guanidinomethyl-phenyl)-amide as the bis- trifluoroacetic acid salt (30 mg) as a white solid. MS: 521 M+H+; 'H NMR (300MHz, dmso) δ = 9.24 (s, 1H), 9.09 (s, 1H), 8.02 (t, J= 5.9 Hz, 1H), 7.85 - 7.70 (m, 1H), 7.62 (d, J= 8.2 Hz, 2H), 7.52 (d, J=9.4 Hz, 2H), 7.20 (d, J= 8.2 Hz, 4H), 6.86 (d, J=8.8 Hz, 2H), 4.28 (d, J= 5.9 Hz, 2H), 4.06 - 3.99 (m, 2H), 3.49 (d, J=5.3 Hz, 2H), 1.82 (s, 12H). [1083] Example 73: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxybc acid [4-( 1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (3-fluoro-4-guanidinomethyl-phenyl)- amide.

[1084] Synthesis of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2-fluoro-4- nitrophenyl)methyl] carbamate. To a mixture of di-tert-butyl iminodicarboxylate (1.01 g, 4.64 mmol) in dimethylformamide (5.8 mL) was added a 60% dispersion of sodium hydride in mineral oil (252 mg, 6.31 mmol). The reaction was stirred for 15 minutes, then a mixture of l-bromomethyl-2-fluoro- 4-nitro-benzene (983 mg, 4.20 mmol) in N,N-dimethylformamide (2 mL) was added dropwise. The reaction was stirred for 16 hours, then was treated with water (120 mL), and was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (15 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate: hexanes), to give tert-butyl N-[(tert- butoxy)carbonyl]-N-[(2-fluoro-4-nitrophenyl)methyl]carbamate (1.32 g) as a pale yellow solid.

[1085] Synthesis of tert-butyl N-[(4-amino-2-fluorophenyl)methyl]-N-[(tert- butoxy)carbonyl] carbamate. A mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2-fluoro-4- nitrophenyl)methyl] carbamate (1.32 g, 3.56 mmol) and 5% Pd/C (320 mg) in methanol (19 mL) was placed under a hydrogen atmosphere, and stirred for 16 hours. The reaction was filtered through Celite. The Celite was washed with methanol (3 x 10 mL), then the combined filtrates were concentrated, to give tert-butyl N-[(4-amino-2-fluorophenyl)methyl]-N-[(tert- butoxy)carbonyl] carbamate (1.12 g) as a white solid.

[1086] Synthesis of methyl 4-{[4-({bis[(tert-butoxy)carbonyl]amino}methyl)-3- fluorophenyl]carbamoyl}bicyclo[2.2.2]octane-l-carboxylate. To a mixture of bicyclo[2.2.2]octane- 1,4-dicarboxylic acid monomethyl ester (628 mg, 2.95 mmol), tert-butyl N-[(4-amino-2- fluorophenyl)methyl]-N-[(tert-butoxy)carbonyl] carbamate (1.11 g, 3.26 mmol), and triethylamine (696 mg, 940 μL, 5.88 mmol) in N,N-dimethylformamide (8.7 mL) was added 1- [Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate

(1672 mg, 4.42 mmol). The reaction was stirred for 3 days, then was treated with water (135 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give xx (1.31 g) as an orange solid.

[1087] Synthesis of 4-[4-(tert-butoxycarbonylamino-methyl)-3-fluoro-phenylcarbam oyl]- bicyclo[2.2.2]octane-l-carboxylic acid. To a mixture ofxx (1.31 g, 2.45 mmol) in 1,4-dioxane (11.6 mL) was added a ION aqueous NaOH solution (2.5 mL). The reaction was heated at 90 °C for 16 hours, then was concentrated. The residue was treated with water (100 mL), then was adjusted to pH 1 using IN HC1. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with water (2 x 10 mL), and was dried under high vacuum, to give 4-[4-(tert-butoxycarbonylamino- methyl)-3-fluoro-phenylcarbamoyl]-bicyclo [2.2.2] octane- 1 -carboxylic acid (903 mg) as a pale yellow solid.

[1088] Synthesis of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]- amino}-2-fluoro-benzyl)-carbamic acid tert-butyl ester. To a mixture of 4-[4-(tert- butoxycarbonylamino-methyl)-3-fluoro-phenylcarbamoyl]-bicycl o[2.2.2]octane-l-carboxylic acid (903 mg, 2.15 mmol), 4-bromo-phenylamine (406 mg, 2.36 mmol), and triethylamine (505 mg, 680 μL, 4.26 mmol) in dimethylformamide (7.2 mL) was added l-[Bis(dimethylamino)methylene]-lH- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1210 mg, 3.19 mmol). The reaction was stirred for 16 hours, then was treated with water (140 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 30 mL), saturate aqueous NaHCO ₃ (30 mL), and was treated with brine (20 mL). The mixture was shaken, then was filtered through Celite. The fdtrate layers were separated, and the organic layer was dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-90% ethyl acetate: hexanes), to give (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]-amino}-2- fluoro-benzyl)-carbamic acid tert-butyl ester (645 mg) as a pale orange solid.

