TW202317516A - Novel bis-amide containing compounds exhibiting antifungal activity and their method of use - Google Patents

Abstract

Pharmaceutical compositions of the invention comprise herteroaromatic compounds having a disease-modifying action in the treatment of fungal infections and diseases associated with fungal infection.

Description

Novel bisamide-containing compounds exhibiting antifungal activity and methods of use thereof

The present invention describes compounds that are antifungal agents that are useful in the treatment of fungal infections and related conditions. The present invention further describes a novel chemotype useful in the treatment of fungal infections and other diseases involving fungal infections.

Fungal infections are a growing problem in many healthcare settings. Modern medical practice includes anticancer chemotherapy, immunosuppressive drugs, broad-spectrum antibiotics that disrupt the microbiome, and indwelling medical devices that disrupt and breach the protective immune system. This creates an opportunity for infection by opportunistic fungal pathogens. Fungal infections are most common in immunocompromised patients with HIV or who are undergoing cancer treatment, hematopoietic stem cell replacement, or organ transplantation. Fungal infections may also occur in immunocompetent individuals, most commonly due to skin and soft tissue wounds resulting from trauma. These types of injuries have significant morbidity, as localized invasive infections often require frequent and extensive surgical debridement in combination with systemic antifungal therapy. However, resection is still required in many cases, and the mortality rate can be as high as 25%. In immunosuppressed and immunocompetent patients, the most common fungal pathogens were Candida , Aspergillus , Cryptococcus , Mucorales , and Fusarium ), infection is associated with a significant incidence of treatment failure and high mortality. Invasive candidiasis (IC) is the fourth leading health care-associated bloodstream infection in the United States and is associated with a 47% mortality rate. Invasive aspergillosis (IA) is emerging as a major invasive fungal disease in hematology-oncology, organ transplantation, and exacerbation of chronic obstructive pulmonary disease. According to reports, the incidence of IA in hematopoietic stem cell transplantation is as high as 15%, and the mortality rate is in the range of 20% to 50%.

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

The disclosed compounds have excellent activity against pathogenic fungi of the genera Candida, Aspergillus, Fusarium, Cryptococcus and Mucormyces. They are indicated for the treatment of fungal diseases caused by these and other susceptible fungal pathogens, such as candidemia, oral candidiasis, vulvovaginal candidiasis (VVC) and recurrent VVC, aspergillosis (including allergic bronchial aspergillosis of the lung, allergic aspergillus sinusitis, and invasive and disseminated aspergillosis), cryptococcosis (including pulmonary cryptococcosis and meningeal cryptococcosis), mucormycosis, blastomycosis, Superficial infections (including cutaneous keratitis, athlete's foot, ringworm, ocular keratitis, and onychomycosis) and other invasive infections (including sinusitis, endophthalmitis, otitis, endocarditis, pneumonia, bone marrow inflammation, meningitis, and ventriculitis).

The disclosed compounds are also useful in the treatment of fungal infections of agricultural crops, including wilt in tomato and cotton caused by Fusarium oxysporus , chickpea wilt caused by Fusarium orthacereas Grain powdery mildew caused by Sclerospora graminicola , seedling blight caused by species of the genus Phythium , root rot of ginger caused by Phythium debaryaum , Potato late blight caused by Phytophthora infestan , potato early blight caused by Alternaria solani , rice blast caused by Phyricularia oryzae , powdery mildew caused by Erysiphe powdery mildew caused by the species Cerecospora personata , Haemelia vastatrix and Cellectotrichum falcatum ; Tikka Disease caused by Brown rot in pears, plums and peaches caused by Sclerotinia fruiticola , oat leaf spot caused by Helminthosporium avenae , coffee leaf rust caused by Haemelia vastatrix , Sugarcane red rot caused by Collectotrichum falcatum , potato black wart caused by Synchytrium endobioticum, wheat yellow rust caused by Puccinia striiformis , Corn smut caused by Ustilago maydis , wheat smut caused by Ustilago tritici , oat hard smut caused by Ustilago avenae wheat stem smut caused by Urocystis tritici , barley stem smut caused by Ustilago hordei , wheat stem rust caused by Puccinia graminis tritici Wheat black rust, Bankanese Disease and foot rot caused by Gibberealla fujikuri , and ergot in rye caused by Claviceps purpurea .

The compounds of the present disclosure are also useful for the treatment or prevention of fungal infections in domesticated animals, livestock and companion animals, including those selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffaloes, bulls, llamas, camels, dogs, cats Candidiasis infection in the group consisting of , horses, rabbits, ferrets and guinea pigs.

Compounds of the present disclosure are also useful in the treatment or prevention and domestication of animals, livestock and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffaloes, bulls, llamas, camels, dogs, cats, horses, rabbits, A disease or condition associated with fungal infection in ferrets and guinea pigs, wherein said disease or condition is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, pneumonia granulomatous A group consisting of rhinitis, intestinal granuloma, and empyema.

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

Compounds of the present disclosure are also useful in the treatment or prevention of diseases or conditions associated with aspergillus infection in horses, cattle, sheep, goats, dogs, and cats, including such diseases or conditions as laryngeal bloat, corneal mycosis, pneumonia, mycotic pneumonia, Diseases or conditions of gastroenteritis, mastitis, and placenta.

Compounds of the present disclosure can also be used to treat or prevent white mycosis infections in horses, cattle, sheep, goats, dogs and cats.

The compounds of the present disclosure are also useful in the treatment or prevention of diseases or conditions associated with white mycosis infections in horses, cattle, sheep, goats, dogs and cats, including such diseases as mucormycotic ruminitis, lymphadenitis and A disease or condition of enteritis.

The compounds of the present disclosure are also useful for treating or preventing Coccidioides immitis infection in dogs and cats caused by organisms selected from the group consisting of Coccidioides immitis and Coccidioides posadasii sick.

The disclosed compounds are also useful for treating or preventing blastomycosis in dogs and cats caused by Blastomyces dermatitidis infection.

The disclosed compounds can also be used to treat or prevent paracoccidioidomycosis in dogs caused by Paracoccidioides brasiliensis infection.

The compounds of the present disclosure are also useful in the treatment or prevention of organisms selected from the group consisting of Microsporum canis , Microsporum gypseum and Trichophyton mentagrophytes in cats and dogs Dermatophytosis (ringworm) caused by a body infection.

Compounds of the present disclosure are also useful for treating or preventing cryptococcosis in dogs and cats caused by infection with organisms selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii .

The compounds of the present disclosure are also useful for treating or preventing histoplasmosis in dogs caused by Histoplasma capsulatum infection.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽、前驅藥和複合物，其中： A ¹選自由以下組成之群組：

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； A ²在每次出現時獨立地選自由以下組成之群組：

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； A ³在每次出現時獨立地選自由以下組成之群組：

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； A ⁴在每次出現時獨立地選自由以下組成之群組：

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； A ⁵在每次出現時獨立地選自由以下組成之群組：

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； q在每次出現時獨立地為0、1、2或3； t在每次出現時獨立地為1、2或3； R ¹在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^1a在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ²在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^2a在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2b在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2c在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2d在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2e在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2f在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2g在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2h在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ²ⁱ在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2j在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2k在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2l在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ³在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3a在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3c在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3d在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3y在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3z在每次出現時獨立地選自由H和C _1-4烷基組成之群組； 在一些實施方式中，R ^2e和R ^3z連接形成由五或六個成員組成的雜環； 在一些實施方式中，R ²ⁱ和R ^3y連接形成由五或六個成員組成的雜環； 在一些實施方式中，R ³和R ^3c連接形成由五個成員組成的雜環； R ^4a在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4b在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4c在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4d在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4e在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4f在每次出現時獨立地選自由H和C _1-4烷基組成之群組。 The present invention relates to novel compounds of formula (I):

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: ^A1 is selected from the group consisting of:

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; ^A2, at each occurrence, is independently selected from the group consisting of:

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; ^A3, at each occurrence, is independently selected from the group consisting of:

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; ^A4 is independently selected at each occurrence from the group consisting of:

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; A ⁵ is independently selected at each occurrence from the group consisting of:

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; q is independently 0, 1, 2 or 3 at each occurrence; t is independently 1, 2 or 3 at each occurrence; ^{R is} independently selected from H and C _1-4 at each occurrence The group consisting of alkyl; R ^1a at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ² at each occurrence is independently selected from H and C _1-4 alkyl The group consisting of; R ^2a is independently selected from each occurrence of H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF The group consisting of ₃ and CF ₃ ; R ^2b at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl , CN, OCF ₃ and the group consisting of CF ₃ ; R ^2c at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy , the group consisting of F, Cl, CN, OCF ₃ and CF ₃ ; R ^2d at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched The group consisting of alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2e at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C The group consisting of _3-5 branched chain alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2f at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkane The group consisting of oxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2g is independently selected from each occurrence of H, C _1-4 alkyl, C The group consisting of _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2h is independently selected from H, C _1-4 at each occurrence The group consisting of alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ²ⁱ is independently selected from H, The group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2j independently at each occurrence 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 in each 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 when present; R ²¹ is independently selected at each occurrence from the group consisting of H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched chain alkoxy, F, Cl, CN, OCF ₃ and CF ₃ Group; R ³ is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3a is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl ; R ^3c is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3d is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3y is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3z is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; in some embodiments In some embodiments, R ^2e and R ^3z are connected to form a heterocycle consisting of five or six members; In some embodiments, R ²ⁱ and R ^3y are connected to form a heterocycle consisting of five or six members; In some embodiments , R ³ and R ^3c are joined to form a heterocycle consisting of five members; R ^4a at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^4b at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^4c at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^4d at each occurrence is independently selected from The group consisting of H and C _1-4 alkyl; R ^4e at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^4f at each occurrence is independently selected from H and A group consisting of C _1-4 alkyl groups.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( Ia ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( Ib ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( II ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( III ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( IV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( V ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( VI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( VII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( VIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( IX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( X ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XIV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XVI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XVII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XVIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XIX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XXVI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XXVII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XXVIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

The compounds of the present invention also include various synthetic intermediate compounds as described below.

The invention also relates to compositions comprising: An effective amount of one or more compounds according to the invention, and an excipient.

The invention also relates to methods of treating or preventing diseases or conditions associated with fungal infections. The method comprises administering to the subject an effective amount of a compound or composition according to the invention.

The invention also relates to a method of treating or preventing a disease or condition associated with a fungal infection, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The invention also relates to methods of treating or preventing fungal infections, including, for example, infections by organisms from a genus selected from the group consisting of: Candida, Cryptococcus, Saccharomyces, Malassezia , Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Squamous, Rhizomucor , Rhizopus sp., Scedosporium sp. and Arthropodium sp., the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

The invention also relates to methods of treating or preventing fungal infections, including, for example, infections by organisms from a genus selected from the group consisting of: Candida, Cryptococcus, Saccharomyces, Malassezia , Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Squamous, Rhizomucor , Rhizopus sp., Scedosporium sp. and Arthropodium sp., for example selected from the group consisting of: Candida, Cryptococcus, Aspergillus, Fusarium, Mucormyces, and Sedo Sporosporium, wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The invention also relates to methods of treating or preventing fungal infections including, for example, organisms such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida agilimonii, Candida, Candida dublini and Candida auris, Cryptococcus neoformans, Cryptococcus gattii, Saccharomyces axasia, Saccharomyces asteroides, Saccharomyces dermatospora, Saccharomyces dermatospora, Saccharomyces duhasporum, Ink Saccharomyces spp., Saccharomyces spp., Saccharomyces spp., Saccharomyces ovale, Malassezia globosa, Malassezia restrictans, Aspergillus fumigatus, Aspergillus fumigatus, Aspergillus spp. Aspergillus, Fusarium solani, Fusarium fusarium, Fusarium oxysporum, Fusarium verticillium, Fusarium laminarum, Mucor rotifera, Mucor cladoides, Mucor indica, Mucor racemosa , Mucorella piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immosa, Coccidioides posadas, Pneumocystis jirovecii, Pneumocystis jirovecii, Histoplasma capsulatus, Trichophyton schlennensis, Trichophyton barbata Trichophyton, Trichophyton verrucous, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stoloniferum, Apophosphorus variabilis, Rhizomucor minimus, Rhizomucor regularis, Rhizomucor chlamiccum, Rhizomucor cladoides, Transverse umbelliferae, Scedospora apiospora, and Arthropodium inoculum, the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

The present invention still further relates to methods for treating or preventing fungal infections, including, for example, infections by organisms such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida agilimonii, Candida pallidum, Candida dublini and Candida auris, Cryptococcus neoformans, Cryptococcus gattii, Saccharomyces axasia, Saccharomyces asteroides, Saccharomyces dermatospora, Saccharomyces dermatospora, Saccharomyces duhasporum, Saccharomyces japonicus, Saccharomyces spp., Saccharomyces viscosporum, Saccharomyces ovale, Malassezia sphaericus, Malassezia sphaericus, Saccharomyces fumigatus, Flavus spp. Aspergillus niger, Fusarium solani, Fusarium fusarium, Fusarium oxysporum, Fusarium verticillium, Fusarium laminarum, Mucor rotundum, Mucor cladoides, Mucor indica, Racemosa Mold, Mucorella piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immature, Coccidioides posadas, Pneumocystis jirovecii, Pneumocystis jirovecii, Histoplasma capsulatus, Trichophyton scheelephytum, Barbadensis Trichophyton, Trichophyton verrucous, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stoloniferum, Apophosphorus variabilis, Rhizomucor microbiota, Rhizomucor regularis, Rhizomucor chlamicutes, Rhizomucor cladoides , Rhizoma umbelliferae, Scedosporium apiospora, and Arthropodium sterility, wherein the 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 .

The present invention also relates to methods of treating or preventing diseases or conditions associated with fungal infections, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillus, allergic bronchial and pulmonary Aspergillus, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, keratitis dermatitis, athlete's foot, ringworm , Keratitis, Onychomycosis, Sinusitis, Endophthalmitis, Otitis, Endocarditis, Pneumonia, Osteomyelitis, Meningitis, Ventriculitis, COVID-19-Associated Pneumonia (CAPA) and Influenza-Associated Pneumonia mycosis (IAPA). The method comprises administering to the subject an effective amount of a compound or composition according to the invention.

The invention still further relates to methods of treating or preventing diseases or conditions associated with fungal infections, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillus, allergic bronchial and pulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, keratitis dermatitis, athlete's foot, ringworm keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditis, pneumonia, osteomyelitis, meningitis, ventriculitis, COVID-19-associated aspergillosis (CAPA) and influenza-associated pneumonia Aspergillus (IAPA), wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to a method of treating or preventing a disease or condition associated with a fungal infection, including an infection by an organism from a genus selected from the group consisting of: Candida, Cryptococcus, Saccharomyces, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Squamous Infection with organisms of the genera Rhizomucor, Rhizopus, Scedosporium and Arthropodium, for example selected from the group consisting of: Candida, Cryptococcus, Koji , Fusarium, Mucormyces, and Scedosporium. The method comprises administering to the subject an effective amount of a compound or composition according to the invention.

The present invention also relates to a method of treating or preventing a disease or condition associated with a fungal infection, including an infection by an organism from a genus selected from the group consisting of: Candida, Cryptococcus, Saccharomyces, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Squamous Genus, Rhizomucor, Rhizopus, Scedosporium and Arthropodium, for example selected from the group consisting of: Candida, Cryptococcus, Aspergillus, Fusarium, Trichomonas Mold and Scedosporium, wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to methods of treating or preventing diseases or conditions associated with fungal infections, including infections by organisms selected from the group consisting of: Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis parapsilosis, Candida dublini and Candida auris, Cryptococcus neoformans, Cryptococcus gattii, Saccharomyces axasia, Saccharomyces staurosporum, Saccharomyces dermatospora, Saccharomyces dermatospora Saccharomyces, Saccharomyces duhasporum, Saccharomyces fumigatus, Saccharomyces bovis, Saccharomyces viscosporum, Saccharomyces ovale, Malassezia globosa, Malassezia restrictive, Aspergillus fumigatus, Yellow Aspergillus, Solanum Aspergillus, Black Aspergillus, Fusarium solani, Fusarium oxysporum, Fusarium oxysporum, Fusarium verticillium, Fusarium laminarum, Mucor rotifera, Mucor cladoides , Mucorales indica, Mucorales racemosa, Mucorales piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immature, Coccidioides posadas, Pneumocystis jirovecii, Pneumocystis jirovecii, Capsular tissue Plasma, Trichophyton schlennium, Trichophyton mentagrophytes, Trichophyton verrucous, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stoloniferum, Apophosphorus variabilis, Rhizomucor minutum, Rhizomucor regularis, Firmicutes Rhizomucor, Transaline cladoides, Transacia cladoides, Scedosporium apiosporum, and Arthropodium inoculum, the method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

The present invention also relates to methods of treating or preventing diseases or conditions associated with fungal infections, including infections by organisms selected from the group consisting of: Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis parapsilosis, Candida dublini and Candida auris, Cryptococcus neoformans, Cryptococcus gattii, Saccharomyces axasia, Saccharomyces staurosporum, Saccharomyces dermatospora, Saccharomyces dermatospora Saccharomyces, Saccharomyces duhasporum, Saccharomyces fumigatus, Saccharomyces bovis, Saccharomyces viscosporum, Saccharomyces ovale, Malassezia globosa, Malassezia restrictive, Aspergillus fumigatus, Yellow Aspergillus, Solanum Aspergillus, Black Aspergillus, Fusarium solani, Fusarium oxysporum, Fusarium oxysporum, Fusarium verticillium, Fusarium laminarum, Mucor rotifera, Mucor cladoides , Mucorales indica, Mucorales racemosa, Mucorales piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immature, Coccidioides posadas, Pneumocystis jirovecii, Pneumocystis jirovecii, Capsular tissue Plasma, Trichophyton schlennium, Trichophyton mentagrophytes, Trichophyton verrucous, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stoloniferum, Apophosphorus variabilis, Rhizomucor minutum, Rhizomucor regularis, Firmicutes Rhizomucor, Transaline cladoides, Transacia cladoides, Scedospora apiospora, and Arthropodium inoculum, wherein the method comprises administering to the subject a drug comprising an effective amount of one or more of the compounds according to the present invention Composition of compounds and excipients.

The present invention also relates to methods of treating or preventing fungal infections of plants including tomato wilt, cotton wilt, banana wilt, chickpea wilt, cereal powdery mildew, seedling blight , Ginger root rot, potato late blight, potato early blight, rice blast, powdery mildew, peanut tika, coffee leaf rust, sugarcane red rot, pear brown rot, plum brown rot, peach brown rot, Oat leaf spot, potato black wart, wheat yellow rust, cruciferous white rust, corn smut, wheat bare smut, wheat stem smut, barley hard smut, wheat black rust, rice leggy disease , rice rot and rye ergot. The method comprises administering to the plant an effective amount of a compound or composition according to the invention.

The present invention also relates to methods of treating or preventing fungal infections of plants including tomato wilt, cotton wilt, banana wilt, chickpea wilt, cereal powdery mildew, seedling blight , Ginger root rot, potato late blight, potato early blight, rice blast, powdery mildew, peanut tika, coffee leaf rust, sugarcane red rot, pear brown rot, plum brown rot, peach brown rot, Oat leaf spot, potato black wart, wheat yellow rust, cruciferous white rust, corn smut, wheat bare smut, wheat stem smut, barley hard smut, wheat black rust, rice leggy disease , Rice rot and rye ergot, wherein the method comprises administering to the plant a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to a method of treating or preventing fungal infections in domesticated animals, livestock and companion animals, including those selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffaloes, bulls, llamas, camels, dogs, cats, Candida infection in animals of the group consisting of rabbits, ferrets and guinea pigs, the method comprising administering to the subject an effective amount of a compound or composition according to the invention.

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

The present invention also relates to the treatment or prevention of disease in domesticated animals, livestock and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffaloes, bulls, llamas, camels, dogs, cats, rabbits, ferrets and guinea pigs. A method for a disease or condition associated with a fungal infection, wherein said disease or condition associated with a fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa , keratitis, pneumoniae granulomatous rhinitis, intestinal granuloma, and empyema, wherein the method comprises administering to the subject an effective amount of a compound or composition according to the present invention.

The present invention also relates to the treatment or prevention of disease in domesticated animals, livestock and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffaloes, bulls, llamas, camels, dogs, cats, rabbits, ferrets and guinea pigs. A method for a disease or condition associated with a fungal infection, wherein said disease or condition associated with a fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa , keratitis, pneumoniae granulomatous rhinitis, intestinal granuloma, and empyema, wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient .

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

The present invention also relates to a method of treating or preventing aspergillosis infection in horses, cattle, sheep, goats, dogs and cats, wherein said method comprises administering to a subject a compound comprising an effective amount of one or more compounds according to the present invention and Composition of excipients.

The present invention also relates to methods of treating or preventing diseases or conditions associated with Aspergillus infection in horses, cattle, sheep, goats, dogs and cats, including such as laryngeal bloat, corneal fungal disease, pneumonia, fungal pneumonia, gastroenteritis , a disease or condition of mastitis and placenta, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.

The present invention also relates to methods of treating or preventing diseases or conditions associated with Aspergillus infection in horses, cattle, sheep, goats, dogs and cats, including such as laryngeal bloat, corneal fungal disease, pneumonia, fungal pneumonia, gastroenteritis , a disease or condition of mastitis and placenta, wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to a method of treating or preventing white mycosis infection in horses, cattle, sheep, goats, dogs and cats, said method comprising administering to the subject an effective amount of a compound or composition according to the present invention.

The present invention also relates to a method of treating or preventing white mycosis infection in horses, cattle, sheep, goats, dogs and cats, wherein said method comprises administering to a subject a compound comprising an effective amount of one or more compounds according to the present invention and Composition of excipients.

The invention also relates to methods of treating or preventing diseases or conditions associated with white mycosis infection in horses, cattle, sheep, goats, dogs and cats, including diseases or conditions such as mucormycosis rumenitis, lymphadenitis and enteritis, The method comprises administering to the subject an effective amount of a compound or composition according to the invention.

The invention also relates to methods of treating or preventing diseases or conditions associated with white mycosis infection in horses, cattle, sheep, goats, dogs and cats, including diseases or conditions such as mucormycosis rumenitis, lymphadenitis and enteritis, Wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to a method of treating or preventing coccidioidomycosis in dogs and cats caused by an infection by an organism selected from the group consisting of Coccidioides immobilis and Coccidioides posadas, said method comprising administering to a subject The patient is administered an effective amount of a compound or composition according to the present invention.

The present invention also relates to a method of treating or preventing coccidioidomycosis in dogs and cats caused by an infection by an organism selected from the group consisting of Coccidioides immobilis and Coccidioides posadas, wherein said method comprises administering A subject is administered a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to the treatment or prevention of blastomycosis caused by Blastomyces dermatitidis infection in dogs and cats, said method comprising administering to the subject an effective amount of a compound or composition according to the present invention.

The present invention also relates to the treatment or prevention of blastomycosis caused by Blastomyces dermatitidis infection in dogs and cats, wherein the method comprises administering to the subject a compound comprising an effective amount of one or more compounds according to the present invention and an excipient. Composition.

The present invention also relates to the treatment or prevention of Paracoccidioidomycosis in dogs caused by Paracoccidioides brasiliensis infection, said method comprising administering to the subject an effective amount of a compound or composition according to the present invention.

The present invention also relates to the treatment or prevention of paracoccidioidomycosis in dogs caused by Paracoccidioides brasiliensis infection, wherein said method comprises administering to the subject a compound comprising an effective amount of one or more compounds according to the present invention and an excipient. The composition of the agent.

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

The present invention also relates to a method of treating or preventing dermatophytosis (ringworm) in cats and dogs caused by an infection by an organism selected from the group consisting of Microsporum canis, Microsporum plasterosa and Trichophyton mentagrophytes , wherein the method comprises administering to the subject a composition comprising an effective amount of one or more compounds according to the invention and an excipient.

The present invention also relates to a method of 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 comprising administering to the subject an effective amount of compounds or compositions according to the present invention.

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

The invention also relates to the treatment or prevention of histoplasmosis in dogs caused by H. capsulatus infection, said method comprising administering to the subject an effective amount of a compound or composition according to the invention.

The present invention also relates to the treatment or prevention of histoplasmosis in dogs caused by a Histoplasma capsulatus infection, wherein the method comprises administering to the subject an effective amount of one or more compounds according to the present invention and an excipient of composition.

The invention also provides compounds of the invention for use in the treatment or prevention of a disease or condition associated with a fungal infection as described herein.

The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with a fungal infection as described herein.

The present invention also relates to processes for the preparation of the antifungal agents of the present invention.

These and other objects, features and advantages will become apparent to those skilled in the art by reading 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 indicated. All documents cited are, in relevant part, incorporated herein by reference; citation of any document should not be construed as an admission that it is prior art with respect to the present invention.

Cross References to Related Applications

This application claims the benefit of US Provisional Application No. 63221425, filed July 13, 2021, which is hereby incorporated by reference in its entirety. Federally Sponsored Research Statement

This invention was made with government support under Grant No. R44AI106270 awarded by the National Institutes of Health and W81XWH1810638 awarded by the U.S. Department of Defense. The government has certain rights in this invention.

The disclosed compounds act on pathogenic fungi to inhibit their growth. The compounds of the present disclosure can also kill fungi. As antifungal agents, the compounds of the present disclosure are useful in the treatment of topical, superficial and disseminated infections in animals, including humans, and in the prevention of disseminated fungal infections that develop from topical or superficial fungal infections. In another aspect of the invention, the compounds can be administered to agricultural plants, shrubs and trees for the treatment and prevention of fungal infections and fungal diseases.

Throughout the specification, where compositions are described as having, containing, or comprising particular components, or where methods are described as having, containing, or comprising particular method steps, it is contemplated that compositions of the present teachings may also Consisting essentially of or consisting of said components, and the methods of the present teachings also consist essentially of or consist of said processing steps.

In this application, when an element or component is referred to as being included in and/or selected from a recited list of elements or components, it is to be understood that the element or component may is any one of the listed elements or components, and can be selected from the group consisting of two or more of the listed elements or components.

The use of the singular herein includes the plural (and vice versa) unless expressly stated otherwise. Furthermore, where the term "about" is used preceding a quantitative value, the present teachings also include the specific quantitative value itself unless expressly stated otherwise.

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. Furthermore, two or more steps or actions may be performed simultaneously.

As used herein, the term "halogen" shall refer to chlorine, bromine, fluorine and iodine.

As used herein, unless otherwise stated, "alkyl" and/or "aliphatic", whether used alone or as part of a substituent, means a group having from 1 to 20 carbon atoms or any number within the range (e.g. 1 to 6 carbon atoms or 1 to 4 carbon atoms) straight and branched carbon chains. Designated numbers of carbon atoms (eg, C _1-6 ) shall refer independently to the number of carbon atoms in the alkyl portion or the number of carbon atoms in the alkyl portion of larger alkyl-containing substituents. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, and the like. Alkyl groups can be optionally substituted. In some embodiments, the alkyl group is unsubstituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3 -Carboxypropyl etc. In a substituent having multiple alkyl groups such as (C _1-6 alkyl) ₂ amine group, the alkyl groups may be the same or different.

As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent, refer to any group having 2 or more, preferably 2 to 20, carbon atoms. chains and branched carbon chains where alkenyl chains have at least one double bond in the chain and alkynyl chains have at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkynyl group is unsubstituted. Non-limiting examples of alkenyl include ethenyl, 3-propenyl, 1-propenyl (also known as 2-methylvinyl), isopropenyl (also known as 2-methylethen-2-yl), Buten-4-yl, etc. Non-limiting examples of substituted alkenyl groups include 2-chlorovinyl (also known as 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-ene -2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl, etc. Non-limiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also known as propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethynyl Base hept-3-ynyl etc.

As used herein, "cycloalkyl" whether used alone or as part of another group refers to groups containing, for example, 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms. Cyclized alkyl, alkenyl and alkynyl groups of carbon atoms or even 3 to 4 ring carbon atoms and optionally containing one or more (for example, 1, 2 or 3) double or triple bonds Contains carbon rings. Cycloalkyl groups can be monocyclic (eg, cyclohexyl) or polycyclic (eg, 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 a cycloalkyl group can be covalently attached to the defined chemical structure. Cycloalkyl rings can be optionally substituted. In some embodiments, cycloalkyl ring systems are unsubstituted. Non-limiting examples of cycloalkyl include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, Cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclo Hexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1 H -indenyl, 3a,4,5,6, 7,7a-hexahydro- 3H -inden-4-yl, decahydroazenyl; bicyclo[6.2.0]decyl, decahydronaphthyl and dodecahydro- 1H -perylene. The term "cycloalkyl" also includes carbocycles which are bicyclic hydrocarbon rings, non-limiting examples of which include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1. 1] Heptyl, 1,3-dimethyl[2.2.1]hept-2-yl, bicyclo[2.2.2]octanyl and bicyclo[3.3.3]undecyl.

"Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted by one or more halogens. Haloalkyl includes perhaloalkyl in which all hydrogens of the alkyl group have been replaced by halogen (eg, -CF ₃ , -CF ₂ CF ₃ ). Haloalkyl groups may be optionally substituted with one or more substituents other than halogen. In some embodiments, haloalkyl is unsubstituted with one or more substituents other than halo. Examples of haloalkyl include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined above. Alkoxy groups can be optionally substituted. In some embodiments, the alkoxy group is unsubstituted. The term C ₃ -C ₆ cycloalkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (for example, tetrahydrofuran, tetrahydro-2H-pyran). The C ₃ -C ₆ cycloalkoxy group can be optionally substituted. In some embodiments, the C ₃ -C ₆ cycloalkoxy group is unsubstituted.

The term "aryl" when used alone or as part of another group is defined herein as an unsaturated aromatic monocyclic ring of 6 carbon members or an unsaturated aromatic polycyclic ring of 10 to 14 carbon members. Aryl rings may be, for example, phenyl or naphthyl rings, each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. In some embodiments, the aromatic ring system is unsubstituted. Non-limiting examples of aryl include: phenyl, naphthalene-1-yl, naphthalene-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino- 4-fluorophenyl, 2-( N , N -diethylamino)phenyl, 2-cyanophenyl, 2,6-ditertiary butylphenyl, 3-methoxyphenyl, 8 -Hydroxynaphthalene-2-yl, 4,5-dimethoxynaphthalene-1-yl and 6-cyano-naphthalene-1-yl. Aryl also includes, for example, phenyl or naphthyl fused to one or more saturated or partially saturated carbocycles (e.g. bicyclo[4.2.0]oct-1,3,5-trienyl, indenyl) ring, such phenyl or naphthyl rings may be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated ring.

The term "arylalkyl" or "aralkyl" refers to the group -alkyl-aryl, wherein alkyl and aryl are as defined herein. The aralkyl groups of the present invention are optionally substituted. In some embodiments, the arylalkyl group is unsubstituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, perylenemethyl and the like.

The terms "heterocycle" and/or "heterocyclyl", whether used alone or as part of another group, are defined herein as having one or more rings of 3 to 20 atoms, at least one of which is At least one atom of is a heteroatom selected from nitrogen (N), oxygen (O) or sulfur (S), and wherein further, the ring system comprising the heteroatom is non-aromatic. In a heterocyclic group comprising 2 or more fused rings, the ring bearing a non-heteroatom may be an aryl group (eg, indolinyl, tetrahydroquinolyl, chromanyl). Exemplary heterocyclic groups have 3 to 14 ring atoms, of which 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocyclic group may be oxidized. Heterocyclic groups can be optionally substituted. In some embodiments, a heterocyclic group is unsubstituted.

Non-limiting examples of heterocyclic units having a single ring include: diaziridinyl, aziridinyl, ureazolidinyl, tetrahydroaziridinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, iso Oxazolinyl, Isoxazolyl, Tetrahydrothiazolyl, Isothiazolyl, Isothiazolinyl, Othiazolone, Ozolidinone, Hydantoyl, Tetrahydrofuryl, Pyrrolidinyl, 𠰌linyl, piper𠯤yl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1 H -azepinyl, 2,3-dihydro-1 H -indole and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro- 1H -pyrrolyl, 3a,4,5,6,7,7a-hexahydro- 1H -benzo[ d] imidazolyl, 3a,4,5,6,7,7a-hexahydro-1 H -indolyl, 1,2,3,4-tetrahydroquinolyl, chromanyl, iso chromanyl, indolinyl, isoindolinyl and decahydro- 1H -cyclooct[b]pyrrolyl.

The term "heteroaryl", whether used alone or as part of another group, is defined herein as having one or more rings of 5 to 20 atoms, wherein at least one atom in at least one ring is selected from Heteroatoms of nitrogen (N), oxygen (O) or sulfur (S), and further wherein at least one of the rings containing the heteroatoms is aromatic. In heteroaryl groups containing 2 or more fused rings, the rings bearing non-heteroatoms can be carbocyclic (e.g., 6,7-dihydro- 5H -cyclopentapyrimidine) or aryl (e.g., benzofuryl, benzothienyl, indolyl). Exemplary heteroaryl groups have 5 to 14 ring atoms and contain 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 may be oxidized. Heteroaryl groups may be substituted. In some embodiments, a heteroaryl is 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, triazolyl, thioxyl, thiazolyl, 1H -imidazolyl, oxazolyl, furyl, thienyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridyl, 3-methylpyridyl and 4-dimethylaminopyridine base. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuryl, benzothienyl, benzozozolyl, benzothiazolyl, benzotriazolyl, phenoline base, phenidyl, phenanthridinyl, 7 H-purinyl, 9 H - purinyl, 6-amino-9 H -purinyl, 5 H -pyrrolo[3,2- d ]pyrimidinyl, 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrido[2,3- d ]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 H -indolyl, 4,5,6, 7-tetrahydro-1- H -indolyl, quinolinyl, 5-methylquinazolinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl and isoquinolinyl.

A non-limiting example of a heteroaryl group as described above is a C ₁ -C ₅ heteroaryl group having 1 to 5 carbon ring atoms and at least one is independently selected from nitrogen (N), oxygen (O) or Additional ring atoms that are heteroatoms of sulfur (S) (preferably 1 to 4 additional ring atoms that are heteroatoms). Examples of C ₁ -C ₅ heteroaryl groups include, but are not limited to, trioxyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1 H -imidazol-2-yl, 1 H -imidazol- 4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine -5-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

Unless otherwise stated, when two substituents are taken together to form a ring having the specified number of ring atoms, the ring may have carbon atoms and optionally one or more (for example, 1 to 3) independently selected Additional heteroatoms from nitrogen (N), oxygen (O) or sulfur (S). The ring can be saturated or partially saturated and optionally substituted.

被認為是雜環單元。出於本發明之目的，具有下式的6,7-二氫-5 H-環戊嘧啶：

被認為是雜芳基單元。當稠環單元在飽和環和芳環中都含有雜原子時，芳環將占主導地位並決定該環所屬的類別類型。例如，出於本發明之目的，具有下式的1,2,3,4-四氫-[1,8]㖠啶：

被認為是雜芳基單元。 For the purposes of this invention, fused ring units containing a single heteroatom, as well as spirocycles, bicycles, etc., will be considered to belong to the cyclic family corresponding to heteroatom-containing rings. For example, for the purposes of the present invention, 1,2,3,4-tetrahydroquinolines have the formula:

considered to be a heterocyclic unit. For the purposes of the present invention, 6,7-dihydro- 5H -cyclopentapyrimidine has the formula:

considered to be a heteroaryl unit. When the fused ring unit contains heteroatoms in both the saturated ring and the aromatic ring, the aromatic ring will dominate and determine the class to which the ring belongs. For example, for the purposes of the present invention, 1,2,3,4-tetrahydro-[1,8]pyridine has the formula:

considered to be a heteroaryl unit.

Whenever a term or any of its prefixed roots appears in the name of a substituent, that name should be construed as including those limitations provided herein. For example, whenever the term "alkyl" or "aryl" or any of their prefixed roots appears in the name of a substituent (e.g., arylalkyl, alkylamino), that name should be construed to include the above Those limitations given above for "alkyl" and "aryl".

The term "substituted" is used throughout the specification. The term "substituted" is defined herein as an acyclic or cyclic moiety having one or more hydrogen atoms replaced by a substituent or several (eg, 1 to 10) substituents as defined below. Substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, such substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, substituent units requiring replacement of a single hydrogen atom include halogen, hydroxyl, and the like. Two hydrogen atom replacements include carbonyl, hydroxyimino, and the like. Replacement of two hydrogen atoms from adjacent carbon atoms includes epoxy and the like. The term "substituted" as used throughout this specification means that a moiety may have one or more hydrogen atoms replaced by a substituent. When a moiety is described as "substituted," any number of hydrogen atoms may be replaced. For example, C ₁ alkyl substituted by difluoromethyl; C ₁ alkyl substituted by trifluoromethyl; aromatic ring substituted by 4-hydroxyphenyl; (N,N-dimethyl-5-amino ) octyl is a substituted C _alkyl ; 3-guanidinopropyl is a substituted C alkyl; and ₂ -carboxypyridyl 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," that moiety is unsubstituted.

The variable groups defined herein (such as alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl as defined herein), whether used alone or as another Some of the groups used may be optionally substituted. Optionally substituted groups are so indicated. In some embodiments, all variable groups are unsubstituted. For the avoidance of doubt, where a moiety is not a variable group (eg methyl, _OCF3 , ethylenyl, etc.), unless otherwise stated, that moiety is not optionally substituted.

The following are non-limiting examples of substituents that can replace a hydrogen atom on a moiety: Halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine (I)), -CN, -NO ₂ , pendant oxygen group (=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 alkyl, haloalkyl, alkenyl, alkynyl, alk Each of oxy, cycloalkyl, aryl, heterocycle and heteroaryl is optionally independently selected from 1-10 of halogen, -CN, -NO ₂ , pendant oxy and R ⁵ (e.g. , 1-6 or 1-4) group substitution; where R ⁵ at each occurrence is independently 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 OR 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 (for example, C _3-6 cycloalkyl), aryl, heterocycle or heteroaryl, or two R ^units are taken together with the atoms to which they are bonded to form an optionally substituted carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring has 3 to 7 ring atoms; wherein each occurrence of R ^is independently is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, cycloalkyl (for example, C _3-6 cycloalkyl), aryl, Heterocyclic or heteroaryl, or two ^R units together with the atoms to which they are bonded form an optionally substituted carbocyclic or heterocyclic ring, wherein the carbocyclic or heterocyclic ring preferably has 3 to 7 rings atom.

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 CH2CH3} ; iv) -C(O)N( ^R7 ) ₂ ; for example, _-CONH2 , _-CONHCH3 , -CON( _{CH3 ) 2} ; v) -N( ^R7 ) ₂ ; for example, - NH ₂ , —NHCH ₃ , —N(CH ₃ ) ₂ , —NH(CH ₂ CH ₃ ); vi) halogens: —F, —Cl, —Br, and —I; vii) —CH _e X _g ; where X is halogen, e+g=3; for example, -CH ₂ F, -CHF ₂ , -CF ₃ , -CCl ₃ 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) pendant oxy (=0); xiv) heterocycle; and xv) heteroaryl. wherein each R ⁷ is independently hydrogen, optionally substituted C ₁ -C ₆ straight or branched chain alkyl (eg, optionally substituted C ₁ -C ₄ straight or branched chain alkyl), or optionally substituted 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 of atoms. In certain aspects, each R ⁷ is independently hydrogen, C ₃ -C ₆ straight or branched chain alkyl or C ₃ -C ₆ cycloalkane optionally substituted with halogen or C ₁ -C ₆ cycloalkyl base.

Throughout this specification, substituents of compounds are disclosed in groups or ranges. Specifically, this specification is intended to include each individual subcombination of members of such groups and ranges. For example, the term "C _1-6 alkyl" is specifically intended to disclose individually 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.

For the purposes of the present invention, the terms "compound", "analogue" and "composition of matter" apply equally to the antifungal agents described herein, including all enantiomer forms, diastereomer forms, salts, etc. , and the terms "compound", "analogue" and "composition of matter" are used interchangeably throughout this specification.

The compounds described herein may contain asymmetric atoms (also known as chiral centers), and some compounds may contain one or more asymmetric atoms or centers, thus giving rise to optical isomers (mirror images) and non-mirror images. isomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as racemic and resolved enantiomers, pure R and S stereoisomers, and R and S stereoisomers. Other mixtures of constructs and pharmaceutically acceptable salts thereof. Optical isomers may be obtained in pure form by standard procedures known to those skilled in the art, including, but not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric syntheses. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (eg, alkenes and imines). It is also to be understood that the present teaching encompasses all possible regioisomers and mixtures thereof, which may be obtained in pure form by standard separation procedures known to those skilled in the art, and including but not limited to column chromatography, thin layer chromatography and high performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings, which may have acidic moieties, can be formed using organic and inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, monoanionic and polyanionic salts are considered. Suitable salts with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium; pyridine, mono-, di-, or tri-lower alkylamines (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethylpropylamine) or Those formed from mono-, di- or trihydroxy lower alkylamines such as 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 . Inner salts may also be formed. Similarly, when the compounds disclosed herein contain a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethylenesulfonic acid, formic acid, fumaric acid , gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid and camphorsulfonic acid and other known pharmaceutically acceptable acids.

When any variable occurs more than once in any composition or in any formula, its definition at each occurrence is independent of its definition at all other occurrences (for example, in N(R ⁹ ) ₂ , each R ⁹ may be the same or different from the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, the term "treating" refers to the partial or complete alleviation, inhibition, amelioration and/or alleviation of a condition suspected of being suffered by a patient.

As used herein, "therapeutically effective" and "effective dose" refer to a substance or amount that elicits a desired biological activity or effect.

Unless otherwise stated, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as laboratory animals such as rabbits, rats and mice, and other animal. Accordingly, the term "subject" or "patient" as used herein refers to any mammalian patient or subject to whom a compound of the invention may be administered, eg, a mammalian patient or subject in need of treatment. In an exemplary embodiment of the invention, to identify subject patients for treatment according to the methods of the invention, acceptable screening methods are employed to determine risk factors associated with a target or suspected disease or condition or to determine the subject's State of existing disease or condition. Such screening methods include, for example, routine examinations to identify risk factors that may be associated with a target or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of treatment using the methods and compounds of the invention. antifungal agent

包括其水合物、溶劑合物、藥學上可接受的鹽、前驅藥和複合物，其中： A ¹選自由以下組成之群組：

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； A ³在每次出現時獨立地選自由以下組成之群組：

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； A ⁴在每次出現時獨立地選自由以下組成之群組：

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； A ⁵在每次出現時獨立地選自由以下組成之群組：

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； q在每次出現時獨立地為0、1、2或3； t在每次出現時獨立地為1、2或3； R ¹在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^1a在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ²在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^2a在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2b在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2c在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2d在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2e在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2f在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2g在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2h在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ²ⁱ在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2j在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2k在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ^2l在每次出現時獨立地選自由H、C _1-4烷基、C _1-4烷氧基、C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； 在一些實施方式中，R ^2e和R ^3z連接形成由五或六個成員組成的雜環； 在一些實施方式中，R ²ⁱ和R ^3y連接形成由五或六個成員組成的雜環； 在一些實施方式中，R ³和R ^3c連接形成由五個成員組成的雜環； R ³在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3a在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3c在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3d在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3y在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^3z在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4a在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4b在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4c在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4d在每次出現時獨立地選自由H和C _1-4烷基組成之群組； R ^4e在每次出現時獨立地選自由H和C _1-4烷基組成之群組。 The antifungal agents of the present invention include all enantiomer and diastereomer forms of formula (I) and pharmaceutically acceptable salts thereof:

Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: ^A1 is selected from the group consisting of:

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; ^A2, at each occurrence, is independently selected from the group consisting of:

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; ^A3, at each occurrence, is independently selected from the group consisting of:

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; ^A4 is independently selected at each occurrence from the group consisting of:

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; A ⁵ is independently selected at each occurrence from the group consisting of:

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,

and

; q is independently 0, 1, 2 or 3 at each occurrence; t is independently 1, 2 or 3 at each occurrence; ^{R is} independently selected from H and C _1-4 at each occurrence The group consisting of alkyl; R ^1a at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ² at each occurrence is independently selected from H and C _1-4 alkyl The group consisting of; R ^2a is independently selected from each occurrence of H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF The group consisting of ₃ and CF ₃ ; R ^2b at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl , CN, OCF ₃ and the group consisting of CF ₃ ; R ^2c at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy , the group consisting of F, Cl, CN, OCF ₃ and CF ₃ ; R ^2d at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched The group consisting of alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2e at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C The group consisting of _3-5 branched chain alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2f at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkane The group consisting of oxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2g is independently selected from each occurrence of H, C _1-4 alkyl, C The group consisting of _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2h is independently selected from H, C _1-4 at each occurrence The group consisting of alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ²ⁱ is independently selected from H, The group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2j independently at each occurrence 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 in each 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 when present; R ²¹ is independently selected at each occurrence from the group consisting of H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched chain alkoxy, F, Cl, CN, OCF ₃ and CF ₃ Group; In some embodiments, R ^2e and R ^3z are connected to form a heterocycle consisting of five or six members; In some embodiments, R ²ⁱ and R ^3y are connected to form a heterocycle 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 independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3a is in Each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^3c is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3d is independently selected at each occurrence independently selected from the group consisting of H and C _1-4 alkyl at each occurrence; R ^3y at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^3z at each occurrence independently selected from the group consisting of H and C _1-4 alkyl; R ^4a is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^4b is independently selected at each occurrence selected from the group consisting of H and C _1-4 alkyl; R ^4c at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ^4d at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; each occurrence of R ^4e is independently selected from the group consisting of H and C _1-4 alkyl.

For the avoidance of doubt, the orientations of A ¹ , A ² and A ³ in compounds of formula (I) are as follows: the depicted linkage on the left hand side of A ¹ is connected to A ³ via an amide moiety, and the depicted A ¹ to The linkage on the right hand side is attached to ^A2 via the amide moiety; the linkage on the left hand side of ^A2 is depicted to be attached to ^A4 , and the linkage on the right hand side of ^A2 is depicted to be attached to ^A1 via the amide moiety and the depicted linkage on the left hand side of ^A3 is connected to ^A5 , and the depicted linkage on the right hand side of ^A3 is connected to ^A1 via an amide moiety.

In some embodiments of the compound of formula (I), A ¹ , A ² and A ³ are as defined in embodiments D1 to D25 in Table A below.

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

[Table A]: Embodiments D1 to D25 Implementation A1 A2 A3 D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( Ia ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( Ib ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( II ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( III ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( IV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( V ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( VI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( VII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds having formula ( VIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( IX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( X ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XIV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XVI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XVII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XVIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XIX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XXVI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XXVII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物、藥學上可接受的鹽和複合物。 Compounds of the present invention include compounds of formula ( XXVIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included.

The following compounds are excluded from the scope of the compounds claimed in Claim 1: Pyrimidine-4,6-dicarboxylic acid bis{[4-(1-formamimidino-1,2,3,6-tetrahydropyridine -4-yl)-phenyl]-amide} (CAS registry number 1453839-10-5, see WO 2013/130738).

時，則A ²和A ³為不同的部分和/或A ⁴和A ⁵為不同的部分。 In some embodiments of the compound of formula (I), when ^A is a pyrimidine moiety

, then ^A2 and ^A3 are different parts and/or ^A4 and ^A5 are different parts.

時，則A ²和A ³為不同的部分。 In some embodiments of the compound of formula (I), when ^A is a pyrimidine moiety

, then A ² and A ³ are different parts.

時，則A ⁴和A ⁵為不同的部分。 In some embodiments of the compound of formula (I), when ^A is a pyrimidine moiety

, then A ⁴ and A ⁵ are different parts.

時，則A ⁴和A ⁵不都為

。 In some embodiments of the compound of formula (I), when ^A is a pyrimidine moiety

, then A ⁴ and A ⁵ are not both

.

時，則A ⁴為

和/或A ⁵為

。 In some embodiments of the compound of formula (I), when ^A is a pyrimidine moiety

, then A ⁴ is

and/or A ⁵ for

.

。 In some embodiments of compounds of formula (I), ^A is not a pyrimidine moiety

.

、

、

、

、

、

、

、

、

、

、

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

and

.

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

and

.

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

and

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

。 In some embodiments, A ¹ is

.

、

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

,

and

.

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

and

.

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

and

.

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

and

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

。 In some embodiments, ^A2 is

.

、

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

,

and

.

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

and

.

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

and

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

。 In some embodiments, ^A3 is

.

、

、

、

、

、

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

,

,

,

,

,

and

.

、

、

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

,

,

and

.

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

and

.

和

。 In some embodiments, A ^is selected from the group consisting of:

and

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

。 In some embodiments, ^A4 is

.

、

、

、

、

、

、

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

,

,

,

,

,

,

and

.

、

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

,

and

.

、

和

。 In some embodiments, A ^is selected from the group consisting of:

,

and

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

。 In some embodiments, ^A5 is

.

In some embodiments, q is independently 0, 1 or 2 at each occurrence.

In some embodiments, when a compound of the invention has two qs, each q has the same value.

In some embodiments, when a compound of the invention has two qs, each q has a different value.

In some embodiments, q is 0, 1, 2 or 3.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, q is 2.

In some embodiments, q is 3.

In some embodiments, when a compound of the invention has two t's, each t has the same value.

In some embodiments, when a compound of the invention has two t, each t has a different value.

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

In some embodiments, t is 1.

In some embodiments, t is 2.

In some embodiments, t is 3.

In some embodiments, R ^2e and R ^3z are joined to form a five member heterocycle.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H and methyl.

In some embodiments, R ¹ is H.

In some embodiments, R ¹ is C _1-4 alkyl.

In some embodiments, each occurrence of R ^1a is independently selected from the group consisting of H and methyl.

In some embodiments, R ^1a is H.

In some embodiments, R ^1a is C _1-4 alkyl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H and methyl.

In some embodiments, ^R is H.

In some embodiments, R ² is C _1-4 alkyl.

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

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methyl, F, and Cl.

In some embodiments, R ^2a is H.

In some embodiments, R ^2a is C _1-4 alkyl.

In some embodiments, R ^2a is C _1-4 alkoxy.

In some embodiments, R ^2a is C _3-5 branched alkoxy.

In some embodiments, R ^2a is F.

In some embodiments, R ^2a is Cl.

In some embodiments, R ^2a is CN.

In some embodiments, R ^2a is OCF ₃ .

In some embodiments, R ^2a is CF ₃ .

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

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methyl, F, and Cl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H or methyl.

In some embodiments, R ^2b is H.

In some embodiments, R ^2b is C _1-4 alkyl.

In some embodiments, R ^2b is C _1-4 alkoxy.

In some embodiments, R ^2b is C _3-5 branched alkoxy.

In some embodiments, R ^2b is F.

In some embodiments, R ^2b is Cl.

In some embodiments, R ^2b is CN.

In some embodiments, R ^2b is OCF ₃ .

In some embodiments, R ^2b is CF ₃ .

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

In some embodiments, each occurrence ^{of R} is independently selected from the group consisting of H, methyl, F, and Cl.

In some embodiments, R ^2c is H.

In some embodiments, R ^2c is C _1-4 alkyl.

In some embodiments, R ^2c is C _1-4 alkoxy.

In some embodiments, R ^2c is C _3-5 branched alkoxy.

In some embodiments, R ^2c is F.

In some embodiments, R ^2c is Cl.

In some embodiments, R ^2c is CN.

In some embodiments, R ^2c is OCF ₃ .

In some embodiments, R ^2c is CF ₃ .

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

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methyl, F, and Cl.

In some embodiments, each occurrence of R ^2d is independently selected from the group consisting of H or methyl.

In some embodiments, R ^2d is H.

In some embodiments, R ^2d is C _1-4 alkyl.

In some embodiments, R ^2d is C _1-4 alkoxy.

In some embodiments, R ^2d is C _3-5 branched alkoxy.

In some embodiments, R ^2d is F.

In some embodiments, R ^2d is Cl.

In some embodiments, R ^2d is CN.

In some embodiments, R ^2d is OCF ₃ .

In some embodiments, R ^2d is CF ₃ .

In some embodiments, when present, no more than two of R ^2a , R ^2b , R ^2c and R ^2d are not H.

In some embodiments, when present, not more than one of R ^2a , R ^2b , R ^2c and R ^2d is not H.

In some embodiments, R ^2a , R ^2b , R ^2c and R ^2d are H when present.

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

In some embodiments, each occurrence of R ^is independently selected from the group consisting of H, methyl, methoxy, F and Cl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H and methoxy.

In some embodiments, R ^2e is H.

In some embodiments, R ^2e is C _1-4 alkyl.

In some embodiments, R ^2e is C _1-4 alkoxy.

In some embodiments, R ^2e is C _3-5 branched alkoxy.

In some embodiments, R ^2e is F.

In some embodiments, R ^2e is Cl.

In some embodiments, R ^2e is CN.

In some embodiments, R ^2e is OCF ₃ .

In some embodiments, R ^2e is CF ₃ .

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

In some embodiments, each occurrence ^{of R} is independently selected from the group consisting of H, methyl, methoxy, F and Cl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methoxy and F.

In some embodiments, R ^2f is H.

