WO2022192162A1 - Novel heteroaromatic compounds exhibiting antifungal activity and their method of use - Google Patents

Novel heteroaromatic compounds exhibiting antifungal activity and their method of use Download PDF

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WO2022192162A1
WO2022192162A1 PCT/US2022/019220 US2022019220W WO2022192162A1 WO 2022192162 A1 WO2022192162 A1 WO 2022192162A1 US 2022019220 W US2022019220 W US 2022019220W WO 2022192162 A1 WO2022192162 A1 WO 2022192162A1
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carbamimidoyl
tetrahydro
pyridin
phenyl
tetrahydropyridin
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PCT/US2022/019220
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French (fr)
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Simon David Peter BAUGH
Kathryn B. FREEMAN
Jeffrey Claude Pelletier
Allen B. Reitz
Richard W. Scott
Damian G. WEAVER
David B. Whitman
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Fox Chase Chemical Diversity Center, Inc.
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Publication of WO2022192162A1 publication Critical patent/WO2022192162A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Fungal infections are a growing problem in numerous medical settings. Modern medical practices including anticancer chemotherapies, immunosuppressive drugs, broad spectrum antibiotics that disrupt the microbiome and indwelling medical devices that disrupt and breach the protective immune system. This creates an opening for infection by opportunistic fungal pathogens. Fungal infections are most common in immunocompromised patients afflicted with HIV or undergoing cancer therapies, hematological stem cell replacement, or organ transplants. Fungal infections can also occur in immunocompetent individuals and the most common cause is from skin and soft tissue wounds resulting from traumatic injury.
  • IA Invasive Aspergillosis
  • Candida examples include C. albicans, C. glabrata, C. krusei, C. tropicalis, C. guilliermondii, C. parapsilosis, C. dubliniensis and C. auri
  • Cryptococcus examples include C. neoformans and C.
  • the genus Trichosporon examples include T. asahii, T. asteroides, T. cutaneum, T. dermatis, T. dohaense, T. inkin, T. loubieri, T. mucoides, and T. ovoides
  • the genus Malassezia examples include M. globose and M. restricta
  • the genus Aspergillus examples include A. fumigatus. A. flavis, A. terreu and A. niger
  • the genus Fusarium examples include F. solani, F. falciforme, F. oxysporum, F. verticillioides, and F.
  • the genus Mucor examples include M. circinelloides, M, ramosissimus, M. indicus, M. rasemosus, and M. piriformis
  • the genus Blastomyces examples include B. dermatitidis and B. brasiliensis
  • the genus Coccidioides examples include C. immitis, C. and posadasii
  • the genus Pneumocystis examples include P. carinii and P. jiroveci
  • the genus Histoplasma examples include H. capsulatum
  • the genus Trichophyton examples include T.
  • the genus Rhizopus examples include R. oryzae and R. stolonifera
  • the genus Apophysomyces examples include A. variabilis
  • the genus Rhizomucor examples include R. pusillus, R. regularior, and R. chlamydosporus
  • the genus Lichtheimia examples include L. ramose and L. corymbifera
  • the genus Scedosporium examples include S.
  • the compounds of the disclosure have excellent activity against pathogenic fungi of the genera Candida, Aspergillus, Fusarium, Cryptococcus and Mucor.
  • funggal diseases caused by these and other susceptible fungal pathogens, such as Candidemia, Oral Candidiasis, Vulvovaginal Candidiasis (VVC) and Recurrent VVC, Aspergillosis (including Allergic Bronchopulmonary Aspergillosis, Allergic Aspergillus Sinusitis and Invasive and Disseminated Aspergillosis), Cryptococcosis (including Pulmonary Cryptococcosis and Meningeal Cryptococcosis), Mucomycosis, Blastomycosis, Superficial infections (including Skin Keratitis, Athletes Foot, Ringworm, Ocular Keratitis and Onychomycosis) and other Invasive Infections (including Sinusitis, Endophthalmitis, Otitis, Endocarditis, Pneumonia, Osteomyelitis, Meningitis and Ventriculitis).
  • fungal diseases caused by these and other susceptible fungal pathogens, such as Candidemia, Or
  • Compounds of the disclosure can also be used to treat fungal infections in agricultural crops including Wilt disease in tomato and cotton caused by Fusarium oxysporus, Wilt of Gram caused by Fusarium orthacereas, Downy Mildew of cereals caused by Sclerospora graminicola, Damping of Seedling caused by Phythium spp., Rot of Ginger caused by Phythium debaryaum, Late Blight of Potato caused by Phytophthora infestans, Early Blight of Potato caused by Alternaria solani, Blast Disease of Rice caused by Phyricularia oryzae, Powdery Mildews caused by Erysiphe spp., Tikka Disease of Groundnut caused by Cerecospora personata, Haemelia vastatrix and Cellectotrichum falcatum, Brown Rot in Pear, Plum and Peach caused by Sclerotinia fruiticola, Leaf Spot of Oats caused by Helminthosporium avenae, Leaf Ru
  • Compounds of the disclosure can also be used, for example, to treat or prevent fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs.
  • Compounds of the disclosure can also be used, for example, to treat or prevent diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, , pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax.
  • diseases or conditions is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, , pneumoniagranulomatous rhinitis, intestinal
  • Compounds of the disclosure can also be used, for example, to treat or prevent aspergillosis infections in horses, cattle, sheep, goats, dogs and cats.
  • Compounds of the disclosure can also be used, for example, to treat or prevent diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis.
  • Compounds of the disclosure can also be used, for example, to treat or prevent mucormycosis infections in horses, cattle, sheep, goats, dogs and cats.
  • Compounds of the disclosure can also be used, for example, to treat or prevent diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis.
  • Compounds of the disclosure can also be used, for example, to treat or prevent coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii.
  • Compounds of the disclosure can also be used, for example, to treat or prevent blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, [0015] Compounds of the disclosure can also be used, for example, to treat or prevent Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, [0016] Compounds of the disclosure can also be used, for example, to treat or prevent dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes
  • Compounds of the disclosure can also be used, for example, to treat or prevent cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, [0018] Compounds of the disclosure can also be used, for example, to treat or prevent histoplasmosis in dogs caused by infection with Histoplasma capsulatum.
  • the present invention is directed toward novel heteroaromatic compounds of formula (I), Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: X 1 is selected from the group consisting of N and CR 2a ; X 2 is selected from the group consisting of N and CR 2b ; X 3 is selected from the group consisting of O, and S; X 4 is selected from the group consisting of O, S, and NR 1a ;
  • X 5 is selected from the group consisting of N and CR 2c ;
  • X 6 is selected from the group consisting of N and CR 2d ;
  • a 3 is selected from the group consisting of
  • R 3d and R 4c are joined to form a heterocyclic ring consisting of five or six members;
  • the compounds of the present invention include compounds having formula (II): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (III): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (IV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (V): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0024]
  • the compounds of the present invention include compounds having formula (VI):
  • the compounds of the present invention include compounds having formula (VII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (VIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (IX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (X): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (X): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the present invention further relates to compositions comprising: an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing disease or conditions associated with fungal infection. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with fungal infection, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing fungal infection, including, for example, infection with an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor
  • the present invention yet further relates to a method for treating or preventing fungal infection, including, for example, infection with an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Ap
  • the present invention also relates to a method for treating or preventing fungal infection, including, for example, infection with an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus.
  • an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniens
  • 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,
  • the present invention yet further relates to a method for treating or preventing fungal infection, including, for example, infection with an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus.
  • an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dublin
  • the present invention also relates to a method for treating or preventing disease or conditions associated with fungal infection, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, and ventriculitis.
  • candidemia candidemia
  • oral candidiasis vulvovaginal candidiasis
  • aspergillosis aspergillosis
  • allergic bronchopulmonary aspergillosis allergic aspergillus
  • the present invention yet further relates to a method for treating or preventing disease or conditions associated with fungal infection, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal
  • composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism from a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora.
  • a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora.
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism from a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Ap
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism selected from the groups consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus.
  • an organism selected from the groups consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism selected from the groups consisting Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus.
  • an organism selected from the groups consisting Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parap
  • the present invention also relates to a method for treating or preventing fungal infection in plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bankanese disease foot rot of rice, and ergot disease of rye.
  • the present invention also relates to a method for treating or preventing fungal infection in plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bakanese disease, foot rot of rice, and ergot disease of rye
  • the present invention also relates to a method for treating or preventing fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, said wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa, keratitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax, wherein said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis,
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa, keratitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • diseases or conditions associated with fungal infection is selected from the group consisting of keratitis,
  • the present invention also relates to a method for treating or preventing aspergillosis infections in horses, cattle, sheep, goats, dogs and cats said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing aspergillosis infections in horses, cattle, sheep, goats, dogs and cats wherein said method comprises administering to a
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats. including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats.