[1089] Synthesis of 4-[4-({4-[4-(tert-butoxycarbonylamino-methyl)-3-fluoro-pheny l carbamoyl] -bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert-butyl ester. A mixture of (4-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l- carbonyl]-amino}-2-fluoro-benzyl)-carbamic acid tert-butyl ester (645 mg, 1.12 mmol), 4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin e-l-carboxylic acid tert-butyl ester (409 mg, 1.31 mmol), Pd(OAc)2 (13 mg, 0.055 mmol), and 2-Dicyclohexylphosphino-2',6'- dimethoxybiphenyl (48 mg, 0.13 mmol) in 1,4-dioxane (8.1 mL) and 2M K ₂ CO ₃ (2.8 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 °C for 16 hours. The reaction was treated with ethyl acetate (40 mL), then was washed with water (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ). and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate: hexanes), to give 4-[4-({4-[4-(tert-butoxycarbonylamino- methyl)-3 -fluoro-phenylcarbamoyl] -bicyclo [2.2.2] octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro- 2H-pyridine-l -carboxylic acid tert-butyl ester (491 mg) as a pale yellow solid.

[1090] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-3-fluoro- phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[4-(tert- butoxycarbonylamino-methyl)-3-fluoro-phenylcarbamoyl]-bicycl o[2.2.2]octane-l-carbonyl}-amino)- phenyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (488 mg, 0.72 mmol) in CH ₂ CI ₂ (3.6 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 4 hours, then was concentrated. The residue was treated with diethyl ether (30 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (10 mL), to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid (4-aminomethyl-3-fluoro-phenyl)-amide [4-(l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide as the bis-trifluoroacetic acid salt (496 mg) as a pale yellow solid.

[1091] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[(4-{4-[(4-{l-[(lE)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] - 1 ,2,3 ,6-tetrahydropyridin-4- yl }phenyl)carbamoyl]bicyclo[2.2.2] octane- 1 -amido } -2-fluorophenyl)methyl]amino } )methybdene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxybc acid (4-aminomethyl-3-fluoro- phenyl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 2 TFA (491 mg, 0.70 mmol) in N,N-dimethylformamide (3.5 mL) was added triethylamine (490 mg, 672 μL, 4.80 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (686 mg, 2.21 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (55 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0- 100% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[(4-{4-[(4- { 1 - [( 1 E)- { [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] - 1 ,2,3 ,6- tetrahydropyridin-4-yl}phenyl)carbamoyl]bicyclo[2.2.2]octane -l-amido}-2-fluorophenyl)methyl] amino })methylidene] carbamate (372 mg) as a white solid.

[1092] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide (3-fluoro-4-guanidinomethyl-phenyl)-amide. To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({[(4-{4-[(4-{l-[(lE)- {[(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl]imino } )methyl] - 1 ,2,3,6-tetrahydropyridin-4-yl }phenyl)carbamoyl] bicyclo[2.2.2]octane-l-amido}-2-fluorophenyl)methyl]amino})m ethylidene]carbamate (372 mg, 0.39 mmol) in CH ₂ CI ₂ (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with N,N-dimethylformamide (2 mL), followed by 0.1% trifluoroacetic acid in water (2 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (3 x 2 mL), and hexanes (5 mL), to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl] -amide (3-fluoro-4-guanidinomethyl-phenyl)-amide as the bis-trifluoroacetic acid salt (167 mg) as a white solid. MS: 561 M+H+; ¾ NMR (300MHz, dmso) δ = 9.44 (s, 1H), 9.24 (s, 1H), 8.02 - 7.85 (m, 3H), 7.76 - 7.59 (m, 4H), 7.53 - 7.37 (m, 7H), 7.36 - 7.21 (m, 2H), 6.14 (br. s., 1H), 4.34 (d, J=5.3 Hz, 2H), 4.05 (br. s., 2H), 3.60 (br. s., 2H), 2.54 (br. s., 2H), 1.94 - 1.72 (m, 12H).

[1093] Example 74: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (6-guanidinomethyl-pyridin-3-yl)- amide.

[1094] Synthesis of 2-bromomethyl-5-nitro-pyridine. To a mixture of 2-methyl-5-nitro- pyridine (5.28 g, 38.23 mmol) in carbon tetrachloride (79 mL) as added benzoyl peroxide (1.85 g, 7.66 mmol) and N-bromosuccinimide (7.49 g, 42.05 mmol). The reaction was heated at 80 °C for 18 hours, then was concentrated. The crude material was purified by column on silica (0-20% ethyl acetate: hexanes), to give 2-bromomethyl-5-nitro-pyridine (2.39 g) as a dark liquid.

[1095] Synthesis of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-nitropyridin-2- yl)methyl] carbamate. To a mixture of di-tert-butyl iminodicarboxylate (2.65 g, 12.17 mmol) in dimethylformamide (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (661 mg, 16.55 mmol). The reaction was stirred for 15 minutes, then a mixture of 2-bromomethyl-5-nitro- pyridine (2.39 g, 11.01 mmol) in dimethylformamide (5.2 mL) was added dropwise. The reaction was stirred for 3 days, then was treated with water (300 mL), and was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (2 x 50 mL), saturated aqueous NaHCO ₃ (30 mL), and brind (30 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate: hexanes), to give tert-butyl N-[(tert- butoxy)carbonyl]-N-[(5-nitropyridin-2-yl)methyl]carbamate (2.79 g, 72%) as a white solid. [1096] Synthesis of tert-butyl N-[(5-aminopyridin-2-yl)methyl]-N-[(tert- butoxy)carbonyl] carbamate. A mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(5-nitropyridin-2- yl)methyl] carbamate (2.79 g, 7.90 mmol) and 5% Pd/C (700 mg) in methanol (42 mL) was placed under a hydrogen atmosphere. The reaction was stirred for 16 hours, then was filtered through Celite. The Celite was washed with methanol (3 x 15 mL), and the combined filtrates were concentrated. The residue was treated with methanol (42 mL) and 5% Pd/C (700 mg). The mixture was placed under a hydrogen atmosphere, and was stirred for 16 hours, then was filtered through Celite. The Celite was washed with methanol (3 x 15 mL), and the filtrates were combined and concentrated, to give tert- butyl N-[(5-aminopyridin-2-yl)methyl]-N-[(tert-butoxy)carbonyl]car bamate (2.47 g) as a white solid.