In some embodiments, R ^2f is C _1-4 alkyl.

In some embodiments, R ^2f is C _1-4 alkoxy.

In some embodiments, R ^2f is C _3-5 branched alkoxy.

In some embodiments, R ^2f is F.

In some embodiments, R ^2f is Cl.

In some embodiments, R ^2f is CN.

In some embodiments, R ^2f is OCF ₃ .

In some embodiments, R ^2f is CF ₃ .

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

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H and methoxy.

In some embodiments, R ^2g is H.

In some embodiments, R ^2g is C _1-4 alkyl.

In some embodiments, R ^2g is C _1-4 alkoxy.

In some embodiments, R ^2g is C _3-5 branched alkoxy.

In some embodiments, R ^2g is F.

In some embodiments, R ^2g is Cl.

In some embodiments, R ^2g is CN.

In some embodiments, R ^2g is OCF ₃ .

In some embodiments, R ^2g is CF ₃ .

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

In some embodiments, each occurrence ^{of R} is independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methoxy, and F.

In some embodiments, R ^2h is H.

In some embodiments, R ^2h is C _1-4 alkyl.

In some embodiments, R ^2h is C _1-4 alkoxy.

In some embodiments, R ^2h is C _3-5 branched alkoxy.

In some embodiments, R ^2h is F.

In some embodiments, R ^2h is Cl.

In some embodiments, R ^2h is CN.

In some embodiments, R ^2h is OCF ₃ .

In some embodiments, R ^2h is CF ₃ .

In some embodiments, when present, no more than two of R ^2e , R ^2f , R ^2g and R ^2h are not H.

In some embodiments, when present, not more than one of R ^2e , R ^2f , R ^2g and R ^2h is not H.

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

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

In some embodiments, each occurrence ^{of R} is independently selected from the group consisting of H, methyl, methoxy, F and Cl.

In some embodiments, R ²ⁱ is H.

In some embodiments, R ²ⁱ is C _1-4 alkyl.

In some embodiments, R ²ⁱ is C _1-4 alkoxy.

In some embodiments, R ²ⁱ is C _3-5 branched alkoxy.

In some embodiments, R ²ⁱ is F.

In some embodiments, R ²ⁱ is Cl.

In some embodiments, R ²ⁱ is CN.

In some embodiments, R ²ⁱ is OCF ₃ .

In some embodiments, R ²ⁱ is CF ₃ .

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

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methyl, methoxy, F, and Cl.

In some embodiments, R ^2j is H.

In some embodiments, R ^2j is C _1-4 alkyl.

In some embodiments, R ^2j is C _1-4 alkoxy.

In some embodiments, R ^2j is C _3-5 branched alkoxy.

In some embodiments, R ^2j is F.

In some embodiments, R ^2j is Cl.

In some embodiments, R ^2j is CN.

In some embodiments, R ^2j is OCF ₃ .

In some embodiments, R ^2j is CF ₃ .

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

In some embodiments, each occurrence ^{of R} is independently selected from the group consisting of H, methyl, methoxy, F and Cl.

In some embodiments, R ^2k is H.

In some embodiments, R ^2k is C _1-4 alkyl.

In some embodiments, R ^2k is C _1-4 alkoxy.

In some embodiments, R ^2h is C _3-5 branched alkoxy.

In some embodiments, R ^2k is F.

In some embodiments, R ^2k is Cl.

In some embodiments, R ^2k is CN.

In some embodiments, R ^2k is OCF ₃ .

In some embodiments, R ^2k is CF ₃ .

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

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H, methyl, methoxy, F and Cl.

In some embodiments, R ²¹ is H.

In some embodiments, R ²¹ is C _1-4 alkyl.

In some embodiments, R ²¹ is C _1-4 alkoxy.

In some embodiments, R ²¹ is C _3-5 branched alkoxy.

In some embodiments, R ²¹ is F.

In some embodiments, R ²¹ is Cl.

In some embodiments, R ²¹ is CN.

In some embodiments, R ²¹ is OCF ₃ .

In some embodiments, R ²¹ is CF ₃ .

In some embodiments, when present, no more than two of R ²ⁱ , R ^2j , R ^2k and R ²¹ are not H.

In some embodiments, when present, no more than one of R ²ⁱ , R ^2j , R ^2k and R ²¹ is other than H.

In some embodiments, R ²ⁱ , R ^2j , R ^2k and R ²¹ are H when present.

In some embodiments, each occurrence of ^R3 is independently selected from the group consisting of H and methyl.

In some embodiments, R ³ is H.

In some embodiments, R ³ is C _1-4 alkyl.

In some embodiments, each occurrence of R ^3a is independently selected from the group consisting of H and methyl.

In some embodiments, R ^3a is H.

In some embodiments, R ^3a is C _1-4 alkyl.

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

In some embodiments, R ^3c is H.

In some embodiments, R ^3c is C _1-4 alkyl.

In some embodiments, each occurrence of R ^3d is independently selected from the group consisting of H and methyl.

In some embodiments, R ^3d is H.

In some embodiments, R ^3d is C _1-4 alkyl.

In some embodiments, each occurrence of R ^3y is independently selected from the group consisting of H and methyl.

In some embodiments, R ^3y is H.

In some embodiments, R ^3y is C _1-4 alkyl.

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

In some embodiments, R ^3z is H.

In some embodiments, R ^3z is C _1-4 alkyl.

In some embodiments, R ^2e and R ^3z are joined to form a six member heterocycle.

In some embodiments, R ²ⁱ and R ^3y are joined to form a five member heterocycle.

In some embodiments, R ²ⁱ and R ^3y are joined to form a six member heterocycle.

In some embodiments, R ^{and R} are joined to form a five member heterocycle.

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

In some embodiments, R ^2e and R ^3z together form a methylene or ethylidene bridging moiety.

In some embodiments, R ²ⁱ and R ^3y are attached and together with the phenyl moiety to which R ²ⁱ is attached form an isoindoline, tetrahydroquinoline or tetrahydroisoquinoline ring.

In some embodiments, R ²ⁱ and R ^3y together form a methylene or ethylidene bridging moiety.

In some embodiments, R ³ and R ^3c are joined and form a 4,5-dihydro-1H-imidazole ring.

In some embodiments, R ³ and R ^3c together form an ethylidene bridging moiety.

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 ethylidene bridging moiety, wherein R ^2e and R ^3z may together form a methylene or ethylidene bridging moiety, and wherein R ²ⁱ and R ^3y may together form a methylene or ethylidene bridging moiety.

In some embodiments, each occurrence of R ^4a is independently selected from the group consisting of H and methyl.

In some embodiments, R ^4a is H.

In some embodiments, R ^4a is C _1-4 alkyl.

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

In some embodiments, R ^4b is H.

In some embodiments, R ^4b is C _1-4 alkyl.

In some embodiments, each occurrence of R ^4c is independently selected from the group consisting of H and methyl.

In some embodiments, R ^4c is H.

In some embodiments, R ^4c is C _1-4 alkyl.

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

In some embodiments, R ^4d is H.

In some embodiments, R ^4d is C _1-4 alkyl.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H and methyl.

In some embodiments, R ^4e is H.

In some embodiments, R ^4e is C _1-4 alkyl.

In some embodiments, when present, no more than two of R ^4a , R ^4b , R ^4c , R ^4d , and R ^4e are not H.

In some embodiments, when present, not more than one of R ^4a , R ^4b , R ^4c , R ^4d , and R ^4e is not H.

In some embodiments, R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are H when present.

In some embodiments, each occurrence ^of R is independently selected from the group consisting of H and methyl.

In some embodiments, R ^4f is H.

In some embodiments, R ^4f is C _1-4 alkyl.

、

、

、

、

和

； A ³選自由以下組成之群組：

、

、

、

、

和

； A ⁴選自由以下組成之群組：

、

、

、

、

、

、

、

、

和

； A ⁵選自由以下組成之群組：

、

、

、

、

、

、

、

、

和

； q在每次出現時獨立地為0、1、2或3； R ¹、R ^1a和R ²在每次出現時獨立地選自由H和未取代的C _1-4烷基組成之群組； R ^2a、R ^2b、R ^2c、R ^2d、R ^2e、R ^2f、R ^2g、R ^2h、R ²ⁱ、R ^2j、R ^2k、R ^2l在每次出現時獨立地選自由H、未取代的C _1-4烷基、未取代的C _1-4烷氧基、未取代的C _3-5支鏈烷氧基、F、Cl、CN、OCF ₃和CF ₃組成之群組； R ³、R ^3a、R ^3c、R ^3d、R ^3y和R ^3z在每次出現時獨立地選自由H和未取代的C _1-4烷基組成之群組； 或者R ^2e和R ^3z一起形成亞甲基或伸乙基橋連部分； 或者R ²ⁱ和R ^3y一起形成亞甲基或伸乙基橋連部分； 或者R ³和R ^3c一起形成伸乙基橋連部分；以及 R ^4a、R ^4b、R ^4c和R ^4d在每次出現時獨立地選自由H和未取代的C _1-4烷基組成之群組。 In some embodiments (embodiment E1), A ^is selected from the group consisting of:

,

,

,

,

and

; A ³ is selected from the group consisting of:

,

,

,

,

and

; A ⁴ is selected from the group consisting of:

,

,

,

,

,

,

,

,

and

; A ⁵ is selected from the group consisting of:

,

,

,

,

,

,

,

,

and

; q is independently 0, 1, 2 or 3 at each occurrence; R ¹ , R ^1a and R ² are independently selected at each occurrence 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 ²ⁱ , R ^2j , R ^2k , R ^2l are each independently selected from H, unsubstituted A group consisting of 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 independently selected at each occurrence from the group consisting of H and unsubstituted C _1-4 alkyl; or R ^2e and R ^3z together form methylene or ethylenyl bridging moiety; or R ²ⁱ and R ^3y together form methylene or ethylenyl bridging moiety; or R ³ and R ^3c together form ethylenyl bridging moiety; and R ^4a , R ^4b , R ^4c and R ^4d are independently selected at each occurrence from the group consisting of H and unsubstituted C _1-4 alkyl.

、

、

、

和

； A ³選自由以下組成之群組：

、

、

、

和

； A ⁴選自由以下組成之群組：

、

、

和

； A ⁵選自由以下組成之群組：

、

、

和

； q在每次出現時獨立地為0、1、2或3； R ¹、R ^1a和R ²在每次出現時獨立地選自由H和甲基組成之群組； R ^2a、R ^2b、R ^2c、R ^2d、R ^2e、R ^2f、R ^2g、R ^2h、R ²ⁱ、R ^2j、R ^2k、R ^2l在每次出現時獨立地選自由H、甲基、甲氧基、F、Cl、CN、OCF3和CF3組成之群組； R ³、R ^3y和R ^3z在每次出現時獨立地選自由H和甲基組成之群組； 或者R ^2e和R ^3z一起形成亞甲基或伸乙基橋連部分； 或者R ²ⁱ和R ^3y一起形成亞甲基或伸乙基橋連部分；以及 R ^4a、R ^4b、R ^4c和R ^4d在每次出現時獨立地選自由H和甲基組成之群組；並且其中 當存在時，R ^2a、R ^2b、R ^2c和R ^2d中不超過兩個不是H； 當存在時，R ^2e、R ^2f、R ^2g和R ^2h中不超過兩個不是H； 當存在時，R ²ⁱ、R ^2j、R ^2k和R ^2l中不超過兩個不是H；以及 當存在時，R ^4a、R ^4b、R ^4c和R ^4d中不超過兩個不是H。 In some embodiments (embodiment E2), ^A is selected from the group consisting of:

,

,

,

and

; A ³ is selected from the group consisting of:

,

,

,

and

; A ⁴ is selected from the group consisting of:

,

,

and

; A ⁵ is selected from the group consisting of:

,

,

and

; q is independently 0, 1, 2 or 3 at each occurrence; R ¹ , R ^1a and R ² are independently selected at each occurrence 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 ²ⁱ , R ^2j , R ^2k , R ^2l are at each occurrence independently selected from H, methyl, methoxy, F, Cl , the group consisting of CN, OCF3 and CF3; R ³ , R ^3y and R ^3z are independently selected at each occurrence from the group consisting of H and methyl; or R ^2e and R ^3z together form a methylene or an extension an ethyl bridging moiety; or R ²ⁱ and R ^3y together form a methylene or ethylenyl bridging moiety; and R ^4a , R ^4b , R ^4c and R ^4d are independently selected from H and methyl at each occurrence and wherein when present, no more than two of R ^2a , R ^2b , R ^2c and R ^2d are not H; when present, no more than two of R ^2e , R ^2f , R ^2g and R ^2h is not H; when present, not more than two of R ²ⁱ , R ^2j , R ^2k and R ²¹ are not H; and when present, not more than two of R ^4a , R ^4b , R ^4c and R ^4d are not H.

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和

； 並且q、A ²、A ³、A ⁴、A ⁵、R ¹、R ^1a、R ²、R ^2a、R ^2b、R ^2c和R ^2d如實施方式E1中所定義。 In some embodiments (embodiment F1), ^A is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

and

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.

、

、

、

和

； 並且q、A ²、A ³、A ⁴、A ⁵、R ¹、R ^1a、R ²、R ^2a、R ^2b、R ^2c和R ^2d如實施方式E2中所定義。 In some embodiments (F2), A ^is selected from the group consisting of:

,

,

,

and

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.

The following table further describes embodiments of the invention.

[Table B]: Embodiments G to W Implementation compound A ² , A ³ , A ⁴ , A ⁵ , R ¹ , R ^1a , R ² , R ^2a , R ^2b , R ^2c and R ^2d G1 Formula (II) As defined in Embodiment E1 G2 Formula (II) As defined in Embodiment E2 H1 Formula (III) As defined in Embodiment E1 H2 Formula (III) As defined in Embodiment E2 I1 Formula (IV) As defined in Embodiment E1 I2 Formula (IV) As defined in Embodiment E2 J1 Formula (VIII) As defined in Embodiment E1 J2 Formula (VIII) As defined in Embodiment E2 K1 Formula (IX) As defined in Embodiment E1 K2 Formula (IX) As defined in Embodiment E2 L1 Formula (X) As defined in Embodiment E1 L2 Formula (X) As defined in Embodiment E2 M1 Formula (XI) As defined in Embodiment E1 M2 Formula (XI) As defined in Embodiment E2 N1 Formula (XII) As defined in Embodiment E1 N2 Formula (XII) As defined in Embodiment E2 O1 Formula (XIII) As defined in Embodiment E1 O2 Formula (XIII) As defined in Embodiment E2 P1 Formula (XIV) As defined in Embodiment E1 P2 Formula (XIV) As defined in Embodiment E2 Q1 Formula (XV) As defined in Embodiment E1 Q2 Formula (XV) As defined in Embodiment E2 R1 Formula (XVI) As defined in Embodiment E1 R2 Formula (XVI) As defined in Embodiment E2 S1 Formula (XVII) As defined in Embodiment E1 S2 Formula (XVII) As defined in Embodiment E2 T1 Formula (XVIII) As defined in Embodiment E1 T2 Formula (XVIII) As defined in Embodiment E2 U1 Formula (XIX) As defined in Embodiment E1 U2 Formula (XIX) As defined in Embodiment E2 V1 Formula (XX) As defined in Embodiment E1 V2 Formula (XX) As defined in Embodiment E2 W1 Formula (XXVI) as defined in Embodiment E1 W2 Formula (XXVI) As defined in Embodiment E2

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和

； A ²選自由以下組成之群組：

、

、

和

； A ³選自由以下組成之群組：

、

、

、

、

和

； A ⁴選自由以下組成之群組：

、

、

、

、

、

和

； A ⁵選自由以下組成之群組：

、

、

、

、

、

、

、

、

和

； q在每次出現時獨立地為0、1或2； R ¹、R ^1a和R ²在每次出現時獨立地選自由H和甲基組成之群組； R ^2a、R ^2b、R ^2c、R ^2d在每次出現時獨立地選自由H、甲基、F和Cl組成之群組； R ^2e、R ^2f、R ^2g、R ^2h、R ²ⁱ、R ^2j、R ^2k、R ^2l在每次出現時獨立地選自由H、甲基、甲氧基、F和Cl組成之群組； R ³、R ^3a、R ^3c、R ^3d、R ^3y和R ^3z在每次出現時獨立地選自由H和甲基組成之群組； 或者R ^2e和R ^3z一起形成亞甲基或伸乙基橋連部分； 或者R ²ⁱ和R ^3y一起形成亞甲基或伸乙基橋連部分； 或者R ³和R ^3c一起形成伸乙基橋連部分；以及 R ^4a、R ^4b、R ^4c和R ^4d在每次出現時獨立地選自由H和甲基組成之群組。 In some embodiments (embodiment X), ^A is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

and

; A ² is selected from the group consisting of:

,

,

and

; ^A3 is selected from the group consisting of:

,

,

,

,

and

; ^A4 is selected from the group consisting of:

,

,

,

,

,

and

; A ⁵ is selected from the group consisting of:

,

,

,

,

,

,

,

,

and

; q is independently 0, 1 or 2 at each occurrence; R ¹ , R ^1a and R ² are independently selected at each occurrence from the group consisting of H and methyl; R ^2a , R ^2b , R ^2c , R ^2d are independently selected from the group consisting of H, methyl, F and Cl at each occurrence; R ^2e , R ^2f , R ^2g , R ^2h , R ^{2i , R 2j ,} R ^2k , R ^2l in each Each occurrence is 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 each independently selected from the group consisting of A group consisting of H and methyl; or R ^2e and R ^3z together form a methylene or ethylidene bridging moiety; or R ²ⁱ and R ^3y together form a methylene or ethylidene bridging moiety; or R ³ and R ^3c together form an ethylidene bridging moiety; and R ^4a , R ^4b , R ^4c and R ^4d are independently selected at each occurrence from the group consisting of H and methyl.

其中R ^2e、R ^2f和R ^2h之非限制性實例在下文表1中定義。 [表1]：式 ( XXI) 之示例性化合物 條目 R ^2e R ^2f R ^2h 條目 R ^2e R ^2f R ^2h 1 H H Me 8 H F H 2 H H Cl 9 OMe H H 3 H H OMe 10 H OMe H 4 H H CF ₃ 11 Cl H H 5 Me H H 12 H Cl H 6 H Me H 13 CF ₃ H H 7 F H H 14 H CF ₃ H Compounds of the present invention include compounds of formula ( XXI ) or pharmaceutically acceptable salt forms thereof:

wherein non-limiting examples of R ^2e , R ^2f and R ^2h are defined in Table 1 below. [Table 1]: Exemplary compounds of formula ( XXI ) entry R ² R ² R ^2h entry R ² R ² R ^2h 1 h h Me 8 h f h 2 h h Cl 9 OMe h h 3 h h OMe 10 h OMe h 4 h h CF ₃ 11 Cl h h 5 Me h h 12 h Cl h 6 h Me h 13 CF ₃ h h 7 f h h 14 h CF ₃ h

其中R ^2e、R ^2f和R ^2h之非限制性實例在下文表2中定義。 [表2]：式 ( XXII) 之示例性化合物 條目 R ^2e R ^2f R ^2h 條目 R ^2e R ^2f R ^2h 條目 R ^2e R ^2f R ^2h 1 H H Me 6 Me H H 11 H OMe H 2 H H F 7 H Me H 12 Cl H H 3 H H Cl 8 F H H 13 H Cl H 4 H H OMe 9 H F H 14 CF ₃ H H 5 H H CF ₃ 10 OMe H H 15 H CF ₃ H Compounds of the present invention include compounds of formula ( XXII ) or pharmaceutically acceptable salt forms thereof:

wherein non-limiting examples of R ^2e , R ^2f and R ^2h are defined in Table 2 below. [Table 2]: Exemplary compounds of formula ( XXII ) entry R ² R ² R ^2h entry R ² R ² R ^2h entry R ² R ² R ^2h 1 h h Me 6 Me h h 11 h OMe h 2 h h f 7 h Me h 12 Cl h h 3 h h Cl 8 f h h 13 h Cl h 4 h h OMe 9 h f h 14 CF ₃ h h 5 h h CF ₃ 10 OMe h h 15 h CF ₃ h

其中R ^2e、R ^2f和R ^2h之非限制性實例在下文表3中定義。 [表3]：式 ( XXIII) 之示例性化合物 條目 R ^2e R ^2f R ^2h 條目 R ^2e R ^2f R ^2h 條目 R ^2e R ^2f R ^2h 1 H H Me 6 Me H H 11 H OMe H 2 H H F 7 H Me H 12 Cl H H 3 H H Cl 8 F H H 13 H Cl H 4 H H OMe 9 H F H 14 CF ₃ H H 5 H H CF ₃ 10 OMe H H 15 H CF ₃ H Compounds of the present invention include compounds of formula ( XXIII ) or pharmaceutically acceptable salt forms thereof:

wherein non-limiting examples of R ^2e , R ^2f and R ^2h are defined in Table 3 below. [Table 3]: Exemplary compounds of formula ( XXIII ) entry R ² R ² R ^2h entry R ² R ² R ^2h entry R ² R ² R ^2h 1 h h Me 6 Me h h 11 h OMe h 2 h h f 7 h Me h 12 Cl h h 3 h h Cl 8 f h h 13 h Cl h 4 h h OMe 9 h f h 14 CF ₃ h h 5 h h CF ₃ 10 OMe h h 15 h CF ₃ h

其中R ^2e、R ^2f和R ^2h之非限制性實例在下文表4中定義。 [表4]：式 ( XXIV) 之示例性化合物 條目 R ^2h 1 Me 2 F 3 Cl 4 OMe 5 CF ₃ Compounds of the present invention include compounds of formula ( XXIV ) or pharmaceutically acceptable salt forms thereof:

wherein non-limiting examples of R ^2e , R ^2f and R ^2h are defined in Table 4 below. [Table 4]: Exemplary compounds of formula ( XXIV ) entry R ^2h 1 Me 2 f 3 Cl 4 OMe 5 CF ₃

其中R ^2f、R ^2g和R ^2h之非限制性實例在下文表5中定義。 [表5]：式 ( XXV) 之示例性化合物 條目 R ^2f R ^2g R ^2h 條目 R ^2f R ^2g R ^2h 1 H H Me 6 Me H H 2 H H F 7 H Me H 3 H H Cl 8 OMe H H 4 H H OMe 9 H OMe H 5 H H CF ₃ 10 H CF ₃ H Compounds of the present invention include compounds of formula ( XXV ) or pharmaceutically acceptable salt forms thereof:

wherein non-limiting examples of R ^2f , R ^2g and R ^2h are defined in Table 5 below. [Table 5]: Exemplary compounds of formula ( XXV ) entry R ² R ^2g R ^2h entry R ² R ^2g R ^2h 1 h h Me 6 Me h h 2 h h f 7 h Me h 3 h h Cl 8 OMe h h 4 h h OMe 9 h OMe h 5 h h CF ₃ 10 h CF ₃ h

Novel synthetic intermediate compounds are also included within the scope of the present invention.

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物和鹽，其中A ¹、A ²、A ³、A ⁴、A ⁵、R ¹和R ²如對式 (I) 之化合物所定義，並且其中A ⁴和/或A ⁵中之至少一個胍氮原子用合適的保護基團例如三級丁氧基羰基（Boc）、三氟乙醯基、9-茀基甲氧基羰基（Fmoc）或苄氧羰基（Cbz）保護。 Correspondingly, the present invention provides the compound of formula (Int-I):

Including its enantiomers, diastereoisomers, hydrates, solvates and salts, wherein A ¹ , A ² , A ³ , A ⁴ , A ⁵ , R ¹ and R ² are as for formula (I) Compound defined, and wherein at least one guanidine nitrogen atom in A ⁴ and/or A ⁵ is protected with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-fenylmethoxy Carbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection.

In another embodiment of the compound of formula (Int-I), the two primary nitrogen atoms within each guanidine moiety on ^A4 and ^A5 are protected with a suitable protecting group such as tertiary butoxycarbonyl (Boc) , trifluoroacetyl, 9-fenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection.

Where possible, the embodiments described above for compounds of formula (I) to (XX) and (XXVI) to (XXVIII) also apply to compounds of formula (Int-I).

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物和鹽，其中q、A ¹、A ²、A ³、R ¹和R ²如對式 (I) 之化合物所定義，並且R ¹⁰選自由-NH ₂和用合適的保護基團例如三級丁氧基羰基（Boc）、三氟乙醯基、9-茀基甲氧基羰基（Fmoc）或苄氧羰基（Cbz）保護的-NH ₂組成之群組，並且R ¹¹選自由合適的保護基團（例如三級丁氧基羰基（Boc）、三氟乙醯基、9-茀基甲氧基羰基（Fmoc）或苄氧羰基（Cbz））、H、-C(=N)NH和用合適的保護基團例如三級丁氧基羰基（Boc）、三氟乙醯基、9-茀基甲氧基羰基（Fmoc）或苄氧羰基（Cbz）保護的-C(=N)NH組成之群組。 The present invention also provides the compound 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 the compound of formula (I), And R ¹⁰ is selected from -NH ₂ and with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-fenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) The group consisting of protected -NH ₂ , and R ¹¹ is selected from a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-fenylmethoxycarbonyl (Fmoc) or Benzyloxycarbonyl (Cbz)), H, -C(=N)NH and with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-tertylmethoxycarbonyl ( Fmoc) or a group consisting of -C(=N)NH protected by benzyloxycarbonyl (Cbz).

Where possible, the embodiments described above for compounds of formula (I) to (XX) and (XXVI) to (XXVIII) also apply to compounds of formula (Int-II).

包括其鏡像異構物、非鏡像異構物、水合物、溶劑合物和鹽，其中q、A ¹、A ²、R ¹和R ²如對式 (I) 之化合物所定義，並且R ¹⁰選自由-NH ₂和用合適的保護基團例如三級丁氧基羰基（Boc）、三氟乙醯基、9-茀基甲氧基羰基（Fmoc）或苄氧羰基（Cbz）保護的-NH ₂組成之群組，並且R ¹²為鹵素，例如氯或溴。 The present invention also provides the compound 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 the compound of formula (I), and R ¹⁰ selected from -NH and _- protected with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-fenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) The group consisting of NH ₂ and R ¹² is halogen such as chlorine or bromine.

Where possible, the embodiments described above for compounds of formula (I) to (XX) and (XXVI) to (XXVIII) also apply to compounds of formula (Int-III).

To illustrate the manner in which the compounds of the invention are named and referred to herein, a compound having the formula:

Has the chemical name N ² ,N ⁵ -bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,5-dimethylamide.

To illustrate the manner in which the compounds of the invention are named and referred to herein, a compound having the formula:

Has the chemical name N ² ,N ⁴ -bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,4-dimethylamide.

For the purposes of the present invention, a compound depicted by a racemic formula applies equally to either of the two enantiomers or mixtures thereof, or to all diastereoisomers in the presence of a second chiral center. structure.

In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the invention as claimed. Compounds of the invention may contain any substituent or combination of substituents provided herein. method

The invention also relates to a process for the preparation of the antifungal agent according to the invention.

Compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or intermediates readily prepared according to the procedures outlined herein by employing standard synthetic methods and procedures known to those skilled in the art. body preparation. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations are readily available from the relevant scientific literature or standard textbooks in the field. It should be understood that where typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may 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 in order to optimize the formation of the compounds described herein.

The methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be 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 chromatography. Chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC) or thin layer chromatography (TLC) monitoring.

Preparation of compounds may involve protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in Greene et al. Protective Groups in Organic Synthesis [Protective Groups in Organic Synthesis] (2nd Edition, Wiley & Sons, 1991), the full disclosure of which is for all purposes reproduced by Incorporated herein by reference.

The reactions or methods described herein can be performed in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents are generally substantially nonreactive with the reactants, intermediates and/or products at the temperatures at which the reactions are carried out (ie, temperatures that may range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected.

Compounds of these teachings can be prepared by methods known in the art of organic chemistry. Reagents for the preparation of compounds of these teachings are either commercially available or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the methods illustrated in the general synthetic schemes. General synthetic schemes for the preparation of compounds

Reagents for the preparation of compounds of the invention are either commercially available or can be prepared by standard procedures described in the literature. According to the present invention, such compounds can be prepared by one of the following reaction schemes.

Compounds of formula ( I ) can be prepared according to the methods outlined in Schemes 1-120.

In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Optionally by microwave irradiation, the compound of formula ( 1 ) (a known compound or a compound prepared by known method) and the compound of formula ( 2 ) (a known compound or prepared by known method compound) reaction to obtain the compound of formula ( 3 ). Alternatively, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as dichloromethane, chloroform, 1,2- In the presence of dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, 1,2-dimethoxyethane, etc., by heating if necessary, by microwave irradiation if necessary, the formula A compound of ( 4 ) (a known compound or a compound prepared by a known method) is reacted with a compound of the formula ( 2 ) (a known compound or a compound prepared by a known method) to obtain a compound of the formula ( 3 ) compound. In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 3 ) is reacted with the compound of formula ( 5 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 6 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of toluene ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 6 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 7 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 7 ) with the compound of formula ( 8 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 9 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 9 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 10 ).

). On palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., optionally in Organic phosphines such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-bicyclo Hexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary Butylphosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tertiary butylphosphine, 2-bis Cyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'- Triisopropyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-bistri Class butylphosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(di-tertiary butylphosphino)-N,N-dimethyl In the presence of biphenyl-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., 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-lutidine, etc. In the presence of, in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary In the presence of water, optionally by heating, optionally by microwave irradiation, the compound of formula ( 11 ) and the compound of formula ( 12 ) (a known compound or a compound prepared by a known method ) reaction to obtain the compound of formula ( 13 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of toluene ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 13 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 14 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 14 ) with the compound of formula ( 15 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 16 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 16 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 17 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in solvents such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 18 ) reacts with the compound of formula ( 19 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 20 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of toluene ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 20 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 21 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc. , react the compound of formula ( 21 ) with the compound of formula (22) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 23 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 23 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 24 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 25 ) with hydrogen by microwave irradiation to give the compound of formula ( 26 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 25 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 26 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 26 ) with the compound of formula ( 27 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 28 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 28 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 29 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 30 ) with hydrogen by microwave irradiation to give the compound of formula ( 31 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 30 ) can be reacted with hydrogen to obtain the compound of formula ( 31 ) by heating if necessary, and microwave irradiation if necessary. In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc. , react the compound of formula ( 31 ) with the compound of formula (32) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 33 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 33 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 34 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 35 ) with hydrogen by microwave irradiation to give the compound of formula ( 36 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 35 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 36 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc. , react the compound of formula ( 36 ) with the compound of formula (37) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 38 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 38 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 39 ).

In the presence of solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyridine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc. , optionally in the presence of water, optionally by heating, optionally by microwave irradiation, to make the compound of formula ( 40 ) (a known compound or a compound prepared by a known method, wherein Q ¹ is a C1-6 alkyl group) reacts with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc. to obtain a compound of formula ( 41 ). In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 41 ) are reacted with compounds of formula ( 42 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 43 ). In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 43 ) reacts with the compound of formula ( 44 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 45 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of toluene ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 45 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 46 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula (46) is reacted with the compound of formula ( 47 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula (48 ) . In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 48 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 49 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 50 ) with hydrogen by microwave irradiation to give the compound of formula ( 51 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 50 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 51 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc. , react the compound of formula ( 51 ) with the compound of formula (52) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 53 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 53 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 54 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 55 ) reacts with the compound of formula ( 56 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 57 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of toluene ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 57 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 58 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 58 ) with the compound of formula ( 59 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 60 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 60 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 61 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 62 ) with hydrogen by microwave irradiation to give the compound of formula ( 63 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 62 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 63 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 63 ) with the compound of formula ( 64 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 65 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 65 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 66 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in solvents such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 67 ) reacts with the compound of formula ( 68 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 69 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 69 ) is reacted with acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 70 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 70 ) with the compound of formula ( 71 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 72 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 72 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 73 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 74 ) with hydrogen by microwave irradiation to give the compound of formula ( 75 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 74 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 75 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 75 ) with the compound of formula ( 76 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 77 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 77 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. can give the compound of formula ( 78 ).

In the presence of solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyridine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc. , optionally in the presence of water, optionally by heating, optionally by microwave irradiation, to make the compound of formula ( 79 ) (a known compound or a compound prepared by a known method, wherein Q ² is a C1-6 alkyl group) reacts with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc. to obtain a compound of formula ( 80 ). In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 80 ) are reacted with compounds of formula ( 81 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 82 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 82 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 83 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 83 ) with the compound of formula ( 84 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 85 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 85 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 86 ).

In the presence of solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyridine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc. , optionally in the presence of water, optionally by heating, optionally by microwave irradiation, to make the compound of formula ( 87 ) (a known compound or a compound prepared by a known method, wherein Q ³ is a C1-6 alkyl group) reacts with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc. to obtain a compound of formula ( 88 ). In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 88 ) are reacted with compounds of formula ( 89 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 90 ). In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 90 ) reacts with the compound of formula ( 91 ) (a known compound or a compound prepared by a known method) in the presence of , optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 92 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 92 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 93 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 93 ) is reacted with the compound of formula ( 94 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 95 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 95 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 96 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 97 ) with hydrogen by microwave irradiation to give the compound of formula ( 98 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 97 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 98 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 98 ) with the compound of formula ( 99 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 100 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 100 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 101 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in solvents such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 102 ) reacts with the compound of formula ( 103 ) (a known compound or a compound prepared by a known method) in the presence of , optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 104 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 104 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 105 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 105 ) with the compound of formula ( 106 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 107 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 107 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 108 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 109 ) with hydrogen by microwave irradiation to give the compound of formula ( 110 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 109 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 110 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 110 ) with the compound of formula ( 111 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 112 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 112 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 113 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 114 ) reacts with the compound of formula ( 115 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 116 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 116 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 117 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 117 ) with the compound of formula ( 118 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 119 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 119 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 120 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 121 ) with hydrogen by microwave irradiation to give the compound of formula ( 122 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 121 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 122 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 122 ) with the compound of formula ( 123 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 124 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 124 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 125 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., by heating if necessary, and by microwave irradiation if necessary, to make the compound of formula ( 126 ) Reaction with the compound of formula ( 127 ) gives the compound of formula ( 128 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 128 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 129 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 129 ) with the compound of formula ( 130 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 131 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 131 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 132 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 133 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 134 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethyridine, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethyl The compound of formula ( 134 ) and the compound of formula ( 135 ) (a known compound or by known method prepared compound) reaction to obtain the compound of formula ( 136 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In the presence of N-dimethylacetamide, etc., the compound of formula ( 136 ) is reacted with methyl iodide by heating if necessary, and microwave irradiation as necessary to obtain the compound of formula ( 137 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In the presence of N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 137 ) and the compound of formula ( 138 ) (a known compound or borrowed Compounds prepared by known methods) give compounds of formula ( 139 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane etc., by heating if necessary, and by microwave irradiation as necessary, the compound of formula ( 140 ) (a known compound or a compound prepared by a known method) and the compound of formula ( 141 ) Reaction, the compound of formula ( 142 ) is obtained. In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc., in the presence of bases such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide , potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in solvents such as tetrahydrofuran, 1,4-two 㗁𠮿, acetonitrile, In dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in the presence of water, optionally by heating, optionally by microwave Irradiation to react the compound of formula ( 142 ) with the compound of formula ( 139 ) to obtain the compound of formula ( 143 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., react the compound of formula ( 143 ) with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., by heating if necessary, and by microwave irradiation if necessary, to obtain the formula ( 144 ) compounds.

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 145 ) (a known compound or a compound prepared by a known method) and the compound of formula ( 146 ) Reaction, the compound of formula ( 147 ) is obtained. In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc., 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-lutidine, etc., in solvents such as tetrahydrofuran, 1,4-two 㗁𠮿, acetonitrile, In dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in the presence of water, optionally by heating, optionally by microwave Irradiation to react the compound of formula ( 147 ) with the compound of formula ( 148 ) to obtain the compound of formula ( 149 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., react the compound of formula ( 149 ) with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., by heating if necessary, and by microwave irradiation if necessary, to obtain the formula ( 150 ) compounds.

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 151 ) (a known compound or a compound prepared by a known method) and the compound of formula ( 152 ) Reaction, the compound of formula ( 153 ) is obtained. In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc., in the presence of bases such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide , potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in solvents such as tetrahydrofuran, 1,4-two 㗁𠮿, acetonitrile, In dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in the presence of water, optionally by heating, optionally by microwave Irradiation to react the compound of formula ( 153 ) with the compound of formula ( 154 ) to obtain the compound of formula ( 155 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., react the compound of formula ( 155 ) with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., by heating if necessary, and by microwave irradiation if necessary, to obtain the formula ( 156 ) compounds.

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane etc., by heating if necessary, and by microwave irradiation as necessary, the compound of formula ( 157 ) (a known compound or a compound prepared by a known method) and the compound of formula ( 158 ) Reaction, the compound of formula ( 159 ) is obtained. In the presence of ammonium chloride, in solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, dichloromethane, chloroform, 1,2-dichloro In the presence of ethane, tetrahydrofuran, 1,4-dimethoxyethane, methanol, etc., if necessary, by heating, if necessary, by microwave irradiation, the formula The compound of ( 159 ) reacts with zinc to give the compound of formula ( 160 ).

In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 161 ) are reacted with compounds of formula ( 162 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 163 ). In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 163 ) reacts with the compound of formula ( 164 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 165 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 165 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 166 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 166 ) with the compound of formula ( 167 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 168 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 168 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 169 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 170 ) with hydrogen by microwave irradiation to give the compound of formula ( 171 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 170 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 171 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 171 ) with the compound of formula ( 172 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 173 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 173 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 174 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 175 ) reacts with the compound of formula ( 176 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 177 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 177 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 178 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 178 ) with the compound of formula ( 179 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 180 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 180 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 181 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 182 ) with hydrogen by microwave irradiation to give the compound of formula ( 183 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 182 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 183 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 183 ) with the compound of formula ( 184 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 185 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 185 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 186 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 187 ) reacts with the compound of formula ( 188 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 189 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 189 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 190 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 190 ) with the compound of formula ( 191 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 192 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 192 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 193 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 194 ) with hydrogen by microwave irradiation to give the compound of formula ( 195 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 194 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 195 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 195 ) with the compound of formula ( 196 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 197 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 197 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. can give the compound of formula ( 198 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 199 ) React with the compound of formula ( 200 ) to obtain the compound of formula ( 201 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 201 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 202 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 202) is reacted with the compound of formula (203 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 204 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 204 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 205 ).

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, etc., in a solvent such as methanol, ethanol, isopropanol , tetrahydrofuran, 1,4-dimethyridine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyloxide, etc., optionally in the presence of water , react the compound of formula ( 206 ) with the compound of formula ( 207 ) by heating if necessary, and microwave irradiation if necessary to give the compound of formula ( 208 ). In the presence of ammonium chloride, in solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, dichloromethane, chloroform, 1,2-dichloro In the presence of ethane, tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, 1,2-dimethoxyethane, etc., if necessary, by heating, if necessary, by microwave irradiation, the formula ( 208 ) reacts with zinc to give a compound of formula ( 209 ).

In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 210 ) are reacted with compounds of formula ( 211 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation to give compounds of formula ( 212 ). In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 212 ) is reacted with the compound of formula ( 213 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 214 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 214 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 215 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 215 ) with the compound of formula ( 216 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 217 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 217 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 218 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 219 ) with hydrogen by microwave irradiation to give the compound of formula ( 220 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 219 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 220 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 220 ) with the compound of formula ( 221 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 222 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 222 ) and an acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 223 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in solvents such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 224 ) reacts with the compound of formula ( 225 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 226 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 226 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 227 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 227 ) with the compound of formula ( 228 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 229 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 229 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 230 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 231 ) with hydrogen by microwave irradiation to give the compound of formula ( 232 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 231 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 232 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 232 ) with the compound of formula ( 233 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 234 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 234 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 235 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 236 ) reacts with the compound of formula ( 237 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 238 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 238 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 239 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 239 ) is reacted with the compound of formula ( 240 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 241 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 241 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 242 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 243 ) with hydrogen by microwave irradiation to give the compound of formula ( 244 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 243 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 244 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 244 ) with the compound of formula ( 245 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 246 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 246 ) and acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 247 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 248 ) Reaction with the compound of formula ( 249 ) gives the compound of formula ( 250 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 250 ) and an acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 251 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 251 ) with the compound of formula ( 252 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 253 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 253 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 254 ).

In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Optionally by microwave irradiation, the compound of formula ( 255 ) (a known compound or a compound prepared by known method) and the compound of formula ( 256 ) (a known compound or prepared by known method compound) reaction to obtain the compound of formula ( 257 ). Alternatively, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as dichloromethane, chloroform, 1,2- In the presence of dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, 1,2-dimethoxyethane, etc., by heating if necessary, by microwave irradiation if necessary, the formula A compound of ( 258 ) (a known compound or a compound prepared by a known method) reacts with a compound of the formula ( 256 ) (a known compound or a compound prepared by a known method) to obtain a compound of the formula ( 257 ) compound. In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 257 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 259 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 259 ) with the compound of formula ( 260 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 261 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 261 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 262 ).

In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 263 ) are reacted with compounds of formula ( 264 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 265 ). In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 265 ) reacts with the compound of formula ( 266 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 267 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 267 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 268 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 268 ) with the compound of formula ( 269 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 270 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 270 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 271 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 272 ) with hydrogen by microwave irradiation to give the compound of formula ( 273 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 272 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 273 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 273 ) is reacted with the compound of formula ( 274 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 275 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 275 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 276 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in solvents such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 277 ) is reacted with the compound of formula ( 278 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 279 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 279 ) is reacted with acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 280 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 280 ) is reacted with the compound of formula ( 281 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 282 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 282 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 283 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in solvents such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 284 ) with hydrogen by microwave irradiation to give the compound of formula ( 285 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 284 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 285 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 285 ) with the compound of formula ( 286 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 287 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 287 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. can give the compound of formula ( 288 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in solvents such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 289 ) is reacted with the compound of formula ( 290 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 291 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 291 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 292 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula (292) is reacted with the compound of formula ( 293 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 294 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 294 ) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 295 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 296 ) with hydrogen by microwave irradiation to give the compound of formula ( 297 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 296 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 297 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 297 ) is reacted with the compound of formula ( 298 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 299 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 299 ) and an acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 300 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., by heating if necessary, and by microwave irradiation if necessary, to make the compound of formula ( 301 ) Reaction with the compound of formula ( 302 ) gives the compound of formula ( 303 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 303 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 304 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 304 ) is reacted with the compound of formula ( 305 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 306 ).

In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 306 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 307 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 308 ) reacts with the compound of formula ( 309 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 310 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 310 ) is reacted with ammonium chloride, optionally by heating, optionally by microwave irradiation in the presence of , to give the compound of formula ( 311 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 310 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 311 ) is obtained.

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 312 ) is reacted with the compound of formula ( 313 ) (a known compound or a compound prepared by a known method) in the presence of , optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 314 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 314 ) is reacted with ammonium chloride, optionally by heating, optionally by microwave irradiation, in the presence of , to give the compound of formula ( 315 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 314 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 315 ) is obtained. In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of tolyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 315 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 316 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 316 ) with the compound of formula ( 317 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 318 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., optionally in the presence of tolyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 318 ) and acid such as trifluoroacetic acid, hydrochloric acid , sulfuric acid and other reactions to obtain the compound of formula ( 319 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 320 ) with hydrogen by microwave irradiation to give the compound of formula ( 321 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 320 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 321 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 321 ) is reacted with the compound of formula ( 322 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 323 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 323 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 324 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 325 ) compound reacts with ethanol to obtain a compound of formula ( 326 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 326 ) and the compound of formula ( 327 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 328 ). In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 328 ) with hydrogen by microwave irradiation to give the compound of formula ( 328a ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 328 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 328a ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethyloxide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 329 ) compound reacts with ethanol to obtain a compound of formula ( 330 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 330 ) and the compound of formula ( 331 ) (a known compound or compounds prepared by known methods) to obtain compounds of formula ( 332 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 332 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 333 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 334 ) is reacted with the compound of formula ( 335 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 336 ). In solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyloxide, N,N- In dimethylacetamide, etc., the compound of formula ( 336 ) can be reacted with an acid such as trifluoroacetic acid, hydrochloric acid in the presence of cresyl ether, optionally by heating, optionally by microwave irradiation , sulfuric acid and other reactions to obtain the compound of formula ( 337 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , optionally reacting the compound of formula ( 338 ) with hydrogen by microwave irradiation to give the compound of formula ( 339 ). Alternatively, in the presence of platinum on carbon, in solvents such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfoxide, N , N-dimethylacetamide, etc., the compound of formula ( 338 ) can be reacted with hydrogen by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 339 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 339 ) is reacted with the compound of formula ( 340 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 341 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 341 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 342 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 343 ) Reaction with the compound of formula ( 344 ) gives the compound of formula ( 345 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 345 ) is reacted with ammonium chloride in the presence of , optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 346 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 345 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 346 ) is obtained.

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 347 ) compound reacts with ethanol to obtain a compound of formula ( 348 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 348 ) and the compound of formula ( 349 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 350 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 351 ) (a known compound or a compound prepared by a known method) and the compound of formula ( 352 ) (a known compound or a compound prepared by a known method) to give a compound of formula ( 353 ). In the presence of ammonium chloride, in solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, dichloromethane, chloroform, 1,2-dichloro In the presence of ethane, tetrahydrofuran, 1,4-dimethoxyethane, methanol, etc., if necessary, by heating, if necessary, by microwave irradiation, the formula The compound of ( 353 ) reacts with zinc to give the compound of formula ( 354 ). In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in solvents such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating as needed, Compounds of formula ( 354 ) are reacted with compounds of formula ( 355 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 356 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 356 ) reacts with the compound of formula ( 357 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 358 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 358 ) is reacted with ammonium chloride in the presence of , optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 359 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 358 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 359 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 359 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 360 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 361 ) is reacted with the compound of formula ( 362 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 363 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 363 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 364 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 365 ) compound reacts with ethanol to obtain a compound of formula ( 366 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 366 ) and the compound of formula ( 367 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 368 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 368 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid etc. to get the compound of formula ( 369 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 369 ) is reacted with the compound of formula ( 370 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 371 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 371 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 372 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 373 ) is reacted with the compound of formula ( 374 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 375 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 375 ) is reacted with ammonium chloride in the presence of , optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 376 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 375 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 376 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 376 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 377 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 377 ) with the compound of formula ( 378 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 379 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 379 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 380 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethyloxide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 380 ) compound reacts with ethanol to obtain a compound of formula ( 381 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 381 ) and the compound of formula ( 382 ) (a known compound or compounds prepared by known methods) to give compounds of formula ( 383 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 383 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 384 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 385 ) with the compound of formula ( 386 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 387 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 387 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 388 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 389 ) Reaction with the compound of formula ( 390 ) gives the compound of formula ( 391 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 391 ) is reacted with ammonium chloride, optionally by heating, optionally by microwave irradiation in the presence of , to give the compound of formula ( 392 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 391 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 392 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 392 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 393 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 393 ) is reacted with the compound of formula ( 394 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 395 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 395 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 397 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 397 ) compound reacts with ethanol to obtain a compound of formula ( 398 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 398 ) and the compound of formula ( 399 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 400 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 400 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 401 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 401 ) is reacted with the compound of formula ( 402 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 403 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 403 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 404 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 405 ) (a known compound or a compound prepared by a known method) and the compound of formula ( 406 ) (a known compound or a compound prepared by a known method) to give a compound of formula ( 407 ). In the presence of ammonium chloride, in solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, dichloromethane, chloroform, 1,2-dichloro In the presence of ethane, tetrahydrofuran, 1,4-dimethoxyethane, methanol, etc., if necessary, by heating, if necessary, by microwave irradiation, the formula The compound of ( 407 ) reacts with zinc to obtain the compound of formula ( 408 ). In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in a solvent such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating if necessary, Compounds of formula ( 408 ) are reacted with compounds of formula ( 409 ), either a known compound or a compound prepared by known methods, optionally by microwave irradiation, to give compounds of formula ( 410 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 410 ) reacts with the compound of formula ( 411 ) (a known compound or a compound prepared by a known method) in the presence of , optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 412 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. In the presence of , the compound of formula ( 412 ) is reacted with ammonium chloride, optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 413 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 412 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 413 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 413 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 414 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 415 ) with the compound of formula ( 416 ) by heating if necessary, and microwave irradiation if necessary, to obtain the compound of formula ( 417 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 417 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 418 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethyloxide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 419 ) compound reacts with ethanol to obtain a compound of formula ( 420 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 420 ) and the compound of formula ( 421 ) (a known compound or compounds prepared by known methods) to obtain compounds of formula ( 422 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 422 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 423 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 424 ) is reacted with the compound of formula ( 425 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 426 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 426 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 427 ).

In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis-palladium-tris(1,3-dibenzylidene)acetone, etc., optionally in an organic phosphine Such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, 2-cyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine Base-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-ditertiary butyl Phosphino-2',4',6'-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)ditertiary butylphosphine, 2-dicyclohexyl Phosphino-2',6'-diisopropoxybiphenyl, 2-ditertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triiso Propyl-1,1'-biphenyl, 2'-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sodium sulfonate, 2-ditertiary butane Phosphino-2'-methylbiphenyl, 2-dicyclohexylphosphino-2'-methylbiphenyl, 2'-(ditertiary butylphosphino)-N,N-dimethylbiphenyl In the presence of base-2-amine, 2'-(diphenylphosphino)-N,N'-dimethyl-(1,1'-biphenyl)-2-amine, etc., in 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-lutidine, etc. , in a solvent such as tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., optionally in water The compound of formula ( 428 ) reacts with the compound of formula ( 429 ) (a known compound or a compound prepared by a known method) in the presence of, optionally by heating, optionally by microwave irradiation , to obtain the compound of formula ( 430 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 430 ) is reacted with ammonium chloride, optionally by heating, optionally by microwave irradiation, in the presence of , to give the compound of formula ( 431 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 430 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 431 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 431 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 432 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 433 ) is reacted with the compound of formula ( 434 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 435 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 435 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 436 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethylsulfide, N, N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 437 ) compound reacts with ethanol to obtain a compound of formula ( 438 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 438 ) and the compound of formula ( 439 ) (a known compound or compounds prepared by known methods) to obtain compounds of formula ( 440 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 440 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 441 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 442 ) is reacted with the compound of formula ( 443 ) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 444 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 444 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 445 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 446 ) Reaction with the compound of formula ( 447 ) gives the compound of formula ( 448 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 448 ) is reacted with ammonium chloride in the presence of , optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 449 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 448 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 449 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 449 ) and an acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 450 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 451 ) with the compound of formula ( 452 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 453 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 453 ) and acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 454 ).

In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethyloxide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 455 ) compound reacts with ethanol to obtain a compound of formula ( 456 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 456 ) and the compound of formula ( 457 ) (a known compound or compounds prepared by known methods) to obtain compounds of formula ( 458 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 458 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 459 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 460 ) with the compound of formula ( 461 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 462 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 462 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 463 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 464 ) Reaction with the compound of formula ( 465 ) gives the compound of formula ( 466 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 466 ) and acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 467 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane The compound of formula ( 468 ) is reacted with the compound of formula ( 468 ) to obtain the compound of formula ( 470 ) by heating if necessary in the presence of etc. and microwave irradiation if necessary. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 470 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 471 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 472 ) Reaction with the compound of formula ( 473 ) gives the compound of formula ( 474 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 474 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 475 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., the compound of formula ( 476 ) is reacted with the compound of formula (477) by heating if necessary, and by microwave irradiation if necessary, to obtain the compound of formula ( 478 ).

In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 479 ) and an acid such as React with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. to obtain the compound of formula ( 480 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 481 ) Reaction with the compound of formula ( 482 ) gives the compound of formula ( 483 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 483 ) is reacted with ammonium chloride in the presence of , optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 484 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 483 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 484 ) is obtained.

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 485 ) Reaction with the compound of formula ( 486 ) gives the compound of formula ( 487 ). In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 487 ) compound reacts with ethanol to obtain a compound of formula ( 488 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethyl oxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 488 ) and the compound of formula ( 489 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 490 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 491 ) Reaction with the compound of formula ( 492 ) gives the compound of formula ( 493 ). In the presence of trimethylaluminum, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyethane, benzene, toluene, etc. The compound of formula ( 493 ) is reacted with ammonium chloride in the presence of , optionally by heating, optionally by microwave irradiation, to give the compound of formula ( 494 ). Alternatively, in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxyl, diethyl ether, methanol, ethanol, N,N-dimethylformamide, di In the presence of methazine, N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the formula The compound of ( 493 ) reacts with acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Then in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis(2) , diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylene , N,N-dimethylacetamide, etc., reacting the resulting substance with ammonia, optionally in the presence of methylphenyl ether, optionally by heating, optionally by microwave irradiation, The compound of formula ( 494 ) is obtained. In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 494 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 495 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 496 ) with the compound of formula ( 497 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 498 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 498 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 499 ).