  • the present invention also relates to a method for treating or preventing mucormycosis infections in horses, cattle, sheep, goats, dogs and cats said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing mucormycosis infections in horses, cattle, sheep, goats, dogs and cats, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • 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 a method for treating or preventing cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention also relates to a method for treating or preventing histoplasmosis in dogs caused by infection with Histoplasma capsulatum, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.
  • the present invention also relates to a method for treating or preventing histoplasmosis in dogs caused by infection with Histoplasma capsulatum, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.
  • the present invention further relates to a process for preparing the antifungal agents of the present invention.
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein said method comprises: selecting a subject in need of treating and preventing disease or conditions associated with fungal infection; and administering to said subject an effective amount of at least one compound as disclosed herein, thereby treating or preventing disease or conditions associated with fungal infection in the subject.
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject wherein the fungal infection is an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora.
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the fungal infection is an organism selected from the group consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the fungal infection is selected from the group consisting of candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, ventric
  • the disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing fungal infection in a plant or plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat,
  • the disclosure provides a method of treating or preventing fungal infections in an animal selected from the group consisting of domesticated animals, livestock, and companion animals, wherein said domesticated animals, livestock and companion animals are selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs, further wherein said fungal infection includes candidiasis infections, wherein said method comprises: selecting said domesticated animal, livestock, or companion animal in need of treating or preventing fungal infections; and administering to said domesticated animal, livestock, or companion animal an effective amount of a compound as disclosed herein, thereby treating or preventing said fungal infections and said domesticated animal, livestock, or companion animal.
  • the disclosure provides a method of treating or preventing fungal infections in an animal wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing aspergillosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats, wherein said method comprises: selecting said animal in need of treating or preventing aspergillosis infections; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing aspergillosis infections in said animal.
  • the disclosure provides a method of treating or preventing aspergillosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing mucormycosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats wherein said method comprises: selecting said animal in need of treating or preventing mucormycosis infections; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing mucormycosis infections in said animal.
  • the disclosure provides a method of treating or preventing mucormycosis infections in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing coccidioidomycosis in an animal selected from the group consisting of dogs and cats, wherein said coccidioidomycosis infection is caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, wherein said method comprises: selecting an animal in need of treating or preventing coccidioidomycosis; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing coccidioidomycosis in said animal.
  • the disclosure provides a method of treating or preventing coccidioidomycosis in an animal wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing blastomycosis in an animal selected from the group consisting of dogs and cats, wherein said blastomycosis is caused by infection with
  • Blastomyces dermatitidis wherein said method comprises: selecting said animal in need of treating or preventing blastomycosis; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing blastomycosis in said animal.
  • the disclosure provides a method of treating or preventing blastomycosis in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, wherein said method comprises: selecting a dog in need of treating or preventing Paracoccidioidomycosis; and administering to said dog an effective amount of a compound as disclosed herein, thereby treating or preventing Paracoccidioidomycosis in said dog.
  • the disclosure provides a method of treating or preventing Paracoccidioidomycosis in dogs wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing dermatophytosis (ringworm) in an animal selected from the group consisting of cats and dogs, wherein said dermatophytosis (ringworm) is caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, wherein said method comprises: selecting a dog or cat in need of treating or preventing dermatophytosis (ringworm); and administering to said dog or cat an effective amount of a compound as disclosed herein, thereby treating or preventing dermatophytosis (ringworm) in the dog or cat.
  • the disclosure provides a method of treating or preventing dermatophytosis (ringworm) in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing cryptococcosis in an animal selected from the group consisting of dogs and cats, wherein said cryptococcosis is caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, wherein said method comprises: selecting a dog or cat in need of treating or preventing cryptococcosis; and administering to the dog or cat an effective amount of a compound as disclosed herein, thereby treating or preventing cryptococcosis in the dog or cat.
  • the disclosure provides a method of treating or preventing cryptococcosis in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides a method of treating or preventing histoplasmosis in dogs, wherein said histoplasmosis is caused by infection with Histoplasma capsulatum, wherein said method comprises: selecting a dog in need of treating or preventing histoplasmosis caused by infection with Histoplasma capsulatum; and administering to said dog an effective amount of a compound as disclosed herein, thereby treating or preventing histoplasmosis caused by infection with Histoplasma capsulatum in the dog.
  • the disclosure provides a method of treating or preventing histoplasmosis in dogs, wherein the at least one compound is administered in a composition further comprising at least one excipient.
  • the disclosure provides for the use of the compositions of the disclosure for the production of a medicament for preventing and/or treating the indications as set forth herein.
  • the present disclosure provides a use of the pharmaceutical compositions described above, in an amount effective for use in a medicament, and most preferably for use as a medicament for treating a disease or disorder, for example, as set forth in herein, in a subject.
  • the present disclosure provides a use of the pharmaceutical compositions described above, and at least one additional therapeutic agent, in an amount effective for use in a medicament, and most preferably for use as a medicament for treating a disease or disorder associated with disease, for example, as set forth herein, in a subject.
  • the disclosure provides a method for treating and/or preventing a disease or condition as set forth herein in a patient, wherein said method comprises: selecting a patient in need of treating and/or preventing said disease or condition as set forth herein; administering to the patient a composition of the disclosure in a therapeutically effective amount, thereby treating and/or preventing said disease in said patient.
  • the compounds of the disclosure act on pathogenic fungi to suppress their growth.
  • the compounds of the disclosure can also kill fungi.
  • antifungal agents the compounds of the disclosure can be used to treat local, topical and disseminated infections in animals including humans and can be used to prevent disseminated fungal infections developing from local or topical fungal infections.
  • the compounds can be applied to agricultural plants, shrubs and trees to cure and prevent fungal infections and fungal diseases.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • alkyl and/or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C 1-6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.
  • Alkyl groups can be optionally substituted.
  • substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3- carboxypropyl, and the like.
  • substituent groups with multiple alkyl groups such as (C 1-6 alkyl) 2 amino, the alkyl groups may be the same or different.
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain.
  • Alkenyl and alkynyl groups can be optionally substituted.
  • Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like.
  • Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7- hydroxy-7-methyloct-3,5-dien-2-yl, and the like.
  • Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.
  • Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5- hydroxy-5-ethylhept-3-ynyl, and the like.
  • cycloalkyl whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted.
  • Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2- methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5- dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl,
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2 CF 3 ). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups. [0080] The term “alkoxy” refers to the group –O-alkyl, wherein the alkyl group is as defined above.
  • Alkoxy groups optionally may be substituted.
  • C 3 -C 6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran).
  • C 3 -C 6 cyclic alkoxy groups optionally may be substituted.
  • aryl wherein used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members.
  • Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms.
  • aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2- hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl, and 6-cyano-naphthylen-1-yl.
  • Aryl groups also include, for example, phenyl or naphthyl rings fused with one
  • arylalkyl or “aralkyl” refers to the group –alkyl-aryl, where the alkyl and aryl groups are as defined herein.
  • Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2- phenylpropyl, fluorenylmethyl and the like.
  • heterocyclic and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic.
  • the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl).
  • heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocycle group can be oxidized.
  • Heterocycle groups can be optionally substituted.
  • Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4- te
  • Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro- 1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.
  • heteroaryl whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non- heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl).
  • heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted.
  • Non-limiting examples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl.
  • heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H- indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.
  • heteroaryl group as described above is C 1 -C 5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • C 1 -C 5 heteroaryl examples include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4- yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2- yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4- yl.
  • the ring when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R 2 and R 3 taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • the ring can be saturated or partially saturated and can be optionally substituted.
  • fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1,2,3,4-tetrahydroquinoline having the formula: is, for the purposes of the present invention, considered a heterocyclic unit.
  • 6,7-Dihydro-5H- cyclopentapyrimidine having the formula: is, for the purposes of the present invention, considered a heteroaryl unit.
  • the aryl ring will predominate and determine the type of category to which the ring is assigned.
  • substituted is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below.
  • the substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time.
  • these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.
  • a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • a two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like.
  • substituted is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent.
  • any number of the hydrogen atoms may be replaced.
  • difluoromethyl is a substituted C 1 alkyl
  • trifluoromethyl is a substituted C 1 alkyl
  • 4-hydroxyphenyl is a substituted aromatic ring
  • (N,N-dimethyl-5-amino)octanyl is a substituted C 8 alkyl
  • 3-guanidinopropyl is a substituted C 3 alkyl
  • 2-carboxypyridinyl is a substituted heteroaryl.
  • variable groups defined herein e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated.