[1097] Synthesis of methyl 4-{[6-({bis[(tert-butoxy)carbonyl]amino}methyl)pyridin-3- yl]carbamoyl}bicyclo[2.2.2]octane-l-carboxylate. To a mixture of bicyclo[2.2.2]octane-l,4- dicarboxylic acid monomethyl ester (1.47 g, 6.89 mmol), tert-butyl N-[(5-aminopyridin-2-yl)methyl]- N-[(tert-butoxy)carbonyl] carbamate (2.46 g, 7.61 mmol), and triethylamine (1.63 g, 2.19 mL, 13.73 mmol) in N,N-dimethylformamide (20 mL) was added l-[Bis(dimethylamino)methylene]-lH-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (3.90 g, 10.32 mmol). The reaction was stirred for 16 hours, then was treated with water (300 mL), and was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na SCL). and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give methyl 4- { [6-( {bis [(tert- butoxy)carbonyl]amino}methyl)pyridin-3-yl]carbamoyl}bicyclo[ 2.2.2]octane-l-carboxylate (1.81 g) as a pale yellow solid

[1098] Synthesis of 4-[6-(tert-butoxycarbonylamino-methyl)-pyridin-3-ylcarbamoyl ]- bicyclo[2.2.2]octane-l-carboxylic acid. To a mixture of xx (1.181 g, 3.50 mmol) in 1,4-dioxane (16.6 mL) was added a 10N aqueous NaOH solution (3.5 mL). The reaction was heated at 90 °C for 18 hours, then was concentrated. The residue was treated with water (50 mL), then was adjusted to pH 7 using IN HC1 and saturated aqueous NaHCO ₃ . The mixture was filtered, then the solid was washed with water (30 mL), and was dried under high vacuum, to give 4-[6-(tert-butoxycarbonylamino- methyl)-pyridin-3-ylcarbamoyl]-bicyclo [2.2.2] octane- 1 -carboxylic acid (1.22 g) as a white solid.

[1099] Synthesis of (5-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]- amino}-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester. To a mixture of 4-[6-(tert- butoxycarbonylamino-methyl)-pyridin-3-ylcarbamoyl]-bicyclo[2 .2.2]octane-l-carboxylic acid (1.22 g, 3.02 mmol), 4-bromo-phenylamine (571 mg, 3.32 mmol), and triethylamine (710 mg, 956 μL, 5.99 mmol) in N,N-dimethylformamide (10.1 mL) was added l-[Bis(dimethylamino)methylene]-lH-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1702 mg, 4.49 mmol). The reaction was stirred for 3 days, then was treated with water (150 mL), and was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), saturated aqueous NaHCO ₃ (30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-10% methanol: CH ₂ CI ₂ ), to give (5-{[4-(4-bromo-phenylcarbamoyl)- bicyclo[2.2.2]octane-l-carbonyl]-amino}-pyridin-2-ylmethyl)- carbamic acid tert-butyl ester (1.26 g) as a beige solid.

[1100] Synthesis of 4-[4-({4-[6-(tert-butoxycarbonylamino-methyl)-pyridin-3-ylca rbamoyl]- bicyclo[2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester. A mixture of (5-{[4-(4-bromo-phenylcarbamoyl)-bicyclo[2.2.2]octane-l-carb onyl]- amino}-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (1.25 g, 2.24 mmol), 4-(4, 4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin e-l-carboxylic acid tert-butyl ester (819 mg, 2.62 mmol), Pd(OAc)2 (26 mg, 0.11 mmol), and 2-Dicyclohexylphosphino-2',6'- dimethoxybiphenyl (96 mg, 0.26 mmol) in 1,4-dioxane (16.2 mL) and 2M K ₂ CO ₃ (5.6 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 °C for 16 hours. The reaction was treated with ethyl acetate (50 mL), then was washed with water (20 mL, and brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-10% methanol: CH ₂ CI ₂ ), to give 4-[4-({4-[6-(tert-butoxycarbonylamino-methyl)- pyridin-3 -ylcarbamoyl] -bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester (1.32 g) as a white solid.

[1101] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (6-aminomethyl-pyridin-3- yl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[6-(tert- butoxycarbonylamino-methyl)-pyridin-3-ylcarbamoyl]-bicyclo[2 .2.2]octane-l-carbonyl}-amino)- phenyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1.31 g, 1.99 mmol) in CH ₂ CI ₂ (9.9 mL) was added trifluoroacetic acid (5 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (40 mL), then was sonicated for 5 minutes. The mixture was filtered, then the solid was washed with diethyl ether (20 mL), and was dried under high vacuum, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid (6-aminomethyl-pyridin-3-yl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the tris-trifluoroacetic acid salt (1.74 g) as a pale yellow solid, that was used without further purification.

[1102] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[6-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)pyridin-3 - yl]carbamoyl}bicyclo[2.2.2]octane-l-amido)phenyl]-1,2,3,6-te trahydropyridin-l-yl})methylidene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (6-aminomethyl-pyridin-3- yl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 3 TFA (401 mg, 0.50 mmol) in N,N- dimethylformamide (2.5 mL) was added triethylamine (350 mg, 480 μL, 3.43 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (490 mg, 1.58 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (38 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{[6-({[(lE)-{[(tert-butoxy)c arbonyl]amino}({[(tert- butoxy)carbonyl] imino } )methyl] amino } methyl)pyridin-3 -yl] carbamoyl } bicyclo [2.2.2] octane- 1 - amido)phenyl]-1,2,3,6-tetrahydropyridin-l-yl})methylidene]ca rbamate (235 mg) as a white solid.