In bases such as 1,8-diacribicyclo[5.4.0]undec-7-ene, 1,5-diacribicyclo[4.3.0]non-5-ene, 1,4-diacribicyclo[2.2 .2] In the presence of octane, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, etc., in solvents such as tetrahydrofuran, 1,4-dimethoxane, acetonitrile, dichloromethane , chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, etc., if necessary by heating, if necessary by microwave irradiation, the compound of formula ( 500 ) React with the compound of formula ( 501 ) to obtain the compound of formula ( 502 ). In the presence of acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., in solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-bis-dichloromethane, ether, methanol, ethanol, N , in the presence of N-dimethylformamide, dimethyloxide, N,N-dimethylacetamide, etc., optionally by heating, optionally by microwave irradiation, the formula ( 502 ) compound reacts with ethanol to obtain a compound of formula ( 503 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, In the presence of N,N-dimethylacetamide, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 503 ) and the compound of formula ( 504 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 505 ).

). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-two 㗁𠮿, methanol, ethanol, N,N-dimethylformamide, dimethyl sulfide, In N,N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 506 ) and Acids such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. react to give compounds of formula ( 507 ). In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as N,N-dimethylformamide, dimethylmethylene Dimethicone, N,N-Dimethylacetamide, Dichloromethane, Chloroform, 1,2-Dichloroethane, Tetrahydrofuran, 1,4-Dimethoxyethane, Acetonitrile, 1,2-Dimethoxyethane In the presence of etc., react the compound of formula ( 507 ) with the compound of formula ( 508 ) by heating if necessary, and microwave irradiation if necessary to obtain the compound of formula ( 509 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of formula ( 509 ) and an acid such as Reaction of trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 510 ).

In solvents such as methanol, ethanol, isopropanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, dichloromethane, chloroform, 1,2-dichloro In the presence of ethane, tetrahydrofuran, 1,4-dimethoxyethane, acetonitrile, 1,2-dimethoxyethane, etc., if necessary, by heating, if necessary, by microwave irradiation, the formula ( 511 ) compound (a known compound or a compound prepared by a known method) reacts with a compound of the formula ( 512 ) (a known compound or a compound prepared by a known method) to obtain a compound of the formula ( 513 ). In the presence of a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, etc., optionally in the presence of water, in a solvent such as N,N-dimethyl Dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dimethoxane, acetonitrile, 1, In the presence of 2-dimethoxyethane, etc., by heating if necessary, and by microwave irradiation if necessary, the compound of formula ( 513 ) is reacted with ditertiary butyl dicarbonate to obtain formula ( 514 ) compounds. In palladium catalysts such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), [ In the presence of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tris(1,3-dibenzylidene)acetone, etc., in a solvent such as methanol, ethanol , isopropanol, tetrahydrofuran, 1,4-dimethyramide, N,N-dimethylformamide, dimethylsulfide, N,N-dimethylacetamide, etc., if necessary, by heating , reacting the compound of formula ( 514 ) with hydrogen, optionally by microwave irradiation, to give the compound of formula ( 515 ).

In coupling agents 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]-1H-1,2,3-triazolo In the presence of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., optionally in a base such as triethylamine, diisopropylethyl In the presence of amines, N-methyl phenoline, etc., in a solvent such as N,N-dimethylformamide, 1,4-dimethoxylate, tetrahydrofuran, dichloromethane, etc., by heating if necessary, Optionally by microwave irradiation, the compound of formula ( 515 ) (a known compound or a compound prepared by known method) and the compound of formula ( 516 ) (a known compound or prepared by known method compound) reaction to obtain the compound of formula ( 517 ). In solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N, In N-dimethylacetamide, etc., optionally in the presence of methyl phenyl ether, optionally by heating, optionally by microwave irradiation, the compound of the formula ( 517 ) and an acid such as Reaction with trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc., to obtain the compound of formula ( 518 ).

In the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, etc., in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane , tetrahydrofuran, 1,4-two 㗁𠮿, acetonitrile, 1,2-dimethoxyethane, etc., by heating if necessary, and by microwave irradiation if necessary, to make the formula ( 519 ) A compound (a known compound or a compound prepared by a known method) is reacted with a compound of formula ( 520 ) (a known compound or a compound prepared by a known method) to obtain a compound of formula ( 521 ).

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

The following LC/MS procedure was used to analyze the examples described herein. LC/MS data were measured from 210-400 nm using a Waters Alliance 2695 HPLC/MS (Waters Symmetry C18, 4.6 × 75 mm, 3.5 μm) with a 2996 Diode Array Detector; the solvent system was analyzed using a linear gradient of 5%-95% acetonitrile in water (containing 0.1% trifluoroacetic acid), the residence time is in minutes. Mass spectrometry was performed in positive ion mode using electrospray on a Waters ZQ.

Preparative reverse-phase HPLC was performed on a Phenomenex LUNA column (19 × 100 mm, C18, 5 μm), with a 10-minute mobile phase gradient of 10% acetonitrile/water to 90% acetonitrile/water, 0.1% trifluoroacetic acid as a buffer, Use 214 and 254 nm as detection wavelengths. Injection and fraction collection were performed with a Gilson 215 liquid handling device using Trilution LC software.

^1H -NMR was performed on a Varian 300 MHz NMR using tetramethylsilane (TMS) as internal standard (δ = 0.00), with peaks reported downfield from TMS.

The Examples provide methods for preparing representative compounds of Formulas ( I ) to ( XXVIII ). The skilled practitioner will know how to substitute appropriate reagents, starting materials and purification methods known to those skilled in the art to prepare other compounds of the invention.

General Experimental Procedures: One skilled in the art can use the general experimental procedures described herein to prepare the compounds of the present disclosure and the intermediates necessary for the preparation of the compounds of the present disclosure.

Example 1: N ² , N ⁵ -bis[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,5-dimethylamide synthesis

Synthesis of pyridine-2,5-dicarbonyl dichloride: Suspend pyridine-2,5-dicarboxylic acid (0.50 g, 3.2 mmol) in thionyl chloride (5 ml) in a pressure vessel and heat to 100° C for 48 hours. The solvent was evaporated to give a solid (0.63 g, 97%).

Synthesis of N ² , N ⁵ -bis(4-bromophenyl)pyridine-2,5-dimethylamide: to pyridine-2,5-dicarbonyl dichloride (100 mg, 0.49 mmol) in N,N - To a solution in dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.32 g, 2.5 mmol, 0.44 ml) followed by 4-bromoaniline (0.21 g, 1.2 mmol) . The mixture was stirred for 18 hours, then water (3 ml) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered, washed with water and methanol and dried to give the product as a solid (135 mg, 58%).

Synthesis of N ² , N ⁵ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,5-dimethylamide: N ² , N ⁵ - Bis(4-bromophenyl)pyridine-2,5-dimethylamide (50 mg, 0.11 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-di A mixture of cyclohexylphosphino-2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) in water (0.4 ml) and 1,4-di㗁𠮿 ( 1 ml) diluted. 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 reverse 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 pale yellow powder (17 mg, 22%).

Synthesis of N ² , N ⁵ -bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,5-dimethylamide: the N ² ,N ⁵ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,5-dimethylamide (15 mg, 21 μmol), N- [(E)-{[(tertiary-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamic acid tertiary-butyl ester (20 mg, 63 μmol), N, A solution of N-diisopropylethylamine (27 mg, 0.21 mmol, 38 μl) in methanol (2 ml) was stirred for 24 hours, then purified by reverse phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with dichloromethane (2 X 25 ml). The extract was 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 give the bis-trifluoroacetate salt as a white powder (16 mg, 96%). ¹ H-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, _Rt = 3.16 min, purity >95%.

Example 2: N ² , N ⁴ -bis[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,4-dimethylamide synthesis

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

Synthesis of N ² , N ⁴ -bis(4-bromophenyl)pyridine-2,4-dimethylamide: Pyridine-2,4-dicarbonyl dichloride (100 mg, 0.49 mmol) in N,N - To a solution in dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.32 g, 2.5 mmol, 0.44 ml) followed by 4-bromoaniline (0.21 g, 1.2 mmol) . The mixture was stirred for 18 hours, then water (3 ml) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered, washed with water and a little methanol and dried to give the product as a solid (70 mg, 30%).

Synthesis of N ² , N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,4-dimethylamide: N ² , N ⁴ - Bis(4-bromophenyl)pyridine-2,4-dimethylamide (50 mg, 0.11 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-di A mixture of cyclohexylphosphino-2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) in water (0.4 ml) and 1,4-di㗁𠮿 ( 1 ml) diluted. 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 reverse 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 pale yellow powder (25 mg, 32%).

Synthesis of N ² , N ⁴ -bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,4-dimethylamide: the N ² ,N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,4-dimethylamide (25 mg, 35 μmol), N- [(E)-{[(tertiary-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamic acid tertiary-butyl ester (33 mg, 105 μmol), N, A solution of N-diisopropylethylamine (45 mg, 0.35 mmol, 63 μl) in methanol (2 ml) was stirred for 24 hours, then purified by reverse phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with dichloromethane (2 X 25 ml). The extract was 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 give the bis-trifluoroacetate 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, _Rt = 3.18 min, purity > 95%.

Example 3: N ² , N ⁴ -bis[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-3,5-dimethylamide synthesis

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

Synthesis of N ² , N ⁴ -bis(4-bromophenyl)pyridine-3,5-dimethylamide: pyridine-3,5-dicarbonyl dichloride (100 mg, 0.49 mmol) in N,N - To a solution in dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.32 g, 2.5 mmol, 0.44 ml) followed by 4-bromoaniline (0.21 g, 1.2 mmol) . The mixture was stirred for 18 hours, then water (3 ml) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered, washed with water and a little methanol and dried to give the product as a solid (138 mg, 59%).

Synthesis of N ² , N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-3,5-dimethylamide: N ² , N ⁴ - Bis(4-bromophenyl)pyridine-3,5-dimethylamide (50 mg, 0.11 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2-di A mixture of cyclohexylphosphino-2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) in water (0.4 ml) and 1,4-di㗁𠮿 ( 1 ml) diluted. 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 reverse 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 pale yellow powder (29 mg, 37%).

Synthesis of N ² , N ⁴ -bis[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-3,5-dimethylamide: the N ² ,N ⁴ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-3,5-dimethylamide (25 mg, 35 μmol), N- [(E)-{[(tertiary-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamic acid tertiary-butyl ester (33 mg, 105 μmol), N, A solution of N-diisopropylethylamine (45 mg, 0.35 mmol, 63 μl) in methanol (2 ml) was stirred for 24 hours, then purified by reverse phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with dichloromethane (2 X 25 ml). The extract was 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 give the bis-trifluoroacetate 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, _Rt = 2.93 min, purity >95%.

Example 4: N ² , N6-bis[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,6-dimethylamide synthesis

Synthesis of N ² , N ⁶ -bis(4-bromophenyl)pyridine-2,6-dimethylamide: pyridine-2,6-dicarboxylic acid (500 mg, 3.0 mmol), N, To a 0°C solution of N-dimethylformamide (25 μl) and N,N-diisopropylethylamine (1.8 g, 14 mmol, 2.5 ml) in chloroform (25 ml) was added oxalyl chloride (0.84 g, 6.6 mmol, 0.57 ml). After stirring for 30 minutes, the ice bath was removed and 4-bromoaniline (1.3 g, 7.5 mmol) was added to the mixture. Stir for 18 hours, then filter to remove N,N-diisopropylethylamine HCl salt. The filtrate was washed with water (25 ml), dried (Na ₂ SO ₄ ) and evaporated. The crude product was purified by RPHPLC to give major product (0.65 g, monosubstituted pyridoxine) and minor product (desired disubstituted pyridoxine, 70 mg, 5%).

Synthesis of N ² , N ⁶ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,6-dimethylamide: N ² , N ⁶ -Bis(4-bromophenyl)pyridine-2,6-dimethylamide (50 mg, 0.10 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (97 mg, 0.31 mmol), palladium acetate (1.1 mg, 5 μmol), 2 - A mixture of dicyclohexylphosphino-2',6'-dimethoxybiphenyl (2.1 mg, 5 μmol) and potassium carbonate (139 mg, 1.0 mmol) with water (0.4 ml) and 1,4-dimethoxy 𠮿 (1 ml) diluted. 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 give a gray-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 miniemulsion and lyophilized. The product was a powder (53 mg, 75%).

Synthesis of N ² , N6-bis[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyr-2,6-dimethylamide: the N ² ,N ⁶ -bis[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,6-dimethylamide (49 mg, 69 μmol), N- [(E)-{[(tertiary-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamic acid tertiary-butyl ester (64 mg, 208 μmol) and N, A suspension of N-diisopropylethylamine (89 mg, 0.69 mmol, 124 µl) in methanol (2 ml) was stirred for 24 hours. DMSO (3 ml) was added to the suspension to dissolve, and the product was purified by reverse phase HPLC. The product fractions were treated with saturated NaHCO ₃ solution and extracted with ethyl acetate (2 X 50 ml). The extract was 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 give the bis-trifluoroacetate 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, _Rt = 3.22 min, purity >95%.

Example 5: N ⁴ , N ⁶ -bis(4-{2-[(4,5-dihydro-1H-imidazol-2-yl)amino]ethyl}phenyl)pyrimidine-4,6-dimethyl Synthesis of amides

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 hours. The solvent was evaporated, the crude product was dissolved in dichloromethane, filtered through a pad of celite, and the solvent was evaporated to give a solid (0.47 g, 77%).

Synthesis of tertiary butyl 2-{[2-(4-nitrophenyl)ethyl]amino}-4,5-dihydro-1H-imidazole-1-carboxylate: 2-(4-nitro Phenyl)-1-aminoethane (0.50 g, 3.0 mmol) and 2-methylthio-4,5-dihydroimidazolium hydriodide (0.66 g, 2.7 mmol) in ethanol (5 ml) The solution was refluxed for 5 hours and the solvent was evaporated to give a thick oil which was dissolved in dichloromethane (10 ml) and 1 N NaOH (4.5 ml) and Boc anhydride (0.74 g, 3.5 mmol) was added. The mixture was stirred for 2 hours, the organic layer was separated, _dried ( _Na2SO4 ) and evaporated. The crude product was purified by reverse phase HPLC and the product fractions were combined, treated with saturated NaHCO ₃ solution and extracted with ethyl acetate (2×50 ml). The extracts were washed with brine (50 ml), dried (MgSO ₄ ) and evaporated to give a thick oil (455 mg, 50%).

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

N ⁴ , N ⁶ -bis(4-{2-[(4,5-dihydro-1H-imidazol-2-yl)amino]ethyl}phenyl)pyrimidine-4,6-dimethylamide Synthesis: tertiary butyl 2-{[2-(4-aminophenyl)ethyl]amino}-4,5-dihydro-1H-imidazole-1-carboxylate (59 mg, 176 μmol) and A solution of N,N-diisopropylethylamine (28 mg, 219 μmol, 39 μl) in N,N-dimethylformamide (0.5 ml) with pyrimidine-4,6-dicarbonyl dichloride (15 mg, 73 μmol) and stirred for 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 reverse phase HPLC. The product fractions were combined and evaporated. The Boc protecting group was removed during evaporation to give 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, _Rt = 1.08 min, purity >95%.

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

N-[(E)-{[(tertiary butoxy)carbonyl]imino}({methyl[2-(4-nitrophenyl)ethyl]amino})methyl]carbamate Synthesis of tertiary butyl ester: 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) with N-[(E)-{[(tertiary butoxy)carbonyl]imino}(1H -pyrazol-1-yl)methyl]carbamate (0.86 g, 2.8 mmol) and the solution was stirred for 2 hours. The mixture was diluted with ethyl acetate (100 ml), washed with water (50 ml), 1 N HCl (50 ml) and brine (25 ml). The solution was dried ( _MgSO4 ) and evaporated. The crude product was purified by silica gel chromatography (ethyl acetate-hexane gradient 10%-60%) to afford the desired product (242 mg, 25%).

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

Synthesis of N ⁴ , N ⁶ -bis({4-[2-(N-methylaminoformiminoamino)ethyl]phenyl})pyrimidine-4,6-dimethylamide: the N -[(E)-{[2-(4-Aminophenyl)ethyl](methyl)amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino Between tertiary butyl formate (115 mg, 0.29 mmol) and N,N-diisopropylethylamine (39 mg, 0.30 mmol, 54 μl) in N,N-dimethylformamide (2 ml) The solution 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), 1 N HCl (25 ml) and brine (25 ml). The solution was dried ( _MgSO4 ) and evaporated. The crude product was purified by silica gel chromatography eluting with a gradient of ethyl acetate/hexane (30%-100%) to afford 71 mg (65%) of a pale yellow gum. It was dissolved in a 1:1 mixture of trifluoroacetic acid-dichloromethane and stirred for 2 hours. The solvent was evaporated to give a beige 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, _Rt = 1.08 min, purity >95%.

Example 7: Synthesis of N,N'-bis(4-guanidino-phenyl)-terephthalamide

Tertiary butyl N-(4-{4-[(4-{[(tertiary butoxy)carbonyl]amino}phenyl)aminoformyl]benzamido}phenyl)carbamate Synthesis of esters: (4-Amino-phenyl)-carbamic acid tertiary 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 CHCl ₃ (6 mL). The reaction was stirred for 16 hours, then treated with additional _CHCl3 (20 mL), then sonicated for 2 minutes, and filtered. The solid was washed with water (20 mL), isopropanol (20 mL) and hexane (20 mL) to give N-(4-{4-[(4-{[(tertiary butoxy)carbonyl]amino} Tert-butyl phenyl)carbamoyl]benzamido}phenyl)carbamate (1.06 g, 88%) as a white solid.

Synthesis of N,N'-bis(4-amino-phenyl)-terephthalamide: N-(4-{4-[(4-{[(tertiary butoxy)carbonyl]amine tert-Butyl}phenyl)carbamoyl]benzamido}phenyl)carbamate ₍ 1.06 g, 1.94 mmol) in _CH2Cl2 (13 mL) and methanol (7 mL) The mixture was treated with a 4 N solution (5 mL) of HCl in 1,4-dimethoxylate. The reaction was stirred for 4 days then concentrated. The residue was treated with N,N-dimethylformamide (15 mL) and a 4 N solution of HCl in 1,4-dimethoxylate (5 mL). The reaction was stirred for 16 hours, then treated with water (50 mL), and filtered. The solid was washed with isopropanol (30 mL) and then with hexane (30 mL). The solid was treated with DMSO (15 mL) followed by a 4 N solution of HCl in 1,4-dimethoxane (5 mL). The reaction was stirred for 4 days, then treated with water (70 mL), and filtered. The solid was washed with isopropanol (20 mL) and then with hexane (20 mL). The solid was slurried in _CH2Cl2 (10 mL), then treated with trifluoroacetic acid (6 mL) _. The reaction was stirred for 16 hours, then concentrated to give the bis-trifluoroacetate salt of N,N'-bis(4-amino-phenyl)-terephthalamide (604 mg, 54%) as white solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}[(4-{4-[(4-{[(1Z)-{[(tertiary butoxy)carbonyl]amine group}({[(tertiary butoxy)carbonyl]imino})methyl]amino}phenyl)aminoformyl]benzamido}phenyl)amino]methylene] Synthesis of tertiary butyl carbamate (SB-10-126): N,N'-bis(4-amino-phenyl)-terephthalamide 2 trifluoroacetic acid (230 mg, 0.40 mmol ) in N,N-dimethylformamide (3.8 mL) was slowly treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was concentrated, then the residue was treated with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), then treated with 10% aqueous citric acid (20 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}[(4-{4- [(4-{[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}phenyl) Tertiary-butylcarbamoyl]benzamido}phenyl)amino]methylene]carbamate (110 mg, 33%) as a beige solid.

Synthesis of N,N'-bis(4-guanidino-phenyl)-terephthalamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}[(4 -{4-[(4-{[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }phenyl)aminoformyl]benzamido}phenyl)amino]methylene]carbamate (110 _mg , 0.13 mmol) in _CH2Cl2 (1.3 mL) The mixture was treated with trifluoroacetic acid (1.3 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give the bis-trifluoroacetate salt of N,N'-bis(4-guanidino-phenyl)-terephthalamide (64 mg, 75%) as a white solid . MS: 431 M+H+; ¹ H 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).

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

(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-fluoro-benzoylamino}-benzyl)-amino Synthesis of tertiary butyl formate. To 2-fluoro-terephthalic acid (368 mg, 2.00 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (987 mg, 4.44 mmol) and triethylamine (947 mg, 1120 μL, 8.00 mmol) to a mixture in N,N-dimethylformamide (6 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-tris Azolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (2272 mg, 6.00 mmol). The reaction was stirred for 4 days, then treated with water (90 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with water (30 mL), isopropanol (30 mL) and hexane (30 mL) to give (4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylamine tert-Butyl]-2-fluoro-benzoylamino}-benzyl)-carbamate (1.00 g, 84%) as a white solid.

Synthesis of N ¹ , N ⁴ -bis(4-(aminomethyl)phenyl)-2-fluoroterephthalamide: (4-{4-[4-(tertiary butoxycarbonylamine (methyl)-phenylaminoformyl]-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 treated with methanol (10 mL), and concentrated. The residue was treated with ethyl acetate (50 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with hexane (20 mL) to give the bis-trifluoroacetate salt of xxx (0.98 g, 95%) as a white solid.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl ]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}-2-fluorobenzamido)benzene Synthesis of tertiary butyl] methyl} amino) methylene] carbamate. N ¹ , N ⁴ -bis(4-(aminomethyl)phenyl)-2-fluoroterephthalamide 2 trifluoroacetic acid (248 mg, 0.40 mmol) in N,N-dimethylformaldehyde The mixture in amide (3.8 mL) was slowly treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was concentrated, then the residue was treated with water (20 mL) and 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 silica gel column (0%-50% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[4-(4 -{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} yl)phenyl]aminoformyl}-2-fluorobenzamido)phenyl]methyl}amino)methylene]carbamate (299 mg, 85%), as white solid.

Synthesis of 2-fluoro-N1,N4-bis(4-(guanidinomethyl)phenyl)terephthalamide: N-[(1E)-{[(tertiary butoxy)carbonyl]amine Base}({[4-(4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino })methyl]amino}methyl)phenyl]aminoformyl}-2-fluorobenzamido)phenyl]methyl}amino)methylene]carbamate tertiary butyl (299 mg, 0.34 mmol) in _CH2Cl2 (3.4 mL) _was treated with trifluoroacetic acid (3.4 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give 2-fluoro-N1,N4-bis(4-(guanidinomethyl)phenyl)terephthalamide as bis-trifluoroacetate salt (198 mg, 83% ), as a white solid. MS: 477 M+H+; ¹ H 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, 6H) 7.22 - 7.35 (m, 7H) 4.34 (d, J = 5.27 Hz, 4H).

Example 9: Synthesis of trans-cyclohexane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]

[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-trans-cyclohexanecarbonyl}-amino)-benzyl]- Synthesis of tertiary butyl carbamate. According to (4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-fluoro-benzoylamino}-benzyl)-amine The title compound was prepared according to the procedure for tertiary butyl carbamate, except trans-cyclohexane-1,4-dicarboxylic acid (344 mg, 2.00 mmol) was used in place of 2-fluoro-terephthalic acid, and ( tert-butyl 4-amino-benzyl)-carbamate (987 mg, 4.44 mmol) to give [4-({4-[4-(tert-butoxycarbonylamino-methyl)-benzene tert-butylcarbamate]-trans-cyclohexanecarbonyl}-amino)-benzyl]-carbamate (1.09 g, 94%) as a white solid.

Synthesis of trans-cyclohexane-1,4-dicarboxylic acid bis[(4-aminomethyl-phenyl)-amide]. To [4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-trans-cyclohexanecarbonyl}-amino)-benzyl] - To _a mixture of tert-butyl carbamate (1.09 g, 1.88 mmol) in _CH2Cl2 (10 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ether (25 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (30 mL) to give bis-trifluorobis[(4-aminomethyl-phenyl)-amide] of trans-cyclohexane-1,4-dicarboxylate Acetate (1.02 g, 89%) as a white solid.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}[({4-[(1r,4r)-4-{[4-({[(1E)-{[(three Butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}cyclohexaneamino Synthesis of tertiary butyl]phenyl}methyl)amino]methylene]carbamate. Trans-cyclohexane-1,4-dicarboxylic acid bis[(4-aminomethyl-phenyl)-amide] 2 trifluoroacetic acid (243 mg, 0.40 mmol) in N,N-dimethyl The mixture in formamide (3.8 mL) was slowly treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was concentrated, then the residue was treated with water (30 mL) and 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 silica gel column (0%-60% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}[({4-[( 1r,4r)-4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methan Amino]amino}methyl)phenyl]aminoformyl}cyclohexaneamido]phenyl}methyl)amino]methylene]carbamate (156 mg, 45% ), as a white solid.

Synthesis of trans-cyclohexane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]: N-[(1E)-{[(tertiary butoxy) Carbonyl]amino}[({4-[(1r,4r)-4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary Butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}cyclohexaneamido]phenyl}methyl)amino]methylene]amine To _a mixture of tert-butyl carbamate (187 mg, 0.22 mmol) in _CH2Cl2 (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 4 days then concentrated. The crude material was purified by preparative HPLC to give bis-trifluoroacetate salt of trans-cyclohexane-1,4-dicarboxylate bis[(4-guanidinomethyl-phenyl)-amide] (122 mg , 80%), as a white solid. MS: 465 M+H+; ¹ 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, 4H) 1.37 - 1.53 (m, 4H) 1.15 - 1.28 (m, 3H).

Example 10: Synthesis of cis-cyclohexane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]

[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-cis-cyclohexanecarbonyl}-amino)-benzyl]- Synthesis of tertiary butyl carbamate. According to (4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-fluoro-benzoylamino}-benzyl)-amine The title compound was prepared following the procedure for tertiary-butyl carbamate, except trans-cyclohexane-1,4-dicarboxylic acid (344 mg, 2.00 mmol) was used in place of 2-fluoro-terephthalic acid, and ( tert-butyl 4-amino-benzyl)-carbamate (987 mg, 4.44 mmol) to give [4-({4-[4-(tert-butoxycarbonylamino-methyl)-benzene tert-butylcarbamate]-cis-cyclohexanecarbonyl}-amino)-benzyl]-carbamate (0.69 g, 60%) as a white solid.

Synthesis of cis-cyclohexane-1,4-dicarboxylic acid bis[(4-aminomethyl-phenyl)-amide]. To [4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-cis-cyclohexanecarbonyl}-amino)-benzyl] _- To a mixture of tert-butyl carbamate (0.69 g, 1.19 mmol) in _CH2Cl2 (10 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered to give bis-trifluoroacetate salt of cis-cyclohexane-1,4-dicarboxylate bis[(4-aminomethyl-phenyl)-amide] (717 mg, 99%) as Light brown solid.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}[({4-[(1s,4s)-4-{[4-({[(1E)-{[(three Butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}cyclohexaneamino Synthesis of tertiary butyl]phenyl}methyl)amino]methylene]carbamate. According to N-[(1E)-{[(tertiary butoxy)carbonyl]amino}[({4-[(1r,4r)-4-{[4-({[(1E)-{[( Tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}cyclohexane Amino]phenyl}methyl)amino]methylene]carbamate The title compound was prepared by the procedure of tertiary-butyl carbamate except that cis-cyclohexane-1,4-dicarboxylate bis[( 4-aminomethyl-phenyl)-amido]2trifluoroacetic acid (243 mg, 0.40 mmol) in place of trans-cyclohexane-1,4-dicarboxylic acid bis[(4-aminomethyl-phenyl base)-amido]2 trifluoroacetic acid to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}[({4-[(1s,4s)-4-{[4 -({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl ]carbamoyl}cyclohexaneamido]phenyl}methyl)amino]methylene]carbamate (156 mg, 45%) as a white solid.

Synthesis of cis-cyclohexane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]: N-[(1E)-{[(tertiary butoxy) Carbonyl]amino}[({4-[(1s,4s)-4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary Butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}cyclohexaneamido]phenyl}methyl)amino]methylene]amine To _a mixture of tert-butyl carbamate (156 mg, 0.18 mmol) in _CH2Cl2 (1.8 mL) was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give bis-trifluoroacetate salt of cis-cyclohexane-1,4-dicarboxylate bis[(4-guanidinomethyl-phenyl)-amide] (98 mg , 79%), as a white solid. MS: 465 M+H+; ¹ H 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).

Example 11: Synthesis of N,N'-bis(4-guanidinomethyl-cyclohexyl)-terephthalamide

(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-cyclohexylaminoformyl]-benzoylamino}-cyclohexylmethyl)-carbamic acid tri Synthesis of grade butyl esters. To (4-amino-cyclohexylmethyl)-carbamate tertiary butyl ester (799 mg, 3.50 mmol) and diisopropylethylamine (710 mg, 955 μL, 5.50 mmol) in N,N-di To the mixture in methylformamide (4.8 mL) was added dropwise a solution of terephthalamide dichloride (356 mg, 1.75 mmol) in N,N-dimethylformamide (4.8 mL). The reaction was stirred for 16 hours, then filtered. The solid was washed with N,N-dimethylformamide (10 mL), water (20 mL), isopropanol (20 mL) and hexane (20 mL) to give (4-{4-[4-( tertiary-butoxycarbonylamino-methyl)-cyclohexylaminoformyl]-benzoylamino}-cyclohexylmethyl)-carbamic acid tertiary-butyl ester (660 mg, 64%) , as a white solid.

Synthesis of N,N'-bis(4-aminomethyl-cyclohexyl)-terephthalamide. To (4-{4-[4-(tertiary butoxycarbonylamino-methyl)-cyclohexylaminoformyl]-benzoylamino}-cyclohexylmethyl)-carbamic acid To a mixture _of tert-butyl ester (660 mg, 1.13 mmol) in _CH2Cl2 (6 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 5 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min, and filtered. The solid was washed with diethyl ether (20 mL) to give N,N'-bis(4-aminomethyl-cyclohexyl)-terephthalamide 2-trifluoroacetic acid (669 mg, 96%) as a white solid .

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(1r,4r)-4-(4-{[(1r,4r)-4-({[(1E )-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)cyclohexyl]aminoformyl Synthesis of }benzamido)cyclohexyl]methyl}amino)methylene]carbamate tertiary butyl ester. 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was concentrated, then the residue was treated with water (25 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (2 × 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(1r,4r )-4-(4-{[(1r,4r)-4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl] Imino})methyl]amino}methyl)cyclohexyl]carbamoyl}benzamido)cyclohexyl]methyl}amino)methylene]carbamate tertiary butyl ( 96 mg, 28%), as a white solid.

Synthesis of N,N'-bis(4-guanidinomethyl-cyclohexyl)-terephthalamide: to N-[(1E)-{[(tertiary butoxy)carbonyl]amino}( {[(1r,4r)-4-(4-{[(1r,4r)-4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary Butoxy)carbonyl]imino})methyl]amino}methyl)cyclohexyl]aminoformyl}benzamido)cyclohexyl]methyl}amino)methylene]amino _To a mixture of tert-butyl formate (96 mg, 0.11 mmol) in _CH2Cl2 (1.1 mL) was added trifluoroacetic acid (1.1 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to afford N,N'-bis(4-guanidinomethyl-cyclohexyl)-terephthalimide 2-trifluoroacetic acid (50 mg, 65%) as a white solid. MS: 471 M+H+; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ ppm 8.33 (d, J =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, J =6.15 Hz, 2 H) 1.87 (d, J =10.54 Hz, 2 H) 1.76 (d, J =11.72 Hz, 2 H) 1.22 - 1.52 (m , 3 H) 0.95 - 1.17 (m, 2 H).

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

(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-methyl-benzoylamino}-benzyl)-amine Synthesis of tertiary butyl formate. According to (4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-fluoro-benzoylamino}-benzyl)-amine The title compound was prepared according to the procedure for tertiary butyl carbamate, except that 2-fluoro-terephthalic acid (288 mg, 1.60 mmol) was replaced with (4-amino- Benzyl)-tert-butylcarbamate (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 cation 3-oxide hexafluorophosphate (1818 mg, 4.80 mmol) to give (4-{4-[4-(tertiary butoxy tertiary butylcarbonylamino-methyl)-phenylaminoformyl]-2-methyl-benzoylamino}-benzyl)-carbamate (696 mg, 74%), white solid.

Synthesis of N ¹ , N ⁴ -bis(4-(aminomethyl)phenyl)-2-methylterephthalamide. To (4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-methyl-benzoylamino}-benzyl)- To a mixture of tert-butyl carbamate (696 mg, 1.18 mmol) in _CH2Cl2 (6 mL) was added trifluoroacetic acid (3 mL ₎ . The reaction was stirred for 5 hours then concentrated. The residue was treated with ether (30 mL) and sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl)-2-methylterephthalamide (748 mg, > 100%) as a white solid which was used without further purification.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl ]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}-2-methylbenzamido) Synthesis of tertiary butyl phenyl]methyl}amino)methylene]carbamate. According to N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-({[(1E)-{[(tertiary butoxy) Carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}-2-fluorobenzamido) The title compound was prepared by the procedure for tert-butyl phenyl]methyl}amino)methylene]carbamate except that N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl) -2-Methylterephthalamide (247 mg, 0.40 mmol) instead of N ¹ ,N ⁴ -bis(4-(aminomethyl)phenyl)-2-fluoroterephthalamide 2 Tris Fluoroacetic acid, obtains N-[(1E)-{[(tertiary butoxyl)carbonyl]amino}({[4-(4-{[4-({[(1E)-{[(tertiary butyl Oxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}-2-methylbenzyl Amino)phenyl]methyl}amino)methylene]carbamate (219 mg, 63%) as a white solid.

Synthesis of N ¹ , N ⁴ -bis(4-(guanidinomethyl)phenyl)-2-methylterephthalamide: N-[(1E)-{[(tertiary butoxy) Carbonyl]amino}({[4-(4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl] Imino})methyl]amino}methyl)phenyl]aminoformyl}-2-methylbenzamido)phenyl]methyl}amino)methylene]carbamic acid To _a mixture of tert-butyl ester (219 mg, 0.25 mmol) in _CH2Cl2 (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N ¹ ,N ⁴ -bis(4-(guanidinomethyl)phenyl)-2-methylterephthalimide 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, J =5.57, 2.64 Hz, 4H) 2.45 (s, 3H).

Example 13: Synthesis of N,N'-bis[4-(4-formamimidino-piper-1-yl)-phenyl]-terephthalamide

Synthesis of 4,4'-((terephthalylbis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylic acid)ditertiary butyl ester. Following general procedure D, using terephthalyl dichloride (356 mg, 1.75 mmol) and tert-butyl 4-(4-amino-phenyl)-piperone-1-carboxylate (971 mg, 3.50 mmol) , to obtain 4,4'-((terephthaloylbis(azanediyl))bis(4,1-phenylene))bis(pipera-1-carboxylic acid)two tertiary butyl esters (743 mg, 62%), as light yellow solid.

Synthesis of N,N'-bis(4-piperyl-1-yl-phenyl)-terephthalamide: to 4,4'-((terephthalylbis(azanediyl) )bis(4,1-phenylene))bis(piperone-1-carboxylic acid)ditert-butyl ester (743 mg, 1.09 mmol) in CH ₂ Cl ₂ (6 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min, and filtered. The solid was washed with diethyl ether (20 mL) to give N,N'-bis(4-piperone-1-yl-phenyl)-terephthalamide 4-trifluoroacetic acid (878 mg, 86%) as Light green solid.

({4-[4-(4-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-phenyl Synthesis of aminoformyl}-benzoylamino)-phenyl]-piperone-1-yl}-tertiary butoxycarbonylimino-methyl)-carbamic acid tertiary butyl ester . N,N'-bis(4-piperone-1-yl-phenyl)-terephthalamide 4 trifluoroacetate (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 treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (50 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The filtrate 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 silica gel column (0%-100% ethyl acetate: hexane) to obtain ({4-[4-(4-{4-[4-(tertiary butoxycarbonylamino-tertiary Butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-benzoylamino)-phenyl]-piperone-1-yl}-tri Butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (178 mg, 46%) as a pale yellow solid.

Synthesis of N,N'-bis[4-(4-formamidoyl-piper-1-yl)-phenyl]-terephthalamide: to ({4-[4-(4-{4 -[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-benzoylamine yl)-phenyl]-piperone-1-yl}-tert-butoxycarbonylimino-methyl)-tert-butyl carbamate (178 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 concentrated. The residue was treated with N,N-dimethylformamide (1.6 mL), then 0.1% trifluoroacetic acid in water (1.6 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give N,N'-bis[4-(4-carboxamidino-piperone-1-yl)-phenyl]-terephthalene Formamide 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).

Example 14: Synthesis of N,N'-bis[4-(4-formamimidino-piper-1-yl)-phenyl]-isophthalamide

Synthesis of 4,4'-((isophthalylbis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylic acid)ditertiary butyl ester. To tertiary butyl 4-(4-amino-phenyl)-piperone-1-carboxylate (971 mg, 3.50 mmol) and diisopropylethylamine (710 mg, 955 μL, 5.50 mmol) in N, To the mixture in N-dimethylformamide (4.8 mL) was added a solution of terephthalamide dichloride (356 mg, 1.75 mmol) in N,N-dimethylformamide (4.8 mL). The reaction was stirred for 16 hours, then treated with water (150 mL) and ethyl acetate (60 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4,4'-(((isophthaloylbis(azanediyl))bis(4,1-phenylene)) Bis(piperi-1-carboxylic acid) di-tertiary butyl ester. The initial ethyl acetate/water filtrate 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). Shake the mixture, then filter. Wash the solid with isopropanol (20 mL) and hexane (20 mL). Both solids are 4,4'-((isophthalylbis(azanediyl))bis(4,1-phenylene))bis(pipera-1-carboxylic acid)ditertiary butane Ester (595 mg, 50%) as a gray solid.

Synthesis of N,N'-bis(4-piper-1-yl-phenyl)-isophthalamide. To 4,4'-((isophthalylbis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylic acid)ditertiary butyl ester (590 mg , 0.87 mmol) in _CH2Cl2 (5 mL) was added trifluoroacetic acid (2.5 mL) _. The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (25 mL), and the mixture was sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (2 x 10 mL) to give N,N'-bis(4-piperazol-1-yl-phenyl)-m-phthalamide. 4 Trifluoroacetic acid (609 mg, 74%) as a purple solid.

({4-[4-(3-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-phenyl Synthesis of aminoformyl}-benzoylamino)-phenyl]-piperone-1-yl}-tertiary butoxycarbonylimino-methyl)-carbamic acid tertiary butyl ester . N,N'-bis(4-piper-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 treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 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 silica gel column (0%-6% methanol: CH ₂ Cl ₂ ) to obtain ({4-[4-(3-{4-[4-(tertiary butoxycarbonylamino-tertiary Butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-benzoylamino)-phenyl]-piperone-1-yl}-tri Butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (271 mg, 70%) as a light green solid.

Synthesis of N,N'-bis[4-(4-formamidoyl-piper-1-yl)-phenyl]-isophthalamide: to ({4-[4-(3-{4 -[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-benzoylamine yl)-phenyl]-piperone-1-yl}-tert-butoxycarbonylimino-methyl)-tert-butyl carbamate (271 mg, 0.28 mmol) in CH ₂ Cl ₂ (2.8 mL) was added trifluoroacetic acid (2.8 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N,N'-bis[4-(4-carboxamidino-piperol-1-yl)-phenyl]-isophthalamide 4 trifluoroacetic acid (204 mg, 71%), as light yellow solid. MS: 569 M+H+; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 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, 4H).

Example 15: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl) -Synthesis of Terephthalamide

Synthesis of N-(4-bromo-phenyl)-methyl terephthalate. To a mixture of 4-bromo-aniline (516 mg, 3.00 mmol) and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in _CHCl (8 mL) was added 4-chlorocarbonyl-benzoic acid methyl Ester (687 mg, 3.46 mmol) in _CHCl3 (8 mL). The reaction was stirred for 16 hours then 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 1 N HCl (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 )-Methyl terephthalate (860 mg, 86%) as a beige solid.

Synthesis of N-(4-bromo-phenyl)-terephthalic acid. To a mixture of N-(4-bromo-phenyl)-terephthalic acid methyl ester (860 mg, 2.57 mmol) in 1,4-di㗁𠮿 (12 mL) was added 10 N aqueous sodium hydroxide (2.6 mL). The reaction was stirred for 16 h, then treated with additional 10 N aqueous sodium hydroxide (2.6 mL). The reaction was stirred for 3 hours, then heated at 40 °C for 16 hours. The reaction was concentrated, and 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 HCl. The mixture was treated with ethyl acetate (50 mL), then filtered. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give N-(4-bromo-phenyl)-terephthalic 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)-terephthalic acid (267 mg, 33%), as a white solid.

Synthesis of {4-[4-(4-bromo-phenylaminoformyl)-benzoylamino]-benzyl}-carbamic acid tertiary butyl ester. To N-(4-bromo-phenyl)-terephthalic acid (772 mg, 2.41 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (595 mg, 2.67 mmol) and tri To a mixture of ethylamine (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 cation 3-oxide hexafluorophosphate (1369 mg, 3.62 mmol). The reaction was stirred for 1 hour, then additional 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). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give {4-[4-(4-bromo-phenylaminoformyl)-benzoylamino]-benzyl} - Tertiary butyl carbamate (1.00 g, 79%) as a white solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-phenyl)-3,6- Synthesis of tertiary butyl dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen gas through {4-[4-(4-bromo-phenylaminoformyl)-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- tertiary butyl 1-carboxylate (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-Di㗁𠮿 (13.7 mL) and 2M K ₂ CO ₃ (4.8 mL) The mixture was degassed 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). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl [1]-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (898 mg, 75%) as a gray solid.

Synthesis of N-(4-aminomethyl-phenyl)-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephthalamide . To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-phenyl)-3,6 - To a mixture of tert-butyldihydro-2H-pyridine-1-carboxylate ₍ 898 mg, 1.43 mmol) in _CH2Cl2 (8 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ethyl acetate (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with ether (2 × 15 mL) to give N-(4-aminomethyl-phenyl)-N'-[4-(1,2,3,6-tetrahydropyridine- 4-yl)-phenyl]-terephthalamide 2-trifluoroacetic acid (848 mg, 91%) as gray solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)phenyl] -Synthesis of tertiary-butyl 1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. N-(4-aminomethyl-phenyl)-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephthalamide 2 A mixture of 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 treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl Ester (228 mg, 63%) as a pale yellow solid.

N-[4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-p-phenyl Synthesis of dimethylamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)- {[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzene Formamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (228 mg, 0.25 mmol) in CH ₂ Cl ₂ ( 2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 2 days, then concentrated. The crude material was purified by preparative HPLC to give N-[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidine (methyl-phenyl)-terephthalamide 2-trifluoroacetic acid (70 mg, 38%) as a pale yellow solid. MS: 511 M+H+; ¹ H 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).

Example 16: Synthesis of N ¹ , N ⁴ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)-2-chloroterephthalamide

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

4,4'-(((2-Chloroterephthaloyl)bis(azanediyl))bis(4,1-phenylene))bis(pipera-1-carboxylic acid)ditertiary butane Synthesis of esters: 2-chloro-terephthalic acid (315 mg, 1.57 mmol), tertiary butylpiperone-1-carboxylate (967 mg, 3.48 mmol) and triethylamine (744 mg, 880 μL, 6.28 mmol) to a mixture in N,N-dimethylformamide (4.8 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1784 mg, 4.71 mmol). The reaction was stirred for 16 hours, then treated with water (75 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4,4'-(((2-chloroterephthaloyl)bis(azanediyl))bis(4,1 -Phenylylene)) bis(piperone-1-carboxylate) di-tert-butyl ester (740 mg, 66%), as a white solid.

Synthesis of 2-chloro-N1,N4-bis(4-(piper-1-yl)phenyl)terephthalamide: to 4,4'-(((2-chloroterephthalamide )bis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylate)ditertiary butyl ester (740 mg, 1.03 mmol) in CH ₂ Cl ₂ (6 mL) To the mixture was added trifluoroacetic acid (3 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with diethyl ether (20 mL) to give tetrakis-trifluoroacetic acid of 2-chloro-N1,N4-bis(4-(piperone-1-yl)phenyl)terephthalamide Salt (945 mg, 94%) as a pale green solid.

({4-[4-(4-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-phenyl Aminoformyl}-2-chloro-benzoylamino)-phenyl]-piperone-1-yl}-tertiary butoxycarbonylimino-methyl)-carbamic acid tertiary Synthesis of butyl esters. 2-Chloro-N1,N4-bis(4-(piper-1-yl)phenyl)terephthalamide 4 trifluoroacetic acid (390 mg, 0.40 mmol) in N,N-dimethylformaldehyde The mixture in amide (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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-7% methanol: CH ₂ Cl ₂ ) to obtain ({4-[4-(4-{4-[4-(tertiary butoxycarbonylamino-tertiary Butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-2-chloro-benzoylamino)-phenyl]-piperone-1- (4)-tert-butoxycarbonylimino-methyl)-tert-butyl carbamate (262 mg, 65%) as a yellow solid.

Synthesis of N ¹ , N ⁴ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)-2-chloroterephthalamide: to ({4-[4-(4- {4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-2-chloro -Benzylamino)-phenyl]-piperone-1-yl}-tert-butoxycarbonylimino-methyl)-tert-butyl carbamate (262 mg, 0.26 mmol) in To the mixture _{in CH2Cl2} (2.6 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 5 days, then concentrated. The residue was treated with N,N-dimethylformamide (2 mL), then 0.1% trifluoroacetic acid in water (2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (2 mL) and hexane (2 mL) to give N ¹ , N ⁴ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)-2-chloro-p- Tetra-trifluoroacetate of phthalamide (183 mg, 67%), as a pale yellow solid. MS: 604 M+H+; ¹ H 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).

Example 17: Synthesis of N ¹ , N ⁴ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)-2-methylterephthalamide

4,4'-(((2-Methylterephthaloyl)bis(azanediyl))bis(4,1-phenylene))bis(pipera-1-carboxylic acid)ditertiary Synthesis of butyl ester: 2-methyl-terephthalic acid (288 mg, 1.60 mmol), tertiary butyl piper-1-carboxylate (985 mg, 3.55 mmol) and triethylamine (758 mg, 896 μL , 6.40 mmol) to a mixture in N,N-dimethylformamide (4.8 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole A[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1818 mg, 4.80 mmol). The reaction was stirred for 16 hours, then treated with water (75 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4,4'-(((2-methylterephthaloyl)bis(azanediyl))bis(4, 1-Phenylylene)) bis(piperone-1-carboxylate) di-tert-butyl ester (791 mg, 71%), as a white solid.

Synthesis of 2-methyl-N ¹ , N ⁴ -bis(4-(piper-1-yl)phenyl)terephthalamide: to 4,4'-(((2-methyl-p-phenyl Diformyl)bis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylic acid)ditertiary butyl ester (791 mg, 1.13 mmol) in CH ₂ Cl ₂ (6.7 mL) was added trifluoroacetic acid (3.4 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with diethyl ether (20 mL) to give 2-methyl-N ¹ , N ⁴ -bis(4-(piperone-1-yl)phenyl)tetraphthalamide- Trifluoroacetate (964 mg, 89%) as a light green solid.

({4-[4-(4-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-phenyl Aminoformyl}-2-methyl-benzoylamino)-phenyl]-piperone-1-yl}-tertiary butoxycarbonylimino-methyl)-carbamic acid tri Synthesis of grade butyl esters. 2-Methyl-N ¹ , N ⁴ -bis(4-(piper-1-yl)phenyl)terephthalamide 4 trifluoroacetic acid (382 mg, 0.40 mmol) in N,N-di The mixture in methylformamide (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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-7% methanol: CH ₂ Cl ₂ ) to obtain ({4-[4-(4-{4-[4-(tertiary butoxycarbonylamino-tertiary Butoxycarbonylimino-methyl)-pipera-1-yl]-phenylaminoformyl}-2-methyl-benzoylamino)-phenyl]-pipera-1 -yl}-tert-butoxycarbonylimino-methyl)-tert-butyl carbamate (284 mg, 72%) as a yellow solid.

Synthesis of N ¹ , N ⁴ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)-2-methylterephthalamide: to ({4-[4-(4 -{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-2- Methyl-benzoylamino)-phenyl]-piperone-1-yl}-tert-butoxycarbonylimino-methyl)-carbamic acid tertiary-butyl ester (284 mg, 0.29 mmol ) in _CH2Cl2 (2.9 mL ₎ was added trifluoroacetic acid (2.9 mL). The reaction was stirred for 2 days, then concentrated. The residue was treated with N,N-dimethylformamide (2 mL), then 0.1% trifluoroacetic acid in water (2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (2 mL) and hexane (2 mL) to give N ¹ ,N ⁴ -bis(4-(4-carbamimidinopiperol-1-yl)phenyl)-2-methyl Tetraphthalamide tetrakis-trifluoroacetate (188 mg, 62%) as a beige solid. MS: 583 M+H+;

Example 18: Synthesis of N ² , N ⁵ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)pyridine-2,5-dimethylamide

4,4'-(((pyridine-2,5-dicarbonyl)bis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylic acid)di-tertiary butyl ester The synthesis. To pyridine-2,5-dicarboxylic acid (267 mg, 1.60 mmol), tertiary butyl piper-1-carboxylate (985 mg, 3.55 mmol) and triethylamine (758 mg, 896 μL, 6.40 mmol) in N , to a mixture in N-dimethylformamide (4.8 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] Pyridine 3-oxide hexafluorophosphate (1818 mg, 4.80 mmol). The reaction was stirred for 16 h, then treated with dilute aqueous NaHCO ₃ (100 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4,4'-(((pyridine-2,5-dicarbonyl)bis(azanediyl))bis(4,1- Phenylylene)) bis(piperone-1-carboxylate) di-tert-butyl ester (854 mg, 78%), as a yellow solid.

Synthesis of N ² , N ⁵ -bis(4-(piperone-1-yl)phenyl)pyridine-2,5-dimethylamide: to 4,4'-(((pyridine-2,5-di Carbonyl)bis(azanediyl))bis(4,1-phenylene))bis(piperone-1-carboxylic acid)ditertiary butyl ester (854 mg, 1.25 mmol) in CH ₂ Cl ₂ (7 mL ) was added trifluoroacetic acid (3.5 mL). The reaction was stirred for 5 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N ² ,N ⁵ -bis(4-(piper-1-yl)phenyl)pyridine-2,5-dimethylamide penta-tris Fluoroacetate (1.14 g, 86%) as a red solid.

[(4-{4-[(5-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-benzene Aminoformyl}-pyridine-2-carbonyl)-amino]-phenyl}-piperone-1-yl)-tertiary butoxycarbonylimino-methyl]-carbamic acid tertiary Synthesis of butyl esters. N ² ,N ⁵ -bis(4-(piper-1-yl)phenyl)pyridine-2,5-dimethylamide 4 trifluoroacetic acid (422 mg, 0.40 mmol) in N,N-dimethyl The mixture in methylformamide (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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-7% methanol: CH ₂ Cl ₂ ) to give [(4-{4-[(5-{4-[4-(tertiary butoxycarbonylamino-tri Butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-pyridine-2-carbonyl)-amino]-phenyl}-piperone-1- yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (417 mg, >100%) as a yellow solid which was used without further purification.

Synthesis of N ² , N ⁵ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)pyridine-2,5-dimethylamide: to [(4-{4-[(5 -{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-pyridine- 2-Carbonyl)-amino]-phenyl}-piperone-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (417 mg, 0.43 mmol) in To the mixture _{in CH2Cl2} (4.3 mL) was added trifluoroacetic acid (4.3 mL). The reaction was stirred for 2 days, then concentrated. The residue was treated with N,N-dimethylformamide (2 mL), then 0.1% trifluoroacetic acid in water (2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (5 mL) and hexane (5 mL) to give N ² ,N ⁵ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)pyridine-2,5 - Diformamide penta-trifluoroacetate (280 mg, 57%) as an orange solid. MS: 570 M+H+; ¹ H NMR (300 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, J =7.62 Hz, 1 H) 8.24 (d, J =8.20 Hz, 1 H) 7.93 (br. s., 1 H) 7.80 (d, J =8.20 Hz, 3 H) 7.65 (d, J = 8.20 Hz, 3 H) 7.54 (br. s., 10 H) 7.00 (d, J =7.03 Hz, 5 H) 3.57 (br. s., 4 H) 3.21 - 3.27 (m, 4 H).

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

4-(4-{5-[(4-{4-[(tertiary butoxy)carbonyl]piperone-1-yl}phenyl)aminoformyl]furan-2-amido}benzene Base) Synthesis of tertiary butyl piperazine 𠯤-1-carboxylate. To furan-2,5-dicarboxylic acid (250 mg, 1.60 mmol), tertiary butyl 4-(4-amino-phenyl)-piperone-1-carboxylate (985 mg, 3.55 mmol) and triethylamine (758 mg, 896 μL, 6.40 mmol) to a mixture in N,N-dimethylformamide (4.8 mL) was added 1-[bis(dimethylamino)methylene]-1H-1, 2,3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1818 mg, 4.80 mmol). The reaction was stirred for 5 days, then treated with water (75 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexanes (20 mL) to give 4-(4-{5-[(4-{4-[(tertiary butoxy)carbonyl]pipera-1-yl }phenyl)aminoformyl]furan-2-amido}phenyl)piperyl-1-carboxylic acid tert-butyl ester (834 mg, 77%), as a yellow solid.