  • the substituents are selected from i) –OR 12 ; for example, –OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 CH 3 ; ii) –C(O)R 12 ; for example, –COCH 3 , –COCH 2 CH 3 , –COCH 2 CH 2 CH 3 ; iii) –C(O)OR 12 ; for example, –CO 2 CH 3 , –CO 2 CH 2 CH 3 , –CO 2 CH 2 CH 2 CH 3 ; iv) –C(O)N(R 12 ) 2 ; for example, –CONH 2 , –CONHCH 3 , –CON(CH 3 ) 2 ; v) –N(R 12 ) 2 ; for example, –CONH 2 , –CONHCH 3 , –CON(CH 3 ) 2 ; v) –N(R 12 ) 2 ; for example, –CONH
  • each R 12 is independently hydrogen, optionally substituted C 1 -C 6 linear or branched alkyl (e.g., optionally substituted C 1 -C 4 linear or branched alkyl), or optionally substituted C 3 -C 6 cycloalkyl (e.g optionally substituted C 3 -C 4 cycloalkyl); or two R 12 units can be taken together to form a ring comprising 3-7 ring atoms.
  • each R 12 is independently hydrogen, C 1 -C 6 linear or branched alkyl optionally substituted with halogen or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.
  • C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 - C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 , alkyl.
  • composition of matter stand equally well for the antifungal agent described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.
  • Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • asymmetric atom also referred as a chiral center
  • the present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
  • compositions of the present teachings which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert- butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts
  • ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,
  • inorganic bases include NaHCO 3 , Na 2 CO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 , Na 2 HPO 4 , and Na 3 PO 4 .
  • Internal salts also can be formed.
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.
  • any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R 9 ) 2 , each R 9 may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the terms “treat” and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
  • “therapeutically effective” and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. As used herein, the term “subject” or “patient” refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human), and most preferably a human.
  • a non-primate e.g., cows, pigs, horses, cats, dogs, rats etc.
  • a primate e.g., monkey and human
  • the subject is a non-human animal such as a farm animal (e.g., horse, cattle, sheep, goats, pig, or cow) or a pet (e.g., a dog or cat).
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
  • the antifungal agents of the present invention are heteroaromatic compounds, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I): Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A 1 is selected from the group consisting of
  • X 1 is selected from the group consisting of N and CR 2a
  • X 2 is selected from the group consisting of N and CR 2b
  • X 3 is selected from the group consisting of O, and S
  • X 4 is selected from the group consisting
  • a 2 is selected from the group consisting
  • X 5 is selected from the group consisting of N and CR 2c ;
  • X 6 is selected from the group consisting of N and CR 2d ;
  • R R m is 0, 1, or 2;
  • n is 1, 2, or 3;
  • a 4 is selected from the group consisting o a q is 0, 1, 2, or 3;
  • t is 1, 2, or 3;
  • R 1 is selected from the group consisting of H, C 1 - 4 alkyl, and C 3 - 5 branched alkyl;
  • R 1 and R 2c may be taken together to form a ring consisting of 5 or 6 members;
  • R 1a is selected from the group consisting of H and C 1 - 4 alkyl;
  • R 2a is selected from the group consisting of H, C 1 - 4 alkyl, C 3 - 5 branched alkyl, C 1 - 4 alkoxy, C 3 - 5 branched alkoxy, F, Cl, CN, OCF 3 , CHF 2 , CF 3 , N(R 6a )(R 6b ),
  • R 8 is a C 1 - 4 alkyl
  • R 9 is a C 1 - 4 alkyl
  • R 3b and R 4b are joined to form a heterocyclic ring consisting of five or six members
  • R 3d and R 4c are joined to form a heterocyclic ring consisting of five or six members.
  • the compounds of the present invention include compounds having formula (II): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (III): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (IV): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (V): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (VI):
  • the compounds of the present invention include compounds having formula (VII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (VIII): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (IX): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (X): including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.
  • the compounds of the present invention include compounds having formula (X):
  • a 1 is R 2b .
  • a 0116 In some embodiments [ 0117] In some embodiments [0118] In some embodiments [ 0119] In some embodiments [0120] In some embodiments [0121] In some embodiments N R 3b N [0122] In some embodiments A 1 is R2b . [0123] In some embodiments [0124] In some embodiments A [0125] In some embodiments A [0126] In some embodiments A [0127] In some embodiments A 1 is . [0128] In some embodiments A [0129] In some embodiments A
  • X 1 is N.
  • X 1 is CR 2a .
  • X 2 is N.
  • X 3 is O.
  • X 3 is S.
  • X 4 is O.
  • X 4 is S.
  • X 4 is NR 1a .
  • a 2 is .
  • X 5 is N.
  • X 5 is CR 2c .
  • X 6 is N.
  • X 6 is CR 2d .
  • H N R 4 [0175]
  • a 3 is m NH .
  • H N O R4 [0177]
  • a 3 n is NH .
  • [0178] In some embodiments [0179] In some embodiments [0180] In some embodiments
  • NH N [0182] In some embodiments A 3 is HN R4 . [0183] In some embodiments [0184] In some embodiments [0185] In some embodiments [0186] In some embodiments [0187] In some embodiments [0188] In some embodiments [0189] In some embodiments R [0190] In some embodiments A 3 is [0191] In some embodiments A 3 is R [0192] In some embodiments A 3 is R [0193] In some embodiments A 3 is [0194] In some embodiments [0195] In some embodiments [0196] In some embodiments [0197] In some embodiments [0198] In some embodiments
  • n is 1. [0221] In some embodiments n is 2. [0222] In some embodiments n is 3. [0223] In some embodiments q is 0. [0224] In some embodiments q is 1. [0225] In some embodiments q is 2. [0226] In some embodiments q is 3. [0227] In some embodiments t is 1. [0228] In some embodiments t is 2. [0229] In some embodiments t is 3. [0230] In some embodiments R 1 is H. [0231] In some embodiments R 1 is C 1 - 4 alkyl. [0232] In some embodiments R 1 is C 3 - 5 branched alkyl.
  • R 1 and R 2c are taken together to form a carbocyclic ring consisting of 5 members. [0234] In some embodiments R 1 and R 2c are taken together to form a carbocyclic ring consisting of 6 members. [0235] In some embodiments R 1a is H. [0236] In some embodiments R 1a is C 1 - 4 alkyl. [0237] In some embodiments R 2a is H. [0238] In some embodiments R 2a is C 1 - 4 alkyl. [0239] In some embodiments R 2a is C 3 - 5 branched alkyl. [0240] In some embodiments R 2a is C 1 - 4 alkoxy.
  • R 2a is C 3 - 5 branched alkoxy.
  • R 2a is F.
  • R 2a is Cl.
  • R 2a is CN.
  • R 2a is OCF 3 .
  • R 2a is CHF 2 .
  • R 2a is CF 3 .
  • R 2a is N(R 6a )(R 6b ).
  • r [0249] In some embodiments R 2a is .
  • R 2a is [0251] In some embodiments R 2a is SR 8 .
  • R 2a is SO 2 R 9 .
  • Y 1 is O.
  • Y 1 is NR 7 .
  • R 2b is H.
  • R 2b is C 1 - 4 alkyl.
  • R 2b is C3-C5 branched alkyl.
  • R 2b is C 1 - 4 alkoxy.
  • R 2b is C 3 - 5 branched alkoxy.
  • R 2b is F.
  • R 2b is Cl.
  • R 2b is CN. [0263] In some embodiments R 2b is OCF 3 . [0264] In some embodiments R 2b is CHF 2 . [0265] In some embodiments R 2b is CF 3 . [0266] In some embodiments R 2b is N(R 6a )(R 6b ). r [0267] In some embodiments R 2b is . [0268] In some embodiments R 2b is [0269] In some embodiments R 2b is SR 8 . [0270] In some embodiments R 2b is SO 2 R 9 . [0271] In some embodiments R 2c is H. [0272] In some embodiments R 2c is C 1 - 4 alkyl.
  • R 2c is C 3 - 5 branched alkyl. [0274] In some embodiments R 2c is C 1 - 4 alkoxy. [0275] In some embodiments R 2c is C 3 - 5 branched alkoxy. [0276] In some embodiments R 2c is F. [0277] In some embodiments R 2c is Cl. [0278] In some embodiments R 2c is CN. [0279] In some embodiments R 2c is OCF 3 . [0280] In some embodiments R 2c is CHF 2 . [0281] In some embodiments R 2c is CF 3 .
  • R 2c is N(R 6a )(R 6b )/ [0283] In some embodiments [0284] In some embodiments [0285] In some embodiments R 2c is SR 8 . [0286] In some embodiments R 2c is SO 2 R 9 . [0287] In some embodiments Y 2 is O. [0288] In some embodiments Y 2 is NR 7 . [0289] In some embodiments R 2d is H. [0290] In some embodiments R 2d is C 1 - 4 alkyl. [0291] In some embodiments R 2d is C 3 - 5 branched alkyl. [0292] In some embodiments R 2d is C 1 - 4 alkoxy.
  • R 2d is C 3 - 5 branched alkoxy.
  • R 2d is F.
  • R 2d is Cl.
  • R 2d is CN.