[1103] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide (6-guanidinomethyl-pyridin-3-yl)-amide. To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[6-({[(lE)- {[(tert- butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)pyridin-3 - yl]carbamoyl}bicyclo[2.2.2]octane-l-amido)phenyl]-1,2,3,6-te trahydropyridin-l- yl})methylidene] carbamate (235 mg, 0.25 mmol) in CH ₂ CI ₂ (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (6-guanidinomethyl-pyridin-3-yl)- amide as the tris-trifluoroacetic acid salt (147 mg) as a white solid. MS: 544 M+H+; 'H NMR (300MHz, dmso) δ = 9.50 (s, 1H), 9.26 (s, 1H), 8.80 (d, J=23 Hz, 1H), 8.06 (dd, J=2.3, 8.2 Hz, 1H), 7.97 (t, J= 5.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.46 (br. s., 4H), 7.39 (d, J=8.8 Hz, 2H), 7.27 (d, J= 8.2 Hz, 1H), 6.14 (br. s., 1H), 4.41 (d, J= 5.9 Hz, 2H), 4.05 (br. s., 3H), 3.60 (t, J=53 Hz, 3H), 2.55 (br. s., 2H), 1.85 (s, 12H).

[1104] Example 75: Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (5-guanidinomethyl-pyridin-2-yl)- amide. [1105] Synthesis of 5-bromomethyl-2-nitro-pyridine. To a mixture of 5-methyl-2-nitro- pyridine (1.31 g, 9.48 mmol), 2,2'-Azobis(2-methylpropionitrile) (194 mg, 1.05 mmol), and N- bromo-succinimide (1.68 g, 9.43 mmol) in carbon tetrachloride (47 mL) was heated at 80°C for 4 hours. The reaction was concentrated, and the crude material was purified by column on silica (0- 50% ethyl acetate: hexanes), to give a 3:2 mixture of 5-bromomethyl-2-nitro-pyridine: 5-methyl-2- nitro-pyridine ( 1.31 g, 45%) as a white solid, that was used without further purification.

[1106] Synthesis of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(6-nitropyridin-3- yl)methyl] carbamate. To a mixture of di-tert-butyl iminodicarboxylate (1.02 g, 4.69 mmol) in dimethylformamide (5.8 mL) as added a 60% dispersion of sodium hydride in mineral oil (255 mg, 6.37 mmol). The reaction was stirred for 15 minutes, then a 3:2 mixture of 5-bromomethyl-2-nitro- pyridine: 5-methyl-2-nitro-pyridine (920 mg, 4.24 mmol) in N,N=dimethylformamide (2 mL) was added dropwise. The reaction was stirred for 16 hours, then was diluted with water (120 mL), and was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 30 mL), and brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give tert-butyl N-[(tert-butoxy)carbonyl]-N- [(6-nitropyridin-3-yl)methyl]carbamate (1.06 g) as a white solid. [1107] Synthesis of tert-butyl N-[(6-aminopyridin-3-yl)methyl]-N-[(tert-butoxy)carbonyl] carbamate. A mixture of tert-butyl N-[(tert-butoxy)carbonyl]-N-[(6-nitropyridin-3-yl)methyl] carbamate (1.06 g, 3.00 mmol) and 5% Pd/C (265 mg) in methanol (16 mL) was placed under an atmosphere of hydrogen, and was stirred for 16 hours, then was filtered through Celite. The filtrate was concentrated to ~15 mL, then was treated with 5% Pd/C (265 mg) and was placed under an atmosphere of hydrogen. The reaction was stirred for 16 hours, then was filtered through Celite, and the Celite was washed with methanol (2 x 10 mL). The combined filtrates were concentrated, to give tert-butyl N-[(6-aminopyridin-3-yl)methyl]-N-[(tert-butoxy)carbonyl]car bamate (912 mg) as a dark gum.

[1108] Synthesis of methyl 4-{[5-({bis[(tert-butoxy)carbonyl]amino}methyl)pyridin-2- yl]carbamoyl}bicyclo[2.2.2]octane-l-carboxylate. To a mixture of bicyclo[2.2.2]octane-l,4- dicarboxylic acid monomethyl ester (660 mg, 3.10 mmol), tert-butyl N-[(6-aminopyridin-3- yl)methyl]-N-[(tert-butoxy)carbonyl] carbamate (912 mg, 2.82 mmol), and diisopropylethylamine (979 mg, 1.32 mL, 7.61 mmol) in N,N-dimethylformamide (5.8 mL) was added HATU (2.13 g, 5.63 mmol). The reaction was heated at 60 °C for 16 hours, then was treated with water (90 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 25 mL), saturated aqueous NaHCO ₃ (25 mL), and brine (15 mL), dried (Na SOr). and concentrated. The crude material was purified by column on silica (0-70% ethyl acetate: hexanes), to give methyl 4- { [5 -( {bis [(tert-butoxy)carbonyl] amino }methyl)pyridin-2-yl]carbamoyl {bicyclo

[2.2.2]octane-l-carboxylate (528 mg) as a white solid.