Synthesis of furan-2,5-dicarboxylic acid bis[(4-piper-1-yl-phenyl)-amide]. To 4-(4-{5-[(4-{4-[(tertiary butoxy)carbonyl]piperone-1-yl}phenyl)aminoformyl]furan-2-amido} To a mixture _of tert-butyl phenyl)piperone-1-carboxylate (830 mg, 1.23 mmol) in _CH2Cl2 (7 mL) was added trifluoroacetic acid (3.5 mL). The reaction was stirred for 5 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give furan-2,5-dicarboxylic acid bis[(4-piperazol-1-yl-phenyl)-amide] Tetra-trifluoroacetate (959 mg, 84%) as a pale green solid.

[(4-{4-[(5-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-benzene Aminoformyl}-furan-2-carbonyl)-amino]-phenyl}-piperone-1-yl)-tertiary butoxycarbonylimino-methyl]-carbamic acid tertiary Synthesis of butyl esters. To furan-2,5-dicarboxylic acid bis[(4-piperone-1-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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and 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), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-7% methanol: CH ₂ Cl ₂ ) to give [(4-{4-[(5-{4-[4-(tertiary butoxycarbonylamino-tri Butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-furan-2-carbonyl)-amino]-phenyl}-piperone-1- [0]-tert-butyloxycarbonylimino-methyl]-carbamic acid tert-butyl ester (316 mg, 82%) as a yellow solid.

Synthesis of furan-2,5-dicarboxylic acid bis{[4-(4-formamimidino-piper-1-yl)-phenyl]-amide}: to [(4-{4-[(5- {4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-piperone-1-yl]-phenylaminoformyl}-furan-2 -Carbonyl)-Amino]-Phenyl}-Piperol-1-yl)-tert-Butoxycarbonylimino-Methyl]-Ter-Butylcarbamate (316 mg, 0.33 mmol) in CH To the mixture in ₂ Cl ₂ (3.3 mL) was added trifluoroacetic acid (3.3 mL). The reaction was stirred for 3 days, then concentrated. The crude material was purified by preparative HPLC to afford furan-2,5-dicarboxylic acid bis{[4-(4-carbamimidino-piperol-1-yl)-phenyl]-amide} as a yellow solid, Tetrafluoroacetate (174 mg, 52%). MS: 559 M+H+; ¹ 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).

Example 20: Synthesis of N-[4-(4-formamidino-piper-1-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide

Synthesis of tertiary butyl 4-[4-(4-methoxycarbonyl-benzoylamino)-phenyl]-piperone-1-carboxylate. Add 4-(4-amino-phenyl)-piperone-1-carboxylic acid tertiary-butyl ester (832 mg, 3.00 mmol) and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in CHCl ₃ To the mixture in (8 mL) was added a solution of 4-chlorocarbonyl-benzoic acid methyl ester (687 mg, 3.46 mmol) in _CHCl3 (8 mL). The reaction was stirred for 16 hours then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (20 mL). Wash the organic layer with saturated aqueous _NaHCO3 (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 silica gel column (0%-70% ethyl acetate: hexanes) to give 4-[4-(4-methoxycarbonyl-benzoylamino)-phenyl]-piperone- Tert-butyl 1-carboxylate (697 mg, 53%) as a light yellow solid.

Synthesis of tertiary butyl 4-[4-(4-carboxy-benzoylamino)-phenyl]-piperone-1-carboxylate. To tertiary butyl 4-[4-(4-methoxycarbonyl-benzoylamino)-phenyl]-piperone-1-carboxylate (697 mg, 1.59 mmol) in 1,4-di To the mixture in 𠮿 (7.5 mL) was added 10 N aqueous NaOH (1.6 mL). The reaction was heated at 60°C for 24 hours. Treat the mixture with additional 1,4-dimethoxane (3 mL) and 10 N aqueous NaOH (1 mL). The reaction was heated at 60 °C for 18 hours, then concentrated to remove 1,4-di㗁𠮿. The residue was treated with water (20 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give 4-[4-(4-carboxy-benzoylamino)-phenyl]-piperazol-1-carboxylic acid tert-butyl Ester (499 mg, 74%) as a light green solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-phenyl)-piperylaminoformyl-1 -Synthesis of tertiary butyl formate. To tertiary butyl 4-[4-(4-carboxy-benzoylamino)-phenyl]-piperone-1-carboxylate (499 mg, 1.17 mmol), (4-amino-benzyl) - To a mixture of tertiary butyl carbamate (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]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (665 mg, 1.76 mmol) . The reaction was treated with additional N,N-dimethylformamide (2 mL) and stirred for 16 hours. The reaction was treated with additional triethylamine (422 mg, 500 μL, 3.57 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4, 5-b] pyridinium cation 3-oxide hexafluorophosphate (1100 mg, 2.91 mmol) treatment. The reaction was stirred for 24 hours. The reaction was treated with water (90 mL) and ethyl acetate (50 mL), then shaken and filtered. The solid was washed with isopropanol (20 mL) and hexane (20 mL), then dried under high vacuum to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl) -Phenylaminoformyl]-benzoylamino}-phenyl)-piperyl-1-carboxylic acid tert-butyl ester (583 mg, 79%) as a white solid.

Synthesis of N-(4-aminomethyl-phenyl)-N'-(4-piper-1-yl-phenyl)-terephthalamide. To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-phenyl)-piperylamino- To _a mixture of tert-butyl 1-carboxylate (583 mg, 0.93 mmol) in _CH2Cl2 (5.3 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ethyl acetate (25 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with ethyl acetate (10 mL) to give N-(4-aminomethyl-phenyl)-N'-(4-piperazol-1-yl-phenyl)-p-phenyl Diformamide tris-trifluoroacetate (519 mg, 72%) as gray solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)phenyl] Synthesis of tertiary butyl piperamine-1-yl})methylene]carbamate. To N-(4-aminomethyl-phenyl)-N'-(4-piperone-1-yl-phenyl)-terephthalamide 3 trifluoroacetic acid (309 mg, 0.40 mmol) in To the mixture 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 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 silica gel column (0%-5% methanol: CH ₂ Cl ₂ ) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)phenyl]piper-1-yl})methylene]carbamate (155 mg, 42%), as yellow solid.

Synthesis of N-[4-(4-formamidino-piper-1-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide: to N -[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy) Carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)phenyl]- To a mixture of tert-butyl 1-yl})methylene]carbamate (155 mg, 0.17 mmol) in CH2Cl2 (1.7 mL) was added trifluoroacetic acid (1.7 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC afforded N-[4-(4-carbamidino-piperone-1-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-p Tris-trifluoroacetate of phthalamide (84 mg, 58%), as a yellow solid. MS: 514 MH+; ¹ H 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, J =6.15 Hz, 1 H) 7.78 (d, J =8.79 Hz, 2 H) 7.65 (d, J =8.79 Hz, 2 H) 7.49 (s, 4 H) 7.30 (d, J =8.79 Hz, 3 H) 6.99 (d, J =9.37 Hz, 2 H) 4.34 (d, J =5.86 Hz, 2 H) 3.57 (br. s., 4 H) 3.19 (br. s., 4 H).

Example 21: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxy-phenyl]-N'-(4-guanidino Synthesis of Methyl-Phenyl)-Terephthalamide

Synthesis of N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid methyl ester. To (4-amino-benzyl)-carbamate tert-butyl ester (1.33 g, 6.00 mmol) and diisopropylethylamine (1210 mg, 1630 μL, 9.42 mmol) in _CHCl (16 mL) To the mixture was added dropwise a solution of 4-chlorocarbonyl-benzoic acid methyl ester (1.37 mmol) in CHCl ₃ (16 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ethyl acetate (60 mL) and water (60 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give methyl N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalate (1.62 g, 70%), as a white solid.

Synthesis of N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid. N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid methyl ester (1.62 g, 4.21 mmol) in 1,4-di㗁𠮿 (25 mL) The resulting mixture was treated with 10 N aqueous NaOH (4.2 mL). The reaction was heated at 60°C for 24 hours. The mixture was treated with additional 10 N aqueous NaOH (2 mL), then heated at 60 °C for 24 h. The reaction was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was filtered and the solid was washed with isopropanol (20 mL) and hexane (20 mL) to give N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid (1.48 g, 95%) as a white solid.

Synthesis of tertiary butyl {4-[4-(4-bromo-3-methoxy-phenylaminoformyl)-benzoylamino]-benzyl}-carbamate. To N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic 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 cation 3-oxide hexafluorophosphate (1135 mg, 3.00 mmol). The reaction was stirred for 16 hours, then treated with water (90 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give {4-[4-(4-bromo-3-methoxy-phenylaminoformyl)-benzoylamine tert-butyl]-benzyl}-carbamate (936 mg, 84%) as a white solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-2-methoxy-phenyl )-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester synthesis. By bubbling nitrogen through {4-[4-(4-bromo-3-methoxy-phenylaminoformyl)-benzoylamino]-benzyl}-carbamic acid tertiary Butyl ester (936 mg, 1.69 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-di Hydrogen-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'-dimethyl Mixture of oxybiphenyl (73 mg, 0.19 mmol) in 1,4-bis(12 mL) and 2M K ₂ CO ₃ (4.2 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-benzoylamino}-2-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (935 mg, 84%) as a gray solid .

N-(4-aminomethyl-phenyl)-N'-[3-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Synthesis of dimethylamide. To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-2-methoxy-benzene To a mixture of tert _- butyl)-3,6-dihydro-2H-pyridine-1-carboxylate (935 mg, 1.42 mmol) in _CH2Cl2 (8 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(4-aminomethyl-phenyl)-N'-[3-methoxy-4-(1,2,3,6- Tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate salt (977 mg, >100%) as a gray solid which was used without further purification.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)-2- Synthesis of tertiary butyl methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. To N-(4-aminomethyl-phenyl)-N'-[3-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p Phthalamide 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and 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 silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene] Tert-butyl carbamate (244 mg, 65%) as an off-white solid.

N-[4-(1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxy-phenyl]-N'-(4-guanidinomethyl- The synthesis of phenyl)-terephthalamide: to N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-( {[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]amine tertiary butylformyl}benzamido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl)methylene]carbamate ( 244 mg, 0.26 mmol) in _CH2Cl2 (2.6 mL) _was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC afforded N-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxy-phenyl]-N Bis-trifluoroacetate salt of '-(4-guanidinomethyl-phenyl)-terephthalamide (122 mg, 61%) as a white solid. MS: 541 M+H+; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ ppm 10.45 (d, J =4.69 Hz, 2 H) 8.09 (s, 4 H) 7.91 - 8.04 (m, 1 H) 7.79 (d, J =8.79 Hz, 2 H) 7.55 (d, J =1.76 Hz, 1 H) 7.42 (br. s., 6 H) 7.30 (d, J =8.79 Hz, 3 H) 7.16 (d, J =8.20 Hz, 2 H) 5.85 (s, 1 H) 4.34 ( d , J =5.86 Hz, 2 H) 4.02 (br. s., 2 H) 3.78 (s, 3 H) 3.56 (t, J =5.57 Hz, 2H) 2.50 - 2.56 (m, 2H).

Example 22: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-phenyl]-N'-(4-guanidino Synthesis of Methyl-Phenyl)-Terephthalamide

Synthesis of N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid methyl ester. To (4-amino-benzyl)-carbamate tert-butyl ester (1.33 g, 6.00 mmol) and diisopropylethylamine (1210 mg, 1630 μL, 9.42 mmol) in _CHCl (16 mL) To the mixture was added dropwise a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1.37 g, 6.92 mmol) in CHCl ₃ (16 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ethyl acetate (60 mL) and water (60 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give methyl N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalate (1.62 g, 70%), as a white solid.

Synthesis of N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid. N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid methyl ester (1.62 g, 4.21 mmol) in 1,4-di㗁𠮿 (25 mL) The resulting mixture was treated with 10 N aqueous NaOH (4.2 mL). The reaction was heated at 60° C. for 24 hours, then concentrated. The reaction was treated with additional 10 N aqueous NaOH (2 mL) and then heated at 60 °C for 24 h. The reaction was concentrated and the residue was treated with water (50 mL). The mixture was adjusted to pH 1 using 1 N HCl and then sonicated for 5 min. The mixture was filtered and the solid was washed with isopropanol (20 mL) and hexane (20 mL) to give N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic acid (1.48 g, 95%) as a white solid.

Synthesis of tertiary butyl {4-[4-(4-bromo-2-methoxy-phenylaminoformyl)-benzoylamino]-benzyl}-carbamate. To N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-terephthalic 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 cation 3-oxide hexafluorophosphate (1135 mg, 3.00 mmol). The reaction was stirred for 16 hours, then treated with water (90 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give {4-[4-(4-bromo-2-methoxy-phenylaminoformyl)-benzoylamine tert-butyl]-benzyl}-carbamate (892 mg, 80%) as a white solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-3-methoxy-phenyl )-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester synthesis. By bubbling nitrogen through {4-[4-(4-bromo-2-methoxy-phenylaminoformyl)-benzoylamino]-benzyl}-carbamic acid tertiary Butyl ester (892 mg, 1.61 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-di Hydrogen-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'-dimethyl Oxybiphenyl (70 mg, 0.18 mmol) in 1,4-bis(11.5 mL) and 2M K ₂ CO ₃ (4 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-benzoylamino}-3-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (615 mg, 58%) as a gray solid .

N-(4-aminomethyl-phenyl)-N'-[2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Synthesis of dimethylamide. To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-3-methoxy-benzene To a mixture of tert-butyl)-3,6-dihydro-2H-pyridine- ₁ -carboxylate (615 mg, 0.94 mmol) in _CH2Cl2 (5.3 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 5 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(4-aminomethyl-phenyl)-N'-[2-methoxy-4-(1,2,3,6- Tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate (638 mg, 99%) as a gray solid.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)-3- Synthesis of tertiary butyl methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. To N-(4-aminomethyl-phenyl)-N'-[2-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p Phthalamide 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and 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 silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)-3-methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene] Tert-butyl carbamate (237 mg, 63%) as a pale yellow solid.

N-[4-(1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-phenyl]-N'-(4-guanidinomethyl- The synthesis of phenyl)-terephthalamide: to N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-( {[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]amine tertiary butylformyl}benzamido)-3-methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate ( 237 mg, 0.25 mmol) in _CH2Cl2 (2.5 mL) _was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (3 mL), then 0.1% trifluoroacetic acid in water (3 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give N-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-2- Methoxy-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide bis-trifluoroacetate salt (92 mg, 48%) as a light red solid. MS: 541 M+H+; ¹ 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) .

Example 23: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-3-form Synthesis of phenyl-phenyl)-terephthalamide

Synthesis of tertiary butyl N-[(tertiary 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 min and then treated with 1-bromomethyl-2-methyl-4-nitro-benzenemethane (1.00 g, 4.35 mmol) in N,N-dimethylformamide (2 mL) solution processing. The reaction was stirred for 2 days, then 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 silica gel column (0%-20% ethyl acetate: hexane) to give N-[(tertiary butoxy)carbonyl]-N-[(2-methyl-4-nitrophenyl )Methyl]carbamate tertiary butyl ester (815 mg, 51%), a viscous yellow gum.

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

N-[(4-{4-[(4-bromophenyl)aminoformyl]benzamido}-2-methylphenyl)methyl]-N-[(tertiary butoxy ) Synthesis of tertiary butyl carbamate. Tri-butyl N-[(4-amino-2-methylphenyl)methyl]-N-[(tertiary butoxy)carbonyl]carbamate (717 mg, 2.13 mmol), N- (4-Bromo-phenyl)-terephthalic acid (616 mg, 1.92 mmol) and triethylamine (454 mg, 537 μL, 3.85 mmol) in N,N-dimethylformamide (5.7 mL) The mixture was treated with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1091 mg , 2.88 mmol) processing. The reaction was stirred for 16 hours, then 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 silica gel column (0%-50% ethyl acetate: hexane) to give N-[(4-{4-[(4-bromophenyl)aminoformyl]benzamide }-2-Methylphenyl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (1.15 g, 94%) as a beige solid.

4-[4-(4-{[4-({Bis[(tertiary butoxy)carbonyl]amino}methyl)-3-methylphenyl]aminoformyl}benzamido ) Synthesis of phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid tertiary butyl ester. By bubbling nitrogen gas through N-[(4-{4-[(4-bromophenyl)aminoformyl]benzamido}-2-methylphenyl)methyl]-N- [(tertiary-butoxy)carbonyl]carbamate tertiary-butyl ester (1150 mg, 1.80 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa Cyclopentaboran-2-yl)-3,6-dihydro-2H-pyridine-1-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-di㗁𠮿 (13 mL) and 2M K ₂ CO ₃ (4.5 mL) The mixture was degassed 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 (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-(4-{[4-({bis[(tertiary butoxy)carbonyl]amino} Methyl)-3-methylphenyl]aminoformyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid tertiary butyl ester (1.02 g, 77%), as off-white solid.

N-(4-aminomethyl-3-methyl-phenyl)-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephenyl Synthesis of formamide. To 4-[4-(4-{[4-({bis[(tertiary butoxy)carbonyl]amino}methyl)-3-methylphenyl]aminoformyl}benzamide To a mixture of tert-butyl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (1.02 g, 1.38 mmol) in CH ₂ Cl ₂ (8 mL) was added trifluoroacetic acid ( 4 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(4-aminomethyl-3-methyl-phenyl)-N'-[4-(1,2,3,6-tetra Hydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate salt (1.01 g, >100%) as a pale yellow solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)-3-methylphenyl]aminoformyl}benzamide Synthesis of tertiary butyl) phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. To N-(4-aminomethyl-3-methyl-phenyl)-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Diformamide 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and 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), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)-3-methylphenyl]aminoformyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine Tert-butyl carbamate (291 mg, 79%) as a pale yellow solid.

N-[4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-3-methyl-benzene base)-terephthalamide synthesis: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({ [(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)-3-methyl phenyl]carbamoyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tert-butyl ester (291 mg , 0.32 mmol) in _CH2Cl2 (3.2 mL) _was added trifluoroacetic acid (3.2 mL). The reaction was stirred for 2 days, then concentrated. The residue was treated with N,N-dimethylformamide (2 mL), then 0.1% trifluoroacetic acid in water (2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give N-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl ]-N'-(4-guanidinomethyl-3-methyl-phenyl)-terephthalamide bis-trifluoroacetate salt (107 mg, 44%) as a pale orange solid. MS: 525 M+H+; ¹ 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, 2H) 4.07 (br.s., 2H) 3.62 (br.s., 2H) 2.59 (br.s., 2H) 2.27 (s, 3H) .

Example 24: N-(2-Formamimidino-2,3-dihydro-1H-isoindol-5-yl)-N'-[4-(1-Formamimidino-1,2,3,6 Synthesis of -tetrahydropyridin-4-yl)-phenyl]-terephthalamide

Synthesis of tertiary-butyl 5-[4-(4-bromo-phenylaminoformyl)-benzoylamino]-1,3-dihydro-isoindole-2-carboxylate. To N-(4-bromo-phenyl)-terephthalic acid (616 mg, 1.92 mmol), tertiary butyl 5-amino-1,3-dihydro-isoindole-2-carboxylate (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) Methyl]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1091 mg, 2.88 mmol). The reaction was stirred for 16 hours, then treated with water (90 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 5-[4-(4-bromo-phenylaminoformyl)-benzoylamino]-1,3- Tert-butyl dihydro-isoindole-2-carboxylate (743 mg, 72%) as a white solid.

5-{4-[4-(1-tertiary butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylaminoformyl]-benzoylamino Synthesis of }-1,3-dihydro-isoindole-2-carboxylic acid tertiary butyl ester. By bubbling nitrogen gas through 5-[4-(4-bromo-phenylaminoformyl)-benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid Butyl ester (743 mg, 1.39 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-di Hydrogen-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'-dimethyl Mixture of oxybiphenyl (60 mg, 0.16 mmol) in 1,4-bis(10 mL) and 2M K ₂ CO ₃ (3.4 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The mixture was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 5-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4 -yl)-phenylaminoformyl]-benzoylamino}-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (731 mg, 82%) as a gray solid .

N-(2,3-dihydro-1H-isoindol-5-yl)-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p Synthesis of phthalamide. To 5-{4-[4-(1-tertiary butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylaminoformyl]-benzoylamine To a mixture of ter-butyl)-1,3 _- dihydro-isoindole-2-carboxylate (731 mg, 1.14 mmol) in _CH2Cl2 (6.5 mL) was added trifluoroacetic acid (3.3 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (20 mL), then sonicated. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(2,3-dihydro-1H-isoindol-5-yl)-N'-[4-(1,2,3,6 -Tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate salt (879 mg, >100%) as a gray solid which was used without further purification.

{[5-(4-{4-[1-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-1,2,3,6-tetrahydropyridine-4 -yl]-phenylaminoformyl}-benzoylamino)-1,3-dihydro-isoindol-2-yl]-tertiary butoxycarbonylimino-methyl} -Synthesis of tertiary butyl carbamate. To N-(2,3-dihydro-1H-isoindol-5-yl)-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- To a mixture of 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and 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 silica gel column (0%-75% ethyl acetate: hexane) to give {[5-(4-{4-[1-(tertiary butoxycarbonylamino-tertiary butoxy Carbonylimino-methyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenylaminoformyl}-benzoylamino)-1,3-dihydro- Isoindol-2-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (175 mg, 47%) as an off-white solid.

N-(2-Carboxamidino-2,3-dihydro-1H-isoindol-5-yl)-N'-[4-(1-carboxamidino-1,2,3,6-tetrahydro Synthesis of pyridin-4-yl)-phenyl]-terephthalamide: to {[5-(4-{4-[1-(tertiary butoxycarbonylamino-tertiary butoxycarbonyl Imino-methyl)-1,2,3,6-tetrahydropyridin-4-yl]-phenylaminoformyl}-benzoylamino)-1,3-dihydro-iso To a _mixture of indol-2-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (175 mg, 0.19 mmol) in _CH2Cl2 (1.9 mL) was added Trifluoroacetic acid (1.9 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (1.2 mL), then 0.1% trifluoroacetic acid in water (1.2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give N-(2-carbamimidino-2,3-dihydro-1H-isoindol-5-yl)-N'-[ 4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate (131 mg, 92%) , as light red solid. MS: 523 M+H+; ¹ 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, J =8.20 Hz, 3 H) 7.69 (d, J =7.62 Hz, 2 H) 7.31 - 7.61 (m, 15 H) 6.18 (br. s., 1 H) 4.73 (d, J =13.47 Hz, 4 H) 4.06 (br. s., 2 H) 2.58 (br. s., 2 H).

Example 25: Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of Amide (4-guanidinomethyl-phenyl)-amide

Synthesis of 3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylate monomethyl ester (500 mg, 2.94 mmol), 4-bromo-phenylamine (557 mg, 3.23 mmol) and triethylamine (557 mg, 659 μL, 4.70 mmol) to a mixture in N,N-dimethylformamide (9 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1670 mg, 4.41 mmol). The reaction was stirred for 3 days, then 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), 1 N HCl (25 mL), saturated aqueous NaHCO ₃ (25 mL), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexane) to give 3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1- Methyl formate (909 mg, 95%) as a white solid.

Synthesis of 3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid. 3-(4-Bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate (909 mg, 2.80 mmol) in 1,4-bis(13 mL ) was added 10 N aqueous NaOH (2.8 mL). The reaction was heated at 60 °C for 18 h, then treated with additional 10 N aqueous NaOH (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 adjusted to pH 1 with 1 N HCl. The mixture was filtered and the solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1 - Formic acid (385 mg, 44%) as a white solid. The isopropanol and hexane filtrate was concentrated, then the residue was treated with ethyl acetate (100 mL), washed with brine (10 mL), dried ( _Na2SO4 ) and concentrated to give 3-( ₄ -bromo-phenyl Carbamoyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (194 mg, 22%) as a white solid.

(4-{[3-(4-Bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-benzyl)-carbamic acid tertiary butyl Synthesis of esters. To 3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (579 mg, 1.87 mmol), (4-amino-benzyl)-amino To a mixture of tert-butyl formate (459 mg, 2.07 mmol) and triethylamine (441 mg, 522 μL, 3.73 mmol) in N,N-dimethylformamide (5.5 mL) was added 1-[bis (Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1060 mg, 2.80 mmol). The reaction was stirred for 16 hours, then treated with water (90 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give (4-{[3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane- 1-Carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester (786 mg, 82%) as a white solid.

4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}- Synthesis of tertiary-butyl amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-benzyl) - Tertiary-butyl carbamate (786 mg, 1.53 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -3,6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (558 mg, 1.79 mmol), Pd(OAc) ₂ (18 mg, 0.071 mmol) and 2-dicyclohexylphosphino-2' , Mixture of 6'-dimethoxybiphenyl (66 mg, 0.18 mmol) in 1,4-dimethoxybiphenyl (11 mL) and 2M K ₂ CO ₃ (3.7 mL) The mixture was degassed for 10 min. 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 filtered through celite. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (460 mg, 49%), as a white solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of phenyl]-amide. To 4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl} -Amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester ( ₄₆₀ mg, 0.75 mmol) in _CH2Cl2 (4 mL) was added trifluoro Acetic acid (2 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide[4-(1 ,2,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (489 mg, >100%) as a yellow solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane Synthesis of -1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and 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 silica gel column (0%-75% ethyl acetate: hexanes), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}) Tert-Butyl Methylene]carbamate (276 mg, 77%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 4-guanidinomethyl-phenyl)-amide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[ 4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)benzene Base]aminoformyl}bicyclo[1.1.1]pentane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine To _a mixture of tert-butyl carbamate (276 mg, 0.31 mmol) in _CH2Cl2 (3.1 mL) was added trifluoroacetic acid (3.1 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (2 mL), then 0.1% trifluoroacetic acid in water (2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carboxamidino-1,2,3 ,6-Tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (162 mg, 72%), pale orange solid. MS: 501 M+H+; ¹ H 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, J =8.20, 3.52 Hz , 5 H) 7.40 - 7.54 (m, 7 H) 7.22 (d, J =8.79 Hz, 4 H) 6.15 (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) 2.31 (s, 6 H).

Example 26: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of Amide (4-guanidinomethyl-phenyl)-amide

Synthesis of 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylate monomethyl ester (500 mg, 2.36 mmol), 4-bromo-aniline (447 mg, 2.59 mmol) and triethylamine (447 mg, 529 μL , 3.77 mmol) to a mixture in N,N-dimethylformamide (7 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole A[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1341 mg, 3.54 mmol). The reaction was stirred for 16 hours, then 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), 1 N HCl (25 mL), saturated aqueous NaHCO ₃ (25 mL), brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-40% ethyl acetate: hexane) to give 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1- Methyl formate (738 mg, 85%) as a white solid.

Synthesis of 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylic acid. Add 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylate (738 mg, 2.02 mmol) in 1,4-bis(9 mL ) was added 10 N aqueous NaOH (2 mL). The reaction was heated at 80°C for 20 hours. The reaction was treated with additional 10 N aqueous NaOH (2 mL). The reaction was heated at 80°C for 20 hours. The reaction was concentrated, then the residue was adjusted to pH 1 using 1 N HCl. The mixture was filtered and the solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1 - Formic acid (237 mg, 33%) as a white solid. The combined isopropanol/hexane filtrates were concentrated. The residue was treated with ethyl acetate (80 mL), washed with water (10 mL) and brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated to give 4-(4-bromo-phenylaminomethyl Acyl)-bicyclo[2.2.2]octane-1-carboxylic acid (408 mg, 57%) as a white solid.

(4-{[4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-benzyl)-carbamic acid tertiary butyl Synthesis of esters. 4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylic acid (640 mg, 1.82 mmol), (4-amino-benzyl)-amino To a mixture of tert-butyl formate (446 mg, 2.01 mmol) and triethylamine (429 mg, 507 μL, 3.62 mmol) in N,N-dimethylformamide (5.3 mL) was added 1-[bis (Dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1030 mg, 2.72 mmol). The reaction was stirred for 16 hours, then 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), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-70% ethyl acetate: hexane) to give (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2] Octane-1-carbonyl]-amino}-benzyl)-carbamate tert-butyl ester (534 mg, 53%) as a white solid.

4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}- Synthesis of tertiary-butyl amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-benzyl) - Tertiary-butyl carbamate (534 mg, 0.96 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -3,6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (350 mg, 1.12 mmol), Pd(OAc) ₂ (11 mg, 0.046 mmol) and 2-dicyclohexylphosphino-2' , Mixture of 6'-dimethoxybiphenyl (41 mg, 0.11 mmol) in 1,4-dimethoxybiphenyl (7 mL) and 2M K ₂ CO ₃ (2.3 mL) The mixture was degassed for 10 min. 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 (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexane) to give 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (212 mg, 34%), as light yellow solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of phenyl]-amide. To 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl} -Amino)-phenyl]-3,6-dihydro-2H-pyridine-1- _carboxylic acid tert-butyl ester (212 mg, 0.32 mmol) in _CH2Cl2 (2 mL) was added trifluoro Acetic acid (1 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (10 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amide[4-(1 ,2,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (204 mg, 93%) as a pale orange solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane Synthesis of -1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl )-phenyl]-amide 2 Trifluoroacetic acid (202 mg, 0.29 mmol) in N,N-dimethylformamide (2.8 mL) was mixed with triethylamine (206 mg, 282 μL, 2.02 mmol ) to process slowly. The reaction was stirred for 15 minutes and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (288 mg, 0.93 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (45 mL) and 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 silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}) Tert-Butyl Methylene]carbamate (125 mg, 46%) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 4-guanidinomethyl-phenyl)-amide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[ 4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)benzene Base]aminoformyl}bicyclo[2.2.2]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine To _a mixture of tert-butyl carbamate (125 mg, 0.13 mmol) in _CH2Cl2 (1.3 mL) was added trifluoroacetic acid (1.3 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- Bis-trifluoroacetate salt of (4-guanidinomethyl-phenyl)-amide (4-guanidinomethyl-phenyl)-amide (30 mg, 30%) as a white solid. MS: 543 M+H+; ¹ H 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, J =8.20 Hz, 3 H) 6.13 (br. s., 1 H) 4.28 (d, J =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).

Example 27: Pyridine-2,5-dicarboxylic acid 5-{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide} 2- Synthesis of [(4-guanidinomethyl-phenyl)-amide]

Synthesis of 5-(4-bromo-phenylaminoformyl)-pyridine-2-carboxylic acid methyl ester. To 2-methyl pyridine-2,5-dicarboxylate (500 mg, 2.76 mmol), 4-bromo-phenylamine (523 mg, 3.03 mmol) and triethylamine (523 mg, 619 μL, 4.41 mmol) in To a mixture in N,N-dimethylformamide (8.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 -b] pyridine 3-oxide hexafluorophosphate (1568 mg, 4.14 mmol). The reaction was stirred for 1 day, then 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 silica gel column (0%-30% ethyl acetate: hexane) to give 5-(4-bromo-phenylaminoformyl)-pyridine-2-carboxylic acid methyl ester (511 mg, 55 %), as a white solid.

Synthesis of 5-(4-bromo-phenylaminoformyl)-pyridine-2-carboxylic acid. 10 N Aqueous NaOH (1.5 mL). The reaction was heated at 80°C for 20 hours. The reaction was concentrated, then the residue was adjusted to pH 1 using 1 N HCl. The mixture was filtered and the solid was washed with isopropanol (10 mL) and hexane (10 mL) to give 5-(4-bromo-phenylaminoformyl)-pyridine-2-carboxylic acid (381 mg, 79% ), as a white solid. The isopropanol/hexane filtrate was concentrated. The residue was treated with ethyl acetate (30 mL), washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated to give 5-(4-bromo-phenylaminoformyl)-pyridine -2-Carboxylic acid (56 mg, 12%) as a white solid.

Synthesis of tertiary butyl (4-{[5-(4-bromo-phenylaminoformyl)-pyridine-2-carbonyl]-amino}-benzyl)-carbamate. To 5-(4-bromo-phenylcarbamoyl)-pyridine-2-carboxylic acid (437 mg, 1.36 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (334 mg , 1.50 mmol) and triethylamine (321 mg, 379 μL, 2.71 mmol) in N,N-dimethylformamide (4 mL) was added 1-[bis(dimethylamino) Methyl]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (770 mg, 2.03 mmol). The reaction was stirred for 16 hours, then treated with water (60 mL) and ethyl acetate (40 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give (4-{[5-(4-bromo-phenylaminoformyl)-pyridine-2-carbonyl]-amino} -Benzyl)-tert-butyl carbamate (552 mg, 77%) as a white solid.

4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-pyridine-3-carbonyl}-amino)-phenyl]- Synthesis of tertiary-butyl 3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[5-(4-bromo-phenylcarbamoyl)-pyridine-2-carbonyl]-amino}-benzyl)-carbamate tert-butyl (550 mg, 1.05 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro- tert-butyl 2H-pyridine-1-carboxylate (383 mg, 1.23 mmol), Pd(OAc) ₂ (12 mg, 0.050 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy Mixture of biphenyl (45 mg, 0.12 mmol) in 1,4-bis(7.7 mL) and 2M _K2CO3 (2.5 mL) The mixture was degassed 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). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL) to give 4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminomethyl Acyl]-pyridine-3-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (557 mg, 85%) as a pale yellow solid.

Pyridine-2,5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide]5-{[4-(1,2,3,6-tetrahydropyridin-4-yl)- The synthesis of phenyl]-amide}. To 4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-pyridine-3-carbonyl}-amino)-phenyl] _- To a mixture of tert-butyl 3,6-dihydro-2H-pyridine-1-carboxylate (557 mg, 0.89 mmol) in _CH2Cl2 (4.7 mL) was added trifluoroacetic acid (2.4 mL). The reaction was stirred for 20 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and 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-Tetrahydropyridin-4-yl)-phenyl]-amide} tris-trifluoroacetate salt (712 mg, >100%) as light green solid which was used without further purification .

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}pyridin-3-amido)phenyl Synthesis of tertiary butyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. Pyridine-2,5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide]5-{[4-(1,2,3,6-tetrahydropyridin-4-yl) -Phenyl]-amide}3 trifluoroacetic acid (308 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was mixed with triethylamine (280 mg, 384 μL, 2.74 mmol )deal with. The reaction was stirred for 15 minutes, then N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was concentrated, then the residue was treated with water (25 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). 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 silica gel column (0%-50% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (6-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}pyridin-3-amino)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary Butyl ester (242 mg, 66%) as a pale yellow solid.

Pyridine-2,5-dicarboxylic acid 5-{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}2-[(4 -Synthesis of guanidinomethyl-phenyl)-amide]: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(6-{[ 4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)benzene Base]aminoformyl}pyridin-3-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester (242 mg, 0.27 mmol) in _CH2Cl2 (2.7 mL) _was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (1.7 mL), then 0.1% trifluoroacetic acid in water (1.7 mL) was added dropwise. The mixture was filtered and the solid was washed with isopropanol (15 mL) and hexane (15 mL) to give pyridine-2,5-dicarboxylic acid 5-{[4-(1-carboxamidino-1,2,3, Tris-trifluoroacetate salt of 6-tetrahydropyridin-4-yl)-phenyl]-amide} 2-[(4-guanidinomethyl-phenyl)-amide] (94 mg, 41%) , a beige solid. MS: 512 M+H+; ¹ 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, J =8.20 Hz, 1 H) 8.28 (d, J =8.20 Hz, 1 H) 7.94 (d, J =7.62 Hz, 5 H) 7.77 (d, J =8.20 Hz, 3 H) 7.39 - 7.60 (m, 8 H) 7.31 (d, J =8.20 Hz, 3 H) 6.20 (br. s., 1 H) 4.34 (d, J =5.27 Hz, 2 H) 4.07 (br. s., 2 H) 3.62 (br. s., 2 H) 2.59 (br. s., 2 H).

Example 28: Pyridine-2,5-dicarboxylic acid 2-{[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}5- Synthesis of [(4-guanidinomethyl-phenyl)-amide]

Synthesis of 6-(4-bromo-phenylaminoformyl)-nicotinic acid methyl ester. To 2-methyl pyridine-2,5-dicarboxylate (500 mg, 2.76 mmol), 4-bromo-phenylamine (523 mg, 3.03 mmol) and triethylamine (523 mg, 619 μL, 4.41 mmol) in To a mixture in N,N-dimethylformamide (8.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 -b] pyridine 3-oxide hexafluorophosphate (1568 mg, 4.14 mmol). The reaction was stirred for 1 day, then 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 × 30 mL), saturated aqueous NaHCO ₃ (20 mL) and brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated to give 6-(4-bromo-phenyl Carbamoyl)-nicotinic acid methyl ester (620 mg, 67%) as an off-white solid.

Synthesis of 6-(4-bromo-phenylaminoformyl)-nicotinic acid. To a mixture of 6-(4-bromo-phenylaminoformyl)nicotinic acid methyl ester (620 mg, 1.85 mmol) in 1,4-dimethoxane (8.2 mL) was added 10 N aqueous NaOH ( 1.85 mL). The reaction was heated at 80°C for 20 hours. The reaction was concentrated, then the residue was adjusted to pH 1 using 1 N HCl. The mixture was filtered and the solid was washed with isopropanol (10 mL) and hexane (10 mL) to give 6-(4-bromo-phenylaminoformyl)nicotinic acid (318 mg, 54%) as white solid. The isopropanol/hexane filtrate was concentrated. The residue was treated with ethyl acetate (40 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated to give 6-(4-bromo-phenylaminoformyl)-nicotinic acid (48 mg, 8%) as white solid.

Synthesis of tertiary butyl (4-{[6-(4-bromo-phenylaminoformyl)-pyridine-3-carbonyl]-amino}-benzyl)-carbamate. To 6-(4-bromo-phenylcarbamoyl)-nicotinic acid (361 mg, 1.12 mmol), (4-amino-benzyl)-carbamic acid tertiary 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 ]-1H-1,2,3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (636 mg, 1.68 mmol). The reaction was stirred for 16 hours, then treated with water (60 mL) and ethyl acetate (40 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give (4-{[6-(4-bromo-phenylaminoformyl)-pyridine-3-carbonyl]-amino} -Benzyl)-tert-butyl carbamate (486 mg, 83%) as a white solid.

4-[4-({5-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-pyridine-2-carbonyl}-amino)-phenyl]- Synthesis of tertiary-butyl 3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[6-(4-bromo-phenylcarbamoyl)-pyridine-3-carbonyl]-amino}-benzyl)-carbamate tert-butyl ester (484 mg, 0.92 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro- tert-butyl 2H-pyridine-1-carboxylate (336 mg, 1.08 mmol), Pd(OAc) ₂ (11 mg, 0.044 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxy Mixture of biphenyl (40 mg, 0.11 mmol) in 1,4-bis(7 mL) and 2M K ₂ CO ₃ (2.2 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL) to give 4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminomethyl Acyl]-pyridine-3-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (468 mg, 81%) as a pale yellow solid.

Pyridine-2,5-dicarboxylic acid 5-[(4-aminomethyl-phenyl)-amide]2-{[4-(1,2,3,6-tetrahydropyridin-4-yl)- The synthesis of phenyl]-amide}. To 4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-pyridine-3-carbonyl}-amino)-phenyl] - To a mixture of tert-butyl 3,6-dihydro-2H-pyridine-1-carboxylate ₍ 466 mg, 0.75 mmol) in _CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ethyl acetate (30 mL), then sonicated for 5 min. The mixture was filtered and 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-Tetrahydropyridin-4-yl)-phenyl]-amide} tri-trifluoroacetate (495 mg, > 86%), as a light green solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(5-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}pyridin-2-amido)benzene Synthesis of tertiary butyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. Pyridine-2,5-dicarboxylic acid 5-[(4-aminomethyl-phenyl)-amide] 2-{[4-(1,2,3,6-tetrahydropyridin-4-yl) -Phenyl]-amide}3 trifluoroacetic acid (308 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was mixed with triethylamine (280 mg, 384 μL, 2.74 mmol )deal with. The reaction was stirred for 15 minutes, then N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was concentrated, then the residue was treated with water (25 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). 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 silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (5-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}pyridin-2-amino)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary Butyl ester (241 mg, 66%) as a pale yellow solid.

Pyridine-2,5-dicarboxylic acid 2-{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}5-[(4 -Synthesis of guanidinomethyl-phenyl)-amide]: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(5-{[ 4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)benzene Base]aminoformyl}pyridin-2-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester (241 mg, 0.26 mmol) in _CH2Cl2 (2.6 mL) was added trifluoroacetic acid ( _2.6 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (1.7 mL), then 0.1% trifluoroacetic acid in water (1.7 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (6 mL) and hexane (6 mL) to give pyridine-2,5-dicarboxylic acid 2-{[4-(1-carboxamidino-1,2,3,6-tetrahydro Pyridin-4-yl)-phenyl]-amide} 5-[(4-guanidinomethyl-phenyl)-amide] tris-trifluoroacetate 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).

Example 29: N-(1'-Formamimidino-1',2',3',6'-tetrahydro-[3,4']bipyridyl-6-yl)-N'-(4-guanidine Synthesis of (methyl-phenyl)-terephthalamide

Synthesis of N-(5-bromo-pyridin-2-yl)-methyl terephthalate. To monomethyl terephthalate (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, To a mixture in N-dimethylformamide (9 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b ] Pyridinium cation 3-oxide hexafluorophosphate (1704 mg, 4.50 mmol). The reaction was stirred for 16 hours, then 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 silica gel column (0%-30% ethyl acetate: hexanes) to give methyl N-(5-bromo-pyridin-2-yl)-terephthalate (138 mg, 14%), It is a white solid.

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

Synthesis of {4-[4-(5-bromo-pyridin-2-ylaminoformyl)-benzoylamino]-benzyl}-carbamic acid tertiary butyl ester. To N-(5-bromo-pyridin-2-yl)-terephthalic acid (409 mg, 1.27 mmol), (4-amino-benzyl)-carbamic acid tertiary 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] -1H-1,2,3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (721 mg, 1.90 mmol). The reaction was treated with additional N,N-dimethylformamide (2 mL) and then stirred for 3 days. The reaction was treated with water (90 mL) and ethyl acetate (50 mL), then shaken and filtered. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give {4-[4-(5-bromo-pyridin-2-ylaminoformyl)-benzoylamino]- Benzyl}-carbamate tert-butyl ester (422 mg, 66%) as a light gray solid.

6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-3',6'-dihydro-2' Synthesis of tertiary butyl H-[3,4']bipyridyl-1'-carboxylate. By bubbling nitrogen gas through {4-[4-(5-bromo-pyridin-2-ylaminoformyl)-benzoylamino]-benzyl}-carbamic acid tertiary butyl ester ( 422 mg, 0.80 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H -Pyridine-1-carboxylic acid tertiary butyl ester (293 mg, 0.94 mmol), Pd(OAc) ₂ (9 mg, 0.040 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybis Mixture _of Benzene (35 mg, 0.09 mmol) in 1,4-Digifer (6 mL) and 2M _K2CO3 (1.9 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]- Benzoylamino}-3',6'-dihydro-2'H-[3,4']bipyridyl-1'-carboxylic acid tert-butyl ester (233 mg, 46%) as a beige solid . The ethyl acetate/water filtrate 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 silica gel column (0%-100% ethyl acetate: hexane) to give 6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-benzoylamino}-3',6'-dihydro-2'H-[3,4']bipyridyl-1'-carboxylic acid tertiary butyl ester (203 mg, 40%), It is a white solid.

N-(4-aminomethyl-phenyl)-N'-(1',2',3',6'-tetrahydro-[3,4']bipyridyl-6-yl)-p-phenyl Synthesis of dimethylamide. To 6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-3',6'-dihydro-2 To a mixture of _' H-[3,4']bipyridyl-1'-carboxylic acid tert-butyl ester (436 mg, 0.70 mmol) in _CH2Cl2 (3.7 mL) was added trifluoroacetic acid (1.9 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(4-aminomethyl-phenyl)-N'-(1',2',3',6'-tetrahydro-[3 ,4']bipyridyl-6-yl)-terephthalamide tris-trifluoroacetate (497 mg, 92%) as a light brown solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)pyridine-3 -Synthesis of tertiary butyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. N-(4-aminomethyl-phenyl)-N'-(1',2',3',6'-tetrahydro-[3,4']bipyridyl-6-yl)-p A mixture of phthalamide 3-trifluoroacetic acid (308 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was slowly treated with triethylamine (280 mg, 384 μL, 2.74 mmol) . The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)pyridin-3-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate Tertiary butyl ester (164 mg, 45%) as a white solid.

N-(1'-Formamimidino-1',2',3',6'-tetrahydro-[3,4']bipyridyl-6-yl)-N'-(4-guanidinomethyl -Phenyl)-terephthalamide synthesis: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-(4-{[4- ({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl] Aminoformyl}benzamido)pyridin-3-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (164 mg , 0.18 mmol) in _CH2Cl2 (1.8 mL) _was added trifluoroacetic acid (1.8 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave N-(1'-carboxamidino-1',2',3',6'-tetrahydro-[3,4']bipyridyl-6-yl)- N'-(4-guanidinomethyl-phenyl)-terephthalamide tris-trifluoroacetate (110 mg, 72%) as a white solid. MS: 512 M+H+; ¹ H 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).

Example 30: N-[4-(1-Formamimidino-2,5-dihydro-1H-pyrrol-3-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)- Synthesis of Terephthalamide

3-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-phenyl)-2,5- Synthesis of tertiary butyl dihydro-pyrrole-1-carboxylate. By bubbling nitrogen through {4-[4-(4-bromo-phenylaminoformyl)-benzoylamino]-benzyl}-carbamic acid tertiary butyl ester (702 mg, 1.34 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,5-dihydro-pyrrole-1- Tertiary butyl formate (467 mg, 1.58 mmol), Pd(OAc) ₂ (15 mg, 0.068 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (59 mg, 0.15 mmol) in 1,4-Di㗁𠮿 (10.2 mL) and 2M K ₂ CO ₃ (3.2 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 3-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-benzoylamino}-phenyl)-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (597 mg, 73%) as a gray solid.

Synthesis of N-(4-aminomethyl-phenyl)-N'-[4-(2,5-dihydro-1H-pyrrol-3-yl)-phenyl]-terephthalamide. To 3-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-phenyl)-2,5 - To a _mixture of tert-butyldihydro-pyrrole-1-carboxylate (597 mg, 0.97 mmol) in _CH2Cl2 (5.1 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(4-aminomethyl-phenyl)-N'-[4-(2,5-dihydro-1H-pyrrol-3-yl )-phenyl]-terephthalamide 2-trifluoroacetic acid (641 mg, >100%) as a gray solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({3-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)phenyl] -Synthesis of tertiary-butyl 2,5-dihydro-1H-pyrrol-1-yl})methylene]carbamate. N-(4-aminomethyl-phenyl)-N'-[4-(2,5-dihydro-1H-pyrrol-3-yl)-phenyl]-terephthalamide 2 tri A mixture of fluoroacetic 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 and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (980 mg, 3.15 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (150 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({3-[4- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)phenyl]-2,5-dihydro-1H-pyrrol-1-yl})methylene]carbamate tertiary butyl (395 mg, 44%) as a beige solid.

N-[4-(1-Carboxamidino-2,5-dihydro-1H-pyrrol-3-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalene Synthesis of formamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({3-[4-(4-{[4-({[(1E)-{ [(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzyl Amino)phenyl]-2,5-dihydro-1H-pyrrol-1-yl})methylene]carbamate (395 mg, 0.44 mmol) in CH ₂ Cl ₂ (4.4 mL ) was added trifluoroacetic acid (4.4 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N-[4-(1-carboxamidino-2,5-dihydro-1H-pyrrol-3-yl)-phenyl]-N'-(4-guanidino Methyl-phenyl)-terephthalamide, bis-trifluoroacetate (125 mg, 39%), as a white solid. MS: 497 M+H+; ¹ H 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).

Example 31: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl) -Synthesis of N-methyl-terephthalamide

Synthesis of N-(4-bromo-phenyl)-N-methyl-terephthalic 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 _CHCl (8 mL) was added 4-Chlorocarbonyl-benzoic acid methyl ester (687 mg, 3.46 mmol) in _CHCl3 (8 mL). The reaction was stirred for 3 days, then concentrated. The residue was treated with ethyl acetate (100 mL), washed with water (30 mL), 1 N HCl (30 mL), saturated aqueous _NaHCO3 (20 mL) and brine (20 mL), _dried ( _Na2SO4 ), and condensed. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexane) to give N-(4-bromo-phenyl)-N-methyl-terephthalic acid methyl ester (746 mg, 71% ), as a white solid.

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

Synthesis of tertiary butyl (4-{4-[(4-bromo-phenyl)-methyl-aminoformyl]-benzoylamino}-benzyl)-carbamate. To N-(4-bromo-phenyl)-N-methyl-terephthalic acid (462 mg, 1.38 mmol), (4-amino-benzyl)-carbamic acid tertiary 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 base]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (792 mg, 2.08 mmol). The reaction was stirred for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-100% ethyl acetate: hexanes) to give (4-{4-[(4-bromo-phenyl)-methyl-aminoformyl]-benzyl Acylamino}-benzyl)-tert-butylcarbamate (635 mg, 86%) as a white solid.

4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoyl}-methyl-amino)-phenyl ]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester synthesis. By bubbling nitrogen through (4-{4-[(4-bromo-phenyl)-methyl-aminoformyl]-benzoylamino}-benzyl)-carbamic acid tertiary Butyl ester (635 mg, 1.18 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-di Hydrogen-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'-dimethyl Mixture of oxybiphenyl (52 mg, 0.13 mmol) in 1,4-bis(9 mL) and 2M K ₂ CO ₃ (2.8 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL), then washed with water (20 mL), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Carbamoyl]-benzoyl}-methyl-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (655 mg, 87%), For light yellow solid.

N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Synthesis of dimethylamide. To 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoyl}-methyl-amino)-benzene To a mixture of tert _- butyl]-3,6-dihydro-2H-pyridine-1-carboxylate (655 mg, 1.02 mmol) in _CH2Cl2 (5.1 mL) was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6- Tetrahydropyridin-4-yl)-phenyl]-terephthalamide 2-trifluoroacetic acid (724 mg, >100%) as a pale orange solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(N-methyl-4-{[4-({[(1Z)-{[( Tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamide Synthesis of tertiary butyl) phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p A mixture of phthalamide 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 treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 (15 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (N-methyl-4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino}) Methyl]amino}methyl)phenyl]aminoformyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine Tert-butyl carbamate (207 mg, 56%) as a pale yellow solid.

N-[4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-N- Synthesis of methyl-terephthalamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(N-methyl-4-{ [4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl) phenyl]carbamoyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (207 mg , 0.22 mmol) in _CH2Cl2 (2.2 mL) _was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N-[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidine (2-methyl-phenyl)-N-methyl-terephthalamide bis-trifluoroacetate (91 mg, 55%) as a white solid. MS: 525 M+H+; ¹ 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).

Example 32: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl) Synthesis of -2,5-Dimethyl-terephthalamide

Synthesis of 2,5-Dimethyl-Dimethyl Terephthalate. A mixture of 2,5-dimethyl-terephthalic acid (1.21 g, 6.23 mmol) in methanol (50 mL) was heated at reflux for 30 minutes. To the mixture was added thionyl chloride (16.6 mL, 124.6 mmol). The reaction was heated to reflux for 12 hours, then concentrated. The residue was treated with ethyl acetate (80 mL) and washed with 2 N NaOH (25 mL) and brine (10 mL) _, dried ( _Na2SO4 ) and concentrated to give 2,5-dimethyl-p-benzene Dimethyl dicarboxylate (1.16 g, 84%) as an off-white solid.

Synthesis of 2,5-dimethyl-monomethyl terephthalate. A mixture of dimethyl 2,5-dimethyl-terephthalate (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 to reflux for 3.5 hours, then concentrated. The residue was partitioned between ethyl acetate (25 mL) and water (50 mL). The aqueous layer was adjusted to pH 1 using 1 N HCl, and the mixture was filtered. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give monomethyl 2,5-dimethyl-terephthalate (149 mg, 14%) as a white solid. The isopropanol/hexane filtrate was concentrated to give monomethyl 2,5-dimethyl-terephthalate (453 mg, 42%) as a white solid.

Synthesis of N-(4-bromo-phenyl)-2,5-dimethyl-terephthalic acid methyl ester. To 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) to a mixture in N,N-dimethylformamide (9 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4, 5-b] Pyridinium cation 3-oxide hexafluorophosphate (1643 mg, 4.34 mmol). The reaction was stirred for 16 hours, then treated with water (135 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), 1 N HCl (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 silica gel column (0%-40% ethyl acetate: hexane) to give methyl N-(4-bromo-phenyl)-2,5-dimethyl-terephthalate (540 mg , 52%), as a white solid.