  • R 2d is OCF 3 .
  • R 2d is CHF 2 .
  • R 2d is CF 3 .
  • R 2d is N(R 6a )(R 6b ).
  • r [0301] In some embodiments R 2d is .
  • R 2d is [0303] In some embodiments R 2d is SR 8 .
  • R 2d is SO 2 R 9 .
  • Y 3 is O.
  • Y 3 is NR 7 .
  • R 3a is H.
  • R 3a is C 1 - 4 alkyl.
  • R 3a is C 3 - 5 branched alkyl,
  • R 3a is C 1 - 4 alkoxy.
  • R 3a is C 3 - 5 branched alkoxy,
  • R 3a is F.
  • R 3a is Cl.
  • R 3a is CN. [0315] In some embodiments R 3a is OCF 3 . [0316] In some embodiments R 3a is CHF 2 . [0317] In some embodiments R 3a is CF 3 . [0318] In some embodiments R 3a is N(R 6a )(R 6b ). r [0319] In some embodiments R 3a is . [0320] In some embodiments R 3a is [0321] In some embodiments R 3a is SR 8 . [0322] In some embodiments R 3a is, SO 2 R 9 . [0323] In some embodiments Y 4 is O. [0324] In some embodiments Y 4 is NR 7 .
  • R 3b is H. [0326] In some embodiments R 3b is C 1 - 4 alkyl. [0327] In some embodiments R 3b is C 3 - 5 branched alkyl. [0328] In some embodiments R 3b is C 1 - 4 alkoxy. [0329] In some embodiments R 3b is C 3 - 5 branched alkoxy. [0330] In some embodiments R 3b is F. [0331] In some embodiments R 3b is Cl. [0332] In some embodiments R 3b is CN. [0333] In some embodiments R 3b is OCF 3 . [0334] In some embodiments R 3b is CHF 2 .
  • R 3b is CF 3 .
  • R 3b is N(R 6a )(R 6b ).
  • r [0337] In some embodiments R 3b is .
  • R 3b is [0338] In some embodiments R 3b is [0339] In some embodiments R 3b is SR 8 .
  • R 3b is SO 2 R 9 .
  • R 3c is H. [0342] In some embodiments R 3c is C 1 - 4 alkyl. [0343] In some embodiments R 3c is C 3 - 5 branched alkyl, [0344] In some embodiments R 3c is C 1 - 4 alkoxy. [0345] In some embodiments R 3c is C 3 - 5 branched alkoxy, [0346] In some embodiments R 3c is F. [0347] In some embodiments R 3c is Cl. [0348] In some embodiments R 3c is CN. [0349] In some embodiments R 3c is OCF 3 . [0350] In some embodiments R 3c is CHF 2 .
  • R 3c is CF 3 .
  • R 3c is N(R 6a )(R 6b ).
  • R 3c is [0354]
  • R 3ca is SR 8 .
  • R 3c is, SO 2 R 9 .
  • Y 5 is O.
  • Y 5 is NR 7 .
  • R 3d is H. [0360] In some embodiments R 3d is C 1 - 4 alkyl.
  • R 3d is C 3 - 5 branched alkyl, [0362] In some embodiments R 3d is C 1 - 4 alkoxy. [0363] In some embodiments R 3d is C 3 - 5 branched alkoxy, [0364] In some embodiments R 3d is F. [0365] In some embodiments R 3d is Cl. [0366] In some embodiments R 3d is CN. [0367] In some embodiments R 3d is OCF 3 . [0368] In some embodiments R 3d is CHF 2 . [0369] In some embodiments R 3d is CF 3 . [0370] In some embodiments R 3d is N(R 6a )(R 6b ).
  • R 3d is . [0372] In some embodiments R 3d is [0373] In some embodiments R 3d is SR 8 . [0374] In some embodiments R 3d is, SO 2 R 9 . [0375] In some embodiments Y 6 is O. [0376] In some embodiments Y 6 is NR 7 . [0377] In some embodiments r is 0. [0378] In some embodiments r is 1. [0379] In some embodiments r is 2. [0380] In some embodiments r is 3. [0381] In some embodiments R 4 is H. [0382] In some embodiments R 4 is, C 1 - 4 alkyl. [0383] In some embodiments R 4 is CN.
  • R 4 is CH 2 (CH 2 ) g C 1 - 4 alkoxy.. [0385] In some embodiments R 4 is -CH 2 (CH 2 ) g C 3-5 branched alkoxy. [0386] In some embodiments g is 1. [0387] In some embodiments g is 2. [0388] In some embodiments R 4a is H. [0389] In some embodiments R 4a is C 1 - 4 alkyl. [0390] In some embodiments R 4b is H. [0391] In some embodiments R 4b is C 1 - 4 alkyl. [0392] In some embodiments R 4c is H. [0393] In some embodiments R 4c is C 1 - 4 alkyl.
  • R 4d is H. [0395] In some embodiments R 4d is C 1 - 4 alkyl. [0396] In some embodiments R 4e is H. [0397] In some embodiments R 4e is C 1 - 4 alkyl. [0398] In some embodiments R 5a is H. [0399] In some embodiments R 5a is C 1 - 4 alkyl. [0400] In some embodiments R 5b is H. [0401] In some embodiments R 5b is C 1 - 4 alkyl. [0402] In some embodiments R 5c is H. [0403] In some embodiments R 5c is C 1 - 4 alkyl. [0404] In some embodiments R 5d is H.
  • R 5d is C 1 - 4 alkyl.
  • R 5e is H.
  • R 5e is C 1 - 4 alkyl.
  • R 5f is C 1 - 4 alkyl.
  • R 5f is C 3 - 5 branched alkyl.
  • R 5f is C 3 - 5 cycloalkyl.
  • R 6a is hydrogren.
  • R 6a is C 1 - 4 alkyl.
  • R 6b is hydrogen.
  • R 6b is C 1 - 4 alkyl.
  • R 7 is C 1 - 4 alkyl.
  • R 9 is C 1 - 4 alkyl.
  • R 9 is C 1 - 4 alkyl.
  • R 3b and R 4b are joined to form a heterocyclic ring consisting of five members.
  • R 3b and R 4b are joined to form a heterocyclic ring consisting of six members.
  • R 3d and R 4c are joined to form a heterocyclic ring consisting of five members.
  • R 3d and R 4c are joined to form a heterocyclic ring consisting of six members.
  • Compounds of the present invention include compounds having the formula (XI) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R 2b , R 2d , R 3a , R 3c and R 3d are defined herein below in Table 1. Table 1: Exemplary compounds of the formula (XI)
  • Compounds of the present invention include compounds having the formula (XII) or a pharmaceutically acceptable salt form thereof:
  • Compounds of the present invention include compounds having the formula (XIII) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R 2a , R 2b , R 2d , R 3a , R 3b , R 3c , and R 3d are defined herein below in Table 3.
  • Table 3 Exemplary compounds of the formula (XIII)
  • Compounds of the present invention include compounds having the formula (XIV) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 3c , and R 3d are defined herein below in Table 4.
  • Table 4 Exemplary compounds of the formula (XIV)
  • Compounds of the present invention include compounds having the formula (XV) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R 2a , R 2b , R 3a , R 3b , R 3c ,, and R 3d are defined herein below in Table 5.
  • Table 5 Exemplary compounds of the formula (XV)
  • Compounds of the present invention include compounds having the formula (XVI) or a pharmaceutically acceptable salt form thereof: wherein non-limiting examples of R 2a , R 2b , R 2c , R 2d , R 3c ,, and R 3d are defined herein below in Table 6.
  • Table 6 Exemplary compounds of the formula (XVI)
  • the compound having the formula: [0429] has the chemical name N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamide.
  • the compound having the formula: [0431] has the chemical name 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide.
  • the compound having the formula: [0433] has the chemical name 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-N-methylbenzamide [0434]
  • a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.
  • the present invention further relates to a process for preparing the antifungal effect agents of the present invention.
  • Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).
  • HPLC high pressure liquid chromatograpy
  • GC gas chromatography
  • GPC gel-permeation chromatography
  • the chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.
  • the reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than
  • the compounds of these teachings can be prepared by methods known in the art of organic chemistry.
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes. GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS.
  • the reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.
  • Compounds of formula (I) may be prepared according to the process outlined in schemes 1-216.