[1109] Synthesis of 4-[5-(tert-butoxycarbonylamino-methyl)-pyridin-2-ylcarbamoyl ]- bicyclo[2.2.2]octane-l-carboxylic acid. To a mixture of xx (528 mg, 1.02 mmol) in 1,4-dioxane (4.8 mL) was added a 10N aqueous NaOH solution (1 mL). The reaction was heated at 90 °C for 18 hours, then was concentrated. The residue was treated with water (40 mL), then was adjusted to pH 6 using IN HC1. The mixture was filtered, and the solid was washed with water (2 x 10 mL), then was dried under high vacuum, to give 4-[5-(tert-butoxycarbonylamino-methyl)-pyridin-2-ylcarbamoyl ]- bicyclo[2.2.2]octane-l-carboxylic acid (270 mg) as a white solid.

[1110] Synthesis of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-l -carboxylic acid tert-butyl ester. A mixture of 4-bromo-phenylamine (172 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyb c acid tert-butyl ester (340 mg, 1.10 mmol), and Cl2Pd(dppf). CH ₂ CI ₂ (8 mg, 0.010 mmol) in 1,4-dioxane (5 mL) and 2M K ₂ CO ₃ (1.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 °C for 18 hours, then was treated with ethyl acetate (40 mL) and water (20 mL). The mixture was filtered through Celite, and the fdtrate was separated. The organic layer was washed with brine (10 mL), dried (Na2S04), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate: hexanes), to give 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert- butyl ester (189 mg) as a beige solid.

[1111] Synthesis of 4-[4-({4-[5-(tert-butoxycarbonylamino-methyl)-pyridin-2-ylca rbamoyl]- bicyclo [2.2.2]octane- 1 -carbonyl } -amino)-phenyl] -3 ,6-dihydro-2H-pyridine- 1 -carboxylic acid tert- butyl ester. To a mixture of 4-[5-(tert-butoxycarbonylamino-methyl)-pyridin-2-ylcarbamoyl ]- bicyclo[2.2.2]octane-l-carboxylic acid (270 mg, 0.67 mmol), 4-(4-amino-phenyl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester (189 mg, 0.69 mmol), and triethylamine (158 mg, 212 μL, 1.33 mmol) in N,N-dimethylformamide (2.2 mL) was added l-[Bis(dimethylamino)methylene]-lH- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (378 mg, 1.00 mmol). The reaction was stirred for 3 days, then was treated with water (30 mL). The mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (3 x 20 mL), saturated aqueous NaHCO ₃ (20 mL), and brine (10 mL), dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate: hexanes), to give 4-[4-({4-[5-(tert- butoxycarbonylamino-methyl)-pyridin-2-ylcarbamoyl]-bicyclo[2 .2.2]octane-l-carbonyl}-amino)- phenyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (242 mg) as a white solid.

[1112] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (5-aminomethyl-pyridin-2- yl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. To a mixture of 4-[4-({4-[5-(tert- butoxycarbonylamino-methyl)-pyridin-2-ylcarbamoyl]-bicyclo[2 .2.2]octane-l-carbonyl}-amino)- phenyl]-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (240, 0.36 mmol) in CH ₂ CI ₂ (1.8 mL) was added trifluoroacetic acid (0.9 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with diethyl ether (20 mL), then was sonicated for 5 minutes. The liquid was decanted off, and the residue was placed under high vacuum, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid (5-aminomethyl-pyridin-2-yl)-amide [4-(l, 2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide as the tris-trifluoroacetic acid salt (368 mg) as a tacky solid, that was used without further purification.

[1113] Synthesis of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[5-({[(lE)- { [(tert-butoxy)carbonyl] amino }( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)pyridin-2- yl]carbamoyl}bicyclo[2.2.2]octane-l-amido)phenyl]-1,2,3,6-te trahydropyridin-l-yl})methylidene] carbamate. To a mixture of bicyclo[2.2.2]octane-l,4-dicarboxylic acid (5-aminomethyl-pyridin-2- yl)-amide [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide. 3 TFA (368 mg, 0.46 mmol) in dimethylformamide (2.3 mL) was added triethylamine (321 mg, 441 μL, 3.15 mmol). The reaction was stirred for 15 mintues, then N,N’-bis-Boc-guanylpyrazole (450 mg, 1.45 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 °C for 16 hours. The mixture was treated with water (30 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL). The combined aqueous washed were separated. The combined organic layers were dried (Na ₂ SO ₄ ), and concentrated. The crude material was purified by column on silica (0- 100% ethyl acetate: hexanes), to give tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4- {[5-({[(lE)-{ [(tert-butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl) pyridin-2-yl]carbamoyl}bicyclo[2.2.2]octane- 1 -amido)phenyl]- 1 ,2,3,6-tetrahydropyridin- 1 - yl})methylidene]carbamate (221 mg) as a white solid.

[1114] Synthesis of bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl] -amide (5-guanidinomethyl-pyridin-2-yl)-amide. To a mixture of tert-butyl N-[(lE)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{[5-({[(lE)- {[(tert- butoxy)carbonyl] amino } ( { [(tert-butoxy)carbonyl] imino } )methyl] amino } methyl)pyridin-2- yl] carbamoyl }bicyclo [2.2.2] octane- 1 -amido)phenyl] - 1 ,2,3 ,6-tetrahydropyridin- 1 -yl } ) methylidene] carbamate (221 mg, 0.24 mmol) in CH ₂ CI ₂ (2.4 mL) was added trifluoroacetic acid (2.4 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give bicyclo[2.2.2]octane-l,4-dicarboxylic acid [4-(l-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide (5-guanidinomethyl-pyridin-2-yl)-amide as the tris- trifluoroacetic acid salt (143 mg) as a white solid. MS: 544 M+H+; 'H NMR (300MHz, dmso) δ = 9.80 (s, 1H), 9.23 (s, 1H), 8.27 (s, 1H), 8.07 - 7.88 (m, 2H), 7.80 - 7.55 (m, 4H), 7.51 - 7.33 (m, 7H), 6.13 (br. s., 1H), 4.33 (d, J= 5.9 Hz, 2H), 4.05 (br. s., 3H), 2.55 (br. s., 2H), 1.84 (br. s., 12H). FORMULATIONS

[1115] The present invention also relates to compositions or formulations which comprise the antifungal agents according to the present invention. In general, the compositions of the present invention comprise an effective amount of one or more compounds of the disclosure and salts thereof according to the present invention which are effective for providing treatment of a f mgal infection; and one or more excipients.