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

Synthesis of tertiary butyl {4-[4-(4-bromo-phenylaminoformyl)-2,5-dimethyl-benzoylamino]-benzyl}-carbamate. To N-(4-bromo-phenyl)-2,5-dimethyl-terephthalic acid (499 mg, 1.43 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester ( 356 mg, 1.61 mmol) and triethylamine (291 mg, 393 μL, 2.88 mmol) in N,N-dimethylformamide (4.3 mL) were added 1-[bis(dimethyl )methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (823 mg, 2.16 mmol). The reaction was stirred for 16 hours, then treated with water (60 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give {4-[4-(4-bromo-phenylaminoformyl)-2,5-dimethyl-benzoyl tert-butylamino]-benzyl}-carbamate (511 mg, 65%) as a white solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2,5-dimethyl-benzoylamino}- Synthesis of tertiary-butyl phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through {4-[4-(4-bromo-phenylaminoformyl)-2,5-dimethyl-benzoylamino]-benzyl}-carbamic acid Tertiary butyl ester (511 mg, 0.93 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6 -Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (339 mg, 1.09 mmol), Pd(OAc) ₂ (10 mg, 0.046 mmol) and 2-dicyclohexylphosphino-2',6'- Mixture of dimethoxybiphenyl (41 mg, 0.10 mmol) in 1,4-dimethoxyl (7 mL) and 2M K ₂ CO ₃ (2.2 mL) The mixture was degassed for 10 min. 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 filtered. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl [yl]-2,5-dimethyl-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (192 mg, 32%), as white solid. The ethyl acetate filtrate was dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylamine [methylformyl]-2,5-dimethyl-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (65 mg, 11% ), as a white solid.

N-(4-aminomethyl-phenyl)-2,5-dimethyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of terephthalamide. To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2,5-dimethyl-benzoylamino} -Phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (257 mg, 0.39 mmol) in CH ₂ Cl ₂ (2 mL) was added trifluoroacetic acid (1 mL ). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. 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-(1,2,3, 6-Tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate salt (264 mg, 99%) as a light brown solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}-2,5-dimethylbenzene Synthesis of tertiary butyl formamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. To N-(4-aminomethyl-phenyl)-2,5-dimethyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl] - To a mixture of 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 and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (372 mg, 1.20 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-50% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}-2,5-dimethylbenzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene tert-butyl carbamate (108 mg, 30%) as a white solid.

N-[4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-2, Synthesis of 5-dimethyl-terephthalamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4 -({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl ]aminoformyl}-2,5-dimethylbenzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tris To a mixture of butyl ester ₍ 108 mg, 0.12 mmol) in _CH2Cl2 (1.2 mL) was added trifluoroacetic acid (1.2 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidine (2,5-dimethyl-terephthalamide bis-trifluoroacetate salt (59 mg, 64%) as a white solid. MS: 539 M+H+; ¹ 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).

Example 33: Pyridine-2,5-dicarboxylic acid 5-{[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl]-acyl Synthesis of amine}2-[(4-guanidinomethyl-phenyl)-amide]

Synthesis of 6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-nicotinic acid methyl ester. To 5-methyl pyridine-2,5-dicarboxylate (500 mg, 2.76 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (674 mg, 3.03 mmol) and triethylamine ( 523 mg, 619 μL, 4.41 mmol) to a mixture in N,N-dimethylformamide (8.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2 ,3-Triazolo[4,5-b]pyridinium cation 3-oxide 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 silica gel column (0%-100% ethyl acetate: hexane) to give 6-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl]- Methyl nicotinate (907 mg, 85%) as a pale yellow solid.

Synthesis of 6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-nicotinic acid. To 6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-nicotinic acid methyl ester (907 mg, 2.35 mmol) in 1,4-di㗁𠮿 ( 11 mL) was added 10 N aqueous NaOH (2.35 mL). The reaction was heated at 80° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (15 mL) and dried under high vacuum to give 6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-nicotinic acid (739 mg, 85%), as light yellow solid.

Synthesis of tertiary butyl (4-{[5-(4-bromo-3-fluoro-phenylaminoformyl)-pyridine-2-carbonyl]-amino}-benzyl)-carbamate. According to the procedure for (4-{4-[(4-bromo-phenyl)-methyl-aminoformyl]-benzoylamino}-benzyl)-carbamic acid tertiary butyl ester The title compound was prepared except that 6-[4-(tertiary-butoxycarbonylamino-methyl)-phenylaminoformyl]-nicotinic acid was replaced by N-(4-bromo-phenyl) -N-methyl-terephthalic acid was replaced and 4-bromo-3-fluoroaniline was replaced by (4-amino-benzyl)-carbamic acid tert-butyl ester.

4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-pyridine-3-carbonyl}-amino)-2-fluoro- Synthesis of tertiary-butyl phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. According to 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoyl}-methyl-amino) -Phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester procedure to prepare the title compound except that (4-{[5-(4-bromo-3-fluoro-benzene Aminocarbamoyl)-pyridine-2-carbonyl]-amino}-benzyl)-tert-butyl carbamate is covered by (4-{4-[(4-bromo-phenyl)-methyl- carbamoyl]-benzoylamino}-benzyl)-carbamic acid tertiary butyl ester instead.

Pyridine-2,5-dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide]5-{[3-fluoro-4-(1,2,3,6-tetrahydropyridine-4 -Synthesis of -yl)-phenyl]-amide}. According to N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p The title compound was prepared by the procedure for phthalamide except that 4-[4-({6-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]- Pyridine-3-carbonyl}-amino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester by 4-[4-({4-[4- (tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoyl}-methyl-amino)-phenyl]-3,6-dihydro-2H-pyridine -1-Tertiary butyl carboxylate instead.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(6-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}pyridin-3-amido)- Synthesis of tertiary butyl 2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. According to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(N-methyl-4-{[4-({[(1Z)- {[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzene Formamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate The title compound was prepared by the procedure for tert-butyl except that pyridine-2 ,5-Dicarboxylic acid 2-[(4-aminomethyl-phenyl)-amide]5-{[3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl) -Phenyl]-amide} is replaced by N-(4-aminomethyl-phenyl)-N'-methyl-N'-[4-(1,2,3,6-tetrahydropyridine-4- base)-phenyl]-terephthalamide instead.

Pyridine-2,5-dicarboxylic acid 5-{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl]-amide}2 Synthesis of -[(4-guanidinomethyl-phenyl)-amide]: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-( 6-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}pyridin-3-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine To _a mixture of tert-butyl carbamate (142 mg, 0.15 mmol) in _CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction was stirred for 3 days, then concentrated. The residue was treated with N,N-dimethylformamide (1.3 mL), then 0.1% trifluoroacetic acid in water (1.3 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (2 mL) and hexane (2 mL) to give pyridine-2,5-dicarboxylic acid 5-{[4-(1-carboxamidino-1,2,3,6-tetrahydro Pyridin-4-yl)-3-fluoro-phenyl]-amide} 2-[(4-guanidinomethyl-phenyl)-amide] tris-trifluoroacetate salt (64 mg, 49%) , a beige solid. MS: 530 M+H+; ¹ 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, J =6.44 Hz, 1 H) 8.28 (d, J =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, J =5.27 Hz, 2 H) 4.07 (br. s., 2 H) 3.60 (br. s., 2 H) 2.56 (br. s., 2H).

Example 34: N ¹ -[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N4-(4-guanidinomethyl-phenyl) -Synthesis of 2-methyl-terephthalamide

Synthesis of N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-2-methyl-terephthalic acid methyl ester. 2-Methyl-terephthalic acid 1-methyl ester (492 mg, 2.53 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (618 mg, 2.78 mmol) and triethylamine (480 mg, 647 μL, 4.05 mmol) to a mixture in N,N-dimethylformamide (8 mL) was added 1-bis(dimethylamino)methylene-1H-1,2, 3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1441 mg, 3.80 mmol). The reaction was stirred for 16 hours, then treated with water (120 mL) and 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 silica gel column (0%-50% ethyl acetate: hexane) to give N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-2-methyl- Methyl terephthalate (839 mg, 83%) as a white solid.

Synthesis of N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-2-methyl-terephthalic acid. To N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-2-methyl-terephthalic acid methyl ester (839 mg, 2.11 mmol) in 1,3-di㗁𠮿 (10 mL) was added 10 N aqueous NaOH (2.1 mL). The reaction was heated at 80° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was filtered and the solid was washed with water (15 mL) and dried under high vacuum to give N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-2-methyl-p- Phthalic acid (685 mg, 84%) as a white solid.

Synthesis of tertiary butyl {4-[4-(4-bromo-phenylaminoformyl)-3-methyl-benzoylamino]-benzyl}-carbamate. To N-[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-2-methyl-terephthalic 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-dimethylformamide (5.5 mL) was added 1-bis(dimethylamino) Methyl-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1012 mg, 2.67 mmol). The reaction was stirred for 3 days, then treated with water (80 mL) and 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 silica gel column (0%-75% ethyl acetate: hexane) to give {4-[4-(4-bromo-phenylaminoformyl)-3-methyl-benzoyl tert-butylamino]-benzyl}-carbamate (675 mg, 70%) as a white solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-methyl-benzoylamino}-phenyl) -Synthesis of tertiary-butyl 3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen gas through {4-[4-(4-bromo-phenylaminoformyl)-3-methyl-benzoylamino]-benzyl}-carbamic acid tertiary butyl Esters (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'-dimethoxy A mixture of diphenyl (55 mg, 0.13 mmol) in 1,4-bis(2)CO 3 (9.5 mL) and 2M K ₂ CO ₃ (3 mL) was degassed 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). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-2-Methyl-benzoylamino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (498 mg, 62%) as a gray solid.

N4-(4-Aminomethyl-phenyl)-2-methyl-N1-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephthalene Synthesis of amides. To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-2-methyl-benzoylamino}-phenyl )-3,6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester ( ₄₉₈ mg, 0.78 mmol) in _CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (25 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with ether (2 × 15 mL) to give N4-(4-aminomethyl-phenyl)-2-methyl-N1-[4-(1,2,3,6- Tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate salt (568 mg, >100%) as a light gray solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}-2-methylbenzamide Synthesis of tertiary butyl) phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. N ⁴ -(4-aminomethyl-phenyl)-2-methyl-N1-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Diformamide 2 A mixture of trifluoroacetic acid (267 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was slowly treated with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 (15 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}-2-methylbenzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine Tert-butyl carbamate (200 mg, 54%) as a white solid.

N ¹ -[4-(1-Formamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N4-(4-guanidinomethyl-phenyl)-2- Synthesis of methyl-terephthalamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({ [(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]amino Formyl}-2-methylbenzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (200 mg , 0.22 mmol) in _CH2Cl2 (2.2 mL) _was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 3 days, then concentrated. The crude material was purified by preparative HPLC to give N1-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N4-(4-guanidino Methyl-phenyl)-2-methyl-terephthalamide bis-trifluoroacetate (109 mg, 66%) as a white solid. MS: 525 M+H+; ¹ 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).

Example 35: N-[6-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-N'-(4-guanidinomethyl -Synthesis of -phenyl)-terephthalamide

Synthesis of N-(6-bromo-pyridine-3-yl)-methyl terephthalate. To 6-bromo-pyridine-3-ylamine (783 mg, 4.50 mmol), 4-dimethylaminopyridine (45 mg) and diisopropylethylamine (912 mg, 1227 μL, 7.08 mmol) in To the mixture in _CHCl3 (12 mL) was added dropwise a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1032 mg, 5.19 mmol) in _CHCl3 (12 mL). The reaction was stirred for 16 hours then 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 (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexanes) to give methyl N-(6-bromo-pyridium-3-yl)-terephthalate (740 mg, 49%) , as light yellow solid.

Synthesis of tertiary butyl 4-[6-(4-methoxycarbonyl-benzoylamino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through N-(6-bromo-pyridium-3-yl)-methyl terephthalate (977 mg, 2.91 mmol), 4-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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-di㗁𠮿 (22 mL) and The mixture in 2M _K2CO3 (7 mL) was degassed for 10 min _. 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 filtered, and the filtrate 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 silica gel column (0%-75% ethyl acetate: hexane) to give 4-[6-(4-methoxycarbonyl-benzoylamino)-pyrrole-3-yl] -3,6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (470 mg, 37%) as a pale yellow solid.

Synthesis of tertiary butyl 4-[6-(4-carboxy-benzoylamino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. To 4-[6-(4-methoxycarbonyl-benzoylamino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (470 mg, 1.07 mmol) in 1,4-di㗁𠮿 (5 mL) was added 10 N aqueous NaOH (1.1 mL). The reaction was heated at 80° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. 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)-pyridine-3-yl]-3,6-dihydro- 2H-Pyridine-1-carboxylic acid tert-butyl ester (286 mg, 63%) as a pale yellow solid.

4-(6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-pyrrole-3-yl)- Synthesis of tertiary-butyl 3,6-dihydro-2H-pyridine-1-carboxylate. To tertiary butyl 4-[6-(4-carboxy-benzoylamino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (286 mg, 0.67 mmol), (4-amino-benzyl)-carbamate tertiary butyl ester (168 mg, 0.76 mmol) and triethylamine (137 mg, 184 μL, 1.35 mmol) in N,N-dimethylformaldehyde To the mixture in amide (3 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexa Fluorophosphate (387 mg, 1.02 mmol). The reaction was stirred for 16 hours, then treated with water (45 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL) to give 4-(6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-benzoylamino}-pyridine-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (236 mg, 56%) as a white solid.

N-(4-Aminomethyl-phenyl)-N'-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-terephthalylene Synthesis of amides. To 4-(6-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-pyrrole-3-yl) _- To a mixture of 3,6-dihydro-2H-pyridine-1-carboxylic acid ter-butyl ester (236 mg, 0.38 mmol) in _CH2Cl2 (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 2 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with ether (5 x 5 mL) to give N-(4-aminomethyl-phenyl)-N'-[6-(1,2,3,6-tetrahydropyridine- 4-yl)-(Ta(-3-yl)]-terephthalamide tris-trifluoroacetate (266 mg, 91%) as a beige solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)acid 𠯤- Synthesis of tertiary butyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. To N-(4-aminomethyl-phenyl)-N'-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-terephthalene Formamide 3 To a mixture of trifluoroacetic acid (264 mg, 0.34 mmol) in N,N-dimethylformamide (3.3 mL) was added triethylamine (240 mg, 329 μL, 2.35 mmol). The reaction was stirred for 15 minutes and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (336 mg, 1.08 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (45 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)pyridine-3-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amino Tert-butyl formate (191 mg, 62%) as a white solid.

N-[6-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-N'-(4-guanidinomethyl-phenyl )-Terephthalamide synthesis: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-(4-{[4-({[ (1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminomethyl Acyl}benzamido)pyridine-3-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester (191 mg, 0.21 mmol) in _{CH2Cl2 (} 2.1 mL) was added trifluoroacetic acid (2.1 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC afforded N-[6-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-N'- (4-Guanidinomethyl-phenyl)-terephthalamide tris-trifluoroacetate (114 mg, 64%) as a white solid. MS: 513 M+H+; ¹ 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., 2H) 3.65 - 3.73 (m, 2H) 2.81 (br. s., 2H).

Example 36: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl) Synthesis of -N'-Methyl-terephthalamide

Synthesis of tertiary butyl (4-methylamino-benzyl)-carbamate. To a mixture of (4-amino-benzyl)-carbamate tert-butyl ester (1.50 g, 6.84 mmol) and benzotriazole (814 mg, 6.84 mmol) in ethanol (6.5 mL) was added 37% Formaldehyde in water (0.49 mL, 6.51 mmol). The reaction was stirred for 3 days, then 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 additional sodium borohydride (105 mg, 2.93 mmol) was added. The reaction was stirred for 16 hours then 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 (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-40% ethyl acetate: hexane) to give (4-methylamino-benzyl)-carbamic acid tertiary butyl ester (1.01 g, 63%) as Clear viscous liquid.

Synthesis of tertiary butyl (4-{[4-(4-bromo-phenylaminoformyl)-benzoyl]-methyl-amino}-benzyl)-carbamate. To N-(4-bromo-phenyl)-terephthalic acid (614 mg, 1.92 mmol), (4-methylamino-benzyl)-carbamic acid tertiary butyl ester (504 mg, 2.13 mmol) and triethylamine (331 mg, 446 μL, 2.79 mmol) in N,N-dimethylformamide (5.4 mL) were added 1-bis(dimethylamino)methylene-1H- 1,2,3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1091 mg, 2.88 mmol). The reaction was stirred for 16 hours, then treated with water (80 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were washed with water (2 x 30 mL), 1 N HCl (20 mL), saturated aqueous NaHCO ₃ (20 mL), brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give (4-{[4-(4-bromo-phenylaminoformyl)-benzoyl]-methanol tert-Butyl-amino}-benzyl)-carbamate (1.01 g, 98%) as a white solid.

4-[4-(4-{[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-methyl-aminoformyl}-benzoylamino)-phenyl ]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester synthesis. By bubbling nitrogen through (4-{[4-(4-bromo-phenylaminoformyl)-benzoyl]-methyl-amino}-benzyl)-carbamic acid tertiary Butyl ester (1010 mg, 1.88 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-di Hydrogen-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'-dimethyl Oxybiphenyl (83 mg, 0.19 mmol) in 1,4-bis(14 mL) and 2M K ₂ CO ₃ (4.5 mL) The mixture was degassed for 10 min. 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-(4-{[4-(tertiary butoxycarbonylamino-methyl)-phenyl ]-methyl-aminoformyl}-benzoylamino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1180 mg, 98%), It is a white solid.

N-(4-aminomethyl-phenyl)-N-methyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephenyl Synthesis of formamide. To 4-[4-(4-{[4-(tertiary butoxycarbonylamino-methyl)-phenyl]-methyl-aminoformyl}-benzoylamino)-benzene To a mixture of tert-butyl]-3,6-dihydro-2H-pyridine-1-carboxylate ( ₁₁₈₀ mg, 1.84 mmol) in _CH2Cl2 (9.2 mL) was added trifluoroacetic acid (4.6 mL). The reaction was stirred for 3 hours then concentrated. The residue was treated with ether (40 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with ether (3 x 10 mL) to give N-(4-aminomethyl-phenyl)-N-methyl-N'-[4-(1,2,3,6 -Tetrahydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate salt (1.33 g, >100%) as a yellow solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl](methyl)aminoformyl}benzamido ) Synthesis of phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. N-(4-aminomethyl-phenyl)-N-methyl-N'-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Diformamide 2 A mixture of 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 treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl](methyl)aminoformyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amino Tert-butyl formate (131 mg, 35%) as a pale yellow solid.

N-[4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-N' -Synthesis of methyl-terephthalamide: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-( {[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]( Methyl)carbamoyl}benzamido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (131 mg , 0.14 mmol) in _CH2Cl2 (1.4 mL) _was added trifluoroacetic acid (1.4 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N-[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidine (2-methyl-phenyl)-N'-methyl-terephthalamide bis-trifluoroacetate salt (73 mg, 69%) as a white solid. MS: 525 M+H+; ¹ 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, 2H) 2.55 (br. s., 2H).

Example 37: N-[5-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyr-2-yl]-N'-(4-guanidinomethyl -Synthesis of -phenyl)-terephthalamide

Synthesis of N-(5-bromo-pyr-2-yl)-methyl terephthalate. To a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1147 mg, 5.77 mmol) in pyridine (5 mL) was added 5-bromo-pyr-2-ylamine (870 mg, 5.00 mmol) in pyridine (5 mL) of the solution. The reaction was stirred for 2 hours, then heated at 60° C. for 24 hours, then concentrated. The residue was treated with ethyl acetate (100 mL) and 1 N HCl (50 mL), then shaken and filtered. The solid was washed with isopropanol (15 mL) and hexanes (15 mL) to give methyl N-(5-bromo-pyr-2-yl)-terephthalate (601 mg, 36%) as white solid. The ethyl acetate/1 N HCl filtrate was separated and 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 silica gel column (0%-40% ethyl acetate: hexanes) to give methyl N-(5-bromo-pyr-2-yl)-terephthalate (85 mg, 5%) , as a white solid.

Synthesis of tertiary butyl 4-[5-(4-methoxycarbonyl-benzoylamino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through N-(5-bromo-pyr-2-yl)-methyl terephthalate (686 mg, 2.04 mmol), 4-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-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-di㗁𠮿 (15.5 mL) and The mixture in 2M _K2CO3 (5 mL) was degassed for 10 min _. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexanes) to give 4-[5-(4-methoxycarbonyl-benzoylamino)-pyrthiol-2-yl] -3,6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (589 mg, 66%) as a pale yellow solid.

Synthesis of tertiary butyl 4-[5-(4-carboxy-benzoylamino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. To 4-[5-(4-methoxycarbonyl-benzoylamino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (589 mg, 1.34 mmol) in 1,4-di㗁𠮿 (6.3 mL) was added 10 N aqueous NaOH (1.4 mL). The reaction was heated at 80 °C for 4 h, then treated with additional 10 N aqueous NaOH (5 mL). The reaction was heated at 80° C. for 16 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was filtered, and the solid was washed with water (10 mL) and dried under high vacuum to give 4-[5-(4-carboxy-benzoylamino)-pyrox-2-yl]-3,6 -Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (510 mg, 90%) as a white solid.

4-(5-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-pyrroyl-2-yl)- Synthesis of tertiary-butyl 3,6-dihydro-2H-pyridine-1-carboxylate. To tertiary butyl 4-[5-(4-carboxy-benzoylamino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (505 mg, 1.19 mmol), (4-amino-benzyl)-carbamate tertiary butyl ester (296 mg, 1.34 mmol) and triethylamine (242 mg, 327 μL, 2.40 mmol) in N,N-dimethylformaldehyde To the mixture in amide (3.6 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexa Fluorophosphate (685 mg, 1.80 mmol). The reaction was stirred for 16 hours, then treated with water (55 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL) to give 4-(5-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl yl]-benzoylamino}-pyridine-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (540 mg, 72%) as a gray solid.

N-(4-Aminomethyl-phenyl)-N'-[5-(1,2,3,6-tetrahydropyridin-4-yl)-pyroxet-2-yl]-terephthalylene Synthesis of amides. To 4-(5-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-pyrroyl-2-yl) - To a mixture of tert-butyl 3,6-dihydro-2H-pyridine-1- _carboxylate (540 mg, 0.87 mmol) in _CH2Cl2 (4.6 mL) was added trifluoroacetic acid (2.3 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with ether (20 mL) to give N-(4-aminomethyl-phenyl)-N'-[5-(1,2,3,6-tetrahydropyridine-4- yl)-pyr-2-yl]-terephthalamide tris-trifluoroacetate (607 mg, 91%) as a gray solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)pyridine- Synthesis of 2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. N-(4-Aminomethyl-phenyl)-N'-[5-(1,2,3,6-tetrahydropyridin-4-yl)-pyr-2-yl]-terephthalene Formamide 3 A mixture of trifluoroacetic acid (308 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was slowly treated with triethylamine (282 mg, 387 μL, 2.77 mmol). The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 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). 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)pyr-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amino Tert-butyl formate (259 mg, 71%) as a pale yellow solid.

N-[5-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyrthiol-2-yl]-N'-(4-guanidinomethyl-phenyl )-Terephthalamide synthesis: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-(4-{[4-({[ (1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminomethyl Acyl}benzamido)pyr-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester (259 mg, 0.28 mmol) in _{CH2Cl2 (} 2.8 mL) was added trifluoroacetic acid (2.8 mL). The reaction was stirred for 2 days, then concentrated. Purification of the crude material by preparative HPLC afforded N-[5-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyrhamid-2-yl]-N'- (4-Guanidinomethyl-phenyl)-terephthalamide tris-trifluoroacetate (110 mg, 46%) as a white solid. MS: 513 MH+; ¹ H 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, J =1.17 Hz, 1 H) 8.14 - 8.23 (m, 2 H) 8.08 (d, J =8.20 Hz, 3 H) 7.78 (d, J =8.20 Hz, 2 H) 7.58 (br. s., 4 H) 7.29 (d, J =8.79 Hz, 4 H) 6.80 (br. s., 1 H) 4.33 (d, J =5.86 Hz, 2 H) 4.16 (br. s., 2 H) 3.64 (t, J = 5.57 Hz, 2 H) 2.72 (br. s., 2 H).

Example 38: Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of Amide[4-(2-guanidino-ethyl)-phenyl]-amide

[2-(4-{[3-(4-Bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-phenyl)-ethyl] -Synthesis of tertiary butyl carbamate. To 3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (836 mg, 2.70 mmol), [2-(4-amino-phenyl) -Ethyl]-carbamate (717 mg, 3.04 mmol) and triethylamine (549 mg, 742 μL, 5.45 mmol) in N,N-dimethylformamide (8.2 mL) To the mixture was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1554 mg, 4.08 mmol). The reaction was stirred for 16 hours, then treated with water (120 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give [2-(4-{[3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1] Pentane-1-carbonyl]-amino}-phenyl)-ethyl]-carbamic acid tert-butyl ester (840 mg, 59%) as a white solid.

4-[4-({3-[4-(2-tertiary butoxycarbonylamino-ethyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl Synthesis of }-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester. By bubbling nitrogen through [2-(4-{[3-(4-bromo-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}- phenyl)-ethyl]-carbamic acid tert-butyl ester (840 mg, 1.59 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxolane Borane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (578 mg, 1.86 mmol), Pd(OAc) ₂ (16 mg, 0.076 mmol) and 2-bis Mixture of cyclohexylphosphino-2',6'-dimethoxybiphenyl (70 mg, 0.216 mmol) in 1,4-dimethoxy (12 mL) and 2M K ₂ CO ₃ (3.8 mL) 10 The mixture was degassed for 1 minute. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (50 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-[4-({3-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylamine Methylformyl]-bicyclo[1.1.1]pentane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (500 mg , 50%), as a gray solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(2-amino-ethyl)-phenyl]-amido[4-(1,2,3,6-tetrahydropyridine Synthesis of -4-yl)-phenyl]-amide. To 4-[4-({3-[4-(2-tertiary butoxycarbonylamino-ethyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1- Carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (500 mg, 0.79 mmol) in _{CH2Cl2 (} 4 mL) was added Trifluoroacetic acid (2 mL). The reaction was stirred for 5 hours then concentrated. The residue was treated with ether (20 mL) and sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]-amide [4-(1,2,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide (595 mg, >100%) as a gray solid was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[4-(2-{[(1E)-{[(tertiary butyl Oxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]aminoformyl}bicyclo[1.1.1] Synthesis of tertiary butyl pentane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(2-amino-ethyl)-phenyl]-amide[4-(1,2,3,6-tetrahydro A mixture of pyridin-4-yl)-phenyl]-amide 2 trifluoroacetic acid (263 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was mixed with triethylamine (280 mg, 384 μL, 2.74 mmol) was processed slowly. The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (3-{[4-(2-{[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl] Amino}ethyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl }) tertiary-butyl methylene]carbamate (197 mg, 54%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amido[ Synthesis of 4-(2-guanidino-ethyl)-phenyl]-amide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (3-{[4-(2-{[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl] Amino}ethyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl }) To _a mixture of tert-butylmethylene]carbamate (197 mg, 0.22 mmol) in _CH2Cl2 (2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (1.5 mL), then 0.1% trifluoroacetic acid in water (1.5 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carboxamidino-1,2,3 , 6-Tetrahydropyridin-4-yl)-phenyl]-amide[4-(2-guanidino-ethyl)-phenyl]-amide bis-trifluoroacetate salt (85 mg, 52% ), as a light orange solid. MS: 515 M+H+; ¹ 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).

Example 39: Bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro- Synthesis of phenyl]-amide (4-guanidinomethyl-phenyl)-amide

Synthesis of methyl 3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate. Bicyclo[1.1.1]pentane-1,3-dicarboxylate monomethyl ester (751 mg, 4.42 mmol), 4-bromo-3-fluoro-aniline (922 mg, 4.85 mmol) and triethylamine (837 mg, 990 μL, 7.06 mmol) to a mixture in N,N-dimethylformamide (13.5 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3- Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (2508 mg, 6.62 mmol). The reaction was stirred for 16 hours, then 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), 1 N HCl (25 mL), saturated aqueous NaHCO ₃ (25 mL), brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexane) to give 3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane Methyl alkane-1-carboxylate (1.42 g, 94%) as a white solid.

Synthesis of 3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid. 3-(4-Bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate (1.42 g, 4.15 mmol) in 1,4-bis To the mixture in 𠮿 (19 mL) was added 10 N aqueous NaOH (4.1 mL). The reaction was heated at 60° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (20 mL) and dried under high vacuum to give 3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (970 mg, 71%) as a white solid.

(4-{[3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-benzyl)-amino Synthesis of tertiary butyl formate. 3-(4-Bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (970 mg, 2.96 mmol), (4-amino-benzyl )-tert-butylcarbamate (722 mg, 3.27 mmol) and triethylamine (696 mg, 940 μL, 5.88 mmol) in N,N-dimethylformamide (8.8 mL) was added 1-Bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1676 mg, 4.43 mmol). The reaction was stirred for 16 hours, then treated with water (130 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (30 mL) and hexane (30 mL) to give (4-{[3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1 ]pentane-1-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester (1.23 g, 78%) as a white solid.

4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}- Synthesis of tertiary butyl amino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[3-(4-bromo-3-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino} -Benzyl)-tert-butylcarbamate (1.23 g, 2.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (842 mg, 2.69 mmol), Pd(OAc) ₂ (27 mg, 0.11 mmol) and 2-dicyclohexylphosphine A mixture of 2',6'-dimethoxybiphenyl (99 mg, 0.27 mmol) in 1,4-dimethoxybiphenyl (17 mL) and 2M K ₂ CO ₃ (5.6 mL) was allowed to react for 10 minutes The mixture was degassed. 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}-amino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (1.33 g, 91%) as a white solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[3-fluoro-4-(1,2,3,6-tetrahydropyridine- Synthesis of 4-yl)-phenyl]-amide. To 4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl} -Amino)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.33 g, 2.10 mmol) in CH ₂ Cl ₂ (10.6 mL) Trifluoroacetic acid (5.3 mL) was added. The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (25 mL), then sonicated for 5 min. The mixture was filtered, then the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)- Amide[3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amidobis-trifluoroacetate salt (1.60 g, > 100%), as Yellow solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane Synthesis of -1-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[3-fluoro-4-(1,2,3,6-tetrahydropyridine -4-yl)-phenyl]-amide 2 Trifluoroacetic acid (265 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was mixed with triethylamine (280 mg, 384 μL, 2.74 mmol) slowly. The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 × 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1 -yl})methylene]carbamate (153 mg, 42%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl] Synthesis of -amide (4-guanidinomethyl-phenyl)-amide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-( 3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1- _A mixture of tert-butyl)methylene]carbamate (153 mg, 0.17 mmol) in _CH2Cl2 (1.7 mL) was treated with trifluoroacetic acid (1.7 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (1.5 mL), then 0.1% trifluoroacetic acid in water (1.5 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carboxamidino-1,2,3 ,6-Tetrahydropyridin-4-yl)-3-fluoro-phenyl]-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (80 mg, 63%) , as light brown solid. MS: 519 M+H+; ¹ 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, J =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).

Example 40: N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-phenyl]-N'-(4-guanidinomethyl Synthesis of phenyl-phenyl)-terephthalamide

Synthesis of N-(4-bromo-3-methyl-phenyl)-methyl terephthalate. To a mixture of 4-bromo-3-methyl-aniline (558 mg, 3.00 mmol) and diisopropylethylamine (605 mg, 815 μL, 4.71 mmol) in _CHCl (8 mL) was added 4-chloro A mixture of carbonyl-benzoic acid methyl ester (687 mg, 3.46 mmol) in _CHCl3 (8 mL). The reaction was stirred for 16 hours then concentrated. The residue was partitioned between ethyl acetate (70 mL) and washed with water (20 mL), 1 N HCl (20 mL), saturated aqueous _NaHCO3 (20 mL) and brine (10 mL), dried ( _{Na2SO 4} ) and concentrate. The crude material was purified by silica gel column (0%-40% ethyl acetate: hexanes) to give methyl N-(4-bromo-3-methyl-phenyl)-terephthalate (723 mg, 69% ), as a white solid.

Synthesis of N-(4-bromo-3-methyl-phenyl)-terephthalic acid. To a mixture of N-(4-bromo-3-methyl-phenyl)-terephthalic acid methyl ester (723 mg, 2.08 mmol) in 1,4-dimethoxylate (10 mL) was added 10 N NaOH aqueous solution (2.1 mL). The reaction was heated at 90° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was filtered and the solid was washed with water (20 mL) and dried under high vacuum to give N-(4-bromo-3-methyl-phenyl)-terephthalic acid (640 mg, 92%) as white solid.

Synthesis of tertiary-butyl 4-[4-(4-carboxy-benzoylamino)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. To N-(4-bromo-3-methyl-phenyl)-terephthalic acid (640 mg, 1.92 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (467 mg, 2.12 mmol) and triethylamine (450 mg, 608 μL, 3.81 mmol) in N,N-dimethylformamide (5.7 mL) was added 1-bis(dimethylamino)methylene -1H-1,2,3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1084 mg, 2.87 mmol). The reaction was stirred for 16 hours, then treated with water (90 mL) and ethyl acetate (60 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-[4-(4-carboxy-benzoylamino)-2-methyl-phenyl]-3,6- Tert-butyl dihydro-2H-pyridine-1-carboxylate (783 mg, 76%) as a white solid.

4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-2-methyl-phenyl) -Synthesis of tertiary-butyl 3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through 4-[4-(4-carboxy-benzoylamino)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic Butyl ester (783 mg, 1.45 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-di Hydrogen-2H-pyridine-1-carboxylic acid tert-butyl ester (530 mg, 1.69 mmol), Pd(OAc) ₂ (17 mg, 0.069 mmol) and 2-dicyclohexylphosphino-2',6'-dimethyl Oxybiphenyl (62 mg, 0.17 mmol) in 1,4-bis(11 mL) and 2M K ₂ CO ₃ (3.5 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (80 mL) and water (20 mL). Shake the mixture, then filter. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylamine Methylformyl]-benzoylamino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (304 mg, 33%), as Pale yellow solid.

N-(4-aminomethyl-phenyl)-N'-[3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephenyl Synthesis of formamide. To 4-(4-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-2-methyl-phenyl )-3,6-Dihydro-2H-pyridine-1- _carboxylic acid tert-butyl ester (299 mg, 0.47 mmol) in _CH2Cl2 (2.4 mL) was added trifluoroacetic acid (1.2 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (15 mL) to give N-(4-aminomethyl-phenyl)-N'-[3-methyl-4-(1,2,3,6-tetra Hydropyridin-4-yl)-phenyl]-terephthalamide bis-trifluoroacetate (308 mg, 98%) as a pale yellow solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)-2- Synthesis of tertiary butyl methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. N-(4-aminomethyl-phenyl)-N'-[3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-p-phenyl Diformamide 2 A mixture of trifluoroacetic acid (308 mg, 0.46 mmol) in N,N-dimethylformamide (4.4 mL) was treated with triethylamine (323 mg, 442 μL, 3.16 mmol). The reaction was stirred for 15 minutes and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (452 mg, 1.45 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (65 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)-2-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine Tert-butyl carbamate (206 mg, 48%) as a pale yellow solid.

N-[4-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-phenyl]-N'-(4-guanidinomethyl-benzene base)-terephthalamide synthesis: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({ [(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]amino Formyl}benzamido)-2-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (206 mg , 0.22 mmol) in _CH2Cl2 (2.2 mL) _was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to afford N-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-phenyl]-N' -Bis-trifluoroacetate salt of (4-guanidinomethyl-phenyl)-terephthalamide (78 mg, 47%) as a white solid. MS: 525 M+H+; ¹ 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, J =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).

Example 41: Bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro- Synthesis of phenyl]-amide (4-guanidinomethyl-phenyl)-amide

Synthesis of 3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylate monomethyl ester (500 mg, 2.94 mmol), 4-bromo-2-fluoro-aniline (613 mg, 3.22 mmol) and triethylamine (557 mg, 658 μL, 4.69 mmol) to a mixture in N,N-dimethylformamide (9 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3- Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1668 mg, 4.40 mmol). The reaction was stirred for 3 days, then 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), 1 N HCl (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 silica gel column (0%-40% ethyl acetate: hexane) to give 3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane Methyl alkane-1-carboxylate (908 mg, 90%) as a pale yellow solid.

Synthesis of 3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid. To 3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate (908 mg, 2.65 mmol) in 1,4-di To the mixture in 𠮿 (12 mL) was added 10 N aqueous NaOH (2.7 mL). The reaction was heated at 60° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (20 mL) and dried under high vacuum to give 3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (505 mg, 58%) as a white solid.

(4-{[3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-benzyl)-amino Synthesis of tertiary butyl formate. 3-(4-Bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (505 mg, 1.54 mmol), (4-amino-benzyl )-tert-butylcarbamate (374 mg, 1.70 mmol) and triethylamine (361 mg, 487 μL, 3.05 mmol) in N,N-dimethylformamide (4.6 mL) was added 1-Bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (869 mg, 2.30 mmol). The reaction was stirred for 16 hours, then treated with water (75 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give (4-{[3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1 ]pentane-1-carbonyl]-amino}-benzyl)-tert-butyl carbamate (561 mg, 68%) as a white solid.

4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}- Synthesis of tertiary butyl amino)-3-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino} -Benzyl)-tert-butylcarbamate (561 mg, 1.05 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (384 mg, 1.23 mmol), Pd(OAc) ₂ (12 mg, 0.050 mmol) and 2-dicyclohexylphosphine A mixture of 2',6'-dimethoxybiphenyl (45 mg, 0.12 mmol) in 1,4-dimethoxybiphenyl (7.8 mL) and 2M K ₂ CO ₃ (2.6 mL) was allowed to react for 10 minutes The mixture was degassed. 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}-amino)-3-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (509 mg, 76%) as a beige solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[2-fluoro-4-(1,2,3,6-tetrahydropyridine- Synthesis of 4-yl)-phenyl]-amide. To 4-[4-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl} -Amino)-3-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1- _carboxylic acid tert-butyl ester (504 mg, 0.79 mmol) in _CH2Cl2 (4 mL) Trifluoroacetic acid (2 mL) was added. The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered, then the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)- Amide[2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (670 mg, > 100%), as Beige solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane Synthesis of -1-amido)-3-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[2-fluoro-4-(1,2,3,6-tetrahydropyridine -4-yl)-phenyl]-amide 2 Trifluoroacetic acid (265 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 × 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)-3-fluorophenyl]-1,2,3,6-tetrahydropyridine-1 -yl})methylene]carbamate (208 mg, 57%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-phenyl] Synthesis of -amide (4-guanidinomethyl-phenyl)-amide: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-( 3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)-3-fluorophenyl]-1,2,3,6-tetrahydropyridine-1- To a mixture of tert-butyl)methylene]carbamate (203 mg, 0.22 mmol) in _{CH2Cl2 (} 2.2 mL) was added trifluoroacetic acid (2.2 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (1.5 mL), then 0.1% trifluoroacetic acid in water (1.5 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (10 mL) and hexane (10 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carboxamidino-1,2,3 ,6-Tetrahydropyridin-4-yl)-2-fluoro-phenyl]-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (87 mg, 53%) , a beige solid. MS: 519 M+H+; ¹ 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).

Example 42: Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-guanidino-cyclohex-1-enyl)-phenyl]-amide (4-guanidinomethyl Synthesis of -phenyl)-amide

Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-amino-cyclohex-1-enyl)-phenyl]-amide (4-aminomethyl-phenyl )-amide synthesis. By bubbling nitrogen through (4-{[3-(4-bromo-2-fluoro-phenylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino} -Benzyl)-tert-butylcarbamate (929 mg, 1.81 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (684 mg, 2.12 mmol), Pd(OAc) ₂ (21 mg, 0.086 mmol) and 2-dicyclohexylphosphine A mixture of 2',6'-dimethoxybiphenyl (77 mg, 0.21 mmol) in 1,4-dimethoxybiphenyl (13.4 mL) and 2M K ₂ CO ₃ (4.5 mL) was allowed to react for 10 minutes The mixture was degassed. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (70 mL) and water (20 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(4-amino-cyclohex-1-ene [4-aminomethyl-phenyl]-amide (4-aminomethyl-phenyl)-amide (10.5 g, 92%) as a gray solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-amino-cyclohex-1-enyl)-phenyl]-amide (4-aminomethyl-phenyl )-amide synthesis. Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-amino-cyclohex-1-enyl)-phenyl]-amide (4-aminomethyl-benzene To a mixture of (1.05 g, 1.67 mmol) in CH ₂ Cl ₂ (8.4 mL) was added trifluoroacetic acid (4.2 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered, then the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-amino-cyclohexyl- 1-Alkenyl)-phenyl]-amido(4-aminomethyl-phenyl)-amido bis-trifluoroacetate salt (1.34 g, >100%) as a gray solid which was used without further Purified and ready to use.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane Synthesis of -1-amido)phenyl]cyclohex-3-en-1-yl}amino)methylene]carbamic acid tertiary butyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-amino-cyclohex-1-enyl)-phenyl]-amide (4-aminomethyl-benzene To a mixture of trifluoroacetic acid (265 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-carboxamidinopyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (60 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 × 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)phenyl]cyclohex-3-en-1-yl}amino)methylene] Tert-butyl carbamate (257 mg, 69%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-guanidino-cyclohex-1-enyl)-phenyl]-amide (4-guanidinomethyl-phenyl )-amide synthesis: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(3-{[4-({[(1Z)- {[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}di Cyclo[1.1.1]pentane-1-amido)phenyl]cyclohex-3-en-1-yl}amino)methylene]carbamate tert-butyl ester (244 mg, 0.27 mmol) To the mixture in _{CH2Cl2 (} 2.7 mL) was added trifluoroacetic acid (2.7 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid [4-(4-guanidino-cyclohex-1-enyl)-phenyl]-amide (4-Guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (62 mg, 31%) as a white solid. MS: 515 MH+; ¹ 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, J =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, J =8.79 Hz, 4 H) 6.07 (br. s., 1 H) 4.30 (d, J =5.86 Hz, 2H) 3.62 - 3.81 (m, 1H) 2.31 (s, 6H).

Example 43: N-[5-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-6-methyl-pyr-2-yl]-N'-(4 -Synthesis of guanidinomethyl-phenyl)-terephthalamide

Synthesis of N-(5-bromo-6-methyl-pyr-2-yl)-methyl terephthalate. To a mixture of 4-chlorocarbonyl-benzoic acid methyl ester (1196 mg, 6.02 mmol) in pyridine (5.2 mL) was added 5-bromo-6-methyl-pyr-2-ylamine (980 mg, 5.21 mmol ) in pyridine (5.3 mL). The reaction was heated at 60° C. for 16 hours, then concentrated. The residue was partitioned between ethyl acetate (100 mL) and 1 N HCl (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 silica gel column (0%-50% ethyl acetate: hexanes) to give methyl N-(5-bromo-6-methyl-pyr-2-yl)-terephthalate (1.62 g, 89%), as light yellow solid.

4-[5-(4-Methoxycarbonyl-benzoylamino)-3-methyl-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Synthesis of butyl esters. By bubbling nitrogen through N-(5-bromo-6-methyl-pyr-2-yl)-methyl terephthalate (1.62 g, 4.63 mmol), 4-(4,4,5, 5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic 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-di㗁𠮿 (35 mL) and 2M K ₂ CO ₃ (11 mL) for 10 minutes to degas the mixture. 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 silica gel column (0%-50% ethyl acetate: hexane) to give 4-[5-(4-methoxycarbonyl-benzoylamino)-3-methyl-pyrrole -2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (906 mg, 43%) as a pale yellow solid.

tertiary butyl 4-[5-(4-carboxy-benzoylamino)-3-methyl-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate synthesis. To 4-[5-(4-methoxycarbonyl-benzoylamino)-3-methyl-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tris To a mixture of butyl butyl ester (906 mg, 2.00 mmol) in 1,4-di㗁𠮿 (9.4 mL) was added 10 N aqueous NaOH (2 mL). The reaction was heated at 90° C. for 16 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 min, then filtered and the solid washed with water (20 mL). The solid was treated with isopropanol (50 mL) and then sonicated for 5 min. The mixture was filtered, and the solid was washed with hexane (20 mL). The solid was dried under high vacuum to give 4-[5-(4-carboxy-benzoylamino)-3-methyl-pyrox-2-yl]-3,6-dihydro-2H-pyridine - tertiary-butyl-1-carboxylate (718 mg, 82%) as an off-white solid.

4-(5-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-3-methyl-pyrrole- Synthesis of 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester. tertiary butyl 4-[5-(4-carboxy-benzoylamino)-3-methyl-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (718 mg, 1.64 mmol), (4-amino-benzyl)-carbamate tertiary butyl ester (403 mg, 1.82 mmol) and triethylamine (385 mg, 522 μL, 3.25 mmol) in N,N - Mixture in dimethylformamide (4.9 mL) with 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3 -oxide hexafluorophosphate (927 mg, 2.46 mmol) treatment. The reaction was stirred for 16 hours, then 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-(5-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylamine Methylformyl]-benzoylamino}-3-methyl-pyridine-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (841 mg, 80 %), as light yellow solid.

N-(4-Aminomethyl-phenyl)-N'-[6-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-pyrromethalone-2-yl] -Synthesis of terephthalamide. To 4-(5-{4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-benzoylamino}-3-methyl-pyrrole -2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (841 mg, 1.31 mmol) in CH ₂ Cl ₂ (6.6 mL) was added trifluoroacetic acid (3.3 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give N-(4-aminomethyl-phenyl)-N'-[6-methyl-5-(1, 2,3,6-Tetrahydropyridin-4-yl)-pyr-2-yl]-terephthalamide tris-trifluoroacetate (1100 mg, > 100%) as pale yellow solid, It was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}benzamido)-3- Synthesis of tertiary butyl methyl pyridin-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. N-(4-aminomethyl-phenyl)-N'-[6-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-pyridine-2-yl ]-terephthalamide 3 trifluoroacetic acid (392 mg, 0.50 mmol) in N,N-dimethylformamide (4.8 mL) with triethylamine (350 mg, 480 μL, 3.43 mmol )deal with. The reaction was stirred for 15 minutes and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (490 mg, 1.58 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (75 mL) and extracted with ethyl acetate (2 x 50 mL). Wash the combined organic layers with water (2 × 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5- (4-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}benzamido)-3-methylpyridine-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})ylidene Tert-butyl methyl]carbamate (227 mg, 49%) as a white solid.

N-[5-(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-6-methyl-pyr-2-yl]-N'-(4-guanidino Synthesis of methyl-phenyl)-terephthalamide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-(4-{[ 4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)benzene Base]aminoformyl}benzamido)-3-methylpyridine-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amino To _a mixture of tert-butyl formate (227 mg, 0.25 mmol) in _CH2Cl2 (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give N-[5-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-6-methyl-pyroxet-2-yl ]-N'-(4-guanidinomethyl-phenyl)-terephthalamide tris-trifluoroacetate (124 mg, 57%) as a white solid. MS: 527 M+H+; ¹ H 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).

Example 44: Bicyclo[2.2.2]octane-1,4-dicarboxylate [6-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3 Synthesis of -yl]-amide (4-guanidinomethyl-phenyl)-amide

Synthesis of methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate. Add monomethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (1.38 g, 6.50 mmol) in _CHCl (36 mL) and N,N-dimethylformamide (15 drops) Oxalyl chloride (1.33 g, 891 μL, 10.39 mmol) was added dropwise to the mixture. The reaction was stirred for 3 hours then concentrated to afford methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate which was used without further purification.

Synthesis of methyl 4-(6-bromo-pyridine-3-ylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylate. To 6-bromo-pyridine-3-ylamine (981 mg, 5.63 mmol), 4-dimethylaminopyridine (56 mg) and diisopropylethylamine (1142 mg, 1537 μL, 8.87 mmol) in To the mixture in _CHCl3 (15 mL) was added dropwise a mixture of methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate in CHCl3 (15 mL). The reaction was stirred for 16 hours then 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 (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexanes) to give 4-(6-bromo-pyridium-3-ylcarbamoyl)-bicyclo[2.2.2]octane Methyl alkane-1-carboxylate (1.54 g, 74%) as a pale yellow solid.

4-{6-[(4-Methoxycarbonyl-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyrrole-3-yl}-3,6-dihydro-2H- Synthesis of tertiary butyl pyridine-1-carboxylate. By bubbling nitrogen gas through methyl 4-(6-bromo-pyridine-3-ylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylate, 4-(4,4, 5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic 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-bis㗁𠮿 (32 mL) and 2M K ₂ CO ₃ (10 mL) for 10 min. The mixture was degassed. 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-{6-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-1-carbonyl) -Amino]-pyridine-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.47 g, 75%) as a light yellow solid.

4-{6-[(4-Carboxy-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyridine-3-yl}-3,6-dihydro-2H-pyridine-1 -Synthesis of tertiary butyl formate. To 4-{6-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyrrole-3-yl}-3,6-dihydro-2H - To a mixture of tert-butylpyridine-1-carboxylate (1.47 g, 3.12 mmol) in 1,4-di㗁𠮿 (14 mL) was added 10 N aqueous NaOH (3.1 mL). The reaction was heated at 90° C. for 16 hours, then concentrated. The residue was treated with water (100 mL) and adjusted to pH 1 with 1 N HCl. The mixture was filtered and the solid was washed with water (20 mL) and dried under high vacuum to give 4-{6-[(4-carboxy-bicyclo[2.2.2]octane-1-carbonyl)-amino] -Terr-butyl-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (1.04 g, 73%) as a beige solid.

4-[6-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}- Synthesis of tertiary butyl ester of amino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. 4-{6-[(4-carboxy-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyrrole-3-yl}-3,6-dihydro-2H-pyridine- tert-butyl 1-carboxylate (1.04 g, 2.28 mmol), (4-amino-benzyl)-carbamate tert-butyl ester (559 mg, 2.51 mmol) and triethylamine (537 mg, 726 μL, 4.54 mmol) in N,N-dimethylformamide (6.6 mL) with 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4, 5-b] pyridinium cation 3-oxide hexafluorophosphate (289 mg, 3.40 mmol) treatment. The reaction was stirred for 16 h and then treated with additional tert-butyl (4-amino-benzyl)-carbamate (280 mg, 1.26 mmol), triethylamine (269 mg, 363 μL, 2.27 mmol) and 1-Bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (645 mg, 1.70 mmol) treatment . The reaction was stirred for 3 days, then treated with water (100 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give 4-[6-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminomethyl Acyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester ( 677 mg, 45%) as a beige solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[6-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of ???-3-yl]-amide. To 4-[6-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl} -Amino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (672 mg, 1.02 mmol) in CH ₂ Cl ₂ (5.4 mL) Trifluoroacetic acid (2.7 mL) was added. The reaction was stirred for 3 days, then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered, then the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)- Amide[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-amide tris-trifluoroacetate (1139 mg, > 100%), as Light brown solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane Synthesis of tertiary butyl ester of -1-amido)pyridine-3-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[6-(1,2,3,6-tetrahydropyridin-4-yl )-Pyridine-3-yl]-amide (321 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was mixed with triethylamine (280 mg, 384 μL, 2.74 mmol )deal with. The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and extracted with ethyl acetate (2 x 50 mL). Wash the combined organic layers with water (2 × 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amino)pyridine-3-yl]-1,2,3,6-tetrahydropyridine-1- butyl})methylene]carbamate (112 mg, 30%) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylate[6-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl] Synthesis of -amide (4-guanidinomethyl-phenyl)-amide: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-( 4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amido)pyridine-3-yl]-1,2,3,6-tetrahydropyridine-1- To _a mixture of tert-butyl)methylene]carbamate (112 mg, 0.12 mmol) in _CH2Cl2 (1.2 mL) was added trifluoroacetic acid (1.2 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.2]octane-1,4-dicarboxylic acid [6-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- Tris-trifluoroacetate (62 mg, 58%) of amide (4-guanidinomethyl-phenyl)-amide (62 mg, 58%) as a white solid. MS: 545 M+H+; ¹ H 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).

Example 45: Bicyclo[1.1.1]pentane-1,3-dicarboxylate [5-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-2 Synthesis of -yl]-amide (4-guanidinomethyl-phenyl)-amide

Synthesis of methyl 3-chlorocarbonyl-bicyclo[1.1.1]pentane-1-carboxylate. To a mixture of monomethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (981 mg, 5.77 mmol) in diethyl ether (21 mL) was added oxalyl chloride (1024 μL, 11.50 mmol), then Add N,N-dimethylformamide (42 mL). The reaction was stirred for 3 hours then concentrated. The residue was treated with _CH2Cl2 (20 mL) and concentrated to give methyl 3-chlorocarbonyl-bicyclo _[ 1.1.1]pentane-1-carboxylate which was used without further purification.

Synthesis of 3-(5-bromo-pyrro-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate methyl ester. To a mixture of methyl 3-chlorocarbonyl-bicyclo[1.1.1]pentane-1-carboxylate in pyridine (5 mL) was added 5-bromo-pyrox-2-ylamine (870 mg, 5.00 mmol) Mixture in pyridine (5 mL). The reaction was heated at 60° C. for 16 hours, then concentrated. The residue was treated with 1 N HCl (50 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solids were washed with isopropanol (20 mL) and hexanes (20 mL) to give 3-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1 - Methyl formate (235 mg, 14%) as a white solid. The 1 N HCl/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 silica gel column (0%-50% ethyl acetate: hexanes) to give 3-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[1.1.1]pentane Methyl alkane-1-carboxylate (1.21 g, 74%) as a white solid.