  • a compounds of the formula (1) a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (2), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diis
  • a compound of the formula (3) is reacted with a compound of the formula (5), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybipheny
  • a compound of the formula (6) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (7).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide,
  • a compounds of the formula (7) is reacted with a compound of the formula (8) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, dimethyl
  • a compound of the formula (9) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide
  • a compounds of the formula (10), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (11), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the
  • a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like
  • a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
  • a compound of the formula (13), a known compound or a compound prepared by known methods is reacted with a compound of the formula (11), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichlor
  • a compound of the formula (12) is reacted with a compound of the formula (14), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (15) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compounds of the formula (16) is reacted with a compound of the formula (17) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (18).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, dimethyl
  • a compound of the formula (18) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (19).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide
  • a compounds of the formula (20), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (21), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a
  • a compound of the formula (20a), a known compound or a compound prepared by known methods is reacted with a compound of the formula (21), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (22).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichlor
  • a compound of the formula (22) is reacted with a compound of the formula (23), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphen
  • a compound of the formula (24) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (25).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide,
  • a compounds of the formula (25) is reacted with a compound of the formula (26) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (27).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (27) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfox
  • a compound of the formula (31) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, di
  • a compounds of the formula (35) is reacted with a compound of the formula (32), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-diox
  • a compounds of the formula (39), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (40), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on a palladium catalyst
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on
  • organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and
  • a compound of the formula (44) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (45).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohex
  • organophosphine such as dicyclohexyl(2’,6’-dimethoxyb
  • a compounds of the formula (48), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (49), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (50) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide,
  • a compounds of the formula (51) is reacted with a compound of the formula (52) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (53).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (53) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (54).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfox
  • a compounds of the formula (55), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (56), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-
  • dimethylaminopropyl) carbodiimide 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (57).
  • a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like
  • a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,
  • a compound of the formula (57) is reacted with a compound of the formula (58) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7- ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (59).
  • a base such as 1,8-diazabicyclo[5.4.0]undec-7- ene, 1,5-di
  • a compound of the formula (59) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (60) is reacted with a compound of the formula (61) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (62).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (62) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine
  • a compound of the formula (65) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (66).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compound of the formula (66) is reacted with a compound of the formula (67), a known compound of a compound prepared by known methods, in the presence of a solvent such as a methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (68).
  • a solvent such as a methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (68).
  • a compound of the formula (68) is reacted with iodomethane in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (69).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (69).
  • a compound of the formula (69) is reacted with a compound of the formula (70), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-
  • a compound of the formula (72), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (73) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of
  • a compound of the formula (74) is reacted with a compound of the formula (75) in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-di
  • a compound of the formula (76) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (77).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide,
  • a compound of the formula (80) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (81).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compounds of the formula (81) is reacted with a compound of the formula (82) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (83).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (83) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (84).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfox
  • a compound of the formula (85) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula
  • a compound of the formula (85) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-
  • a compounds of the formula (86) is reacted with a compound of the formula (87) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (88).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (88) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (89).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compound of the formula (90), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (91) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (92).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a compound of the formula (92) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (93).
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, and the like, optionally with heating, optional
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II)
  • organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphen
  • a compound of the formula (96) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (97).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide
  • a compounds of the formula (97) is reacted with a compound of the formula (93) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofur
  • a compounds of the formula (99) is reacted with a compound of the formula (100) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (101).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (101) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (102).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (103) is reacted with a compounds of the formula (104) in the presence of a base such as base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (105).
  • a compound of the formula (105) is
  • a compounds of the formula (106) is reacted with a compound of the formula (107) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, m
  • a compound of the formula (108) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (109).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfox
  • a compounds of the formula (109) is reacted with a compound of the formula (110) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (111) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-
  • a compound of the formula (113), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (114) in the presence of in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (115).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and
  • a compound of the formula (115) is reacted with a compound of the formula (116), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (117).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydr
  • a compound of the formula (117) is reacted with a compound of the formula (118), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (119) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (120).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (120) is reacted with a compound of the formula (121) in the presence of in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (122).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (122) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (123).
  • a compound of the formula (124), a known compound or a compound prepared by known methods is reacted with a compound of the formula (125), a known compound or a compound prepared by
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphen
  • a compound of the formula (126) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (127).
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxan
  • a compound of the formula (127) is reacted with a compound of the formula (128), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (129).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetra
  • a compound of the formula (131) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (132) is reacted with a compound of the formula (133) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (134).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (134) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (135).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (136), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (137), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (138).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dich
  • a compounds of the formula (138) is reacted with a compound of the formula (139), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (140) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (141).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide
  • a compounds of the formula (141) is reacted with a compound of the formula (142) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (143).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (143) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (144).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compound of the formula (145), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (146), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (147).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a compounds of the formula (147) is reacted with a compound of the formula (148), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphen
  • a compound of the formula (150), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (151), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (152).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- di
  • a compound of the formula (153) is reacted with a compound of the formula (154), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (155).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran
  • a compounds of the formula (155) is reacted with a compound of the formula (156), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphen
  • biphenyl-3-sulfonate 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride,
  • a compound of the formula (157) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (158).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide,
  • a compounds of the formula (158) is reacted with a compound of the formula (159) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (160).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, dimethyl
  • a compound of the formula (160) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (161).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (162), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (163), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexy
  • a compound of the formula (170) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (171).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacet
  • a compounds of the formula (171) is reacted with a compound of the formula (172) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (173).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (173) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (174).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compound of the formula (175) is reacted with a compound of the formula (176), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (177).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran
  • a compound of the formula (181) is reacted with a compound of the formula (179), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (180).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofur
  • a compound of the formula (180) is reacted with a compound of the formula (181), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxyb
  • a compound of the formula (182) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (183).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacet
  • a compounds of the formula (183) is reacted with a compound of the formula (184) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (185).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (185) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (186).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (187), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (188), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (190), a known compound or a compound prepared by known methods is reacted with a compound of the formula (188), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (189).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dich
  • a compound of the formula (189) is reacted with a compound of the formula (191), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (192) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (193).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacet
  • a compounds of the formula (193) is reacted with a compound of the formula (194) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (195).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (195) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (196).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (197), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (198), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (200), a known compound or a compound prepared by known methods is reacted with a compound of the formula (198), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (199).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dich
  • a compound of the formula (199) is reacted with a compound of the formula (201), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphen
  • a compound of the formula (202) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (203).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide,
  • a compounds of the formula (203) is reacted with a compound of the formula (204) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (205).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (205) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (206).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • biphenyl-3-sulfonate 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride,
  • a compound of the formula (209) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (210).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,
  • a compounds of the formula (213) is reacted with a compound of the formula (210), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dio
  • a compounds of the formula (224), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (225), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like,
  • a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluoro
  • a compound of the formula (226) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (227).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compounds of the formula (227) is reacted with a compound of the formula (228) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (229) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (230).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (231), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (232) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (233).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a compound of the formula (233) is reacted with a compound of the formula (234) wherein Z 3 is selected from the group consisting of iodine, bromine and chlorine, in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine,
  • a compound of the formula (235) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • a compound of the formula (237) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxan
  • a compound of the formula (237) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (238).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (238).
  • a compounds of the formula (238) is reacted with a compound of the formula (239) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (240).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (240) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (241).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (244) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (245).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide
  • a compounds of the formula (245) is reacted with a compound of the formula (246) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydro
  • a compound of the formula (247) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (248).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (248) is reacted with a compound of the formula (249) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (250).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (250) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (251).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (252) is reacted with a compound of the formula (253) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydro
  • a compound of the formula (254) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (255).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (255) is reacted with a compound of the formula (256) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (257).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (257) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (258).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsul
  • a compound of the formula (259) is reacted with a compound of the formula (260), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (261) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (262).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (262) is reacted with a compound of the formula (263) in the presence of in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as
  • N,N-dimethylformamide dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (264).
  • a compound of the formula (264) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (265).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (263).
  • a compounds of the formula (263) is reacted with a compound of the formula (264) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (265).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (265) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (266).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (267) is reacted with a compound of the formula (268), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphos
  • 2-yl)phosphine 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-b
  • a compound of the formula (269) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (270).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide
  • a compounds of the formula (270) is reacted with a compound of the formula (271) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (272).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (272) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • a compounds of the formula (274) is reacted with a compound of the formula (275), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexy
  • a compounds of the formula (277) is reacted with a compound of the formula (278), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile
  • an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-
  • a compound of the formula (279) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (280).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide
  • a compounds of the formula (280) is reacted with a compound of the formula (281) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (282).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (282) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • a compound of the formula (286) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (287).
  • a compounds of the formula (287) is reacted with a compound
  • a compound of the formula (289) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (290).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (291) is reacted with a compound of the formula (292), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimeth
  • a compound of the formula (293) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (294).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (294).
  • a compound of the formula (293) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (294).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (297) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (298).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide
  • a compounds of the formula (298) is reacted with a compound of the formula (299) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,
  • a compound of the formula (300) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (301).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (301).
  • a compound of the formula (300) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (301).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with
  • a compound of the formula (301) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (302).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (302) is reacted with a compound of the formula (303) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (304).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, dimethyl
  • a compound of the formula (304) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (305).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (306) is reacted with a compound of the formula (307) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
  • hexafluorophosphate N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (308).