[1116] For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.” [1117] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

[1118] The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington ’s Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[1119] Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antifungal agents. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99 % of the compound. [1120] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert fdler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., com, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[1121] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[1122] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[1123] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[1124] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefdled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient’s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

[1125] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

[1126] In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze- actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

[1127] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[1128] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[1129] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[1130] Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[1131] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository’s melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[1132] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[1133] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

[1134] Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings inclding its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

[1135] Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more compounds of the disclosure according to the present invention; and one or more excipients.

PROCEDURES

[1136] The following procedures can be utilized in evaluating and selecting compounds as antifungal agents.

[1137] Fungal MIC Protocol: RPMI/MOPS media (Roswell Park Memorial Institute/3- morpholinopropane-1 -sulfonic acid media) is prepared by dissolving 8.4 grams RPMI 1640 (Sigma cat # R1383), 34.52 grams MOPS buffer (Sigma cat # M3183) and 2 grams glucose in 900 mL deionized water. The pH is adjusted to 7.0 with NaOH and fdter sterilized. 0.1 mL of a stock spore suspension (or loop from frozen stock) is inoculated to a 75 mL tissue culture flask (Falcon cat # 353136) containing 50 mL of Potato Dextrose Agar (PDA, 24 grams PD broth (Fisher cat # DF 0549179), 20 grams agar (Fisher cat # BP 1423500) per liter water). Aspergillus and Fusarium strains are grown at 35 °C and Mucor strains are grown at room temperature for 3-5 days. Spores are harvested by flooding the flask with 5 mL phosphate buffered saline (PBS) pH 7.4 + 0.1%Tween-20 and several glass beads (Fisher cat # S800243) are added to aid in agitation. The supernatant is removed and the OD530 of a 1: 100 dilution is measured. Spores are diluted in RPMI/MOPS to a final OD530 of 0.002 for Aspergillus and an OD530 of 0.005 for Fusarium and Mucor. The final concentration of spores is approximately 2 x 10 ⁴ cfii/mL. Test compound(s) are diluted to 200 ug/mL in RPMI/MOPS (28 ul of lOmg/mL DMSO stock in 1400 ul media). Ten (10) serial dilutions are prepared with RPMI/MOPS in a 96-well round bottom plate (Fisher cat # 353136). For Mucor strains a sterile flat-bottom 96-well plate is used. 50 pi of compound dilutions in duplicate are added to a sterile 96-well round bottom plate. 50 ul of diluted spores are added to the compound-containing plates. Control wells include 1) compound but no cells and 2) spores but no compound. Mix the plates gently by hand, place in ziplock bags and incubate at 35 °C for 48 hours. Score the MIC visually (lowest concentration of compound showing > 50% growth inhibition) using an inverted mirror. For Mucorales strains the plates are read at OD530 and the concentration of compound that shows 50% growth inhibition is the MIC-50.

[1138] Candida Minimal Inhibitory Concentration (MIC): RPMI/MOPS media is prepared by dissolving 8.4g RPMI 1640, 34.52g MOPS buffer and 2g glucose in 900mL water. The pH is adjusted to 7.0 with NaOH. The total volume is brought to 1L and the resulting solution is fdter sterilized. The Candida stock is streaked on a Yeast extract Peptone Dextrose (YPD) agar plate and grown at 35 °C for isolation of single colonies. Compounds of the disclosure are diluted to 200 μg/mL in RPMI/MOPS (4.8ul of lOmg/mL DMSO stock in 240ul media). Ten (10) 1:2 serial dilutions are prepared in RPMI/MOPS in a 96-well round bottom plate. Fifty (50) pi of compound dilutions are transferred in duplicate to a sterile tissue culture-treated 96-well flat-bottom, black-sided polypropylene plate. A single colony of Candida from the YPD plate is re-suspended in 5mL phosphate buffered saline (BS) and optical density (OD) at 600nm is measured. The suspension is adjusted to OD = 1.0 and a 1: 1000 dilution is prepared in RPMI/MOPS. Fifty (50) ul aliquots of the diluted yeast are added to the plates containing 50μL of compound to all wells except 12E-H. Control wells include: 12 A-D cells, no compound and 12 E-H no cells, no compound. The plates are mixed gently by hand and placed in Ziplok bags in a 35 °C incubator. The OD600 is measured at 24 and 48 hours. The lowest concentration of a compound that shows a significant (>90%) reduction in fungal growth is recorded as the MIC and MIC-50 is the concentration of compound that shows 50% growth inhibition.

[1139] Table 6: Fungal strains employed in Fungal MIC Protocol

[1140] Table 7: Antifungal activity of exemplary compounds of the disclosure.