Synthesis of 3-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid. 3-(5-Bromo-pyrro-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate (1.45 g, 4.43 mmol) in 1,4-bis To the mixture in 𠮿 (20 mL) was added 10 N aqueous NaOH (4.4 mL). The reaction was stirred for 3 days, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (20 mL) and dried under high vacuum to give 3-(5-Bromo-pyrthiol-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (1.10 g, 80%) as a white solid.

(4-{[3-(5-Bromo-pyr-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-benzyl)-amino Synthesis of tertiary butyl formate. To 3-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (1.10 g, 3.52 mmol), (4-amino-benzyl )-tert-butylcarbamate (867 mg, 3.91 mmol) and triethylamine (829 mg, 1124 μL, 7.00 mmol) in N,N-dimethylformamide (10.5 mL) was added 1-Bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1996 mg, 5.29 mmol). The reaction was stirred for 16 hours, then treated with water (150 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give (4-{[3-(5-bromo-pyrro-2-ylaminoformyl)-bicyclo[1.1.1 ]pentane-1-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester (1.19 g, 66%) as a white solid.

4-[5-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}- Synthesis of amino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester. By bubbling nitrogen gas through (4-{[3-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino} -benzyl)-tert-butylcarbamate (1.19 g, 2.30 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (841 mg, 2.71 mmol), Pd(OAc) ₂ (24 mg, 0.12 mmol) and 2-dicyclohexylphosphine A mixture of 2',6'-dimethoxybiphenyl (102 mg, 0.24 mmol) in 1,4-dimethoxybiphenyl (18 mL) and 2M K ₂ CO ₃ (5.5 mL) was allowed to react for 10 minutes The mixture was degassed. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (100 mL) and water (50 mL), then shaken and filtered. The filtrate was separated, and the organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-[5-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}-amino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (910 mg, 64%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[5-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of pyryr-2-yl]-amide. To 4-[5-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl} -Amino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (910 mg, 1.47 mmol) in CH ₂ Cl ₂ (7.7 mL) Trifluoroacetic acid (3.9 mL) was added. The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (40 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide [5-(1 ,2,3,6-Tetrahydropyridin-4-yl)-pyr-2-yl]-amide tris-trifluoroacetate salt (1117 mg, 100%) as a yellow solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-(3-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane Synthesis of -1-amido)pyr-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester. Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[5-(1,2,3,6-tetrahydropyridin-4-yl )-pyr-2-yl]-amide 3-trifluoroacetic acid (59 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was mixed with triethylamine (280 mg, 384 μL, 2.74 mmol). The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (392 mg, 1.26 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The reaction was treated with water (60 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5- (3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)pyr-2-yl]-1,2,3,6-tetrahydropyridine-1 -yl})methylene]carbamate tertiary butyl ester 192 mg, 53%), as light yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate[5-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyrthiol-2-yl] Synthesis of -amide (4-guanidinomethyl-phenyl)-amide: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-( 3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)pyr-2-yl]-1,2,3,6-tetrahydropyridine-1- To a mixture of tert _- butyl)methylene]carbamate (192 mg, 0.21 mmol) in _CH2Cl2 (2.1 mL) was added trifluoroacetic acid (2.1 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC afforded bicyclo[1.1.1]pentane-1,3-dicarboxylate [5-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- yl)-pyr-2-yl]-amido(4-guanidinomethyl-phenyl)-amido tris-trifluoroacetate salt (58 mg, 33%) as a white solid. MS: 503 M+H+; ¹ H 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).

Example 46: Bicyclo[2.2.2]octane-1,4-dicarboxylate [5-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-2 Synthesis of -yl]-amide (4-guanidinomethyl-phenyl)-amide

Synthesis of methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate. Add monomethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (1.40 g, 6.60 mmol) in _CHCl (37 mL) and N,N-dimethylformamide (15 drops) Oxalyl chloride (1.35 g, 904 μL, 10.54 mmol) was added dropwise to the mixture. The reaction was stirred for 3 hours then concentrated to afford methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate which was used without further purification.

Synthesis of methyl 4-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylate. To a mixture of methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate in pyridine (5.7 mL) was added 5-bromo-pyrox-2-ylamine (995 mg, 6.72 mmol) the mixture. The reaction was heated at 60° C. for 18 hours, then concentrated. The residue was treated with 1 N HCl (50 mL), then 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 ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexanes) to give 4-(5-bromo-pyr-2-ylcarbamoyl)-bicyclo[2.2.2]octane Methyl alkane-1-carboxylate (1.72 g, 82%) as a white solid.

4-{5-[(4-Methoxycarbonyl-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyr-2-yl}-3,6-dihydro-2H- Synthesis of tertiary butyl pyridine-1-carboxylate. By bubbling nitrogen through methyl 4-(5-bromo-pyr-2-ylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylate (1.72 g, 4.67 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tris 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-Di㗁𠮿 (36 mL) and 2M K ₂ CO ₃ (11 mL) The mixture was degassed for 10 min. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (200 mL) and water (50 mL). Shake the mixture, then filter. The filtrate was separated. The organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexane) to give 4-{5-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-1-carbonyl) -Amino]-pyr-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.70 g, 77%) as a pale yellow solid.

4-{5-[(4-Carboxy-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyridine-2-yl}-3,6-dihydro-2H-pyridine-1 -Synthesis of tertiary butyl formate. To 4-{5-[(4-methoxycarbonyl-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyr-2-yl}-3,6-dihydro-2H - To a mixture of tert-butylpyridine-1-carboxylate (1.70 g, 3.61 mmol) in 1,4-di㗁𠮿 (16 mL) was added 10 N aqueous NaOH (3.6 mL). The reaction was heated at 90° C. for 16 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with 1 N HCl (4 x 20 mL) and water (20 mL) to give 4-{5-[(4-carboxy-bicyclo[2.2.2]octane-1-carbonyl)-amino] -Pyr-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.08 g, 66%) as a white solid.

4-[5-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}- Synthesis of amino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester. To 4-{5-[(4-carboxy-bicyclo[2.2.2]octane-1-carbonyl)-amino]-pyr-2-yl}-3,6-dihydro-2H-pyridine- Tert-butyl-1-carboxylate (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) to a mixture in N,N-dimethylformamide (7 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4 ,5-b] pyridinium cation 3-oxide hexafluorophosphate (1343 mg, 3.56 mmol). The reaction was stirred for 16 hours, then 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-[5-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[2.2.2]pentane-1-carbonyl}-amino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (845 mg, 54%) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[5-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of pyryr-2-yl]-amide. To 4-[5-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl} -amino)-pyridine-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4- Aminomethyl-phenyl)-amide[5-(1,2,3,6-tetrahydropyridin-4-yl)-pyrthiol-2-yl]-amide (845 mg, 1.28 mmol) in To the mixture _{in CH2Cl2} (6.8 mL) was added trifluoroacetic acid (3.4 mL). The reaction was stirred for 16 hours, then treated with water (90 mL) and washed with ethyl acetate (2 x 50 mL). The aqueous layer was concentrated, then adjusted to pH 7 using saturated aqueous NaHCO ₃ . The mixture was left to stand for 10 minutes, then filtered. The solid was washed with isopropanol (15 mL) and hexane (15 mL), then dried under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl- Phenyl)-amido[5-(1,2,3,6-tetrahydropyridin-4-yl)-pyrthiol-2-yl]-amido (246 mg, 42%) as a beige solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane Synthesis of -1-amido)pyr-2-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[5-(1,2,3,6-tetrahydropyridin-4-yl )-pyr-2-yl]-amide (246 mg, 0.53 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (153 mg, 210 μL, 1.50 mmol). The reaction was stirred for 15 minutes and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (519 mg, 1.67 mmol). The reaction was stirred for 15 min, then heated at 35 °C for 16 h, then treated with water (75 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amino)pyr-2-yl]-1,2,3,6-tetrahydropyridine-1- tertiary butyl})methylene]carbamate (191 mg, 38%) as a pale yellow solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylate [5-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyrthiol-2-yl] Synthesis of -amide (4-guanidinomethyl-phenyl)-amide: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[5-( 4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amido)pyr-2-yl]-1,2,3,6-tetrahydropyridine-1- To _a mixture of tert-butyl)methylene]carbamate (191 mg, 0.20 mmol) in _CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC afforded bicyclo[2.2.2]octane-1,4-dicarboxylic acid [5-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- yl)-pyr-2-yl]-amido(4-guanidinomethyl-phenyl)-amido tris-trifluoroacetate salt (95 mg, 54%) as a white solid. MS: 545 M+H+; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ ppm 10.20 (s, 1 H) 9.15 - 9.30 (m, 2 H) 8.67 (d, J =1.76 Hz, 1 H) 7.95 (t, J =5.57 Hz, 1 H) 7.62 (d, J =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, J =5.86 Hz, 2 H) 4.13 (br. s., 2 H) 3.62 (t, J =5.57 Hz, 2 H) 2.67 (br. s., 2 H) 1.85 (d, J =7.03 Hz, 12 H).

Example 47: Bicyclo[1.1.1]pentane-1,3-dicarboxylate[6-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3 Synthesis of -yl]-amide (4-guanidinomethyl-phenyl)-amide

Synthesis of methyl 3-chlorocarbonyl-bicyclo[1.1.1]pentane-1-carboxylate. To a mixture of monomethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate (981 mg, 5.77 mmol) in diethyl ether (21 mL) was added oxalyl chloride (1024 μL, 11.50 mmol), then Add N,N-dimethylformamide (42 µL). The reaction was stirred for 3 hours then concentrated. This material was used without further purification.

Synthesis of 3-(6-bromo-pyridyl-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate methyl ester. To 6-bromo-pyridine-3-ylamine (871 mg, 5.00 mmol), 4-dimethylaminopyridine (50 mg) and diisopropylethylamine (1014 mg, 1364 μL, 7.87 mmol) in To the mixture in _CHCl3 (13.3 mL) was added dropwise a mixture of methyl 3-chlorocarbonyl-bicyclo[1.1.1]pentane-1-carboxylate in CHCl3 (13.3 mL). The reaction was stirred for 16 hours then 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 silica gel column (0%-50% ethyl acetate: hexanes) to give 3-(6-bromo-pyridium-3-ylaminoformyl)-bicyclo[1.1.1]pentane Methyl alkane-1-carboxylate (1.41 g, 87%) as a pale yellow solid.

Synthesis of 3-(6-bromo-pyridine-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid. 3-(6-Bromo-pyrrole-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylate (1.39 g, 4.26 mmol) in 1,4-bis The mixture in 𠮿 (19 mL) was treated with 10 N aqueous NaOH (4.3 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (20 mL) and dried under high vacuum to give 3-(6-bromo-pyrro-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (848 mg, 64%) as a beige solid.

(4-{[3-(6-Bromo-pyridyl-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino}-benzyl)-amino Synthesis of tertiary butyl formate. 3-(6-Bromo-pyrrole-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (844 g, 2.70 mmol), (4-amino-benzyl )-tert-butylcarbamate (666 mg, 3.00 mmol) and triethylamine (637 mg, 864 μL, 5.38 mmol) in N,N-dimethylformamide (8 mL) was added 1-Bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1533 mg, 4.06 mmol). The reaction was stirred for 16 hours, then 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 silica gel column (0%-100% ethyl acetate: hexane) to give (4-{[3-(6-bromo-pyrro-3-ylaminoformyl)-bicyclo[ 1.1.1] Pentane-1-carbonyl]-amino}-benzyl)-tert-butyl carbamate (1.02 g, 873%) as a sticky white solid.

4-[6-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl}- Synthesis of tertiary butyl ester of amino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen gas through (4-{[3-(6-bromo-pyridyl-3-ylaminoformyl)-bicyclo[1.1.1]pentane-1-carbonyl]-amino} -Benzyl)-tert-butylcarbamate (1.02 g, 1.97 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (721 mg, 2.32 mmol), Pd(OAc) ₂ (21 mg, 0.10 mmol) and 2-dicyclohexylphosphine A mixture of 2',6'-dimethoxybiphenyl (87 mg, 0.21 mmol) in 1,4-dimethoxybiphenyl (15 mL) and 2M K ₂ CO ₃ (4.7 mL) was allowed to react for 10 minutes The mixture was degassed. The reaction was heated at 95°C for 16 hours. Treat the reaction 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 silica gel column (0%-5% methanol:dichloromethane) to give 4-[6-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylamine Methylformyl]-bicyclo[1.1.1]pentane-1-carbonyl}-amino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl Ester (323 mg, 27%) as a pale yellow solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[6-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of ???-3-yl]-amide. To 4-[6-({3-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[1.1.1]pentane-1-carbonyl} -Amino)-pyridine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (321 mg, 0.51 mmol) in CH ₂ Cl ₂ (2.8 mL) Trifluoroacetic acid (1.4 mL) was added. The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with ether (20 mL) to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amide[6-(1 ,2,3,6-Tetrahydropyridin-4-yl)-pyridine-3-yl]-amide tris-trifluoroacetate (162 mg, 42%) as a pale orange solid. The filtrate was washed with methanol (2 × 10 mL), and the methanol filtrates were combined and concentrated to give bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-yl Amine [6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-amide tris-trifluoroacetate (192 mg, 50%), as a transparent film .

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-(3-{[4-({[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane Synthesis of tertiary butyl ester of -1-amido)pyridine-3-yl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. Bicyclo[1.1.1]pentane-1,3-dicarboxylic acid (4-aminomethyl-phenyl)-amido[6-(1,2,3,6-tetrahydropyridin-4-yl )-Pyramide-3-yl]-amide 3 trifluoroacetic acid (352 mg, 0.46 mmol) in N,N-dimethylformamide (4.4 mL) was added triethylamine (324 mg, 444 μL, 3.17 mmol). The reaction was stirred for 15 minutes and then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (454 mg, 1.46 mmol). The reaction was stirred for 15 min, then heated at 35 °C for 16 h, then treated with water (65 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6- (3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amino)pyridine-3-yl]-1,2,3,6-tetrahydropyridine-1- tertiary butyl})methylene]carbamate (152 mg, 37%) as an off-white solid.

Bicyclo[1.1.1]pentane-1,3-dicarboxylate[6-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl] Synthesis of -amide (4-guanidinomethyl-phenyl)-amide: to N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[6-( 3-{[4-({[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino} Methyl)phenyl]aminoformyl}bicyclo[1.1.1]pentane-1-amido)pyridine-3-yl]-1,2,3,6-tetrahydropyridine-1- To a mixture of tert-butyl)methylene]carbamate (152 mg, 0.17 mmol) in _{CH2Cl2 (} 1.7 mL) was added trifluoroacetic acid (1.7 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[1.1.1]pentane-1,3-dicarboxylic acid [6-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- Tris-trifluoroacetate salt of (4-guanidinomethyl-phenyl)-amide (88 mg, 61%) as a white solid. MS: 503 M+H+; ¹ 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. , 2H) 8.16 - 8.31 (m, 2H) 7.93 - 8.07 (m, 4H) 7.50 - 7.70 (m, 12H) 7.14 - 7.27 (m, 7H) 6.65 - 6.83 (m, 2H) 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).

Example 48: Bicyclo[2.2.1]heptane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of Amide (4-guanidinomethyl-phenyl)-amide

Synthesis of methyl 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carboxylate. To bicyclo[2.2.1]heptane-1,4-dicarboxylate monomethyl ester (500 mg, 2.52 mmol), 4-bromo-aniline (478 mg, 2.77 mmol) and triethylamine (478 mg, 646 μL , 4.03 mmol) to a mixture in N,N-dimethylformamide (7.5 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[ 4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1433 mg, 3.78 mmol). The reaction was stirred for 16 hours, then treated with water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 30 mL), 1 N HCl (25 mL), and saturated aqueous NaHCO ₃ (25 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexane) to give 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1- Methyl formate (856 mg, 96%) as a white solid.

Synthesis of 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carboxylic acid. 4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carboxylate (856 mg, 2.43 mmol) in 1,4-bis(11 mL ) was added 10 N aqueous NaOH (2.4 mL). The reaction was heated at 90° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (20 mL) and dried under high vacuum to give 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carboxylic acid (662 mg, 81%), as a white solid.

(4-{[4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carbonyl]-amino}-benzyl)-carbamic acid tertiary butyl Synthesis of esters. 4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carboxylic acid (662 mg, 1.96 mmol), (4-amino-benzyl)-amino To a mixture of tert-butyl formate (482 mg, 2.17 mmol) and triethylamine (461 mg, 625 μL, 3.89 mmol) in N,N-dimethylformamide (5.8 mL) was added 1-bis( Dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1109 mg, 2.94 mmol). The reaction was stirred for 16 hours, then treated with water (90 mL) and ethyl acetate (50 mL). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL), then dried under high vacuum to give (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[ 2.2.1] Heptane-1-carbonyl]-amino}-benzyl)-tert-butyl carbamate (532 mg, 50%) as a white solid.

4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.1]heptane-1-carbonyl}- Synthesis of tertiary-butyl amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.1]heptane-1-carbonyl]-amino}-benzyl) - Tertiary-butyl carbamate (532 mg, 0.98 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (359 mg, 1.16 mmol), Pd(OAc) ₂ (11 mg, 0.050 mmol) and 2-dicyclohexylphosphino-2' , a mixture of 6'-dimethoxybiphenyl (43 mg, 0.11 mmol) in 1,4-dimethoxybiphenyl (7.5 mL) and 2M K ₂ CO ₃ (2.3 mL) The mixture was degassed for 10 min. 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 filtered through celite. The filtrate was separated. The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenyl Aminoformyl]-bicyclo[2.2.1]heptane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (89 mg, 14%), as a white solid.

Bicyclo[2.2.1]heptane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of phenyl]-amide. To 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.1]heptane-1-carbonyl} -Amino)-phenyl]-3,6-dihydro-2H-pyridine-1- _carboxylic acid tert-butyl ester (87 mg, 0.14 mmol) in _CH2Cl2 (1 mL) was added trifluoro Acetic acid (0.5 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (15 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (10 mL) to give bicyclo[2.2.1]heptane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amide[4-(1 ,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (126 mg, >100%) as a pale yellow solid which was used without further purification .

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[2.2.1]heptane Synthesis of -1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. Bicyclo[2.2.1]heptane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl )-phenyl]-amide 2 trifluoroacetic acid (N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({ [(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]amino Formyl}bicyclo[2.2.1]heptane-1-amino)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl To a mixture of ester (126 mg, 0.19 mmol) in N,N-dimethylformamide (1.8 mL) was added triethylamine (131 mg, 180 μL, 1.28 mmol). The reaction was stirred for 15 minutes, then Treat with N,N'-Bis-Boc-1-carboxamidinopyrazole (184 mg, 0.59 mmol). The reaction is stirred for 15 min, then heated at 35 °C for 16 h, then treated with water (40 mL) , and extracted with ethyl acetate (2 × 40 mL). The combined organic extracts were washed with water (2 × 20 mL) and brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. %-100% ethyl acetate: hexanes) to obtain N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4 -({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl ]aminoformyl}bicyclo[2.2.1]heptane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amino Tertiary butyl formate (40 mg, 23%), a transparent film.

Bicyclo[2.2.1]heptane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 4-guanidinomethyl-phenyl)-amide: N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[ 4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)benzene Base]aminoformyl}bicyclo[2.2.1]heptane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]amine To _a mixture of tert-butyl carbamate (40 mg, 0.043 mmol) in _CH2Cl2 (0.43 mL) was added trifluoroacetic acid (0.43 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.1]heptane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- (4-guanidinomethyl-phenyl)-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (14 mg, 43%) as a beige solid. MS: 529 M+H+; ¹ H 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, J =4.69 Hz, 7 H) 7.21 (d, J =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, J =6.45 Hz, 4 H).

Example 49: Pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}hydrochloride Synthesis of

Synthesis of tert-butyl 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate: by bubbling nitrogen through 4-bromo-phenylamine (0.850 g , 4.95 mmol), 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H )-Mixture of tert _- butyl formate (1.76 g, 5.69 mmol) and 2M _Na2CO3 solution (7.4 mL, 14.85 mmol) in 1,4-di㗁𠮿 (19 mL) The mixture was degassed 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 ( _Na2SO4 ), filtered and concentrated _. Silica gel chromatography (0% to 100% ethyl acetate-hexanes), followed by concentration and vacuum drying afforded the desired compound (0.83 g, 61%) as a white waxy solid.

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide} trifluoroacetate. To pyrimidine-4,6-dicarboxylic acid (0.120 g, 0.714 mmol), tertiary butyl 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (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) in a mixture Add 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 HCl solution, then dried ( _MgSO4 ), 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 give a yellow solid. This material was dissolved in dichloromethane (23 mL), and trifluoroacetic acid (8 mL) was added thereto. After stirring at 23 °C for three hours, the reaction was concentrated. The residue was triturated with ethyl acetate, filtered and dried in vacuo to afford the desired compound (0.420 g, 83%).

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}hydrochloride: To _pyrimidine -4,6-dicarboxylic acid bis{[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}trifluoro Acetate (0.400 g, 0.564 mmol) and N,N-diisopropylethylamine (0.251 g, 0.338 mL, 1.94 mmol) in suspension in N,N-dimethylacetamide (6 mL) Add tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-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 vacuum drying gave a yellow solid (0.255 g). Dissolve this material in 4 N HCl-1,4-dimethoxylate (8 mL), sonicate briefly to aid dissolution, and stir at 23 °C. After six hours, the reaction was concentrated. The residue was triturated with ethyl acetate, filtered and dried in vacuo to afford the desired compound as a yellow solid (0.190 g, 53%).

Example 50: Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(1,1-difluoro-2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate

Synthesis of difluoro-(4-nitro-phenyl)-ethyl acetate: 1-iodo-4-nitro-benzene (6.65 g, 26.7 mmol) and bromo-difluoro-ethyl acetate (5.97 g, 29.4 mmol) in N,N-dimethylformamide (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 _Na2HPO4 solution (67 mL, 67 mmol) _was added. After stirring for 30 minutes, the mixture was filtered through celite, and the filtered solid was 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-hexane), followed by concentration and vacuum drying afforded the desired compound (1.1 g, 17%).

Synthesis of 2,2-difluoro-2-(4-nitro-phenyl)-ethanol: difluoro-(4-nitro-phenyl)-ethyl acetate (0.674 g, 2.75 mmol) in EtOH (9 mL) was added _NaBH4 (0.157 g, 4.15 mmol). The ice bath was removed, and the reaction was stirred at 23 °C for two hours, then quenched with 1 N HCl solution (2 mL) and concentrated. 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 in vacuo gave the desired compound (0.650 g) as a yellow solid.

Synthesis of 2,2-difluoro-2-(4-nitro-phenyl)-ethylamine: 2,2-difluoro-2-(4-nitro-phenyl)-ethanol at 0°C To a solution of (0.650 g, 3.20 mmol) and pyridine (0.405 g, 0.414 mL, 5.12 mmol) in acetonitrile (6 mL) 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 (3x) with dichloromethane. The organic layers were combined, dried, filtered and concentrated. Silica gel chromatography (10% to 100% ethyl acetate-hexane), followed by concentration and vacuum drying afforded the desired compound (0.320 g, 49%).

Synthesis of [2,2-difluoro-2-(4-nitro-phenyl)-ethyl]-carbamic acid tertiary butyl ester: 2,2-difluoro-2-( To a solution of 4-nitro-phenyl)-ethylamine (0.320 g, 1.58 mmol) in tetrahydrofuran (5 mL) was added ditert-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-hexane), followed by concentration and vacuum drying afforded the desired compound (0.280 g, 59%).

Synthesis of [2-(4-amino-phenyl)-2,2-difluoro-ethyl]-carbamic acid tertiary butyl ester: [2,2-difluoro - A mixture of tert-butyl 2-(4-nitro-phenyl)-ethyl]-carbamate (0.280 g, 0.926 mmol) in THF (15 mL) was degassed, then stirred under hydrogen for 16 hours . The reaction was purged with nitrogen, filtered through celite, and concentrated to give the desired compound (0.223 g, 86%).

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(2-amino-1,1-difluoro-ethyl)-phenyl]-amide} trifluoroacetate. To pyrimidine-4,6-dicarboxylic acid (0.067 g, 0.400 mmol), [2-(4-amino-phenyl)-2,2-difluoro-ethyl]-carbamic acid tertiary butyl ester (0.223 g, 0.800 mmol), a mixture of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.192 g, 1.00 mmol) and hydroxybenzotriazole (0.135 g, 1.00 mmol) Add N,N-dimethylformamide (0.5 mL). The suspension was sonicated until homogeneous, then stirred at 23 °C for 72 h. The mixture was partitioned between dichloromethane and 0.5 N HCl 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-hexane), followed by concentration and vacuum drying afforded {2-[4-({6-[4-(2-tertiary butoxycarbonylamino -1,1-Difluoro-ethyl)-phenylaminoformyl]-pyrimidine-4-carbonyl}-amino)-phenyl]-2,2-difluoro-ethyl}-carbamic acid Tertiary butyl ester, as light yellow solid. This compound was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. After stirring at 23 °C for four hours, the reaction was concentrated to afford the desired compound, which was used in the next reaction without further purification.

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(1,1-difluoro-2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate: pyrimidine-4,6 -Dicarboxylic acid bis{[4-(2-amino-1,1-difluoro-ethyl)-phenyl]-amide} trifluoroacetate (0.180 g, 0.256 mmol), N-[(Z) -{[(tertiary-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamic acid tertiary-butyl ester (0.222 g, 0.715 mmol) and N,N-diiso A mixture of propylethylamine (0.185 g, 0.250 mL, 1.43 mmol) in N,N-dimethylformamide (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 ₂ SO ₄ ), filtered and concentrated. Silica gel chromatography (20% to 100% ethyl acetate-hexanes) followed by concentration and vacuum drying gave an off-white foam. This material was dissolved in dichloromethane (8 mL), to which was added trifluoroacetic acid (5 mL). After stirring at 23 °C for 18 h, the reaction was concentrated, then diluted with ethyl acetate and concentrated again (2x). The residue was triturated with ethyl acetate, then filtered and dried in vacuo to afford the desired compound (0.124 g, 61%).

Example 51: Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(4-carboxamidino-piper-l-yl)-phenyl]-amide} trifluoroacetate

The synthesis of 4-(4-amino-phenyl)-piperate-1-formic acid tertiary butyl ester: to 4-(4-nitro-phenyl)-piperate-1-formic acid tertiary butyl ester (1.200 g, 3.90 mmol) in a mixture of MeOH (30 mL) and tetrahydrofuran (15 mL) were added _NH4Cl (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 raised 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 give the desired compound as a black oil (0.840 g, 78%) which was used in the next reaction without further purification.

Synthesis of pyrimidine-4,6-dicarboxylic acid bis[(4-piperone-1-yl-phenyl)-amide]trifluoroacetate: pyrimidine-4,6-dicarboxylate at 23°C under _N Dicarboxylic acid (0.0300 g, 0.181 mmol), N,N-diisopropylethylamine (1.00 mL), and 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo A mixture of [4,5-b]pyridinium cation 3-oxide hexafluorophosphate (0.185 g, 0.486 mmol) in dichloromethane (1.2 mL) was stirred for 30 minutes, then 4-(4-amino-benzene Dichloromethane (0.400 mL) and stirred 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 dichloromethane (1 mL), then trifluoroacetic acid (3 mL) was added to it. After stirring for two hours, the reaction was concentrated. The residue was triturated with ether (15 mL); the ether was then decanted to afford the desired compound as a soft solid which was used without further purification.

[(4-{4-[(6-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-benzene Aminoformyl}-pyrimidine-4-carbonyl)-amino]-phenyl}-piperone-1-yl)-tertiary butoxycarbonylimino-methyl]-carbamic acid tertiary Synthesis of butyl ester: pyrimidine-4,6-dicarboxylic acid bis[(4-piper-1-yl-phenyl)-amide] trifluoroacetate (about 0.0700 g, about 0.250 mmol ) and triethylamine (0.3152 g, 2.17 mL, 1.50 mmol) in dichloromethane (3 mL) were added water (0.200 mL), followed by N,N-dimethylformamide (2 mL) . Additional triethylamine (0.108 mL, 0.750 mmol) was added followed by N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl ] tertiary-butyl carbamate (0.194 g, 0.625 mmol), and the reaction was stirred at 23 °C for 72 h. 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-dichloromethane), followed by concentration and vacuum drying afforded the desired compound (0.0500 g, 21%) as a soft solid.

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(4-formamidoyl-piper-1-yl)-phenyl]-amide} trifluoroacetate: After one minute to [(4- {4-[(6-{4-[4-(tertiary butoxycarbonylamino-tertiary butoxycarbonylimino-methyl)-pipera-1-yl]-phenylaminomethyl Acyl}-pyrimidine-4-carbonyl)-amino]-phenyl}-piperone-1-yl)-tertiary butoxycarbonylimino-methyl]-tertiary butyl carbamate (0.0500 g, 0.0515 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (3 mL) dropwise. 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 afford the desired compound (0.0450 g, quantitative).

Example 52: Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}

Synthesis of pyrimidine-4,6-dicarbonyl dichloride: reaction to pyrimidine- _4,6 -dicarboxylic acid (0.200 g, 11.9 mmol) and N,N-dimethyl To a mixture of formamide (0.109 g, 0.116 mL, 1.49 mmol) in anhydrous dichloromethane was added dropwise oxalyl chloride (0.453 g, 0.306 mL, 3.57 mmol). After 30 minutes, additional oxalyl chloride (0.045 mL in 0.500 mL of anhydrous dichloromethane) was added dropwise, and the reaction was stirred for 72 hours. The nearly homogeneous mixture was used as a solution in the next reaction.

Synthesis of [2-(4-amino-phenyl)-ethyl]-tertiary butyl carbamate: 4-(2-amino-ethyl)-benzene was synthesized over 30 minutes at 23°C Ditert-butyl dicarbonate (5.460 g, 25.0 mmol) in ethyl acetate ( 10 mL). After four hours, the mixture was concentrated and dried under vacuum for 72 hours to afford the desired compound as a white solid (5.40 g, 94%).

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate: the synthesis of [2-(4-amino-phenyl) -Ethyl]-carbamate tert-butyl ester (0.331 g, 1.40 mmol) and N,N-diisopropylethylamine (0.426 g, 0.574 mL, 3.30 mmol) in anhydrous dichloromethane (4 mL) The mixture was briefly sonicated at 23°C under _N until homogeneous, then cooled to 0°C. A solution of pyrimidine-4,6-dicarbonyl dichloride (0.126 g, 0.540 mmol) in dichloromethane (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 ₂ SO ₄ ), filtered and concentrated. The residue was triturated with dichloromethane to form a solid, which was collected by filtration, suspended in dichloromethane (2 mL), and treated with trifluoroacetic acid (4 mL). The reaction was complete within four hours, then concentrated. This material was triturated with diethyl ether (2 x 20 mL) and dried in vacuo to give 0.170 mg. The mother liquor from the first dichloromethane trituration/filtration was treated with trifluoroacetic acid alone in a similar manner to the filtered solid and then analyzed by reverse phase HPLC (5% to 37% MeCN-water (both containing 0.1% trifluoroacetic acid) over 11 min). Fractions containing the title compound were lyophilized to yield 50 mg. This material was combined with the product from ether trituration to give the desired product (0.220 g, 64%).

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}: One minute synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4- (2-Amino-ethyl)-phenyl]-amide} trifluoroacetate (0.220 g, 0.350 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (3 mL ) to the slurry in the mixture was added dropwise triethylamine (0.636 g, 900 mL, 6.30 mmol). After ten minutes, the reaction was cooled to 0°C with an ice bath, and N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H-pyrazol-1-yl) was added Tert-butyl methyl]carbamate (0.520 g, 1.68 mmol). After five minutes the ice bath was removed, 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-dichloromethane) followed by concentration and vacuum drying afforded the desired guanidinated intermediate. The compound was deprotected by dissolving in dichloromethane (2 mL) and treating with trifluoroacetic acid (3 mL). Concentration followed by lyophilization from 1,4-di㗁𠮿/water afforded the desired compound (0.102 g, 41%).

Example 53: Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamidino-tetrahydroacrin-3-yloxy)-phenyl]-amide}trifluoroacetate

Synthesis of tertiary butyl 3-(4-nitro-phenoxy)-tetrahydroacridine-1-carboxylate: 3-Hydroxy-tetrahydroacridine-1-carboxylate synthesis at 23 °C under _N To a mixture of tert-butyl ester (1.580 g, 9.13 mmol) in dry tetrahydrofuran (12 mL) was added potassium tert-butoxide (1.155 g, 10.3 mmol). After 30 minutes, 1-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 in vacuo to afford the desired compound (1.7 g, 64.5%) as a solid.

Synthesis of tertiary butyl 3-(4-amino-phenoxy)-tetrahydroazia-1-carboxylate: 3-(4-nitro-phenoxy) synthesis at 23 °C under _N - To a solution of tert-butyl tetrahydroacridine-1-carboxylate (2.590 g, 8.80 mmol) in a mixture of tetrahydrofuran (10 mL) and MeOH (20 mL) was added ammonium chloride (4.750 g, 88.0 mmol), Then zinc powder (2.900 g, 44.0 mmol) was added. 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-dichloromethane), followed by concentration and vacuum drying gave the title compound (0.710 g, quantitative).

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(tetrahydroazan-3-yloxy)-phenyl]-amide} trifluoroacetate: at 23°C under _N2 Mix tertiary butyl 3-(4-amino-phenoxy)-tetrahydroazia-1-carboxylate (0.317 g, 1.20 mmol) and N,N-diisopropylethylamine (0.774 g, 1.1 mL, 6.0 mmol) in anhydrous dichloromethane (4 mL) was cooled to 0°C. A solution of pyrimidine-4,6-dicarbonyl dichloride (0.126 g, 0.540 mmol) in dichloromethane (2.5 mL) was added dropwise. After five minutes the ice bath was removed 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 give a yellow solid (0.390 g), which was dissolved/suspended in dichloromethane (4 mL) and treated with trifluoroacetic acid (8 mL). After stirring at 23°C for 18 hours, the reaction was concentrated. This material was triturated with diethyl ether (2 x 15 mL) and dried in vacuo to give the title compound.

Synthesis of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carbamidino-tetrahydroacri-3-yloxy)-phenyl]-amide} trifluoroacetate: at 23°C Downward pyrimidine-4,6-dicarboxylic acid bis{[4-(tetrahydroazil-3-yloxy)-phenyl]-amide} trifluoroacetate (0.220 g, 0.480 mmol) and triethylamine (1.200 g, 1.70 mL) to a suspension in a mixture of dichloromethane (2 mL) and N,N-dimethylformamide (2 mL) was added N-[(Z)-{[(tertiary Butoxy)carbonyl]imino}(1H-pyrazol-1-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 dichloromethane, 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 dichloromethane (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, and then stirred at 23 °C for 18 h. The solid was collected by filtration, washed with ethyl acetate, and dried in a vacuum oven for 18 hours to afford the title compound (0.144 g, 85%).

Example 54: Synthesis of pyridine-2,4-dicarboxylic acid bis{[4-(4-formamimidino-piper-l-yl)-phenyl]-amide}trifluoroacetate

Synthesis _of pyridine-2,4-dicarbonyl dichloride: Conversion of pyridine-2,4-dicarboxylic acid (0.207 g, 1.24 mmol) and N,N-dimethyl To a mixture of formamide (0.118 g, 0.128 mL, 1.61 mmol) in anhydrous dichloromethane (4 mL) was added dropwise oxalyl chloride (0.456 g, 0.309 mL, 3.59 mmol) in dichloromethane (1 mL) solution. After 30 minutes, additional oxalyl chloride (0.100 mL) was added and the reaction was stirred for 90 minutes. Additional dichloromethane (1 mL) was added and the soluble portion of the mixture was withdrawn by syringe and used without further purification.

Synthesis of pyridine-2,4-dicarboxylic acid bis[(4-piperyl-1-yl-phenyl)-amide] trifluoroacetate: 4-(4-amino-phenyl)-piperyl- A mixture of tert-butyl 1-carboxylate (0.609 g, 2.20 mmol) and N,N-diisopropylethylamine (2.600 g, 3.60 mL, 20.0 mmol) in dry dichloromethane (15 mL) was cooled to 0 °C. A solution of pyridine-2,4-dicarbonyl dichloride (1.00 mmol) in dichloromethane (ca. 4 mL) was added dropwise over five minutes. After 10 minutes the cooling bath was removed 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 give a light brown solid (0.454 g). This material was dissolved in dichloromethane (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) and decanted. This material was purified by reverse phase HPLC (5% to 45% MeCN-water (both with 0.1% trifluoroacetic acid) over 15 minutes). Fractions containing the title compound were lyophilized to give the desired product as a brown solid (0.0500 g, 6%).

Synthesis of pyridine-2,4-dicarboxylic acid bis{[4-(4-formamidoyl-piper-1-yl)-phenyl]-amide} trifluoroacetate: at 23°C to pyridine- 2,4-Dicarboxylic acid bis[(4-piperone-1-yl-phenyl)-amide] trifluoroacetate (0.716 g, 0.660 mmol) and triethylamine (0.800 g, 1.14 mL, 7.92 mmol) To a solution in a mixture of dichloromethane (5 mL) and N,N-dimethylformamide (5 mL) was added N-[(Z)-{[(tertiary butoxy)carbonyl]imine tert-butyl}(1H-pyrazol-1-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 dichloromethane, 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 ₂ SO ₄ ), filtered and concentrated. Silica gel chromatography (5% to 100% ethyl acetate-dichloromethane) followed by concentration and vacuum drying afforded 0.440 g of the desired intermediate. This compound was dissolved in dichloromethane (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)). Fractions containing the title compound were combined, concentrated, and lyophilized. The freeze-drying was repeated using 1 : 1 1,4-di㗁𠮿: water with the same result. The residue was concentrated, then dried in a vacuum oven to give the desired compound (0.082 g, 14%).

Example 55: Synthesis of pyrimidine-4,6-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide] trifluoroacetate

Synthesis of tertiary butyl (4-amino-benzyl)-carbamate: 4-aminomethyl-phenylamine (2.170 g, 17.8 mmol) in ethyl acetate over 30 minutes at 0°C (30 mL) was added dropwise ditertiary butyl dicarbonate (4.080 g, 18.7 mmol). The ice bath was removed, and the suspension was stirred at 23°C for 18 hours. The mixture was concentrated and dried in vacuo to afford the title compound as a white solid (5.30 g, quantitative).

Synthesis of pyrimidine-4,6-dicarboxylic acid bis[(4-aminomethyl-phenyl)-amide] trifluoroacetate: ₂ min at 0 °C (cooled with ice bath) under N (4-Amino-benzyl)-tert-butyl carbamate (0.400 g, 1.80 mmol) and N,N-diisopropylethylamine (0.774 g, 1.10 mL, 6.00 mmol) in anhydrous dichloro To the mixture in methane (6 mL) was added dropwise a solution of pyrimidine-4,6-dicarbonyl dichloride (0.600 mmol) in dichloromethane. 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 dichloromethane (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 afford the title compound.

Synthesis of pyrimidine-4,6-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide] trifluoroacetate: synthesis 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 dichloromethane (6 mL) and N,N-dimethyl N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl] was added to a solution in a mixture of methylformamide (4 mL) Tertiary butyl carbamate (0.426 g, 1.375 mmol). The mixture was stirred at 23°C for 18 hours. The reaction was partially concentrated to remove dichloromethane, 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 ₂ SO ₄ ), filtered and concentrated. Silica gel chromatography (0% to 100% ethyl acetate-dichloromethane) followed by concentration and vacuum drying afforded 0.240 g of a white solid. This compound was dissolved in dichloromethane (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)). Fractions containing the title compound were combined, concentrated, and then freeze-dried from 1,4-di㗁𠮿-water to give the title compound (0.110 g, 29%).

Example 56: Synthesis of pyridine-2,4-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate

Synthesis of pyridine-2,4-dicarboxylic acid bis{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate: at 0°C (with ice bath cooling) under N [ _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 dichloromethane (4 mL) was added dropwise a solution of pyridine-2,4-dicarbonyl dichloride (0.067 g, 0.33 mmol) in dichloromethane. 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-dichloromethane) followed by concentration and drying in vacuo afforded the desired intermediate as a solid. This material was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (7 mL) was added. After two hours at 23°C, the mixture was concentrated. The residue was triturated with diethyl ether (20 mL), then decanted to afford the title compound.

Synthesis of pyridine-2,4-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate: synthesis of pyridine-2,4-dicarboxylate at 23°C Formic acid bis{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate (0.09 mmol) and triethylamine (0.091 g, 0.130 mL, 0.90 mmol) in dichloromethane ( 2 mL) and N,N-dimethylformamide (2 mL) were added N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H- Pyrazol-1-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 dichloromethane (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 diethyl ether (15 mL), then decanted, and the resulting material was lyophilized from MeCN-water to give the title compound (0.055 g, 74%).

Example 57: Synthesis of thiophene-2,5-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate

Synthesis _of thiophene-2,5-dicarbonyl dichloride: Conversion of thiophene-2,5-dicarboxylic acid (0.190 g, 1.10 mmol) and N,N-dimethyl To a mixture of formamide (0.072 g, 0.077 mL, 0.99 mmol) in anhydrous dichloromethane (4 mL) was added dropwise oxalyl chloride (0.421 g, 0.284 mL, 3.31 mmol) in dichloromethane (2 mL) solution. The mixture was stirred for 30 minutes, and a portion of it was used immediately for the next reaction.

Synthesis of thiophene-2,5-dicarboxylic acid bis{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate: at 0°C (with ice bath cooling) under N [ _2- (4-Amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.270 g, 1.14 mmol) and N,N-diisopropylethylamine ( To a mixture of 0.350 g, 0.501 mL, 2.72 mmol) in anhydrous dichloromethane (5 mL) was added dropwise a solution of thiophene-2,5-dicarbonyl dichloride (0.114 g, 0.544 mmol) in dichloromethane. After 10 minutes the ice bath was removed 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 briefly sonicated, then allowed to stand for three hours. The solid was collected by filtration and air dried for 18 hours. Suspend this material in dichloromethane and add trifluoroacetic acid (5 mL). After two hours at 23°C, the mixture was concentrated. The residue was triturated with diethyl ether (20 mL), then decanted to afford the desired compound, which was used in the next reaction without further purification.

Synthesis of thiophene-2,5-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate: synthesis of thiophene-2,5-dicarboxylate at 23°C Formic 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 dichloromethane (7 mL) and N,N-dimethylformamide (2 mL) was added to a solution of N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H-pyridine Azol-1-yl)methyl]carbamate tert-butyl ester (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. Suspend this material in dichloromethane (2 mL) and add trifluoroacetic acid (4 mL). The mixture was stirred at 23° C. for 18 hours, then concentrated. The residue was lyophilized from MeCN-water to give the title compound (0.072 g, 28%) as an off-white solid.

Example 58: Synthesis of N,N'-bis[4-(2-guanidino-ethyl)-phenyl]-terephthalamide trifluoroacetate

Synthesis of N,N'-bis[4-(2-amino-ethyl)-phenyl]-terephthalamide trifluoroacetate: [2-(4-amino -Phenyl)-ethyl]-tert-butyl carbamate (0.290 g, 1.23 mmol) and N,N-diisopropylethylamine (0.210 g, 0.300 mL, 1.62 mmol) in anhydrous dichloromethane ( 8 mL) 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, air-dried briefly, and dissolved in dichloromethane (4 mL). Trifluoroacetic acid (6 mL) was added, and the reaction was stirred for four hours, then concentrated. The residue was purified by reverse phase HPLC (10% to 55% MeCN-water (both with 0.1% trifluoroacetic acid)). Fractions containing the title compound were combined, concentrated, and lyophilized from MeCN-water to afford the title compound.

Synthesis of N,N'-bis[4-(2-guanidino-ethyl)-phenyl]-terephthalamide trifluoroacetate: synthesis 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) To a suspension in a mixture of dichloromethane (5 mL) and N,N-dimethylformamide (4 mL) was added N-[(Z)-{[(tertiary butoxy)carbonyl] Amino}(1H-pyrazol-1-yl)methyl]carbamate tert-butyl ester (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 min). Fractions containing the title compound were combined, concentrated, then lyophilized from 33% MeCN-water to afford the title compound (0.171 g, 60%) as a white solid.

Example 59: Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(4-carbamimidino-piper-1-yl)-phenyl]-amide}trifluoroacetate

Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis[(4-piper-1-yl-phenyl)-amide]trifluoroacetate: 1H-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-dimethylformamide (2 mL) at 23°C Stir for five minutes, then add 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (0.255 g, 0.850 mmol) and stirred for 30 minutes. After addition of tert-butyl 4-(4-amino-phenyl)-piperone-l-carboxylate (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 allowed to stand for 30 minutes. The resulting solid was collected by filtration and air dried to afford the desired intermediate as a gray solid. Suspend this material in dichloromethane (3 mL), then add trifluoroacetic acid (5 mL). After stirring for two hours, the reaction was concentrated. The residue was triturated with ether (10 mL); the ether was then decanted to afford the title compound as a gray solid which was used without further purification.

Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(4-formamimidino-piper-1-yl)-phenyl]-amide} trifluoroacetate: at 23°C To 1H-pyrazole-3,5-dicarboxylic acid bis[(4-piper-1-yl-phenyl)-amide] trifluoroacetate (0.200 g, 0.285 mmol) and NEt ₃ (0.231 g, 0.330 mL, 2.29 mmol) to a suspension in a mixture of dichloromethane (3 mL) and N,N-dimethylformamide (2 mL) was added N-[(Z)-{[(tertiary butoxy yl)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.221 g, 0.713 mmol). The reaction was stirred at 23°C for 18 hours, then heated at 52°C for 18 hours. The mixture has become homogeneous. Heating was stopped and stirring was continued for 18 hours at 23°C. 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% dichloromethane); 100% to 0% dichloromethane) followed by concentration and vacuum drying afforded the desired intermediate. This compound was dissolved in dichloromethane (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 allowed to stand for 18 hours. After a short time on the centrifuge, the ethyl acetate was decanted and the residue was lyophilized from 25% MeCN-water to give the title compound (0.058 g, 26%).

Example 60: Synthesis of N,N'-bis(4-guanidinomethyl-phenyl)-terephthalamide trifluoroacetate

Synthesis of N,N'-bis(4-aminomethyl-phenyl)-terephthalamide trifluoroacetate: synthesis of (4-amino-benzyl)-carbamic acid at 23°C To a solution of tert-butyl ester (0.273 g, 1.23 mmol) and N,N-diisopropylethylamine (0.202 g, 0.290 mL, 1.56 mmol) in dichloromethane (5 mL) was added terephthalamide Dichloro (0.113 g, 0.560 mmol). The suspension was stirred at 23°C for 18 hours and then heated at 30°C for a further 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 h. The resulting solid was collected by filtration and air dried for 72 hours. This material was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (5 mL) was added at 23 °C. After three hours, the reaction was concentrated, then triturated twice with ether (20 mL) to afford the title compound.

Synthesis of N,N'-bis(4-guanidinomethyl-phenyl)-terephthalamide trifluoroacetate: synthesis of N,N'-bis(4-aminomethyl) at 23°C -Phenyl)-terephthalamide trifluoroacetate (0.260 mmol) and NEt ₃ (0.500 g, 5.00 mmol) in N,N-dimethylformamide (2.4 mL) was added with N - Ter-butyl [(Z)-{[(tert-butoxy)carbonyl]imino}(lH-pyrazol-l-yl)methyl]carbamate (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 dichloromethane (3 mL), then filtered. The solid and mother liquor were treated separately with trifluoroacetic acid and stirred at 23°C for 18 hours. Reactions were combined and purified by reverse phase HPLC (3% to 50% MeCN-water (both with 0.1% trifluoroacetic acid) over 18 min). Fractions containing the title compound were combined, concentrated, then lyophilized from 20% MeCN-water to afford the desired compound (0.100 g, 56%).

Example 61: Synthesis of N,N'-bis[4-(4-carboxamidino-piperol-1-yl)-phenyl]-terephthalamide trifluoroacetate

Synthesis of N,N'-bis(4-piperyl-1-yl-phenyl)-terephthalamide trifluoroacetate: 4-(4-amino-phenyl) at 23°C -tert-butylpiperyl-1-carboxylate (0.300 g, 1.08 mmol) and N,N-diisopropylethylamine (0.186 g, 0.270 mL, 1.44 mmol) in dichloromethane (3 mL) and N, To a solution in a mixture of N-dimethylformamide (3 mL) was added terephthalyl 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 a further 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 dichloromethane (3 mL), and trifluoroacetic acid (4 mL) was added at 23 °C. After four hours, the reaction was concentrated, then triturated twice with ether (20 mL) to afford the title compound.

Synthesis of N,N'-bis[4-(4-formamimidino-piper-1-yl)-phenyl]-terephthalamide trifluoroacetate: N,N reaction at 23°C '-Bis(4-piperone-1-yl-phenyl)-terephthalamide trifluoroacetate (0.450 mmol) and NEt ₃ (0.490 g, 4.85 mmol) in dichloromethane (3 mL) and To a suspension in a mixture of N,N-dimethylformamide (3 mL) was added N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H-pyrazole- tert-butyl 1-yl)methyl]carbamate (0.412 g, 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), allowed to stand for five minutes, then the solid was collected by filtration and air-dried for 18 hours. This material was dissolved in dichloromethane (10 mL), treated with trifluoroacetic acid (19 mL), stirred at 23 °C for three hours, then concentrated. The residue was purified by reverse phase HPLC (3% to 45% MeCN-water (both with 0.1% trifluoroacetic acid) over 20 min). Fractions containing the title compound were combined and lyophilized to afford the desired compound (0.108 g, 30%).

Example 62: Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate

Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate: the synthesis of 1H-pyrazole-3,5- A mixture of dicarboxylic acid (0.0620 g, 0.181 mmol) and N,N-diisopropylethylamine (0.164 g, 0.240 mL, 1.27 mmol) in N,N-dimethylformamide (1.2 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (0.452 g, 1.19 mmol ) and 1-hydroxy-7-azabenzotriazole (0.124 g, 0.913 mmol). The reaction was stirred for 60 minutes, then [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.220 g, 0.93 mmol) was added, stirred for another ten minutes, and then heated 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 dichloromethane (2 mL) and treated with trifluoroacetic acid (5 mL). After stirring for two hours, the reaction was concentrated. The residue was triturated with diethyl ether (15 mL) to give the title compound.

Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide} trifluoroacetate: 1H-pyrazole at 23°C -3,5-Dicarboxylic acid bis{[4-(2-amino-ethyl)-phenyl]-amide} trifluoroacetate (0.360 mmol) and NEt ₃ (0.350 g, 3.46 mmol) in dichloro To a suspension in methane (3 mL) was added N,N-dimethylformamide (2 mL), followed by N-[(Z)-{[(tertiary butoxy)carbonyl]imino} (1H-Pyrazol-1-yl)methyl]carbamate (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 in vacuo. The residue was dissolved in dichloromethane (2 mL), treated with trifluoroacetic acid (4 mL), and stirred at 23 °C for 18 h. After concentration, the residue was purified by reverse phase HPLC (5% to 47% MeCN-water (both with 0.1% trifluoroacetic acid) over 20 min). Fractions containing the title compound were combined, concentrated and lyophilized to afford the title compound (0.177 g, 70%).

Example 63: 1-Methyl-1H-pyrazole-3,5-dicarboxylic acid bis{[4-(4-formamimidino-piperazol-1-yl)-phenyl]-amide}trifluoroacetate Synthesis of

Synthesis of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid bis[(4-piper-1-yl-phenyl)-amide] trifluoroacetate: 1- Methyl-1H-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 To a solution in formamide (1 mL) was added 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide Hexafluorophosphate (0.570 g, 1.50 mmol). After stirring for 45 minutes, tert-butyl 4-(4-amino-phenyl)-piperone-1-carboxylate (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). After two hours, the black solid was collected by filtration, washed with diethyl ether (5 mL) and air dried to give a brown solid. Suspend this material in dichloromethane (5 mL), then add trifluoroacetic acid (7 mL). 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 give the title compound as a soft solid which was used without further purification.

Synthesis of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid bis{[4-(4-formamimidino-piper-1-yl)-phenyl]-amide} trifluoroacetate: Addition of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid bis[(4-piperone-1-yl-phenyl)-amide]trifluoroacetate (0.480 mmol) and NEt at 23°C N- _[ (Z)-{[ (tertiary-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.447 g, 1.44 mmol). After three hours, another portion (0.140 g, 0.452 mmol) of N-[(Z)-{[(tertiary butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl] was added tertiary butyl carbamate, and the reaction was stirred at 23 ^°C for 18 h. 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 dichloromethane (4 mL), treated with trifluoroacetic acid (6 mL), then stirred at 23 °C for 90 min, then concentrated again. The residue was purified by reverse phase HPLC (5% to 47% MeCN-water (both with 0.1% trifluoroacetic acid) over 18 min). Fractions containing the title compound were combined, concentrated and lyophilized to afford the title compound (0.216 g, 56%).