  • a base such as triethylamine, diisopropylethylamine, N-methylmorpholine
  • a compound of the formula (308) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (309).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (309).
  • a compound of the formula (308) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylform
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (309).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (309) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (310).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (310) is reacted with a compound of the formula (311) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (312).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, di
  • a compound of the formula (312) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (313).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (316) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (317).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (317).
  • a compound of the formula (316) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (317).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (318) is reacted with a compound of the formula (319), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimeth
  • a compound of the formula (320) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (320) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (321).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (321) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (322).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (322) is reacted with a compound of the formula (323) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (324).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (324) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (325).
  • a compound of the formula (326) is reacted with a compound of the formula (327), a known
  • a palladium catalyst 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-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-di
  • organophosphine such as dicyclo
  • a compound of the formula (328) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (329).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (329).
  • a compound of the formula (328) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (329).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (329) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol,
  • N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (330).
  • a compound of the formula (333) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (334).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like
  • a compound of the formula (333) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (334).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating,
  • a compound of the formula (334) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (335).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (335) is reacted with a compound of the formula (336) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (337).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (337) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (338).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (339) is reacted with a compound of the formula (340), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (341) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compound of the formula (341) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (342).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (342) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (343).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (343) is reacted with a compound of the formula (344) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (345).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (345) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (346).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (347) is reacted with a compound of the formula (348), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (349) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (350).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (350).
  • a compound of the formula (349) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (350).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (350) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (351).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (351) is reacted with a compound of the formula (352) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (353).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (353) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (354).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compound of the formula (357) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compound of the formula (357) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (358).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating,
  • a compound of the formula (358) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (359).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (359) is reacted with a compound of the formula (360) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (361).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (361) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (362).
  • a compound of the formula (363) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N
  • a compound of the formula (363) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (364).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (364).
  • a compound of the formula (364) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (365).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (365).
  • a compound of the formula (364) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • a compound of the formula (366) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N
  • a compound of the formula (366) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (367).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (367).
  • a compound of the formula (367) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (368).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (368).
  • a compound of the formula (367) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (368).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (368) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (369).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (369) is reacted with a compound of the formula (370) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (371).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (371) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (372).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (373) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a palladium catalyst such as
  • a compound of the formula (373) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (374).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (374).
  • a compound of the formula (374) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (375).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (375).
  • a compound of the formula (374) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide,
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (375).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to
  • a compound of the formula (375) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (376).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (376) is reacted with a compound of the formula (377) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (378).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (378) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (379).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (380) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
  • a compound of the formula (380) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-
  • a compound of the formula (381) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (382).
  • a compound of the formula (381) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (382).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (383) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
  • a compound of the formula (384) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (385).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (385).
  • a compound of the formula (384) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (385).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (385) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (386).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (386) is reacted with a compound of the formula (387) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (388).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (388) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (389).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (390) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
  • a compound of the formula (390) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (391).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (391).
  • a compound of the formula (391) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (392).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (392).
  • a compound of the formula (391) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (392).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (392) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol,
  • N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (393).
  • a compound of the formula (394) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
  • a compound of the formula (394) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (395).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (395).
  • a compound of the formula (395) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (396).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (396).
  • a compound of the formula (395) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide,
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (396).
  • a compound of the formula (396) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (397).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (397) is reacted with a compound of the formula (398) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (399).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (399) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (400).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (401) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (40
  • a compound of the formula (401) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (402).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (402).
  • a compound of the formula (402) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (403).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (403).
  • a compound of the formula (402) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • the resulting material is then reacted with ammonia in a solvent
  • a compound of the formula (403) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (404).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (404) is reacted with a compound of the formula (405) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (406).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (406) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (407).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (408) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
  • a compound of the formula (408) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (409).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (409).
  • a compound of the formula (409) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (410).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (410).
  • a compound of the formula (409) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (410).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (410) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (411).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (411) is reacted with a compound of the formula (412) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (413).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (413) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (414).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (415) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the
  • a compound of the formula (415) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (416).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (416).
  • a compound of the formula (416) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (417).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (417).
  • a compound of the formula (416) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave
  • a compound of the formula (417) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (418).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (418) is reacted with a compound of the formula (419) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (420).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (420) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (421).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (422) is reacted with a compound of the formula (423), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),
  • a compound of the formula (424) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (425).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (425) is reacted with a compound of the formula (426) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (427).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (427) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (428).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (432).
  • a compounds of the formula (432) is reacted with a compound of the formula (433) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,
  • a compound of the formula (434) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (435).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (435) is reacted with a compound of the formula (436) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (437).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (437) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (438).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (439) is reacted with a compound of the formula (440) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydro
  • a compound of the formula (441) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (442).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (442) is reacted with a compound of the formula (443) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (444).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (444) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (445).
  • a compound of the formula (446) wherein Z 8 is selected from the group consisting of iodine, bromine and chlorine is reacted with a compound of the formula (447) in the presence of in the presence
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane
  • a compound of the formula (448) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (449).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (449) is reacted with a compound of the formula (450) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (451).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (451) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (452).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (453) is reacted with a compound of the formula (454), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),
  • a compound of the formula (455) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (456).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (456) is reacted with a compound of the formula (457) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (458).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (458) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (459).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (460) is reacted with a compound of the formula (461), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (462) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (463).
  • a compounds of the formula (463) is reacted with a compound
  • a compound of the formula (465) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (466).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to
  • a compound of the formula (469) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (470).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (470) is reacted with a compound of the formula (471) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (472).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (472) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (473).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (474) is reacted with a compound of the formula (475), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-
  • a compound of the formula (476) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (477).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (477) is reacted with a compound of the formula (478) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (479).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (479) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (480).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (481) is reacted with a compound of the formula (482), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (483) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (484).
  • a compounds of the formula (484) is reacted with a compound of the formula (485) in the presence of a base such as triethylamine, N,N-
  • a compound of the formula (486) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (487).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • potassium hydroxide triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (490).
  • a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (490).
  • a compound of the formula (490) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (491).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (491) is reacted with a compound of the formula (492) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (493).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (493) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (494).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (495), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (496), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (497) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (498).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compounds of the formula (498) is reacted with a compound of the formula (499) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (500).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (500) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (501).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (502) is reacted with a compound of the formula (503) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-
  • a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-
  • a compound of the formula (504) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (505).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (505) is reacted with a compound of the formula (506) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (507).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (507) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (508).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsul
  • a compound of the formula (511) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (512).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacet
  • a compounds of the formula (512) is reacted with a compound of the formula (513) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran
  • a compound of the formula (514) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (515).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • potassium hydroxide triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (518).
  • a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (518).
  • a compound of the formula (518) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (519).
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-diox
  • a compound of the formula (519) is reacted with a compound of the formula (520), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (521).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, te
  • a compound of the formula (523) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (524).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (524) is reacted with a compound of the formula (525) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (526).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (526) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (527).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichlor
  • a compounds of the formula (530) is reacted with a compound of the formula (531), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (532) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (533).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide
  • a compounds of the formula (533) is reacted with a compound of the formula (534) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (535).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (535) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (536).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (539) is reacted with a compound of the formula (540), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphen
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-d
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(tripheny
  • a compounds of the formula (548), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (549), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (553) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (554).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compounds of the formula (554) is reacted with a compound of the formula (555) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (556).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (556) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (557).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (560) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (561).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (562) is reacted with a compound of the formula (563) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (564).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (564) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (565).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (566) is reacted with a compound of the formula (567), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (568) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane,
  • a compounds of the formula (569) is reacted with a compound of the formula (570) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (571).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (571) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (572).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (573) is reacted with a compound of the formula (574), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicy
  • a compound of the formula (578) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (579).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (579).
  • a compound of the formula (578) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (579).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (579) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (580).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide
  • a compounds of the formula (580) is reacted with a compound of the formula (581) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (582).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (582) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (583).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (584) is reacted with a compound of the formula (585) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like,
  • a compound of the formula (586) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (587).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like
  • a compound of the formula (586) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (587).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (587) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (588).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (588) is reacted with a compound of the formula (589) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (590).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (590) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (591).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (594) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (595).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (595).
  • a compound of the formula (594) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • the resulting material is then reacted with ammonia in a solvent
  • a compound of the formula (598) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,
  • a compound of the formula (599) is reacted with a compound of the formula (600), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (601).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, te
  • dichloroethane, 1,2-dimethoxyethane, and the like optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (603).
  • a compound of the formula (603) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (604).
  • a compound of the formula (603) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (604).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (604) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (605).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (605) is reacted with a compound of the formula (606) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (607).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (607) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • a compound of the formula (609), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (610), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (611).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dich
  • a compounds of the formula (611) is reacted with a compound of the formula (612), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • dichloroethane, 1,2-dimethoxyethane, and the like optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (613).
  • a compound of the formula (613) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (614).