[1141] Several compounds have been tested for their ability to control fungal infection in a mouse model disseminated aspergillosis. In the model, male CD-I mice were made neutropenic by Intraperitoneal (IP) injection of cyclophosphamide 3 days (150 mg/kg) before and 2 days (100 mg/kg) after infection. At Day 0, mice were inoculated intravenously (IV) with 4.4 - 4.7 log10 spores of Aspergillus fumigatus UNTO 17-6. At 24 hours post-infection, compounds were administered subcutaneously (SC) daily for 5 days (n = 10/dose group). In most cases, treatments were done twice daily (BID) with an initial higher first (loading) dose followed by nine lower maintenance doses over the 5 -day treatment period, however single daily dose (QD) regimens were also tested in some studies. Survival was monitored during the course of treatment and 24 hours after the last dose livers and kidneys were harvested for determination of fungal burdens by serial dilution and plating of the tissue homogenates to count colony forming units (cfu)/gram of tissue. Tissue samples from infected but untreated mice were harvested at Day 1 (time of treatment) and Day 6. Statistical significance of comparisons in fungal burdens between groups (p < 0.05) was determined using one-way ANOVA with Tukey’s multiple comparison test.

[1142] Figure 1 and Table 8 show activity of Example 15 on liver and kidney fungal burdens in the disseminated aspergillosis model. In liver, doses of 0.5 mg/kg BID with a 1 mg/kg loading dose or 0.25 mg/kg BID with a 0.5 mg/kg loading dose significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 2.05 log10 cfu/g and 1.67 log10 cfu/g, respectively.

Significant reductions of 1.26 log10 cfu/g and 0.88 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment (Day 1), consistent with fungicidal activity. In kidney, both doses of Example 15 reduced fungal burdens to the limit of detection (LOD) in all treated mice producing significant reductions of 2.17 log10 cfu/g and 1.76 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1143] Five deaths occurred in the untreated group by Day 6 whereas only 1 and 2 mice were lost in the low and high dose groups, respectively, treated with Example 15.

[1144] Figure 2 and Table 8 show activity of Example 25 on liver and kidney fungal burdens in the disseminated aspergillosis model. In liver, doses of 1 mg/kg BID with a 2 mg/kg loading dose or 0.25 mg/kg BID with a 0.5 mg/kg loading dose significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 1.87 log10 cfu/g and 1.7 log10 cfu/g, respectively.

Significant reductions of 0.81 log10 cfu/g and 0.64 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both doses of Example 25 reduced fungal burdens to or near the limit of detection in all treated mice producing significant reductions of > 1.66 log10 cfu/g and > 0.62 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1145] Four deaths occurred in the untreated group by Day 6 whereas no mice were lost in either group treated with Example 25.

[1146] Figure 3 and Table 8 show activities of Examples 26 and 27 on liver and kidney fungal burdens in the disseminated aspergillosis model.

[1147] For Example 26 in liver, doses of 1 mg/kg BID with a 2 mg/kg loading dose or 0.5 mg/kg BID with a 1 mg/kg loading dose significantly reduced fungal burdens to or near the limit of detection producing reductions relative to burdens in the untreated mice at Day 6 of 1.71 log10 cfu/g and 1.6 log10 cfu/g, respectively. Significant reductions of 1.04 log10 cfu/g and 0.93 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both doses of Example 26 reduced fungal burdens to the limit of detection in nearly all treated mice producing significant reductions of > 1.26 log10 cfu/g and > 0.65 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1148] For Example 27 in liver, doses of 1 mg/kg BID with a 2 mg/kg loading dose or 0.5 mg/kg BID with a 1 mg/kg loading dose significantly reduced fungal burdens to or near the limit of detection in many of the mice producing reductions relative to burdens in the untreated mice at Day 6 of 1.63 log10 cfu/g and 1.17 log10 cfu/g, respectively. Significant reductions of 0.96 log10 cfu/g and 0.5 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both doses of Example 27 reduced fungal burdens to the limit of detection in all treated mice producing significant reductions of 1.3 log10 cfu/g and > 0.69 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1149] One death occurred in the untreated group by Day 6 but no mice were lost in any group treated with Examples 26 or 27.

[1150] Figure 4 and Table 8 show activities of Examples 26 and 27 tested in low dose regimens on liver and kidney fungal burdens in the disseminated aspergillosis model.

[1151] For Example 26 in liver, doses of 0.25 mg/kg BID with a 0.5 mg/kg loading dose or 0.125 mg/kg BID with a 0.25 mg/kg loading dose significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 1.72 log10 cfu/g and 1.28 log10 cfu/g, respectively. A significant reduction of 0.49 log10 cfu/g was also observed in the high dose group relative to the burden at the time of treatment, consistent with fungicidal activity, but no significant reduction was seen in the low dose group. In kidney, both the high and low doses of Example 26 significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 2.3 log10 cfu/g and 1.97 log10 cfu/g, respectively. A significant reduction of 0.73 log10 cfu/g was also observed in the high dose group relative to the burden at the time of treatment, but no significant reduction was seen in the low dose group.

[1152] For Example 27 in liver, doses of 1 mg/kg BID with a 2 mg/kg loading dose or 0.5 mg/kg BID with a 1 mg/kg loading dose significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 1.8 log10 cfu/g and significant reductions of 0.57 log10 cfu/g were also observed in the high and low dose groups relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both the high and low doses of Example 27 significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 2.37 log10 cfu/g and 2.28 log10 cfu/g, respectively. Significant reductions of 0.8 log10 cfu/g and 0.71 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment.

[1153] Six deaths occurred in the untreated group by Day 6 but no mice were lost in any group treated with Examples 26 or 27.

[1154] Figure 5 and Table 8 show activity of Example 75 on liver and kidney fungal burdens in the disseminated aspergillosis model. In liver, a dose of 0.5 mg/kg QD reduced the fungal burden relative to the burden in the untreated mice at Day 6 by 1.23 log10 cfu/g. A significant reduction of 1.26 log10 cfu/g was also observed relative to the burden at the time of treatment, consistent with fungicidal activity. In kidney, Example 75 reduced the fungal burden to the limit of detection in all treated mice producing significant reductions of 1.67 log10 cfu/g and 0.97 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1155] Four deaths occurred in the untreated group by Day 6 whereas no mice were lost in the group treated with Example 75.