Example 64: Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(1-carbamimidino-tetrahydroacrin-3-yl)-phenyl]-amide}trifluoroacetate

Synthesis of 1H-pyrazole-3,5-dicarbonyl dichloride: Conversion of 1H-pyrazole-3,5-dicarboxylic acid (0.240 g, 1.38 mmol) and N over 10 min at 23 °C under _N , To a suspension of N-dimethylformamide (0.020 g, 0.022 mL, 0.276 mmol) in CHCl ₃ (6 mL) was added dropwise oxalyl chloride (0.490 g, 0.335 mL, 3.86 mmol). 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 in vacuo to give a solid which was used without further purification.

Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis[(4-tetrahydroazil-3-yl-phenyl)-amide] trifluoroacetate: 3- (4-Amino-phenyl)-tert-butyl tetrahydroazia-1-carboxylate (0.230 g, 0.930 mmol) and N,N-diisopropylethylamine (0.225 g, 1.74 mmol) in CHCl ₃ (5 mL) was added dropwise a solution of 1H-pyrazole-3,5-dicarbonyl dichloride (0.390 mmol) in CHCl ₃ (7 mL). After 15 min, add another portion of tert-butyl 3-(4-amino-phenyl)-tetrahydroazia-1-carboxylate (0.045 g) and N,N-diisopropylethylamine (0.200 mL ), and the reaction was 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), and 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 washed with ether (5 mL). The two batches of crystals were combined and suspended in dichloromethane (3 mL), then trifluoroacetic acid (4 mL) was added. After stirring at 23°C for 18 hours, the reaction was concentrated. The residue was triturated with diethyl ether (2 x 15 mL) to give the desired compound as a soft solid which was used without further purification.

Synthesis of 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(1-formamidinyl-tetrahydroazine-3-yl)-phenyl]-amide} trifluoroacetate: at 23° 1H-Pyrazole-3,5-dicarboxylic acid bis[(4-tetrahydroazil-3-yl-phenyl)-amide] trifluoroacetate (0.300 mmol) and NEt ₃ (0.600 g, 6.00 mmol) to a suspension in a mixture of dichloromethane (3 mL) and N,N-dimethylformamide (2 mL) was added N-[(Z)-{[(tertiary butoxy) Carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate tert-butyl ester (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 in vacuo. The residue was dissolved in dichloromethane (3 mL), treated with trifluoroacetic acid (4 mL), and stirred at 23 °C for 18 h. After concentration, the residue was purified by reverse phase HPLC (5% to 47% MeCN-water (both with 0.1% trifluoroacetic acid) over 18 min). Fractions containing the title compound were combined, concentrated and lyophilized to afford the desired compound (0.102 g, 47%).

Example 65: Synthesis of N,N'-bis[4-(1-carboxamidino-tetrahydroazan-3-yl)-phenyl]-terephthalamide trifluoroacetate

Synthesis of N,N'-bis(4-tetrahydroazine-3-yl-phenyl)-terephthalamide trifluoroacetate: 3-(4-amino-benzene at 23°C A solution of tertiary-butyl tetrahydroacridine-1-carboxylate (0.225 g, 0.907 mmol) and N,N-diisopropylethylamine (0.156 g, 1.21 mmol) in CHCl ₃ (7 mL) Terephthalyl dichloride (0.087 g, 0.432 mmol) was added. Over 30 minutes, the suspension became homogeneous and N,N-dimethylformamide (2 mL) was added to increase 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 dichloromethane (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 diethyl ether (15 mL) to give the desired compound which was used without further purification.

Synthesis of N,N'-bis[4-(1-formamimidino-tetrahydroazine-3-yl)-phenyl]-terephthalamide trifluoroacetate: at 23°C under N , N'-bis(4-tetrahydroazil-3-yl-phenyl)-terephthalamide trifluoroacetate (0.360 mmol) and NEt ₃ (0.290 g, 0.420 mL, 2.88 mmol) in di To a suspension in a mixture of methyl chloride (3 mL) and N,N-dimethylformamide (2 mL) was added N-[(Z)-{[(tertiary butoxy)carbonyl]imino }(1H-pyrazol-1-yl)methyl]carbamate tert-butyl ester (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 started to form in the biphasic mixture. The combined layers were concentrated, then dissolved in dichloromethane (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)). Fractions containing the title compound were combined, concentrated and lyophilized to afford the title compound (0.098 g, 37%).

Example 66: Synthesis of N,N'-bis(2-carboxamidino-1,2,3,4-tetrahydroisoquinolin-7-yl)-terephthalamide trifluoroacetate

Synthesis of N,N'-bis(1,2,3,4-tetrahydroisoquinolin-7-yl)-terephthalamide trifluoroacetate: 7-amino- 3,4-Dihydro-1H-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 CHCl To the solution in ₃ (4 mL) 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 dichloromethane (4 mL), treated with trifluoroacetic acid (4 mL), and stirred at 23 °C for 18 h. Concentrate the mixture. The residue was triturated with diethyl ether (2 x 20 mL) to give the desired compound which was used without further purification.

Synthesis of N,N'-bis(2-carboxamidino-1,2,3,4-tetrahydroisoquinolin-7-yl)-terephthalamide trifluoroacetate: at 23°C Add N,N'-bis(1,2,3,4-tetrahydroisoquinolin-7-yl)-terephthalamide trifluoroacetate (0.500 mmol) and NEt ₃ (0.455 g, 0.650 mL , 4.50 mmol) to a suspension in a mixture of dichloromethane (3 mL) and N,N-dimethylformamide (2 mL) was added N-[(Z)-{[(tertiary butoxy )carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate tert-butyl ester (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, 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 in vacuo to give the desired intermediate. This material was dissolved in dichloromethane (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)). Fractions containing the title compound were combined, concentrated and lyophilized to afford the title compound (0.105 g, 28%).

Example 67: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of Amide (4-guanidinomethyl-phenyl)-amide

Synthesis of tertiary-butyl 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through 4-bromo-aniline (3.00 g, 17.44 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.93 g, 19.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]bis A mixture of chloropalladium(II) dichloromethane complex (142 mg, 0.18 mmol) in 1,4-dimethan (40 mL) and 2M _K2CO3 (26 _mL ) The mixture was degassed for 10 min . The reaction was heated at 80°C for 18 hours. The reaction was cooled, treated with ethyl acetate (200 mL), then washed with water (75 mL), brine (30 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexane) to give 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (4.09 g, 86%) as a beige solid.

Synthesis of 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylate monomethyl ester (3.18 g, 14.91 mmol), (4-amino-benzyl)-carbamic acid tertiary butyl ester (3.48 g, 15.66 mmol) and triethylamine (3.52 g, 4.75 mL, 29.73 mmol) in N,N-dimethylformamide (40 mL) was added 1-[bis(dimethylamino)methylene ]-1H-1,2,3-Triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (8.47 g, 22.34 mmol). The reaction was treated with additional monomethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (1.59 g, 7.48 mmol), tertiary butyl (4-amino-benzyl)-carbamate (1.74 g, 7.83 mmol), triethylamine (1.76 g, 2.38 mL, 14.87 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium cation 3-oxide hexafluorophosphate (4.24 g, 11.17 mmol) and N,N-dimethylformamide (10 mL). The reaction was stirred for 16 hours, then poured into water (750 mL). The mixture was treated with ethyl acetate (150 mL) and shaken. The mixture was filtered and the solid was washed with isopropanol (50 mL) and hexane (50 mL) to give 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl] - Methyl bicyclo[2.2.2]octane-1-carboxylate (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), brine (20 mL), and dried (Na ₂ SO ₄ ). The _isopropanol /hexane filtrate was dried ( _Na2SO4 ). The ethyl acetate and isopropanol/hexanes were combined and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate:hexane) to give 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl]- Methyl bicyclo[2.2.2]octane-1-carboxylate (1.31 g, 14%) as a white solid.

Synthesis of 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid. To 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (5.69 g, 13.66 mmol ) to the mixture in 1,4-di㗁𠮿 (63 mL) was added 10 N aqueous NaOH (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 adjusted to pH=1 with 1 N HCl. The mixture was left to stand for 5 minutes, then filtered. The solid was washed with water (50 mL) and dried under high vacuum to give 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2. 2] Octane-1-carboxylic acid (5.63 g, >100%) as a white solid which was used without further purification.

4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}- Synthesis of tertiary-butyl amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. To 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid ((5.62 g, 13.96 mmol) , tertiary-butyl 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.02 g, 14.66 mmol) and triethylamine (3.30 g, 4.44 mL, 27.85 mmol) to a mixture in N,N-dimethylformamide (37 mL) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium cation 3-oxide hexafluorophosphate (7.93 g, 20.91 mmol).The reaction was stirred for 18 hours, then poured into water (590 mL) and ethyl acetate (150 mL). The mixture was shaken, then filtered. The solid was washed with isopropanol (50 mL) and hexane (50 mL), then dried under high vacuum to give 4-[4-({4-[4-(tertiary butoxy Carbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine - Tertiary-butyl 1-carboxylate (5.10 g, 56%) as an off-white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl) -Synthesis of phenyl]-amide. To 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl} -Amino)-phenyl]-3,6 _- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.10 g, 7.74 mmol) in _CH2Cl2 (39 mL) was added trifluoro Acetic acid (20 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (70 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (50 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amide[4-(1 ,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (7.25 g, >100%) as a pale yellow solid which was used without further purification .

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane Synthesis of -1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamic acid tertiary butyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl )-phenyl]-amide 2 trifluoroacetic acid (7.25 g, 10.56 mmol) in N,N-dimethylformamide (53 mL) was added triethylamine (7.27 g, 9.97 mL, 70.93 mmol). The reaction was stirred for 15 minutes, then treated with N,N'-bis-Boc-1-carboxamidinopyrazole (10.19 g, 32.71 mmol). The reaction was stirred for 15 minutes then 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 silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}) Tert-butyl methylene]carbamate (4.15 g, 42%) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 4-guanidinomethyl-phenyl)-amide. To N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-({[(1E)-{[(tertiary butoxy base)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]aminoformyl}bicyclo[2.2.2]octane Alk-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene _] carbamate (4.15 g, 4.40 mmol) in CH To the mixture in _Cl2 (22 mL) was added trifluoroacetic acid (22 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (50 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with ether (30 mL) and isopropanol (30 mL). The solid was treated with ethanol (100 mL), then the mixture was heated to boiling and filtered hot. The solid was washed with ethanol (20 mL) and dried under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3, 6-Tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (2.40 g, 71%) as a white solid. The ethanol filtrate was concentrated to about 50 mL, then heated to boiling, and filtered hot. The solid was washed with hexane (20 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine- 4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (246 mg, 7%) as a white solid. The filtrate was left to stand at 20°C for 16 hours and then filtered to obtain bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-formamido-1,2,3,6- Tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (118 mg, 3%) as a white solid. MS: 543 M+H+; ¹ H 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, J =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).

Example 68: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of di-HCl dihydrate salt of amide (4-guanidinomethyl-phenyl)-amide hydrochloride

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of the di-HCl dihydrate salt of 4-guanidinomethyl-phenyl)-amide hydrochloride: A methanolic solution of HCl was prepared by adding concentrated HCl (3 mL) dropwise to methanol (27 mL). To heated bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Amide (4-guanidinomethyl-phenyl)-amide 2 To a mixture of trifluoroacetic acid (2.10 g, 2.73 mmol) in methanol (40 mL) was added HCl in methanol (10 mL). The mixture was allowed to stand at 20°C for 30 minutes, then concentrated. The residue was treated with methanol (40 mL), heated, and to it was added HCl in methanol (10 mL). The mixture was allowed to stand at 20°C for 30 minutes, then concentrated. The residue was treated with methanol (40 mL), heated, and to it was added HCl in methanol (10 mL). The mixture was allowed to stand at 20°C for 30 minutes, then concentrated. The residue was lyophilized to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)- Phenyl]-amide (4-guanidinomethyl-phenyl)-amide 2 hydrochloride 2 H ₂ O (1.60 g, 99%) as a white solid. MS: 543 M+H+; ¹ 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). Micro analysis: C: expected value is 55.30%, measured value is 55.88%; H: expected value is 6.81%, measured value is 6.34%; N: expected value is 17.20%; measured value is 17.19%.

Example 69: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of Amide[4-(2-guanidino-ethyl)-phenyl]-amide

Synthesis of 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylate monomethyl ester (1.00 g, 4.71 mmol), 4-bromoaniline (894 mg, 5.18 mmol) and triethylamine (894 mg, 1208 μL, 7.54 mmol) to a mixture in N,N-dimethylformamide (14 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium cation 3-oxide hexafluorophosphate (2679 mg, 7.07 mmol). The reaction was stirred for 3 days, then 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), 1 N HCl (30 mL), and saturated aqueous NaHCO ₃ (30 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-40% ethyl acetate: hexane) to give 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1- Methyl formate (1.51 g) as a white solid.

Synthesis of 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylic acid. 4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylate (1.51 g, 4.12 mmol) in 1,4-bis(19 mL ) was added 10 N aqueous NaOH (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 adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (15 mL), 1 N HCl (15 mL), and water (15 mL), then dried under high vacuum to give 4-(4-bromo-phenylaminoformyl)-bicyclo[ 2.2.2] Octane-1-carboxylic acid (1.26 g) as a white solid.

[2-(4-{[4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-phenyl)-ethyl] -Synthesis of tertiary butyl carbamate. 4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carboxylic acid (630 mg, 1.79 mmol), [2-(4-amino-phenyl) To a mixture of tert-butyl-ethyl]-carbamate (468 mg, 1.98 mmol) and triethylamine (421 mg, 571 μL, 3.55 mmol) in dimethylformamide (5.3 mL) was added 1 -[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1013 mg, 2.69 mmol) . The reaction was stirred for 16 hours, then 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 silica gel column (20%-60% ethyl acetate: hexane) to give [2-(4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2 .2] Octane-1-carbonyl]-amino}-phenyl)-ethyl]-carbamic acid tert-butyl ester (696 mg) as a white solid.

4-[4-({4-[4-(2-tertiary butoxycarbonylamino-ethyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl Synthesis of }-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester. By bubbling nitrogen through [2-(4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}- phenyl)-ethyl]-carbamic acid tert-butyl ester (694 mg, 1.22 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxolane Boran-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic 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-Di㗁𠮿 (9.3 mL) and 2M K ₂ CO ₃ (2.9 mL) The mixture was degassed for 10 min. 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({4-[4-(2-tertiary butoxycarbonylamino-ethyl)- Phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester (480 mg) as a pale yellow solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-amino-ethyl)-phenyl]-amido[4-(1,2,3,6-tetrahydropyridine Synthesis of -4-yl)-phenyl]-amide. To 4-[4-({4-[4-(2-tertiary butoxycarbonylamino-ethyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1- Carbonyl}-amino)-phenyl]-3,6-dihydro-2H _- pyridine-1-carboxylic acid tert-butyl ester (480 mg, 0.71 mmol) in _CH2Cl2 (3.7 mL) was added Trifluoroacetic acid (1.9 mL). The reaction was stirred for 3 hours then concentrated. The residue was treated with ether (25 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]-amide [4-(1,2,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (512 mg) as a yellow solid which was used without further purification .

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-(2-{[(1E)-{[(tertiary butyl Oxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]aminoformyl}bicyclo[2.2.2] Synthesis of tertiary butyl octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate. Bicyclo[2.2.2]octane-1,4-dicarboxylate [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-carboxamidinopyrazole (708 mg, 2.27 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was then cooled, diluted 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[4-(2-{[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl] Amino}ethyl)phenyl]aminoformyl}bicyclo[2.2.2]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl }) Tertiary-butyl methylene]carbamate (427 mg) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide[ Synthesis of 4-(2-guanidino-ethyl)-phenyl]-amide. To N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[4-(2-{[(1E)-{[(tertiary Butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]aminoformyl}bicyclo[2.2.2 ]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (427 mg, 0.45 mmol) in To the mixture _{in CH2Cl2} (4.5 mL) was added trifluoroacetic acid (4.5 mL). The reaction was stirred for 3 days, then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- yl)-phenyl]-amide[4-(2-guanidino-ethyl)-phenyl]-amide bis-trifluoroacetate salt (117 mg) as a white solid. MS: 557 M+H+; ¹ H NMR (300MHz, dmso) δ = 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).

Example 70: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of amide (4-guanidino-phenyl)-amide.

Bicyclo[2.2.2]octane-1,4-dicarboxylate[4-(1-(4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2] Octane-1-carbonyl]-amino}-phenyl)-carbamic acid tertiary butyl ester synthesis. To 4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2] Octane-1-carboxylic acid (630 mg, 1.79 mmol), tert-butyl (4-amino-phenyl)-carbamate (412 mg, 1.98 mmol) and triethylamine (421 mg, 571 μL, 3.55 mmol) to a mixture in N,N-dimethylformamide (5.3 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1013 mg, 2.69 mmol). The reaction was stirred for 16 hours, then diluted with water (75 mL) and ethyl acetate (50 mL). The mixture was shaken, It was then filtered. The solid was washed with isopropanol (20 mL) and hexane (20 mL) to give (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2] Octane-1-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (450 mg) as a white solid.

4-(4-{[4-(4-tertiary butoxycarbonylamino-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-benzene Base)-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester synthesis. By bubbling nitrogen through (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-phenyl) - Tert-butyl carbamate (450 mg, 0.83 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (303 mg, 0.98 mmol), Pd(OAc) ₂ (10 mg, 0.042 mmol) and 2-dicyclohexylphosphino-2' , a mixture of 6'-dimethoxybiphenyl (36 mg, 0.095 mmol) in 1,4-dimethoxybiphenyl (6.3 mL) and 2M K ₂ CO ₃ (2 mL) The mixture was degassed for 10 min. 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). Shake the mixture, then filter. The solid was washed with isopropanol (15 mL) and hexane (15 mL) to give 4-(4-{[4-(4-tertiary butoxycarbonylamino-phenylaminoformyl)-di Cyclo[2.2.2]octane-1-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (413 mg) as gray solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-amino-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl)-benzene Synthesis of base]-amide. To 4-(4-{[4-(4-tertiary butoxycarbonylamino-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}- To a mixture of phenyl)-3,6-dihydro-2H-pyridine-1- _carboxylic acid tert-butyl ester (411 mg, 0.64 mmol) in _CH2Cl2 (3.3 mL) was added trifluoroacetic acid (1.7 mL) . The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (25 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (15 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-amino-phenyl)-amide[4-(1,2 ,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (476 mg) as a gray solid which was used without further purification.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}[4-(4-{4-[(4-{[(1Z)-{[(tertiary butoxy)carbonyl ]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}phenyl)aminoformyl]bicyclo[2.2.2]octane-1-amide Synthesis of tertiary butyl)-1,2,3,6-tetrahydropyridin-1-yl]methylene]carbamate. To bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-amino-phenyl)-amido[4-(1,2,3,6-tetrahydropyridin-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 before adding N,N'-Bis-Boc-carboxamidinopyrazole (686 mg, 2.20 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (75 mL), then 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), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}[4-(4-{ 4-[(4-{[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}benzene base)aminoformyl]bicyclo[2.2.2]octane-1-amido}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylene]amino Tert-butyl formate (241 mg) as an off-white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 4-guanidino-phenyl)-amide. To N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}[4-(4-{4-[(4-{[(1Z)-{[(tertiary butoxy) Carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}phenyl)aminoformyl]bicyclo[2.2.2]octane-1-yl Amino}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylene]carbamate ( ₂₄₁ mg, 0.26 mmol) in _CH2Cl2 (2.6 mL) To the mixture was added trifluoroacetic acid (2.6 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- (4-guanidino-phenyl)-amide (4-guanidino-phenyl)-amide bis-trifluoroacetate salt (113 mg) as a white solid. MS: 529 M+H+; ¹ H NMR (300MHz, dmso) 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).

Example 71: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-guanidino-ethyl)-phenyl]-amide(4-guanidinomethyl-phenyl)- Synthesis of amides.

Synthesis of methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate. Add monomethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (2.00 g, 9.40 mmol) in _CHCl (50 mL) and N,N-dimethylformamide (20 drops) Oxalyl chloride (1918 mg, 1289 μL, 15.05 mmol) was added to the mixture. The reaction was stirred for 4 hours then concentrated to afford methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate which was used without further purification.

Synthesis of 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester. To (4-amino-benzyl)-carbamate tert-butyl ester (1.81 g, 8.15 mmol) and N,N-diisopropylethylamine (1644 mg, 2214 μL, 12.80 mmol) in CHCl ₃ ( 2 mL) was added dropwise a mixture of methyl 4-chlorocarbonyl-bicyclo[2.2.2]octane-1-carboxylate in CHCl ₃ (22 mL). The reaction was stirred for 3 days, then concentrated. The residue was treated with ethyl acetate (50 mL) and water (75 mL). Shake the mixture, then filter. The solid was washed with isopropanol (30 mL) and hexane (30 mL) to give 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl]-bicyclo[ 2.2.2] Octane-1-carboxylic acid methyl ester (1.91 g) as a white solid.

Synthesis of 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid. To 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (1.90 g, 4.56 mmol ) to the mixture in 1,4-di㗁𠮿 (21 mL) was added 10 N aqueous NaOH (4.6 mL). The reaction was heated at 90° C. for 18 hours, then cooled and concentrated. The residue was treated with water (50 mL), then adjusted to pH 1 with 1 N HCl. The mixture was filtered and the solid was washed with water (25 mL) and dried under high vacuum to give 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylcarbamoyl]-di Cyclo[2.2.2]octane-1-carboxylic acid (1.72 g) as a white solid.

{2-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl} -Amino)-phenyl]-ethyl}-carbamic acid tertiary butyl ester synthesis. To 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid (430 mg, 1.07 mmol), [2-(4-Amino-phenyl)-ethyl]-carbamate tert-butyl ester (270 mg, 1.14 mmol) and triethylamine (243 mg, 329 μL, 2.06 mmol) in N,N- To a mixture in dimethylformamide (3 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine Cationic 3-oxide hexafluorophosphate (585 mg, 1.55 mmol). The reaction was stirred for 16 hours, then 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 silica gel column (0%-100% ethyl acetate: hexane) to give {2-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-benzene tertiary butylcarbamoyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-ethyl}-carbamate (495 mg), pale yellow solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-amino-ethyl)-phenyl]-amide (4-aminomethyl-phenyl)-amide synthesis. To {2-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl }-Amino)-phenyl _] -ethyl}-carbamic acid tert-butyl ester (490 mg, 0.79 mmol) in _CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-amino-ethyl) -Phenyl]-amide (4-aminomethyl-phenyl)-amide bis-trifluoroacetate salt (377 mg) as a beige solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]aminoformyl}bicyclo[2.2.2]octane -Synthesis of tertiary butyl 1-amido)phenyl]methyl}amino)methylene]carbamate. Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-amino-ethyl)-phenyl]-amide (4-aminomethyl-phenyl)-amide 2 To a mixture of 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-carboxamidinopyrazole (550 mg, 1.77 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was cooled and diluted with water (75 mL), then 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[4-(4 -{[4-(2-{[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }ethyl)phenyl]carbamoyl}bicyclo[2.2.2]octane-1-amido)phenyl]methyl}amino)methylene]carbamate tertiary butyl ester ( 247 mg), as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-guanidino-ethyl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide synthesis. To N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(1E)-{[(tertiary butoxy base)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]aminoformyl}bicyclo[2.2.2]octane To a mixture of tert-butyl alk-1-amido)phenyl]methyl}amino)methylene]carbamate (247 mg, 0.27 mmol) in CH ₂ Cl ₂ (2.7 mL) was added three Fluoroacetic acid (2.7 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-guanidino-ethyl)-phenyl]-amide (4-guanidino Methyl-phenyl)-amide bis-trifluoroacetate (81 mg) as a white solid. MS: 505 M+H+; ¹ H NMR (300MHz, dmso) δ = 9.22 (s, 1H), 9.14 (s, 1H), 7.91 (t, J =6.2 Hz, 1H), 7.59 (dd, J =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, J =7.0 Hz, 2H), 1.83 (s, 12H).

Example 72: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-guanidino-ethoxy)-phenyl]-amide (4-guanidinomethyl-phenyl) - Synthesis of amides.

{2-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl} -Amino)-phenoxy]-ethyl}-carbamic acid tertiary butyl ester synthesis. To 4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid (430 mg, 1.03 mmol), [2-(4-Amino-phenoxy)-ethyl]-carbamate tert-butyl ester (288 mg, 1.14 mmol) and triethylamine (243 mg, 329 μL, 2.06 mmol) in dimethyl To the mixture in formamide (3 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3- oxide hexafluorophosphate (585 mg, 1.55 mmol). The reaction was stirred for 16 hours, then 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 (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give {2-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-benzene tertiary butylcarbamoyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenoxy]-ethyl}-carbamate (505 mg) as shallow Purple solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-amino-ethoxy)-phenyl]-amide (4-aminomethyl-phenyl)-amide The synthesis. To {2-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl }-amino)-phenoxy]-ethyl}-carbamate tert-butyl ester ( ₅₀₀ mg, 0.77 mmol) in _CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL) . The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered and the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-amino-ethoxy )-Phenyl]-amide (4-aminomethyl-phenyl)-amide bis-trifluoroacetate salt (480 mg) as a gray solid.

N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(1Z)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethoxy)phenyl]aminoformyl}bicyclo[2.2.2]octane Synthesis of tertiary butyl alk-1-amido)phenyl]methyl}amino)methylene]carbamate. Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-amino-ethoxy)-phenyl]-amide (4-aminomethyl-phenyl)-amide Amine 2 To a mixture of 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-carboxamidinopyrazole (690 mg, 2.22 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (75 mL), then 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[4-(4 -{[4-(2-{[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }ethoxy)phenyl]carbamoyl}bicyclo[2.2.2]octane-1-amido)phenyl]methyl}amino)methylene]carbamate tertiary butyl (254 mg), as a beige solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(2-guanidino-ethoxy)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide The synthesis. To N-[(1Z)-{[(tertiary butoxy)carbonyl]amino}({[4-(4-{[4-(2-{[(1Z)-{[(tertiary butoxy yl)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}ethoxy)phenyl]aminoformyl}bicyclo[2.2.2] To a mixture of tert-butyl octane-1-amido)phenyl]methyl}amino)methylene]carbamate (254 mg, 0.28 mmol) in _CH2Cl2 ( _2.8 mL) was added Trifluoroacetic acid (2.8 mL). The reaction was stirred for 16 hours then concentrated. The crude material was purified by preparative HPLC to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-guanidino-ethoxy)-phenyl]-amide (4-guanidine Bis-trifluoroacetate salt of (methyl-phenyl)-amide (30 mg) as a white solid. MS: 521 M+H+; ¹ 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).

Example 73: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of amide (3-fluoro-4-guanidinomethyl-phenyl)-amide.

Synthesis of tertiary butyl N-[(tertiary 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 1-bromomethyl-2-fluoro-4-nitro-benzene (983 mg, 4.20 mmol) in N,N-dimethylformamide (2 mL) was added dropwise mixture. The reaction was stirred for 16 hours, then treated with water (120 mL) and 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 silica gel column (0%-30% ethyl acetate: hexane) to give N-[(tertiary butoxy)carbonyl]-N-[(2-fluoro-4-nitrophenyl) Tert-butyl methyl]carbamate (1.32 g) as a pale yellow solid.

Synthesis of tertiary butyl N-[(4-amino-2-fluorophenyl)methyl]-N-[(tertiary butoxy)carbonyl]carbamate. Tert-butyl N-[(tertiary-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 an atmosphere of hydrogen and stirred for 16 hours. The reaction was filtered through celite. The Celite was washed with methanol (3 × 10 mL), and the combined filtrates were concentrated to give N-[(4-amino-2-fluorophenyl)methyl]-N-[(tertiary butoxy) Tertiary-butyl carbonyl]carbamate (1.12 g) as a white solid.

4-{[4-({bis[(tertiary butoxy)carbonyl]amino}methyl)-3-fluorophenyl]aminoformyl}bicyclo[2.2.2]octane-1- Synthesis of methyl formate. Bicyclo[2.2.2]octane-1,4-dicarboxylate monomethyl ester (628 mg, 2.95 mmol), N-[(4-amino-2-fluorophenyl)methyl]-N-[ (Tertiary butoxy)carbonyl]carbamate (tertiary butyl) (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 cation 3-oxide hexafluorophosphoric acid Salt (1672 mg, 4.42 mmol). The reaction was stirred for 3 days, then 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 silica gel column (0%-50% ethyl acetate: hexanes) to afford xx (1.31 g) as an orange solid.

Synthesis of 4-[4-(tertiary butoxycarbonylamino-methyl)-3-fluoro-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid. To a mixture of xx (1.31 g, 2.45 mmol) in 1,4-di㗁𠮿 (11.6 mL) was added 10 N aqueous NaOH (2.5 mL). The reaction was heated at 90° C. for 16 hours, then concentrated. The residue was treated with water (100 mL), then adjusted to pH 1 with 1 N HCl. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with water (2 x 10 mL) and dried under high vacuum to give 4-[4-(tertiary butoxycarbonylamino-methyl)-3-fluoro-phenylaminoformyl] - Bicyclo[2.2.2]octane-1-carboxylic acid (903 mg) as a pale yellow solid.

(4-{[4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-2-fluoro-benzyl)-amino Synthesis of tertiary butyl formate. To 4-[4-(tertiary butoxycarbonylamino-methyl)-3-fluoro-phenylaminoformyl]-bicyclo[2.2.2]octane-1-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) were added 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1210 mg, 3.19 mmol). The reaction was stirred for 16 hours, then 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), saturated aqueous NaHCO ₃ (30 mL), and treated with brine (20 mL). The mixture was shaken, then filtered through celite. The filtrate layers were separated, and the organic layer was dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-90% ethyl acetate: hexane) to give (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2] Octane-1-carbonyl]-amino}-2-fluoro-benzyl)-carbamic acid tert-butyl ester (645 mg) as a pale orange solid.

4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-3-fluoro-phenylaminoformyl]-bicyclo[2.2.2]octane-1 Synthesis of -carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl ester. By bubbling nitrogen through (4-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-2-fluoro -Benzyl)-tert-butylcarbamate (645 mg, 1.12 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (409 mg, 1.31 mmol), Pd(OAc) ₂ (13 mg, 0.055 mmol) and 2-dicyclohexylphosphine A mixture of 2',6'-dimethoxybiphenyl (48 mg, 0.13 mmol) in 1,4-dimethoxybiphenyl (8.1 mL) and 2M K ₂ CO ₃ (2.8 mL) was allowed to react for 10 minutes The mixture was degassed. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (40 mL), then washed with water (20 mL), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-75% ethyl acetate: hexane) to give 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-3- Fluoro-phenylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (491 mg), as a pale yellow solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-3-fluoro-phenyl)-amido[4-(1,2,3,6-tetrahydropyridine- Synthesis of 4-yl)-phenyl]-amide. To 4-[4-({4-[4-(tertiary butoxycarbonylamino-methyl)-3-fluoro-phenylaminoformyl]-bicyclo[2.2.2]octane- 1-Carbonyl}-amino)-phenyl]-3,6-dihydro-2H _- pyridine-1-carboxylic acid tert-butyl ester (488 mg, 0.72 mmol) in _CH2Cl2 (3.6 mL) Trifluoroacetic acid (1.8 mL) was added. The reaction was stirred for 4 hours then concentrated. The residue was treated with ether (30 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with diethyl ether (10 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-3-fluoro-phenyl)-amide [ 4-(1,2,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide bis-trifluoroacetate salt (496 mg) as a pale yellow solid.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(4-{4-[(4-{1-[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)aminoformyl Synthesis of tertiary butyl]bicyclo[2.2.2]octane-1-amido}-2-fluorophenyl)methyl]amino})methylene]carbamate. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (4-aminomethyl-3-fluoro-phenyl)-amido[4-(1,2,3,6-tetrahydropyridine -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 before adding N,N'-Bis-Boc-carboxamidinopyrazole (686 mg, 2.21 mmol). The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (55 mL) and 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), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(4-{ 4-[(4-{1-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]-1 ,2,3,6-Tetrahydropyridin-4-yl}phenyl)aminoformyl]bicyclo[2.2.2]octane-1-amino}-2-fluorophenyl)methyl]amine tert-butyl)methylene]carbamate (372 mg) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 3-fluoro-4-guanidinomethyl-phenyl)-amide. To N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(4-{4-[(4-{1-[(1E)-{[(tertiary butoxy base)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)aminomethyl Acyl]bicyclo[2.2.2]octane-1-amino}-2-fluorophenyl)methyl]amino})methylene]carbamate (372 mg, 0.39 mmol) To the mixture _{in CH2Cl2} (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with N,N-dimethylformamide (2 mL), then 0.1% trifluoroacetic acid in water (2 mL) was added dropwise. The mixture was sonicated for 5 minutes, then filtered. The solid was washed with isopropanol (3 × 2 mL) and hexane (5 mL) to give bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carboxamidino-1,2 ,3,6-Tetrahydropyridin-4-yl)-phenyl]-amide (3-fluoro-4-guanidinomethyl-phenyl)-amide bis-trifluoroacetate salt (167 mg), It is a white solid. MS: 561 M+H+; ¹ H 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).

Example 74: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of amide (6-guanidinomethyl-pyridin-3-yl)-amide.

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) was added benzoyl peroxide (1.85 g, 7.66 mmol) and N-bromo Succinimide (7.49 g, 42.05 mmol). The reaction was heated at 80° C. for 18 hours, then concentrated. The crude material was purified by silica gel column (0%-20% ethyl acetate: hexanes) to give 2-bromomethyl-5-nitro-pyridine (2.39 g) as a dark liquid.

Synthesis of tertiary butyl N-[(tertiary 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 treated with water (300 mL) and 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 brine (30 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-40% ethyl acetate: hexane) to give N-[(tertiary butoxy)carbonyl]-N-[(5-nitropyridin-2-yl)methanol tert-butyl carbamate (2.79 g, 72%) as a white solid.

Synthesis of tertiary butyl N-[(5-aminopyridin-2-yl)methyl]-N-[(tertiary butoxy)carbonyl]carbamate. Tert-butyl N-[(tertiary butoxy)carbonyl]-N-[(5-nitropyridin-2-yl)methyl]carbamate (2.79 g, 7.90 mmol) and 5% Pd/ A mixture of C (700 mg) in methanol (42 mL) was placed under an atmosphere of hydrogen. The reaction was stirred for 16 hours, then filtered through celite. Wash the Celite with methanol (3 × 15 mL), and concentrate the combined filtrates. The residue was treated with methanol (42 mL) and 5% Pd/C (700 mg). The mixture was placed under an atmosphere of hydrogen and stirred for 16 hours, then filtered through celite. The Celite was washed with methanol (3 × 15 mL), and the filtrates were combined and concentrated to give N-[(5-aminopyridin-2-yl)methyl]-N-[(tertiary butoxy)carbonyl ] Tertiary butyl carbamate (2.47 g) as a white solid.

4-{[6-({bis[(tertiary butoxy)carbonyl]amino}methyl)pyridin-3-yl]aminoformyl}bicyclo[2.2.2]octane-1-carboxylic acid Synthesis of methyl esters. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid monomethyl ester (1.47 g, 6.89 mmol), N-[(5-aminopyridin-2-yl)methyl]-N-[( Tert-butyloxy)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 ) to the mixture in which 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate was added (3.90 g, 10.32 mmol). The reaction was stirred for 16 hours, then treated with water (300 mL) and 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 ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give 4-{[6-({bis[(tertiary butoxy)carbonyl]amino}methyl)pyridine-3 -yl]aminoformyl}bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (1.81 g) as a pale yellow solid.

Synthesis of 4-[6-(tertiary butoxycarbonylamino-methyl)-pyridin-3-ylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid. To a mixture of xx (1.181 g, 3.50 mmol) in 1,4-di㗁𠮿 (16.6 mL) was added 10 N aqueous NaOH (3.5 mL). The reaction was heated at 90° C. for 18 hours, then concentrated. The residue was treated with water (50 mL), then adjusted to pH 7 with 1 N HCl and saturated aqueous NaHCO ₃ . The mixture was filtered and the solid was washed with water (30 mL) and dried under high vacuum to give 4-[6-(tertiary butoxycarbonylamino-methyl)-pyridin-3-ylaminoformyl ]-bicyclo[2.2.2]octane-1-carboxylic acid (1.22 g) as a white solid.

(5-{[4-(4-Bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-pyridin-2-ylmethyl)-amine Synthesis of tertiary butyl formate. To 4-[6-(tertiary butoxycarbonylamino-methyl)-pyridin-3-ylaminoformyl]-bicyclo[2.2.2]octane-1-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) Add 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (1702 mg, 4.49 mmol). The reaction was stirred for 3 days, then treated with water (150 mL) and 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 silica gel column (0%-10% methanol: CH ₂ Cl ₂ ) to give (5-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2] Octane-1-carbonyl]-amino}-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (1.26 g) as a beige solid.

4-[4-({4-[6-(tertiary butoxycarbonylamino-methyl)-pyridin-3-ylaminoformyl]-bicyclo[2.2.2]octane-1- Synthesis of tertiary butyl carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through (5-{[4-(4-bromo-phenylaminoformyl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-pyridine-2 -Methyl)-tert-butyl carbamate (1.25 g, 2.24 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane -2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (819 mg, 2.62 mmol), Pd(OAc) ₂ (26 mg, 0.11 mmol) and 2-dicyclohexyl A mixture of phosphino-2',6'-dimethoxybiphenyl (96 mg, 0.26 mmol) in 1,4-dimethoxybiphenyl (16.2 mL) and 2M K ₂ CO ₃ (5.6 mL) was incubated for 10 minutes The mixture was degassed. The reaction was heated at 95°C for 16 hours. The reaction was treated with ethyl acetate (50 mL), then washed with water (20 mL), brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-10% methanol: CH ₂ Cl ₂ ) to give 4-[4-({4-[6-(tertiary butoxycarbonylamino-methyl)-pyridine- 3-ylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl Ester (1.32 g) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (6-aminomethyl-pyridin-3-yl)-amido[4-(1,2,3,6-tetrahydropyridine-4 -Synthesis of -yl)-phenyl]-amide. To 4-[4-({4-[6-(tertiary butoxycarbonylamino-methyl)-pyridin-3-ylaminoformyl]-bicyclo[2.2.2]octane-1 -Carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.31 g, 1.99 mmol) in _{CH2Cl2 (} 9.9 mL) Add trifluoroacetic acid (5 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (40 mL), then sonicated for 5 min. The mixture was filtered, and the solid was washed with diethyl ether (20 mL) and dried under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (6-aminomethyl-pyridine-3- yl)-amido[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amido tris-trifluoroacetate (1.74 g) as a light yellow solid, which Used without further purification.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[6-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)pyridin-3-yl]aminoformyl}bicyclo[2.2.2 Synthesis of ]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester. To bicyclo[2.2.2]octane-1,4-dicarboxylic acid (6-aminomethyl-pyridin-3-yl)-amido[4-(1,2,3,6-tetrahydropyridine- 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-carboxamidinopyrazole (490 mg, 1.58 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (38 mL) and 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 silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[6-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)pyridin-3-yl]aminoformyl}bicyclo[2.2.2]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridine-1- tert-butyl)methylene]carbamate (235 mg) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 6-guanidinomethyl-pyridin-3-yl)-amide. To N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[6-({[(1E)-{[(tertiary butoxy base)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)pyridin-3-yl]aminoformyl}bicyclo[2.2. 2] Octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (235 mg, 0.25 mmol) To the mixture _{in CH2Cl2} (2.5 mL) was added trifluoroacetic acid (2.5 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- yl)-phenyl]-amide(6-guanidinomethyl-pyridin-3-yl)-amide tris-trifluoroacetate salt (147 mg) as a white solid. MS: 544 M+H+; ¹ H NMR (300MHz, dmso) δ = 9.50 (s, 1H), 9.26 (s, 1H), 8.80 (d, J =2.3 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 =5.3 Hz, 3H), 2.55 (br. s., 2H), 1.85 (s, 12H).

Example 75: Bicyclo[2.2.2]octane-1,4-dicarboxylate [4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- Synthesis of amide (5-guanidinomethyl-pyridin-2-yl)-amide.

Synthesis of 5-bromomethyl-2-nitro-pyridine. 5-Methyl-2-nitro-pyridine (1.31 g, 9.48 mmol), 2,2'-azobis(2-methylpropionitrile) (194 mg, 1.05 mmol) and N-bromo-succinyl A mixture of the imine (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 silica gel column (0%-50% ethyl acetate: hexane) to give 5-bromomethyl-2-nitro-pyridine: 5-methyl-2-nitro- A 3:2 mixture of pyridines (1.31 g, 45%) as a white solid was used without further purification.

Synthesis of tertiary butyl N-[(tertiary 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) was added a 60% dispersion of sodium hydride in mineral oil (255 mg, 6.37 mmol). The reaction was stirred for 15 minutes, then 5-bromomethyl-2-nitro-pyridine was added dropwise: 5-methyl-2-nitro-pyridine in N,N-dimethylformamide (2 mL) 3:2 mixture (920 mg, 4.24 mmol). The reaction was stirred for 16 hours, then diluted with water (120 mL) and 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 silica gel column (0%-50% ethyl acetate: hexane) to give N-[(tertiary butoxy)carbonyl]-N-[(6-nitropyridin-3-yl)methanol tert-butyl]carbamate (1.06 g) as a white solid.

Synthesis of tertiary butyl N-[(6-aminopyridin-3-yl)methyl]-N-[(tertiary butoxy)carbonyl]carbamate. N-[(tertiary butoxy)carbonyl]-N-[(6-nitropyridin-3-yl)methyl]carbamic acid tertiary butyl ester (1.06 g, 3.00 mmol) and 5% Pd/ A mixture of C (265 mg) in methanol (16 mL) was placed under an atmosphere of hydrogen and stirred for 16 hours, then filtered through celite. The filtrate was concentrated to about 15 mL, then treated with 5% Pd/C (265 mg) and placed under an atmosphere of hydrogen. The reaction was stirred for 16 hours, then 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]carbamate (912 mg) as Dark gum.

4-{[5-({bis[(tertiary butoxy)carbonyl]amino}methyl)pyridin-2-yl]aminoformyl}bicyclo[2.2.2]octane-1-carboxylic acid Synthesis of methyl esters. Bicyclo[2.2.2]octane-1,4-dicarboxylate monomethyl ester (660 mg, 3.10 mmol), N-[(6-aminopyridin-3-yl)methyl]-N-[( Tert-butyloxy)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 h, then 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 ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-70% ethyl acetate: hexane) to give 4-{[5-({bis[(tertiary butoxy)carbonyl]amino}methyl)pyridine-2 -yl]carbamoyl}bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (528 mg) as a white solid.

Synthesis of 4-[5-(tertiary butoxycarbonylamino-methyl)-pyridin-2-ylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid. To a mixture of xx (528 mg, 1.02 mmol) in 1,4-di㗁𠮿 (4.8 mL) was added 10 N aqueous NaOH (1 mL). The reaction was heated at 90° C. for 18 hours, then concentrated. The residue was treated with water (40 mL), then adjusted to pH 1 with 6 N HCl. The mixture was filtered, and the solid was washed with water (2 × 10 mL), then dried under high vacuum to give 4-[5-(tertiary butoxycarbonylamino-methyl)-pyridin-2-ylaminomethanol Acyl]-bicyclo[2.2.2]octane-1-carboxylic acid (270 mg) as a white solid.

Synthesis of tertiary-butyl 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate. By bubbling nitrogen through 4-bromo-aniline (172 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (340 mg, 1.10 mmol) and Cl ₂ Pd(dppf).CH ₂ Cl ₂ (8 mg, 0.010 mmol) in A mixture of 1,4-dimethoxane (5 mL) and 2M K ₂ CO ₃ (1.5 mL) The mixture was degassed for 10 min. The reaction was heated at 95 °C for 18 h, then treated with ethyl acetate (40 mL) and water (20 mL). The mixture was filtered through celite, and the filtrate was separated. The organic layer was washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-50% ethyl acetate: hexane) to give 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary Butyl ester (189 mg), as a beige solid.

4-[4-({4-[5-(tertiary butoxycarbonylamino-methyl)-pyridin-2-ylaminoformyl]-bicyclo[2.2.2]octane-1- Synthesis of tertiary butyl carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate. To 4-[5-(tertiary butoxycarbonylamino-methyl)-pyridin-2-ylaminoformyl]-bicyclo[2.2.2]octane-1-carboxylic acid (270 mg, 0.67 mmol), tertiary-butyl 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (189 mg, 0.69 mmol) and triethylamine (158 mg, 212 μL , 1.33 mmol) to a mixture in N,N-dimethylformamide (2.2 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole Do[4,5-b]pyridinium cation 3-oxide hexafluorophosphate (378 mg, 1.00 mmol). The reaction was stirred for 3 days, then 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 silica gel column (0%-100% ethyl acetate: hexane) to give 4-[4-({4-[5-(tertiary butoxycarbonylamino-methyl)-pyridine- 2-ylaminoformyl]-bicyclo[2.2.2]octane-1-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tertiary butyl Ester (242 mg), as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (5-aminomethyl-pyridin-2-yl)-amido[4-(1,2,3,6-tetrahydropyridine-4 -Synthesis of -yl)-phenyl]-amide. To 4-[4-({4-[5-(tertiary butoxycarbonylamino-methyl)-pyridin-2-ylaminoformyl]-bicyclo[2.2.2]octane-1 -Carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (240 _, 0.36 mmol) in _CH2Cl2 (1.8 mL) was added Trifluoroacetic acid (0.9 mL). The reaction was stirred for 16 hours then concentrated. The residue was treated with ether (20 mL), then sonicated for 5 min. The liquid was decanted and the residue was placed under high vacuum to give bicyclo[2.2.2]octane-1,4-dicarboxylic acid (5-aminomethyl-pyridin-2-yl)-amide[4- Tris-trifluoroacetate salt of (1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (368 mg) as a sticky solid was used without further purification.

N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[5-({[(1E)-{[(tertiary butoxy )carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)pyridin-2-yl]aminoformyl}bicyclo[2.2.2 Synthesis of ]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate tertiary butyl ester. Bicyclo[2.2.2]octane-1,4-dicarboxylic acid (5-aminomethyl-pyridin-2-yl)-amido[4-(1,2,3,6-tetrahydropyridine- 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 minutes, then N,N'-bis-Boc-carboxamidinopyrazole (450 mg, 1.45 mmol) was added. The reaction was stirred for 15 minutes then heated at 35 °C for 16 hours. The mixture was treated with water (30 mL), then extracted with ethyl acetate (2 x 50 mL). Wash the combined organic extracts with water (3 × 20 mL). Wash the combined organic extracts with water (3 × 20 mL). The combined aqueous solutions were separated. The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel column (0%-100% ethyl acetate: hexane) to give N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4- (4-{[5-({[(1E)-{[(tertiary butoxy)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino }methyl)pyridin-2-yl]aminoformyl}bicyclo[2.2.2]octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridine-1- tert-butyl)methylene]carbamate (221 mg) as a white solid.

Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( Synthesis of 5-guanidinomethyl-pyridin-2-yl)-amide. To N-[(1E)-{[(tertiary butoxy)carbonyl]amino}({4-[4-(4-{[5-({[(1E)-{[(tertiary butoxy base)carbonyl]amino}({[(tertiary butoxy)carbonyl]imino})methyl]amino}methyl)pyridin-2-yl]aminoformyl}bicyclo[2.2. 2] Octane-1-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylene]carbamate (221 mg, 0.24 mmol) To the mixture _{in CH2Cl2} (2.4 mL) was added trifluoroacetic acid (2.4 mL). The reaction was stirred for 16 hours then concentrated. Purification of the crude material by preparative HPLC gave bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridine-4- yl)-phenyl]-amide(5-guanidinomethyl-pyridin-2-yl)-amide tris-trifluoroacetate salt (143 mg) as a white solid. MS: 544 M+H+; ¹ 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). preparation

The invention also relates to compositions or preparations comprising an antifungal agent according to the invention. In general, compositions of the present invention comprise an effective amount of one or more compounds and salts thereof according to the present disclosure, which are effective to provide treatment of fungal infections; and one or more excipients.

For the purposes of the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the specification of the present invention, and the terms are defined herein as "used in the practice of formulating a safe and effective pharmaceutical composition ingredients".

Formulators should understand that excipients are primarily used to deliver safe, stable and functional drugs, not only as part of an overall delivery vehicle, but also as a means to achieve efficient absorption of the active ingredient by the recipient. The excipient can function simply as an inert filler, or as used herein, an excipient can be part of a pH stabilizing system or coating to ensure safe delivery of the ingredients into the stomach. Formulators can also take advantage of the fact that compounds of the invention have improved cellular potency, pharmacokinetic properties, and improved oral bioavailability.

The present teachings also provide pharmaceutical compositions comprising 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 according to accepted pharmaceutical procedures, for example Remington's Pharmaceutical Sciences , 17th edition, ed. [Remington's Pharmaceutical Sciences, 17th Edition] Alfonoso R. Gennaro, Mack Those described in Publishing Company, Easton, PA [Mark Publishing Company of Easton, PA] (1985), the entire disclosure of which is incorporated herein by reference for all purposes. As used herein, "pharmaceutically acceptable" refers to a substance that is acceptable for pharmaceutical use from a toxicological point of view and that does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are compatible with the other ingredients of the formulation and are those that are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

Compounds of the present teachings can be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Suitable solid carriers may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents. or packaging material. The compounds may be formulated in conventional manner, for example in a manner analogous to that used for known antifungal agents. Oral formulations containing the compounds disclosed herein may comprise any conventionally used oral forms 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 a mixture with the finely divided compound. In tablets, a compound disclosed herein may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets can contain up to 99% of the compound.

Capsules may contain one or more compounds disclosed herein in admixture with inert fillers and/or diluents, such as pharmaceutically acceptable starches (e.g., corn starch, potato starch, or tapioca starch). ), sugar, artificial sweeteners, powdered cellulose (such as crystalline and microcrystalline cellulose), flour, gelatin, gums, etc.

Usable tablet formulations can be prepared by conventional compression, wet granulation or dry granulation methods, and use pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants) ), suspending or stabilizing agents, including but not limited to magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose Sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidine, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, sucrose, sorbic acid Sugar Alcohols, Dicalcium Phosphate, Calcium Sulfate, Lactose, Kaolin, Mannitol, Sodium Chloride, Low Melting Waxes and Ion Exchange Resins. Surface modifiers include nonionic surface modifiers and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, phthalate ammonium chloride, calcium stearate, cetearyl alcohol, pecitodol emulsifying wax, sorbitol esters, colloidal bismuth Silicon Oxide, Phosphate, Sodium Lauryl Sulfate, Magnesium Aluminum Silicate and Triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the compound. Oral formulations may also consist of administering the compounds disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and for delivery by inhalation. 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 oil or fat. 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 (especially with additives as described herein, such as cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols). Alcohols, such as diols) and their derivatives, and oils, such as fractionated coconut and peanut oils. 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 propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in liquid or solid form.

Preferably, the pharmaceutical composition is in unit dosage form, such as tablet, capsule, powder, solution, suspension, emulsion, granule or suppository. In such form, the pharmaceutical composition can be subdivided into unit doses containing appropriate quantities of the compound. The unit dosage form can be a packaged composition, for example, packeted powders, vials, ampoules, prefilled 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 packaged form. Such unit dosage forms may contain from about 1 mg/kg of compound to about 500 mg/kg of compound and may be administered in a single dose or in two or more doses. Such doses may be administered by any means used to introduce the compound into the recipient's bloodstream, including orally, via an implant, parenterally (including intravenous, intraperitoneal, and subcutaneous injections), rectally, vaginally, and transdermally.

When administered to treat or inhibit a particular disease state or disorder, it is to be understood that effective dosages may vary depending on the particular compound employed, the mode of administration and the severity of the disorder being treated, as well as various physical factors associated with the individual being treated . In therapeutic applications, compounds of the present teachings may 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 used to treat a particular individual must generally be determined subjectively 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.

In some cases, it may be desirable to use devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry powder inhalers, pumps, squeeze-actuated aerosol spray dispensers, aerosol dispensers, and aerosol nebulizers to Compounds are administered directly into the airways of the patient. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated as liquid, solid or spray compositions. Illustratively, liquid compositions may comprise one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents, and may be nebulized by means of, for example, a pump or squeeze actuated atomizer. Dispenser casts. The solvent can be, for example, isotonic saline or bacteriostatic water. For example, a solid composition may be a powder formulation comprising one or more compounds of the present teachings in admixture with lactose or other inert powder acceptable for endobronchial use, and may be administered, for example, by means of an aerosol dispenser or by breaking or prodding. A device that breaks a capsule of a solid composition and delivers the solid composition for inhalation administration. For example, an aerosol composition can include one or more compounds of the present teachings, a propellant, a surfactant, and a co-solvent, and can be administered by, for example, a metered device. The propellants may be chlorofluorocarbons (CFCs), hydrofluoroalkanes (HFAs), or other propellants that are physiologically and environmentally acceptable.

The compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds, or pharmaceutically acceptable salts, hydrates or esters thereof, can be prepared in water suitably mixed with a surfactant, such as hypromellose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations usually contain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection may include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In some embodiments, the form can be sterile and its viscosity allows it to flow through a syringe. The form is preferably stable under the conditions of manufacture and storage and protected 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 such as glycerol, propylene glycol, and liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils.

The compounds described herein can be administered transdermally, that is, through the surfaces of the body and the linings of bodily passages, including epithelial and mucosal tissues. Such administration may use 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) ) in the form of.

Transdermal administration can be accomplished through the use of a transdermal patch comprising a compound, such as a compound disclosed herein, and a carrier that is inert to the compound, nontoxic to the skin, and that allows for systemic application Absorbed compounds are delivered through the skin into the bloodstream. The carrier can take any form, such as creams and ointments, pastes, gels and occlusive devices. Creams and ointments may be viscous liquid or semisolid emulsions of the oil-in-water or water-in-oil type. Pastes consisting of absorbent powder dispersed in petroleum or hydrophilic petroleum containing the compound may also be suitable. A variety of occlusive devices can be used to release the compound into the bloodstream, such as a semipermeable 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.

The compounds described herein may be administered rectally or vaginally in the form of conventional suppositories. Suppository formulations may 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, may also be used.

Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

In order to increase the effectiveness of the compounds of the present teachings, it may be desirable to combine the compounds with other agents effective in treating the disease of interest. For example, other active compounds (ie, other active ingredients or agents) effective to treat the disease of interest may be administered with the compounds of the present teachings. Additional agents can be administered at the same time or at different times as the compounds disclosed herein.

Compounds of the present teachings are useful for treating or inhibiting a pathological condition or disorder in a mammal, such as a human subject. Accordingly, the teachings provide a compound (including a pharmaceutically acceptable salt thereof) or a pharmaceutical composition (comprising one or more compounds of the teachings, and a pharmaceutically acceptable salt) of the teachings to a mammal. carrier combination or combination) to treat or inhibit a pathological condition or disorder. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies to treat or inhibit a pathological condition or disorder.

Non-limiting examples of compositions according to the present invention comprise from about 0.001 mg to about 1000 mg of one or more compounds according to the present disclosure, and one or more excipients; from about 0.01 mg to about 100 mg of the compounds according to the present disclosure One or more compounds according to the present disclosure, and one or more excipients; and about 0.1 mg to about 10 mg of one or more compounds according to the present disclosure, and one or more excipients. program

The following procedure can be used to evaluate and select compounds as antifungal agents.

Fungal MIC Protocol: RPMI/MOPS Medium (Roswell Park Memorial Institute/3-Polinopropane-1-Sulfonic Acid Medium) was prepared by dissolving 8.4 grams of RPMI 1640 (Sigma Cat. No. R1383), Prepare by dissolving 34.52 g of MOPS buffer (Sigma cat# M3183) and 2 g of glucose in 900 mL of deionized water. The pH was adjusted to 7.0 with NaOH and filter sterilized. Inoculate 0.1 mL of stock spore suspension (or a loop from a frozen stock) to a solution containing 50 mL of potato dextrose agar (PDA), 24 g of PD broth (Fisher cat. no. DF 0549179), 20 g of agar (Fisher cat. no. BP 1423500) in a 75 mL tissue culture flask (Falcon cat# 353136). Koji and Fusarium strains were grown for 3-5 days at 35°C and Mucor mold strains at room temperature. Spores were harvested by filling the flask with 5 mL of phosphate buffered saline (PBS) pH 7.4 + 0.1% Tween-20, and several glass beads (Fisher cat# S800243) were added to aid agitation. Remove the supernatant and measure the _OD530 of a 1:100 dilution. Spores were diluted in RPMI/MOPS to a final _OD530 of 0.002 for Koji and _0.005 for Fusarium and Mucor. The final concentration of spores was about 2 x ¹⁰⁴ cfu/mL. Test compounds were diluted to 200 μg/mL in RPM I/MOPS (28 μl of a 10 mg/mL DMSO stock solution in 1400 μl medium). Ten (10) serial dilutions were prepared in RPMI/MOPS in 96-well round-bottom plates (Fisher Cat# 353136). For mucormyces strains, use sterile flat-bottomed 96-well plates. Add 50 μl of compound dilutions in duplicate to sterile 96-well round bottom plates. Add 50 μl of the diluted spores to the plate containing the compound. Control wells contained 1) compound but no cells and 2) spores but no compound. Mix the plate gently by hand, place in a ziplock bag and incubate at 35°C for 48 hours. MIC (lowest compound concentration showing >50% growth inhibition) was scored visually using an inverted mirror. For Mucormyces strains, plates were read at OD530 and the concentration of compound showing 50% growth inhibition was the MIC-50.

Candida Minimum Inhibitory Concentration (MIC): Prepare RPMI/MOPS medium by dissolving 8.4 g RPMI 1640, 34.52 g MOPS buffer, and 2 g glucose in 900 mL water. The pH was adjusted to 7.0 with NaOH. The total volume was brought to 1 L and the resulting solution was filter sterilized. Candida stocks were streaked on yeast extract protein dextrose (YPD) agar plates and grown at 35 °C to isolate single colonies. Compounds of the present disclosure were diluted to 200 μg/mL in RPMI/MOPS (4.8 μl of a 10 mg/mL DMSO stock solution in 240 μl medium). Ten (10) 1:2 serial dilutions were prepared in RPMI/MOPS in 96-well round bottom plates. Fifty (50) μl compound dilutions were transferred in duplicate to sterile tissue culture-treated 96-well flat-bottomed black-rimmed polypropylene plates. Resuspend single colonies of Candida from the YPD plate in 5 mL of phosphate buffered saline (BS) and measure the optical density (OD) at 600 nm. The suspension was adjusted to OD = 1.0 and a 1:1000 dilution was made in RPMI/MOPS. Add fifty (50) µl diluted yeast aliquots to the plate containing 50 µL of compound to all wells except 12E-H. Control wells included: 12 A-D cells, no compound; and 12 E-H no cells, no compound. Gently mix the plate by hand and place it in a ziplock bag in a 35 °C incubator. OD600 was measured at 24 and 48 hours. The lowest compound concentration showing a significant (>90%) reduction in fungal growth was recorded as the MIC, and MIC-50 refers to the compound concentration showing 50% growth inhibition.

[Table 6]: Fungal strains used in the fungal MIC protocol ATCC Fungal Strains supplier catalog number Flavus AFL1 ATCC MYA-3631 Koji fumigatus T33439 ATCC MYA-3626 Fusarium Fusarium FS1 ATCC MYA-3636 Fusarium solani ATCC 58877 Mucor rotifera 1463(62) ATCC 26759 Cladomyces 057718 ATCC 90286

[Table 7]: Antifungal activity of exemplary compounds of the present disclosure. example MIC (mcg/mL) MIC-50 (mcg/mL) Flavus 3631 Fumigation Koji 3626 Fusarium fusarium 3636 Fusarium solani 58877 Mucor rotundum 26579 Cladomyces 90286 Candida albicans GDH2346 1 0.1 0.1 0.39 2 0.2 0.1 0.27 3 1.56 0.39 0.78 4 0.78 0.39 3.13 5 12.5 6.2 20.7 6 6.25 25 7.81 7 3.13 25 0.78 0.39 25 25 8 0.78 0.78 0.2 0.2 12.5 25 9 1.56 1.56 0.39 0.2 25 25 10 25 25 6.25 3.13 25 25 11 25 25 25 6.25 25 25 12 1.56 1.56 0.39 0.39 6.25 25 13 0.78 0.39 0.39 0.39 25 25 14 25 25 12.5 6.25 25 25 15 0.024 0.024 0.024 0.024 0.2 0.39 0.024 16 0.78 0.39 0.39 0.78 6.25 25 17 0.78 0.39 0.78 0.78 6.25 12.5 18 0.78 0.2 0.2 0.024 12.5 3.13 19 0.78 0.78 12.5 0.78 0.78 0.39 20 0.2 0.2 0.39 0.2 6.25 12.5 twenty one 0.78 0.39 0.78 0.39 0.78 3.13 twenty two 1.56 12.5 0.78 0.39 25 25 twenty three 0.39 0.2 0.1 0.1 0.39 3.13 0.05 twenty four 0.78 0.39 0.39 0.2 1.56 6.25 25 0.2 0.2 0.1 0.1 0.39 3.13 0.1 26 0.1 0.1 0.024 0.05 0.78 3.13 0.2 27 0.024 0.024 0.024 0.024 0.1 0.78 0.024 28 0.024 0.024 0.024 0.024 0.1 0.78 29 0.1 0.024 0.024 0.024 0.39 0.78 0.05 30 0.78 0.39 0.2 0.012 6.25 12.5 0.78 31 6.25 12.5 6.25 3.13 12.5 12.5 32 0.78 0.78 0.1 0.024 1.56 6.25 33 0.39 0.1 0.1 0.1 1.56 12.5 0.39 34 0.39 0.2 0.012 0.012 0.78 1.56 35 0.024 0.012 0.012 0.012 0.78 3.13 36 1.56 0.78 0.78 3.13 12.5 12.5 37 0.2 0.1 0.012 0.1 0.39 1.56 38 0.39 0.1 0.1 0.1 0.39 0.78 39 0.2 0.39 0.05 0.05 0.2 1.56 40 0.39 0.39 0.39 0.78 0.78 3.13 41 0.2 0,2 0,1 0.2 1.56 12.5 42 0.78 3.13 0.39 0.78 3.13 12.5 43 0.39 0.78 0.39 0.39 3.13 12.5 44 0.2 0.2 0.1 0.05 6.25 12.5 45 0.39 0.39 0.1 0.05 3.13 >12.5 46 0.2 0.2 0.1 0.05 1.56 >12.5 47 0.78 0.78 0.39 0.2 >12.5 >12.5 48 0.39 0.39 0.05 0.1 1.56 12.5 49 0.39 0.39 1.2 50 3.10 1.60 2.83 51 0.30 0.60 0.02 52 3.13 0.78 0.24 53 1.56 0.78 1.43 54 1.56 0.20 1.12 55 2.50 0.16 0.1 56 25 2 100 57 6.25 6.25 0.9 58 6.25 25 3.13 0.78 25 25 0.9 59 0.78 0.39 0.39 0.39 25 25 1.25 60 1.56 6.25 0.39 0.39 25 25 0.39 61 0.39 0.3 3.2 62 6.25 1.56 0.78 63 1.56 0.39 1.8 64 1.56 0.78 4 65 1.56 1.56 100 66 0.39 0.78 1.56 0.78 1.56 12.5 6.25 69 0.39 0.39 0.1 0.2 0.78 12.5 70 0.05 0.1 0.024 0.05 0.39 6.25 71 12.5 12.5 1.56 0.78 12.5 12.5 72 12.5 12.5 0.39 0.39 12.5 12.5 73 0.2 0.1 0.024 0.1 0.78 3.13 74 0.1 0.1 0.024 0.024 0.78 3.13 75 0.1 0.1 0.05 0.024 1.56 12.5

Several compounds have been tested for their ability to control fungal infection in a mouse model of disseminated aspergillosis. In this model, neutrophils in male CD-1 mice were neutralized by intraperitoneal (IP) injection of cyclophosphamide 3 days before infection (150 mg/kg) and 2 days after infection (100 mg/kg). reduce. On day 0, mice were inoculated intravenously (IV) with 4.4–4.7 log10 spores of Aspergillus fumigatus UNT017-6. Compounds were administered subcutaneously (SC) daily for 5 days 24 hours post-infection (n = 10/dose group). In most cases, an initial higher first (loading) dose was administered twice daily (BID) followed by nine lower maintenance doses twice daily (BID) during the 5-day treatment period, however, in some A single daily dose (QD) regimen was also tested in the study. Survival was monitored during treatment and 24 hours after the last dose, and liver and kidneys were harvested for determination of fungal burden by serial dilution and plating of tissue homogenates to enumerate colony forming units (cfu) per gram of tissue . Tissue samples from infected but untreated mice were collected on day 1 (time of treatment) and day 6. Statistical significance (p < 0.05) of fungal burden comparisons between groups was determined using one-way analysis of variance with Tukey's multiple comparison test.

Figure 1 and Table 8 show the activity of Example 15 on liver and kidney fungal burden in a disseminated aspergillosis model. In the liver, doses of 0.5 mg/kg BID (1 mg/kg loading dose) or 0.25 mg/kg BID (0.5 mg/kg loading dose), respectively, significantly reduced the burden of untreated mice by 2.05 log10 cfu/g and a fungal burden of 1.67 log10 cfu/g. Relative to the burden at the time of treatment (day 1), significant reductions of 1.26 log10 cfu/g and 0.88 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses of Example 15 reduced the fungal burden in all treated mice to the limit of detection (LOD) relative to the burden of the untreated group on day 6 and day 1, yielding 2.17 log10 cfu/g and Significant reduction of 1.76 log10 cfu/g.

By day 6, five deaths had occurred in the untreated group, while only 1 and 2 mice had been lost in the low-dose and high-dose groups treated with Example 15, respectively.

Figure 2 and Table 8 show the activity of Example 25 on liver and kidney fungal burden in a disseminated aspergillosis model. In the liver, doses of 1 mg/kg BID (2 mg/kg loading dose) or 0.25 mg/kg BID (0.5 mg/kg loading dose), respectively, significantly reduced the burden of untreated mice by 1.87 log10 cfu/g and a fungal burden of 1.7 log10 cfu/g. Relative to the burden on treatment, significant reductions of 0.81 log10 cfu/g and 0.64 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses of Example 25 reduced the fungal burden in all treated mice to or near the limit of detection, yielding >1.66 log10 cfu/ g and a significant reduction of >0.62 log10 cfu/g.

By day 6, four deaths occurred in the untreated group, while no mice were lost in either group treated with Example 25.

Figure 3 and Table 8 show the activity of Examples 26 and 27 on liver and kidney fungal burden in a disseminated aspergillosis model.

For Example 26, in the liver, a dose of 1 mg/kg BID (2 mg/kg loading dose) or 0.5 mg/kg BID (1 mg/kg loading dose) would Fungal burden was significantly reduced to or near the limit of detection, yielding reductions of 1.71 log10 cfu/g and 1.6 log10 cfu/g, respectively. Relative to the burden on treatment, significant reductions of 1.04 log10 cfu/g and 0.93 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses of Example 26 reduced the fungal burden to the limit of detection in almost all treated mice relative to the burden of the untreated group on Day 6 and Day 1, yielding ≥ 1.26 log10 cfu/g and ≥ Significant reduction of 0.65 log10 cfu/g.

For Example 27, doses of 1 mg/kg BID (2 mg/kg loading dose) or 0.5 mg/kg BID (1 mg/kg loading dose) in the liver relative to the burden of untreated mice on day 6 were at The fungal burden was significantly reduced to or near the limit of detection in a number of mice, resulting in reductions of 1.63 log10 cfu/g and 1.17 log10 cfu/g, respectively. Relative to the burden on treatment, significant reductions of 0.96 log10 cfu/g and 0.5 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses of Example 27 reduced the fungal burden to the limit of detection in all treated mice, yielding 1.3 log10 cfu/g and ≥ 0.69 log10, respectively, relative to the burden of the untreated group on Day 6 and Day 1 Significant reduction in cfu/g.

By day 6, one death occurred in the untreated group, but no mice were lost in either group treated with Examples 26 or 27.

Figure 4 and Table 8 show the activity of Examples 26 and 27 tested in a low dose regimen against liver and kidney fungal burden in a disseminated aspergillosis model.

For Example 26, in the liver, relative to the burden of untreated mice on day 6, doses of 0.25 mg/kg BID (0.5 mg/kg loading dose) or 0.125 mg/kg BID (0.25 mg/kg loading dose) were Significantly reduced fungal burden of 1.72 log10 cfu/g and 1.28 log10 cfu/g. A significant reduction of 0.49 log10 cfu/g was also observed in the high-dose group relative to the burden on treatment, consistent with fungicidal activity, but no significant reduction was observed in the low-dose group. In the kidney, the high and low doses of Example 26 significantly reduced the fungal burden by 2.3 log10 cfu/g and 1.97 log10 cfu/g, respectively, relative to the burden in untreated mice on day 6. A significant reduction of 0.73 log10 cfu/g was also observed in the high-dose group relative to the burden on treatment, but not in the low-dose group.

For Example 27, doses of 1 mg/kg BID (2 mg/kg loading dose) or 0.5 mg/kg BID (1 mg/kg loading dose) were significantly significant relative to the burden of untreated mice on day 6 in the liver The fungal burden was reduced by 1.8 log10 cfu/g, and a significant reduction of 0.57 log10 cfu/g was also observed in the high and low dose groups relative to the burden on treatment, consistent with fungicidal activity. In the kidney, the high and low doses of Example 27 significantly reduced the fungal burden by 2.37 log10 cfu/g and 2.28 log10 cfu/g, respectively, relative to the burden of untreated mice on day 6. Relative to on-treatment burden, significant reductions of 0.8 log10 cfu/g and 0.71 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively.

By day 6, six deaths had occurred in the untreated group, but no mice had been lost in either group treated with Examples 26 or 27.

Figure 5 and Table 8 show the activity of Example 75 on liver and kidney fungal burden in a disseminated aspergillosis model. In the liver, a dose of 0.5 mg/kg QD reduced the fungal burden by 1.23 log10 cfu/g relative to the burden in untreated mice on day 6. A significant reduction of 1.26 log10 cfu/g was also observed relative to the burden on treatment, consistent with fungicidal activity. In the kidney, Example 75 reduced the fungal burden to the limit of detection in all treated mice relative to the burden of the untreated group on Day 6 and Day 1, producing a significant reduction of 1.67 log10 cfu/g and 0.97 log10 cfu/g, respectively .

By day 6, four deaths had occurred in the untreated group, while no mice had been lost in the Example 75-treated group.

Figure 6 and Table 8 show the activity of Examples 74 and 75 on liver and kidney fungal burden in a disseminated aspergillosis model tested in a low dose regimen with no loading dose.

For Example 75, the 0.25 mg/kg BID dose significantly reduced the fungal burden by 0.83 log10 cfu/g relative to the burden in untreated mice on day 6 in the liver. 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 significantly reduced liver burden relative to burden on treatment by 1.07 log10 cfu/g and 0.74 log10 cfu/g, consistent with fungicidal activity. In the kidney, the high and low doses of Example 75 significantly reduced the fungal burden by 2.85 log10 cfu/g and 2.71 log10 cfu/g, respectively, relative to the burden in untreated mice on day 6. Relative to on-treatment burden, significant reductions of 1.02 log10 cfu/g and 0.88 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively.

For Example 74, doses of 0.25 mg/kg BID or 0.125 mg/kg BID significantly reduced fungi by 1.15 log10 cfu/g and 0.64 log10 cfu/g, respectively, relative to the burden of untreated mice on day 6 burden. Relative to the burden on treatment, significant reductions of 1.39 log10 cfu/g and 0.88 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses of Example 75 reduced the fungal burden to the limit of detection in almost all treated mice relative to the burden of the untreated group on Day 6 and Day 1, yielding ≥ 2.95 log10 cfu/g and ≥ Significant reduction of 1.12 log10 cfu/g.

By day 6, three deaths occurred in the untreated group, but no mice were lost in either group treated with Example 75. The high dose group treated with Example 74 lost one mouse.

Several compounds were also tested for their ability to control disseminated infection with F. solani in mice. The model was performed as described for the disseminated aspergillosis mouse model, except neutropenic mice were inoculated IV with 6-6.2 log10 spores of F. solanisis UNT044-6.

Figure 7 and Table 8 show the activity of Example 26 on liver and kidney fungal burden in a disseminated Fusarium solani infection model. In the liver, doses of 1 mg/kg BID (2 mg/kg loading dose) or 0.25 mg/kg BID (0.5 mg/kg loading dose) respectively significantly reduced the burden relative to the burden of a single remaining untreated mouse on day 6 Fungal burdens of 4.91 log10 cfu/g and 4.57 log10 cfu/g were achieved. Relative to the burden on treatment, significant reductions of 1.95 log10 cfu/g and 1.61 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses of Example 25 reduced the fungal burden to the limit of detection in almost all treated mice relative to the burden of the untreated group on Day 6 and Day 1, yielding ≥4.89 log10 cfu/g and ≥ Significant reduction of 1.69 log10 cfu/g. The widely used and broadly active polyene antifungal amphotericin B (AmphB) was also tested at a daily SC dose of 18 mg/kg QD. Mortality was evident in this group, and the remaining surviving mice had a reduction in liver burden of 3.07 log10 cfu/g on day 6, but infection in the kidneys was not controlled.

Nine out of ten mice died in the untreated and AmphB-treated groups, while only 1 and 3 mice were lost in the high-dose and low-dose groups treated with Example 26. By day 6, four deaths occurred in the untreated group, while no mice were lost in either group treated with Example 25.

Figure 8 and Table 8 show the activity of Examples 25 and 27 on liver and kidney fungal burden in a disseminated Fusarium solani infection model.

For Example 25, in the liver, relative to the burden of untreated mice on day 6, doses of 1 mg/kg BID (2 mg/kg loading dose) or 0.5 mg/kg BID (0.25 mg/kg loading dose) were Significantly reduced fungal burden of 2.7 log10 cfu/g and 1.99 log10 cfu/g. Relative to the burden at the time of treatment (day 1), significant reductions of 2.44 log10 cfu/g and 1.73 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively, consistent with fungicidal activity. In the kidney, both doses reduced the fungal burden to the limit of detection in all treated mice, yielding ≥ 2.35 log10 cfu/g and ≥ 2.26 log10 cfu/g relative to the burden in the untreated group on Day 6 and Day 1, respectively. g significantly decreased.

For Example 27, the 1 mg/kg BID dose (2 mg/kg loading dose) significantly reduced the fungal burden by 1.16 log10 cfu/g relative to the burden of untreated mice on day 6 in the liver. A significant reduction of 0.9 log10 cfu/g was also observed at this dose relative to the burden on treatment, consistent with fungicidal activity. No significant reduction in liver burden was observed with the lower 0.25 mg/kg BID dose (0.5 mg/kg loading dose) relative to the burden of untreated mice or the burden on treatment at day 6. In the kidney, the high and low doses of Example 27 significantly reduced the fungal burden by 2.35 log10 cfu/g and 1.19 log10 cfu/g, respectively, relative to the burden in untreated mice on day 6. Relative to on-treatment burden, significant reductions of 2.26 log10 cfu/g and 1.1 log10 cfu/g were also observed in the high-dose and low-dose groups, respectively.

By day 6, six deaths occurred in the untreated group, 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 in the high-dose and low-dose groups treated with Example 27 died, respectively.

In summary, several examples of compounds of the invention have been tested in mouse models of disseminated infection against Aspergillus fumigatus and Fusarium solani. Significant efficacy, as measured by a reduction in fungal burden in liver and kidney tissue in treated mice relative to untreated mice, was generally observed, which also correlated with increased survival during treatment. These results support the utility of the compounds exemplified in the present invention for the treatment of fungal infections.

[Table 8]: Organizational Burden

none

In the accompanying drawings, "CFU" refers to the count of colony forming units, "D" refers to the number of days after the inoculation day (defined as day 0), "SC" refers to subcutaneous administration, and "BID" refers to daily For two treatments, "QD" refers to once-daily dose treatment.

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

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

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

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

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

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

[ FIG. 7 ] shows the activity of Example 26 in a model of disseminated Fusarium solanisis infection of liver ( 7A ) and kidney ( 7B ).

[ FIG. 8 ] shows the activity of Examples 25 and 27 in a model of disseminated Fusarium solanisis infection of the liver ( 8A ) and kidney ( 8B ).

none

Claims (70)

A compound having the formula (I):

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: ^A1 is selected from the group consisting of:

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; ^A2, at each occurrence, is independently selected from the group consisting of:

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; ^A3, at each occurrence, is independently selected from the group consisting of:

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; ^A4 is independently selected at each occurrence from the group consisting of:

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; A ⁵ is independently selected at each occurrence from the group consisting of:

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; q is independently 0, 1, 2 or 3 at each occurrence; t is independently 1, 2 or 3 at each occurrence; ^{R is} independently selected from H and C _1-4 at each occurrence The group consisting of alkyl; R ^1a at each occurrence is independently selected from the group consisting of H and C _1-4 alkyl; R ² at each occurrence is independently selected from H and C _1-4 alkyl The group consisting of; R ^2a is independently selected from each occurrence of H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF The group consisting of ₃ and CF ₃ ; R ^2b at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl , CN, OCF ₃ and the group consisting of CF ₃ ; R ^2c at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy , the group consisting of F, Cl, CN, OCF ₃ and CF ₃ ; R ^2d at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched The group consisting of alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2e at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkoxy, C The group consisting of _3-5 branched chain alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2f at each occurrence is independently selected from H, C _1-4 alkyl, C _1-4 alkane The group consisting of oxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2g is independently selected from each occurrence of H, C _1-4 alkyl, C The group consisting of _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2h is independently selected from H, C _1-4 at each occurrence The group consisting of alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ²ⁱ is independently selected from H, The group consisting of C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched alkoxy, F, Cl, CN, OCF ₃ and CF ₃ ; R ^2j independently at each occurrence 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 in each 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 when present; R ²¹ is independently selected at each occurrence from the group consisting of H, C _1-4 alkyl, C _1-4 alkoxy, C _3-5 branched chain alkoxy, F, Cl, CN, OCF ₃ and CF ₃ Group; R ³ is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3a is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl ; R ^3c is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3d is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3y is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^3z is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; or R ^2e and R ^3z are connected to form a heterocycle consisting of five or six members; or R ²ⁱ and R ^3y are connected to form a heterocycle consisting of five or six members; or R ³ and R ^3c are connected to form a heterocycle consisting of five members Ring; R ^4a is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^4b is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^4c is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^4d is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^4e is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; R ^is independently selected at each occurrence from the group consisting of H and C _1-4 alkyl; and wherein the formula ( The compound of I) is not pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. As the compound of claim 1, wherein when A ¹ is a pyrimidine moiety

, then A ⁴ and A ⁵ are not both

. Such as the compound of claim 1, having formula ( Ia )

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. As the compound of claim 1, it has formula ( Ib ):

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof. Such as the compound of claim 1, having formula ( II ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. The compound as claimed in item 1 has formula ( III ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( IV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. As the compound of claim 1, it has formula ( V ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( VI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( VII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( VIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. As the compound of claim 1, it has formula ( IX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( X ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. As the compound of claim 1, it has formula ( XIV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XV ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XVI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XVII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. As the compound of claim 1, it has formula ( XVIII ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. As the compound of claim 1, it has formula ( XIX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having the formula ( XX ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. Such as the compound of claim 1, having formula ( XXVI ):

Enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts and complexes thereof are included. The compound of claim 1 or claim 2, wherein A ^is selected from the group consisting of:

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. The compound of claim 1 or claim 2, wherein A ^is selected from the group consisting of:

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. As the compound of claim 1, wherein ^A is selected from the group consisting of:

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. The compound according to any one of claims 1 to 27, wherein A ^is selected from the group consisting of:

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; ^A3 is selected from the group consisting of:

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; ^A4 is selected from the group consisting of:

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; A ⁵ is selected from the group consisting of:

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,

and

; q is independently 0, 1, 2 or 3 at each occurrence; R ¹ , R ^1a and R ² are independently selected at each occurrence 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 ²ⁱ , R ^2j , R ^2k , R ^2l are each independently selected from H, unsubstituted A group consisting of 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 independently selected at each occurrence from the group consisting of H and unsubstituted C _1-4 alkyl; or R ^2e and R ^3z together form methylene or ethylenyl bridging moiety; or R ²ⁱ and R ^3y together form methylene or ethylenyl bridging moiety; or R ³ and R ^3c together form ethylenyl bridging moiety; and R ^4a , R ^4b , R ^4c and R ^4d are independently selected at each occurrence from the group consisting of H and unsubstituted C _1-4 alkyl. The compound according to any one of claims 1 to 27, wherein A ^is selected from the group consisting of:

,

,

,

and

; ^A3 is selected from the group consisting of:

,

,

,

and

; ^A4 is selected from the group consisting of:

,

,

and

; A ⁵ is selected from the group consisting of:

,

,

and

; q is independently 0, 1, 2 or 3 at each occurrence; R ¹ , R ^1a and R ² are independently selected at each occurrence 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 ²ⁱ , R ^2j , R ^2k , R ^2l are at each occurrence independently selected from H, methyl, methoxy, F, Cl , CN, OCF ₃ and the group consisting of CF ₃ ; R ³ , R ^3y and R ^3z are independently selected at each occurrence from the group consisting of H and methyl; or R ^2e and R ^3z together form methylene or an ethylenyl bridging moiety; or R ²ⁱ and R ^3y together form a methylene or ethylenyl bridging moiety; and R ^4a , R ^4b , R ^4c and R ^4d are each independently selected from H and The group consisting of methyl groups; and wherein when present, no more than two of R ^2a , R ^2b , R ^2c and R ^2d are not H; when present, no more than two of R ^2e , R ^2f , R ^2g and R ^2h two are not H; when present, not more than two of R ²ⁱ , R ^2j , R ^2k and R ^2l are not H; and when present, not more than two of R ^4a , R ^4b , R ^4c and R ^4d are not H. As the compound of claim 1, the compound is selected from the group consisting of: N ² , N ⁵ -bis[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl) Phenyl]pyridine-2,5-dimethylamide; N ² ,N ⁴ -bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl] Pyridine-2,4-dimethylamide; N ² ,N ⁴ -bis[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-3 ,5-Diformamide; N ² ,N6-bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,6- Diformamide; N ⁴ ,N ⁶ -bis(4-{2-[(4,5-dihydro-1H-imidazol-2-yl)amino]ethyl}phenyl)pyrimidine-4,6- Diformamide; N ⁴ ,N ⁶ -bis({4-[2-(N-methylformamimidinoamino)ethyl]phenyl})pyrimidine-4,6-dimethylamide; N, N'-bis(4-guanidino-phenyl)-terephthalamide;2-fluoro-N1,N4-bis(4-(guanidinomethyl)phenyl)terephthalamide; trans Formula - cyclohexane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]; cis-cyclohexane-1,4-dicarboxylic acid bis[(4-guanidino Methyl-phenyl)-amide]; N,N'-bis(4-guanidinomethyl-cyclohexyl)-terephthalamide; N ¹ ,N ⁴ -bis(4-(guanidinomethyl Base) phenyl) -2-methyl-terephthalamide; Amine; N,N'-bis[4-(4-formamido-piper-1-yl)-phenyl]-isophthalamide; N-[4-(1-formamido-1 ,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; N ¹ ,N ⁴ -bis( 4-(4-Carboxamidinopiper-1-yl)phenyl)-2-chloroterephthalamide; N ¹ , N ⁴ -bis(4-(4-carboxamidinopiper-1- base)phenyl)-2-methylterephthalamide; N ² ,N ⁵ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)pyridine-2,5-di Formamide; Furan-2,5-dicarboxylic acid bis{[4-(4-formamimidino-piper-1-yl)-phenyl]-amide}; N-[4-(4-formamidine Base-piperyl-1-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; N-[4-(1-formamidino-1, 2,3,6-tetrahydropyridin-4-yl)-3-methoxy-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; N-[ 4-(1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-phenyl]-N'-(4-guanidinomethyl-phenyl) - Terephthalamide; -3-methyl-phenyl)-terephthalamide; N-(2-carboxamido-2,3-dihydro-1H-isoindol-5-yl)-N'-[4 -(1-Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephthalamide; Bicyclo[1.1.1]pentane-1,3- Dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide; Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide ( 4-guanidinomethyl-phenyl)-amide; )-phenyl]-amide} 2-[(4-guanidinomethyl-phenyl)-amide]; pyridine-2,5-dicarboxylic acid 2-{[4-(1-formamido-1 ,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}5-[(4-guanidinomethyl-phenyl)-amide]; N-(1'-formamidine Base-1',2',3',6'-tetrahydro-[3,4']bipyridyl-6-yl)-N'-(4-guanidinomethyl-phenyl)-terephthalene Formamide: N-[4-(1-Formamimidino-2,5-dihydro-1H-pyrrol-3-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl) - Terephthalamide; Base-phenyl)-N-methyl-terephthalamide; N-[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl] -N'-(4-guanidinomethyl-phenyl)-2,5-dimethyl-terephthalamide; pyridine-2,5-dicarboxylic acid 5-{[4-(1-formamidine N1 -[4-(1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N4-(4-guanidinomethyl-phenyl)-2-methyl - Terephthalamide; N-[6-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-N'-(4 -guanidinomethyl-phenyl)-terephthalamide; N-[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]- N'-(4-guanidinomethyl-phenyl)-N'-methyl-terephthalamide; N-[5-(1-carboxamidino-1,2,3,6-tetrahydro Pyridin-4-yl)-pyr-2-yl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; Bicyclo[1.1.1]pentane-1,3 -Dicarboxylic acid [4-(1-formamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amido[4-(2-guanidino-ethyl)-benzene Base]-amide; -Fluoro-phenyl]-amide (4-guanidinomethyl-phenyl)-amide; N-[4-(1-carboxamido-1,2,3,6-tetrahydropyridine-4- base)-3-methyl-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; bicyclo[1.1.1]pentane-1,3-dicarboxylic acid [4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-phenyl]-amido(4-guanidinomethyl-phenyl)-acyl Amine; bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(4-guanidino-cyclohex-1-enyl)-phenyl]-amide (4-guanidinomethyl- phenyl)-amide; '-(4-guanidinomethyl-phenyl)-terephthalamide; ,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-amide (4-guanidinomethyl-phenyl)-amide; Bicyclo[1.1.1]pentane-1 ,3-Dicarboxylic acid [5-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-pyr-2-yl]-amide (4-guanidinomethyl- Phenyl)-amide; Pyr-2-yl]-amide (4-guanidinomethyl-phenyl)-amide; Bicyclo[1.1.1]pentane-1,3-dicarboxylate[6-(1-carboxamidino -1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-amide (4-guanidinomethyl-phenyl)-amide; bicyclo[2.2.1] Heptane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidinomethyl- Phenyl)-amide; Pyrimidine-4,6-dicarboxylic acid bis{[4-(1,1-difluoro-2-guanidino-ethyl)-phenyl]-amide}; Pyrimidine-4,6 -Dicarboxylic acid bis{[4-(4-formamidoyl-piper-1-yl)-phenyl]-amide}; pyrimidine-4,6-dicarboxylic acid bis{[4-(2-guanidino- Ethyl)-phenyl]-amide}; }; Pyridine-2,4-dicarboxylic acid bis{[4-(4-formamidoyl-piper-1-yl)-phenyl]-amide}; Pyridine-4,6-dicarboxylic acid bis[(4 -guanidinomethyl-phenyl)-amide]; pyridine-2,4-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}; thiophene-2,5 -Dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}; N,N'-bis[4-(2-guanidino-ethyl)-phenyl]-para Phthalamide; 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(4-formamimidino-piper-1-yl)-phenyl]-amide}; N,N'- Bis[4-(4-formamidino-piper-1-yl)-phenyl]-terephthalamide; 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(2-guanidine base-ethyl)-phenyl]-amide}; N ,N'-bis[4-(1-formamimidino-tetrahydroazil-3-yl)-phenyl]-terephthalamide;N,N'-bis(2-formamido-1,2,3,4-tetrahydroisoquinolin-7-yl)-terephthalamide; Bicyclo[2.2.2]octane-1,4-dicarboxylate[4-(1-carboxamido -1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide[4-(2-guanidino-ethyl)-phenyl]-amide; bicyclo[2.2.2 ]octane-1,4-dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidino-benzene base)-amide; bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-guanidino-ethyl)-phenyl]-amide Base)-amide; Bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-guanidino-ethoxy)-phenyl]-amide (4- Phenyl)-amide; Phenyl]-amide (3-fluoro-4-guanidinomethyl-phenyl)-amide; Bicyclo[2.2.2]octane-1,4-dicarboxylate[4-(1-carboxamido -1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide(6-guanidinomethyl-pyridin-3-yl)-amide; and bicyclo[2.2.2] Octane-1,4-dicarboxylic acid [4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (5-guanidinomethyl- pyridin-2-yl)-amide; or a pharmaceutically acceptable form thereof. A composition comprising an effective amount of at least one compound according to any one of claims 1-30. The composition according to claim 31, wherein the composition is a pharmaceutical composition. The composition of claim 31 or claim 32, further comprising at least one excipient. The composition according to any one of claims 31 to 33, wherein the at least one compound is at least one member selected from the group consisting of: N ² , N ⁵ -bis[4-(1-formamidinyl-1 ,2,3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,5-dimethylamide; N ² ,N ⁴ -bis[4-(1-carboxamidino-1,2, 3,6-tetrahydropyridin-4-yl)phenyl]pyridine-2,4-dimethylamide; N ² ,N ⁴ -bis[4-(1-carboxamidino-1,2,3,6 -tetrahydropyridin-4-yl)phenyl]pyridine-3,5-dimethylamide; N ² ,N6-bis[4-(1-carboxamidino-1,2,3,6-tetrahydropyridine -4-yl)phenyl]pyridine-2,6-dimethylamide; N ⁴ ,N ⁶ -bis(4-{2-[(4,5-dihydro-1H-imidazol-2-yl) Amino]ethyl}phenyl)pyrimidine-4,6-dimethylamide; N ⁴ ,N ⁶ -bis({4-[2-(N-methylformamidoamino)ethyl]phenyl })pyrimidine-4,6-dimethylamide; N,N'-bis(4-guanidino-phenyl)-terephthalamide; 2-fluoro-N1,N4-bis(4-(guanidine (methyl)phenyl)terephthalamide; trans-cyclohexane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]; cis-cyclohexane Alkane-1,4-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]; N,N'-bis(4-guanidinomethyl-cyclohexyl)-terephthalamide ; N ¹ , N ⁴ -bis(4-(guanidinomethyl)phenyl)-2-methylterephthalamide; N,N'-bis[4-(4-formamidino-piperamide -1-yl)-phenyl]-terephthalamide; N,N'-bis[4-(4-formamimidino-piper-1-yl)-phenyl]-isophthalamide Amine; N-[4-(1-Formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)- Terephthalamide; N ¹ , N ⁴ -bis(4-(4-carbamimidinopiper-1-yl)phenyl)-2-chloroterephthalamide; N ¹ ,N ⁴ - Bis(4-(4-carboxamidinopiper-1-yl)phenyl)-2-methylterephthalamide; N ² , N ⁵ -bis(4-(4-carboxamidinopiperone -1-yl)phenyl)pyridine-2,5-dimethylamide; furan-2,5-dicarboxylic acid bis{[4-(4-formamidoyl-piper-1-yl)-phenyl] -amide}; N-[4-(4-formamido-piper-1-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide ; -Phenyl)-terephthalamide; N-[4-(1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxy-phenyl] -N'-(4-guanidinomethyl-phenyl)-terephthalamide; N-[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl )-phenyl]-N'-(4-guanidinomethyl-3-methyl-phenyl)-terephthalamide; N-(2-formamimidino-2,3-dihydro-1H -Isoindol-5-yl)-N'-[4-(1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-terephthalamide ; Bicyclo[1.1.1]pentane-1,3-dicarboxylate [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide; Bicyclo[2.2.2]octane-1,4-dicarboxylate Hydropyridine-4-yl)-phenyl]-amide (4-guanidinomethyl-phenyl)-amide; Pyridine-2,5-dicarboxylic acid 5-{[4-(1-formamimidino- 1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}2-[(4-guanidinomethyl-phenyl)-amide]; pyridine-2,5-di Formic acid 2-{[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}5-[(4-guanidinomethyl-benzene base)-amido]; (4-Guanidinomethyl-phenyl)-terephthalamide: N-[4-(1-carbamimidino-2,5-dihydro-1H-pyrrol-3-yl)-phenyl] -N'-(4-guanidinomethyl-phenyl)-terephthalamide; N-[4-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl )-phenyl]-N'-(4-guanidinomethyl-phenyl)-N-methyl-terephthalamide; N-[4-(1-carboxamido-1,2,3 ,6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-2,5-dimethyl-terephthalamide; pyridine-2, 5-Dicarboxylic acid 5-{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl]-amide} 2-[(4 -guanidinomethyl-phenyl)-amide]; N1-[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-N4-( 4-guanidinomethyl-phenyl)-2-methyl-terephthalamide; N-[6-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl )-(1-formamido-3-yl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide;6-tetrahydropyridin-4-yl)-phenyl]-N'-(4-guanidinomethyl-phenyl)-N'-methyl-terephthalamide; N-[5-(1 -Carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyr-2-yl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide Amines; Amine [4-(2-guanidino-ethyl)-phenyl]-amide; ,3,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl]-amide (4-guanidinomethyl-phenyl)-amide; N-[4-(1-formamidino -1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-phenyl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; two Cyclo[1.1.1]pentane-1,3-dicarboxylate[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-phenyl]- Amide (4-guanidinomethyl-phenyl)-amide; bicyclo[1.1.1]pentane-1,3-dicarboxylate[4-(4-guanidino-cyclohex-1-enyl) -Phenyl]-amide (4-guanidinomethyl-phenyl)-amide; N-[5-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl) -6-Methyl-pyr-2-yl]-N'-(4-guanidinomethyl-phenyl)-terephthalamide; Bicyclo[2.2.2]octane-1,4- Dicarboxylic acid [6-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridyl-3-yl]-amide (4-guanidinomethyl-phenyl) -Amide; Bicyclo[1.1.1]pentane-1,3-dicarboxylate[5-(1-formamimidino-1,2,3,6-tetrahydropyridin-4-yl)-pyridine- 2-yl]-amide (4-guanidinomethyl-phenyl)-amide; 2,3,6-tetrahydropyridin-4-yl)-pyr-2-yl]-amide (4-guanidinomethyl-phenyl)-amide; bicyclo[1.1.1]pentane- 1,3-Dicarboxylic acid [6-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-pyridine-3-yl]-amide (4-guanidinomethyl -phenyl)-amide; -Phenyl]-amide (4-guanidinomethyl-phenyl)-amide; pyrimidine-4,6-dicarboxylic acid bis{[4-(1,1-difluoro-2-guanidino-ethyl )-phenyl]-amide}; 6-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}; pyrimidine-4,6-dicarboxylic acid bis{[4-(1-formamido-tetrahydroacridine Ai-3-yloxy)-phenyl]-amide}; Amine}; Pyrimidine-4,6-dicarboxylic acid bis[(4-guanidinomethyl-phenyl)-amide]; Pyridine-2,4-dicarboxylic acid bis{[4-(2-guanidino-ethyl )-phenyl]-amide}; Thiophene-2,5-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}; N,N'-bis[4- (2-guanidino-ethyl)-phenyl]-terephthalamide; 1H-pyrazole-3,5-dicarboxylic acid bis{[4-(4-formamimidino-pipera-1-yl )-phenyl]-amide}; N,N'-bis[4-(4-formamimidino-piper-1-yl)-phenyl]-terephthalamide; 1H-pyrazole- 3,5-dicarboxylic acid bis{[4-(2-guanidino-ethyl)-phenyl]-amide}; 1-methyl-1H-pyrazole-3,5-dicarboxylic acid bis{[4- (4-Formamidino-piper-1-yl)-phenyl]-amide}; -3-yl)-phenyl]-amide}; N,N'-bis[4-(1-carboxamido-tetrahydroazine-3-yl)-phenyl]-terephthalamide ; N,N'-bis(2-carboxamidino-1,2,3,4-tetrahydroisoquinolin-7-yl)-terephthalamide; Bicyclo[2.2.2]octane- 1,4-Dicarboxylic acid [4-(1-formamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amido[4-(2-guanidino-ethyl )-phenyl]-amide; )-phenyl]-amide (4-guanidino-phenyl)-amide; bicyclo[2.2.2]octane-1,4-dicarboxylic acid [4-(2-guanidino-ethyl)- Phenyl]-amide (4-guanidinomethyl-phenyl)-amide; bicyclo[2.2.2]octane-1,4-dicarboxylate[4-(2-guanidino-ethoxy) -Phenyl]-amide (4-guanidinomethyl-phenyl)-amide; 2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (3-fluoro-4-guanidinomethyl-phenyl)-amide; bicyclo[2.2.2]octane- 1,4-Dicarboxylic acid [4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide (6-guanidinomethyl-pyridine-3 -yl)-amide; and bicyclo[2.2.2]octane-1,4-dicarboxylate[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl) -phenyl]-amide(5-guanidinomethyl-pyridin-2-yl)-amide; or a pharmaceutically acceptable form thereof. A method of treating or preventing a disease or condition associated with a fungal infection, wherein the method comprises administering to a subject an effective amount of at least one compound according to any one of claims 1 to 30 or an effective amount of pyrimidine-4 ,6-Dicarboxylic acid bis{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 35, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the fungal infection is an organism from a genus selected from the group consisting of: Candida , Cryptococcus , Trichosporon , Mara Malassezia , Aspergillus , Fusarium , Mucor , Blastomyces , Coccidioides , Pneumocystis ), Histoplasma , Trichophyton , Rhizopus , Apophysomyces , Rhizomucor , Lichtheimia , Sedo Scedosporium and Lomentospora . The method of claim 35, wherein the fungal infection is an organism from a genus selected from the group consisting of: Candida, Cryptococcus, Aspergillus, Fusarium, Mucor, and Scedosporum Fungus. The method of claim 37 or claim 38, wherein the at least one compound is administered as a composition further comprising at least one excipient. The method of claim 35, wherein the fungal infection is an organism selected from the group consisting of Candida albicans, Candida glabrata , Candida krusei , tropical Candida tropicalis , Candida guilliermondii, Candida parapsilosis , Candida dubliniensis , Candida auris , Cryptococcus neoformans , Grid Cryptococcus gatti , Trichosporon asahii , Trichosporon asteroides , Trichosporon cutaneum , Trichosporon dermatis , Duhasporum Trichosporon dohaense , Trichosporon inkin , Trichosporon loubieri, Trichosporon mucoides , Trichosporon ovoides , Malassezia globosa 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 mentatrophytes , Trichophyton verrucosum , Trichophyton rubrum , Rhizopus oryzae ( Rhizopus oryzae ), Rhizopus stolonifera , Apophysomyces variabilis , Rhizomucor pusillus , Rhizomucor regularior , Rhizomucor chlamydosporus , Lichtheimia ramosa , Lichtheimia corymbifera, Scedosporium apiospermum and Lomentospora prolificans . The method of claim 40, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of treating or preventing a disease or condition associated with a fungal infection in a subject, the disease or condition comprising candidemia, oral candidiasis, vulvovaginal candidiasis , aspergillosis, allergic bronchial and pulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, Cutaneous keratitis, athlete's foot, ringworm, keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditis, pneumonia, osteomyelitis, meningitis, ventriculitis, COVID-19-related pneumonia Aspergillus (CAPA) and influenza-associated pulmonary aspergillosis (IAPA), wherein the method comprises administering to the subject an effective amount of at least one compound according to any one of claims 1 to 30 or an effective amount of a pyrimidine -4,6-Dicarboxylic acid bis{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 42, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of treating or preventing fungal infections of plants, wherein the fungal infections include tomato wilt, cotton wilt, banana wilt, chickpea wilt, and cereal powdery mildew , seedling blight, ginger root rot, potato late blight, potato early blight, rice blast, powdery mildew, peanut tika, coffee leaf rust, sugarcane red rot, pear brown rot, plum brown rot, Peach brown rot, oat leaf spot, potato black wart, wheat yellow rust, cruciferous white rust, corn smut, wheat naked smut, wheat stem smut, barley hard smut, wheat black Rust, rice overgrown disease, rice hem rot and rye ergot, and wherein said method comprises administering an effective amount of a compound as any one of claims 1 to 30 or an effective amount of pyrimidine-4 to the plant, 6-Dicarboxylic acid bis{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 44, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of treating or preventing fungal infection in a human, wherein the method comprises administering to the human an effective amount of a compound according to any one of claims 1 to 30 or an effective amount of Pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 46, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of treating or preventing a fungal infection in a subject selected from domesticated animals, livestock and companion animals, including cattle, sheep, pigs, goats, horses, donkeys, mules, Candida infection of animals in the group consisting of buffaloes, bulls, llamas, camels, dogs, cats, horses, rabbits, ferrets and guinea pigs, wherein the method comprises administering to the subject an effective amount of to any one of 30 compounds or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-benzene base]-amide}. The method of claim 48, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method according to claim 35, wherein the method is a method of treating or preventing a yeast infection in a subject selected from horses, cattle, sheep, goats, dogs and cats, wherein the method comprises administering to the subject an effective Amount of compound as any one of claims 1 to 30 or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamidino-1,2,3,6-tetrahydropyridine- 4-yl)-phenyl]-amide}. The method of claim 50, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of treating or preventing white mycosis infection in a subject selected from horses, cattle, sheep, goats, dogs and cats, wherein the method comprises administering to the subject An effective amount of the compound of any one of claims 1 to 30 or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-formamido-1,2,3,6-tetrahydropyridine -4-yl)-phenyl]-amide}. The method of claim 52, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of treating or preventing coccidioidomycosis in dogs and cats caused by an infection by an organism selected from the group consisting of Coccidioides immobilis and Coccidioides posadas, Wherein the method comprises administering an effective amount of a compound according to any one of claims 1 to 30 or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-( 1-Carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 54, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method according to claim 35, wherein the method is a method for treating or preventing blastomycosis caused by Blastomyces dermatitidis infection in dogs and cats, wherein the method comprises administering an effective amount of the following claims 1 to 1 to dogs or cats. Any one of the compounds in 30 or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl ]-amide}. The method of claim 56, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method according to claim 35, wherein the method is a method for treating or preventing paracoccidioidomycosis caused by Paracoccidioides brasiliensis infection in dogs, wherein the method comprises administering to the dog an effective amount of Any one of the compounds in 30 or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carbamimidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl ]-amide}. The method of claim 58, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is to treat or prevent cats and dogs from the group consisting of Microsporum canis , Microsporum gypseum and Trichophyton mentatrophytes A method for dermatophytosis (ringworm) caused by a group of organisms infected, wherein the method comprises administering to cats or dogs an effective amount of a compound as claimed in any one of claims 1 to 30 or an effective amount of Pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamidino-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 60, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method of claim 35, wherein the method is a method of 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 an effective amount of the compound of any one of claims 1 to 30 or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-formamimidino-1,2,3) to cats or dogs ,6-tetrahydropyridin-4-yl)-phenyl]-amide}. The method of claim 62, wherein the at least one compound is administered in a composition further comprising at least one excipient. The method according to claim 35, wherein the method is a method of treating or preventing histoplasmosis in dogs caused by Histoplasma capsulatus infection, wherein the method comprises administering to the dog an effective amount of the following claims 1 to 30 Any one of the compounds or an effective amount of pyrimidine-4,6-dicarboxylic acid bis{[4-(1-carboxamido-1,2,3,6-tetrahydropyridin-4-yl)-phenyl] -amide}. The method of claim 64, wherein the at least one compound is administered in a composition further comprising at least one excipient. A compound according to any one of claims 1 to 30 for use in the treatment or prevention of diseases or conditions associated with fungal infections. Use of a compound according to any one of claims 1 to 30 in the manufacture of a medicament for the treatment or prevention of diseases or conditions associated with fungal infections. A compound of formula (Int-I):

Including its enantiomers, diastereoisomers, hydrates, solvates and salts, wherein A ¹ , A ² , A ³ , A ⁴ , A ⁵ , R ¹ and R ² are as in claim 1 to 30 as defined by the compound of formula (I), and wherein at least one guanidine nitrogen atom in A ⁴ and/or A ⁵ is protected with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoro Acetyl, 9-fluorenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz) protection. A compound of formula (Int-II):

Including its mirror image isomers, diastereomers, hydrates, solvates and salts, wherein q, A ¹ , A ² , A ³ , R ¹ and R ² are as in any one of claims 1 to 30 As defined by the compound of formula (I) in term, and R ¹⁰ is selected from -NH ₂ and with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-permylmethoxy The group consisting of -NH ₂ protected by carbonyl (Fmoc) or benzyloxycarbonyl (Cbz), and R ¹¹ is selected from suitable protecting groups (such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9 -Fmocylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz)), H, -C(=N)NH and with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl A group consisting of -C(=N)NH protected by radical, 9-fenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz). A compound of formula (Int-III):

Including its enantiomers, diastereoisomers, hydrates, solvates and salts, wherein q, A ¹ , A ² , R ¹ and R ² are as in the formula of any one of claims 1 to 30 (I), and R ¹⁰ is selected from -NH ₂ and with a suitable protecting group such as tertiary butoxycarbonyl (Boc), trifluoroacetyl, 9-fenylmethoxycarbonyl (Fmoc ) or benzyloxycarbonyl (Cbz) protected group consisting of -NH ₂ , and R ¹² is halogen such as chlorine or bromine.

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