  • a compound of the formula (613) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (614).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (614) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (615).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (615) is reacted with a compound of the formula (616) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (617) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (618).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a compounds of the formula (621) is reacted with a compound of the formula (622), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphen
  • a compound of the formula (623) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (624).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (624).
  • a compound of the formula (623) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (624).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (624) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (625).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (625) is reacted with a compound of the formula (626) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (627).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (627) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (628).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (629), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (630), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (631).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-
  • a compounds of the formula (635), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (636), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compounds of the formula (638), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (639), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (640) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (641).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (641).
  • a compound of the formula (640) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (641).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (641) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the
  • a compounds of the formula (642) is reacted with a compound of the formula (643) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (644).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (644) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (645).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (648) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (649).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (649).
  • a compound of the formula (648) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (649).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (649) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (650).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (650) is reacted with a compound of the formula (651) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane,
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane,
  • a compound of the formula (652) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (653).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (654) is reacted with a compound of the formula (655), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (656) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (657).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like
  • a compound of the formula (656) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (657).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (657) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (658).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide
  • a compounds of the formula (658) is reacted with a compound of the formula (659) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (660).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (660) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,
  • a compounds of the formula (662) is reacted with a compound of the formula (663), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compounds of the formula (665), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (666), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (667) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (668).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (668).
  • a compound of the formula (667) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (668).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (668) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (669) is reacted with a compound of the formula (670) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (671).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (671) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (672).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (673) is reacted with a compound of the formula (674) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like,
  • a compound of the formula (675) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (676).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like
  • a compound of the formula (675) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (676).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (676) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (677).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (677) is reacted with a compound of the formula (678) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (679).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (679) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palla
  • a compound of the formula (683) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (684).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (684).
  • a compound of the formula (683) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • dimethylacetamide, and the like optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (684).
  • a compound of the formula (667) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane,
  • a compound of the formula (668) is reacted with a compound of the formula (669), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (670).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, te
  • dichloroethane, 1,2-dimethoxyethane, and the like optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (672).
  • a compound of the formula (672) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (673).
  • a compound of the formula (672) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (673).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (673) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (674).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (674) is reacted with a compound of the formula (675) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (676).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (676) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • a compound of the formula (678), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (679), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (680).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dich
  • a compounds of the formula (680) is reacted with a compound of the formula (681), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (682) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (683).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like
  • a compound of the formula (682) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (683).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (683) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (684).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (684) is reacted with a compound of the formula (685) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (686).
  • a compound of the formula (686) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as
  • a compound of the formula (688), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (689), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (690).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a compounds of the formula (690) is reacted with a compound of the formula (691), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphen
  • biphenyl)-2-amine, and the like in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (692).
  • a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine,
  • a compound of the formula (692) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (693).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (693).
  • a compound of the formula (692) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethyl
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (693).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (693) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (694).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (694) is reacted with a compound of the formula (695) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (696).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (696) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (697).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- di
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-
  • a compounds of the formula (704), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (705), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compounds of the formula (707), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (708), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as
  • a compound of the formula (709) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (710).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (710).
  • a compound of the formula (709) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- di
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (710).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally
  • a compound of the formula (710) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the
  • a compounds of the formula (711) is reacted with a compound of the formula (712) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (713).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (713) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (714).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (717) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (718).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (718).
  • a compound of the formula (717) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (718).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (718) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (719).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylace
  • a compounds of the formula (719) is reacted with a compound of the formula (720) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (721).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (721) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (722).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (723) is reacted with a compound of the formula (724), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimeth
  • a compound of the formula (725) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • the resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (726).
  • a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optional
  • a compound of the formula (726) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (727).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide
  • a compounds of the formula (727) is reacted with a compound of the formula (728) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (729).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (729) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-
  • a compounds of the formula (731) is reacted with a compound of the formula (732), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexy
  • a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (736).
  • a compound of the formula (737) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (738).
  • a compound of the formula (738) is reacted with a compound of the formula (739), a known compound or a
  • a compound of the formula (741) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (742).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (742) is reacted with a compound of the formula (743), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (744).
  • a compound of the formula (745) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as
  • a compound of the formula (746) is reacted with a compound of the formula (747), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (748).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (749) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (750).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (750) is reacted with a compound of the formula (751), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (752).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (753) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (754).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (754) is reacted with a compound of the formula (755), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (756).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (757) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (758).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • compound of the formula (758) is reacted with a compound of the formula (759), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (760).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave i
  • a compounds of the formula (761) is reacted with a compound of the formula (762), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropyleth
  • a compound of the formula (763) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (764).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (764) is reacted with a compound of the formula (765), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,
  • a compound of the formula (766) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (767).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (766) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (767).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (767) is reacted with a compound of the formula (768) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (769).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (769) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (770).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (771) is reacted with a compound of the formula (772), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropyleth
  • a compound of the formula (773) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (774).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (774) is reacted with a compound of the formula (775), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (776).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (776) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on a catalyst
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on
  • a compound of the formula (776) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (777).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (777) is reacted with a compound of the formula (778) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (779).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (779) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (780).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (784), a known compound or a compound prepared by known methods is reacted with a compound of the formula (782), a a known compound or a compound made by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (784).
  • a base such as triethylamine, N,N- diisopropylethylamine,
  • a compound of the formula (784) is reacted with a compound of the formula (785), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybi
  • a compound of the formula (786) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (787).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (787) is reacted with a compound of the formula (788), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (789).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (789) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (790).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (789) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (790).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (790) is reacted with a compound of the formula (791) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide,
  • a compound of the formula (792) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (793).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a base such as triethyl
  • a compound of the formula (796) is reacted with a compound of the formula (797), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (798).
  • a compound of the formula (798) is reacted with
  • a compound of the formula (799), a known compound or a compound prepared by known methods in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphos
  • a compound of the formula (800) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (801).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (801) is reacted with a compound of the formula (802), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (803).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (803) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (804).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (804).
  • a compound of the formula (805), a known compound or a compound prepared by known methods is reacted with a compound of the formula (806) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2
  • a compound of the formula (807) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane,
  • a compound of the formula (808) is reacted with a compound of the formula (809), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (810).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, te
  • a compounds of the formula (810) is reacted with a compound of the formula (811), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexyl
  • a compound of the formula (812) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (813).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (813) is reacted with a compound of the formula (814), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (815).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (815) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (816).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (815) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (816).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (816) is reacted with a compound of the formula (817) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (818).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (818) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,
  • a base such as triethylamine,
  • a compounds of the formula (822) is reacted with a compound of the formula (823), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (824) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (825).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (825) is reacted with a compound of the formula (826), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (827).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (827) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (828).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (827) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene
  • a compounds of the formula (828) is reacted with a compound of the formula (829) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (830).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (830) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (831).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (834) is reacted with a compound of the formula (834) is reacted with a compound
  • formula (835) a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-
  • a compound of the formula (836) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (837).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (837) is reacted with a compound of the formula (838), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (839).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (839) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (840).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (840).
  • a compounds of the formula (840) is reacted with a compound of the formula (841) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (842).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (842) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (843).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (846) is reacted with a compound of the formula (847), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybi
  • a compound of the formula (848) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (849).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (849) is reacted with a compound of the formula (850), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (851).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (851) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (852).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (851) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (852).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4
  • a compounds of the formula (852) is reacted with a compound of the formula (853) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (854).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (854) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (855).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compound of the formula (858) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (859).
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, methanol, and the like, optionally with heating,
  • a compounds of the formula (859) is reacted with a compound of the formula (860) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,
  • a compound of the formula (861) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (862) is reacted with a compound of the formula (863), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (864).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like
  • a compound of the formula (864) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (865).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (865) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (865).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4
  • a compounds of the formula (865) is reacted with a compound of the formula (866) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (867).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (867) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • a compound of the formula (872) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (873).
  • a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradi
  • a compounds of the formula (873) is reacted with a compound of the formula (874) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran,
  • a compound of the formula (876) is reacted with a compound of the formula (877), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (878).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (878) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (879).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (878) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (879).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4
  • a compounds of the formula (879) is reacted with a compound of the formula (880) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (881).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (881) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,
  • a compound of the formula (883) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the
  • a compound of the formula (883) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (884).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (884).
  • a compound of the formula (884) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (885).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-d
  • a compound of the formula (885) is reacted with a compound of the formula (886), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with a solvent such as methylene chloride, chloroform, 1,2-dich
  • a compound of the formula (887) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (888).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (887) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (888).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (888) is reacted with a compound of the formula (889) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (890).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (890) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (891).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (892) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile
  • dibenzylidene)acetone and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (893).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (893).
  • a compound of the formula (892) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (893).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (893).
  • a compound of the formula (893) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (894).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-d
  • a compound of the formula (894) is reacted with a compound of the formula (894), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (896).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (896) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (897).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (896) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (897).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compound of the formula (898) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N
  • a compound of the formula (898) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (899).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (899).