[1156] Figure 6 and Table 8 show activities of Examples 74 and 75 tested in low dose regimens without a loading dose on liver and kidney fungal burdens in the disseminated aspergillosis model.

[1157] For Example 75 in liver, the 0.25 mg/kg BID dose significantly reduced the fungal burden relative to the burden in the untreated mice at Day 6 by 0.83 log10 cfu/g. The lower 0.125 mg/kg BID dose reduced the fungal burden by 0.5 log10 cfu/g but this reduction was not statistically significant. However, both the 0.25 and 0.125 mg/kg BID doses produced significant reductions in liver burdens of 1.07 log10 cfu/g and 0.74 log10 cfu/g relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both the high and low doses of Example 75 significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 2.85 log10 cfu/g and 2.71 log10 cfu/g, respectively. Significant reductions of 1.02 log10 cfu/g and 0.88 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to the burden at the time of treatment.

[1158] For Example 74 in liver, doses of 0.25 mg/kg BID or 0.125 mg/kg BID significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 1.15 log10 cfu/g and

0.64 log10 cfu/g, respectively. Significant reductions of 1.39 log10 cfu/g and 0.88 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both doses of Example 75 reduced fungal burdens to the limit of detection in nearly all treated mice producing significant reductions of > 2.95 log 10 cfu/g and > 1.12 log 10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1159] Three deaths occurred in the untreated group by Day 6 but no mice were lost in either group treated with Example 75. One mouse was lost in the high dose group treated with Example 74.

[1160] Several compounds were also tested for their ability to control a disseminated infection of Fusarium solani in mice. The model was conducted as described for the disseminated aspergillosis mouse model except neutropenic mice were inoculated IV with 6 - 6.2 log 10 spores of Fusarium solani UNT044-6.

[1161] Figure 7 and Table 8 show activity of Example 26 on liver and kidney fungal burdens in the disseminated Fusarium solani infection model. In liver, doses of 1 mg/kg BID with a 2 mg/kg loading dose or 0.25 mg/kg BID with a 0.5 mg/kg loading dose significantly reduced fungal burdens relative to the burden in the single remaining untreated mouse at Day 6 by 4.91 log10 cfu/g and 4.57 log10 cfu/g, respectively. Significant reductions of 1.95 log10 cfu/g and 1.61 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment, consistent with fungicidal activity. In kidney, both doses of Example 25 reduced fungal burdens to the limit of detection in nearly all treated mice producing significant reductions of > 4.89 log10 cfu/g and > 1.69 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively. The widely used and broadly active polyene antifungal agent, amphotericin B (AmphB), was also tested at daily SC doses of 18 mg/kg QD. Significant mortality was evident in the group and in the remaining surviving mouse the liver burden at Day 6 was reduced by 3.07 log10 cfu/g but the infection was not controlled in the kidney.

[1162] Nine of ten mice died in both the untreated and AmphB-treated groups whereas only 1 and 3 mice were lost in the high and low dose groups treated with Example 26. Four deaths occurred in the untreated group by Day 6 whereas no mice were lost in either group treated with Example 25.

[1163] Figure 8 and Table 8 show activities of Examples 25 and 27 on liver and kidney fungal burdens in the disseminated Fusarium solani infection model.

[1164] For Example 25 in liver, doses of 1 mg/kg BID with a 2 mg/kg loading dose or 0.25 mg/kg BID with a 0.5 mg/kg loading dose significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 2.7 log10 cfu/g and 1.99 log10 cfu/g, respectively. Significant reductions of 2.44 log10 cfu/g and 1.73 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment (Day 1), consistent with fungicidal activity. In kidney, both doses reduced fungal burdens to the limit of detection in all treated mice producing significant reductions of > 2.35 log10 cfu/g and > 2.26 log10 cfu/g relative to burdens in the Day 6 and Day 1 untreated groups, respectively.

[1165] For Example 27 in liver, the 1 mg/kg BID dose with a 2 mg/kg loading dose significantly reduced fungal burden relative to the burden in the untreated mice at Day 6 by 1.16 log10 cfu/g. A significant reduction of 0.9 log10 cfu/g was also observed with this dose relative to the burden at time of treatment, consistent with fungicidal activity. No significant reductions in liver burden were observed with the lower 0.25 mg/kg BID dose with a 0.5 mg/kg loading dose relative to burdens at Day 6 in untreated mice or at the time of treatment. In kidney, both the high and low doses of Example 27 significantly reduced fungal burdens relative to burdens in the untreated mice at Day 6 by 2.35 log10 cfu/g and 1.19 log10 cfu/g, respectively. Significant reductions of 2.26 log10 cfu/g and 1.1 log10 cfu/g were also observed in the high and low dose groups, respectively, relative to burdens at the time of treatment.

[1166] Six deaths occurred in the untreated group by Day 6 but no mice were lost in the high dose group treated with Example 25 and 2 mice died in the low dose group. One and four mice died in the high and low dose groups, respectively, treated with Example 27. [1167] In summary, several compound examples in the invention have been tested in mouse models of disseminated infection against Aspergillus fumigatus and Fusarium solani. Significant efficacy measured by reductions of fungal burdens in liver and kidney tissues from treated versus untreated mice was commonly observed that was also associated with improved survival over the treatment periods. These results support the utility of compounds exemplified in this invention for treatment fungal infections.

[1168] Table 8: Tissue burdents