  • a compound of the formula (899) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (900).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-d
  • a compound of the formula (900) is reacted with a compound of the formula (901), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (902).
  • a compound of the formula (902) is
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (903).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like
  • a solvent such as methanol, ethanol,
  • a compound of the formula (902) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (903).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (903) is reacted with a compound of the formula (904) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (905).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (905) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (906).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (907) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N
  • a compound of the formula (907) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (908).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (908).
  • a compound of the formula (908) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (909).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-d
  • a compound of the formula (909) is reacted with a compound of the formula (910), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (911).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (911) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (912).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (911) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (912).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (912) is reacted with a compound of the formula (913) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide,
  • a compound of the formula (914) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (915).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (916) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N
  • a compound of the formula (916) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (917).
  • a compound of the formula (917) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-
  • a compound of the formula (918) is reacted with a compound of the formula (919), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (920).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (920) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (921).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (920) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (921).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (921) is reacted with a compound of the formula (922) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (923).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (923) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (924).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (925) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N
  • a compound of the formula (925) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (926).
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (926).
  • a compound of the formula (926) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (927).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-d
  • a compound of the formula (927) is reacted with a compound of the formula (928), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (929).
  • a compound of the formula (929) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate,
  • a compound of the formula (929) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (930).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (930) is reacted with a compound of the formula (931) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (932).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (932) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (933).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (31) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (937).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,
  • a compounds of the formula (937) is reacted with a compound of the formula (938), a known compound or a compound made by known methods, in the presence of a coupling agent such as O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and
  • a compound of the formula (939) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (940).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (940) is reacted with a compound of the formula (941), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (942).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (942) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (943).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (942) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (943).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (943) is reacted with a compound of the formula (944) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (945).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (945) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (946).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (947) is reacted with a compound of the formula (948) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (949).
  • a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo
  • a compound of the formula (949) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (950).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (950) is reacted with a compound of the formula (951), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (952).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (952) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (953).
  • a compound of the formula (952) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like,
  • a compounds of the formula (953) is reacted with a compound of the formula (954) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (955).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (955) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (956).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)d
  • a compound of the formula (959) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (960).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (960) is reacted with a compound of the formula (961), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (962).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (962) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (963).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (962) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, dieth
  • a compounds of the formula (963) is reacted with a compound of the formula (964) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (965).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (965) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (966).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichlor
  • a compounds of the formula (969) is reacted with a compound of the formula (970), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-
  • a compound of the formula (971) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (972).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-
  • a compound of the formula (972) is reacted with a compound of the formula (973), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (974).
  • a compound of the formula (974) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis
  • a compound of the formula (974) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (975).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4
  • a compounds of the formula (975) is reacted with a compound of the formula (976) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (977).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylform
  • a compound of the formula (977) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (978).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • a compounds of the formula (979) is reacted with a compound of the formula (980), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as
  • dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-t
  • a compound of the formula (981) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (982).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (982) is reacted with a compound of the formula (983), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (984).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (984) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (985).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (984) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (985).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (985) is reacted with a compound of the formula (986) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (987).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (987) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (988).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (991) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (992).
  • a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like
  • a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide
  • a compounds of the formula (992) is reacted with a compound of the formula (993) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydro
  • a compound of the formula (994) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (995).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (995) is reacted with a compound of the formula (996), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (997).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (997) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (998).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (997) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (998).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (998) is reacted with a compound of the formula (999) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1000).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1000) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1001).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (1002) is reacted with a compound of the formula (1003), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl
  • a compound of the formula (1004) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,
  • a compound of the formula (1005) is reacted with a compound of the formula (1006), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1007).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (1007) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1008).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1007) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1008).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1008) is reacted with a compound of the formula (1009) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1010).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1010) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1011).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compounds of the formula (1012) is reacted with a compound of the formula (1013), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl
  • a compound of the formula (1014) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1015).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (1015) is reacted with a compound of the formula (1016), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1017).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (1017) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1018).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1017) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1018).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4
  • a compounds of the formula (1018) is reacted with a compound of the formula (1019) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1020).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1020) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1021).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • a compound of the formula (1024) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1025).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (1025) is reacted with a compound of the formula (1026), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1027).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • formula (1027) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1028).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like,
  • a compound of the formula (1027) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1028).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1028) is reacted with a compound of the formula (1029) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1030).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1030) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1031).
  • a compound of the formula (1032) a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl
  • a compound of the formula (1033) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1034).
  • a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 1,
  • a compound of the formula (1034) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1035).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (1035) is reacted with a compound of the formula (1036), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1037).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (1037) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1038).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1037) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1038).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1038) is reacted with a compound of the formula (1039) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1040).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1040) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like,
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dich
  • a compound of the formula (1045) is reacted with a compound of the formula (1046), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1047).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (1047) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1048).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1047) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1048).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1048) is reacted with a compound of the formula (1049) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1050).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1050) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1051).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (1052) is reacted with a compound of the formula (1053), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl
  • a compound of the formula (1054) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1055).
  • a compound of the formula (1045) is
  • a compound of the formula (1056) a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1057).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of
  • a compound of the formula (1057) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1058).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1057) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1058).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1058) is reacted with a compound of the formula (1059) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1060).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide
  • a compound of the formula (1060) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the
  • a compounds of the formula (1062) is reacted with a compound of the formula (1063), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in
  • a compound of the formula (1065) is reacted with a compound of the formula (1066), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1067).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (1067) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1068).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1067) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1068).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1068) is reacted with a compound of the formula (1069) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (1070) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1071).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compound of the formula (1074) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1075).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (1075) is reacted with a compound of the formula (1076), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating,
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating,
  • a compound of the formula (1077) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1078).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1077) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1078).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1078) is reacted with a compound of the formula (1079) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1080).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1080) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1081).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsul
  • hydrochloric acid, sulfuric acid, and the like in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1085).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1085).
  • a compound of the formula (1085) is reacted with a compound of the formula (1086), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1087).
  • a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave
  • a compound of the formula (1087) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1088).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1087) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1088).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-
  • a compounds of the formula (1088) is reacted with a compound of the formula (1089) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1090).
  • a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1090) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1091).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyl
  • a compounds of the formula (1092) is reacted with a compound of the formula (1093), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl
  • a compound of the formula (1094) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1095).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N
  • a compound of the formula (1095) is reacted with a compound of the formula (1096), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1097).
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with
  • a compound of the formula (1097) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1098).
  • a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II),
  • a compound of the formula (1097) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1098).
  • a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4
  • a compounds of the formula (1098) is reacted with a compound of the formula (1099) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1100).
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like
  • a solvent such as N,N-dimethylformamide,
  • a compound of the formula (1100) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1101).
  • an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like
  • a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethyls
  • Preparative reverse phase HPLC was performed on a Phenomenex LUNA column (19 ⁇ 100 mm, C18, 5 ⁇ m) with a 10 minute mobile phase gradient of 10% acetonitrile/water to 90% acetonitrile/ water with 0.1% TFA as buffer using 214 and 254 nm as detection wavelengths. Injection and fraction collection were performed with a Gilson 215 liquid handling apparatus using Trilution LC software.
  • Example 1 Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamide
  • Step 1 Synthesis of tert-butyl N- ⁇ 2-[4-(4-bromo-3-fluorobenzamido) phenyl]ethyl ⁇ carbamate: To a stirred, ice-cold solution of tert-butyl N-[2-(4-aminophenyl) ethyl]carbamate (900 mg, 3.8 mmol) and N,N-diisopropylethyl amin (0.36 mL, 2.0 mmol) in CH 2 Cl 2 (15 mL) was added dropwise over 10 min a solution of 4-bromo-3-fluorobenzoyl chloride (905 mg, 3.8 mmol) in CH 2
  • Step 2 Synthesis of tert-butyl 4-(4- ⁇ [4-(2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ ethyl) phenyl]carbamoyl ⁇ -2-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate: A flask equipped with a magnetic stir bar was charged with tert-butyl N- ⁇ 2-[4-(4-bromo-3-fluorobenzamido)phenyl]ethyl ⁇
  • N 2 -sparged 3:11,4-dioxane/H 2 O (20 mL) was introduced by syringe and the mixture was stirred at 100 0C under N 2 for 4 hours. The mixture was concentrated. The residue was taken up in ethyl acetate (80 mL), washed with water (20 mL) and brine (20 mL), and dried over Na 2 SO 4 .
  • Step 3 Synthesis of N-[4-(2-aminoethyl)phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro pyridin-4- yl)benzamide: tert-butyl 4-(4- ⁇ [4-(2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ ethyl)phenyl] carbamoyl ⁇ -2- fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (1.05 g, 1.95 mmol) was dissolved in 1:1 CH 2 Cl 2 /trifluoroacetic acid (10 mL), stirred for 18 hours and concentrated.

Abstract

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

Description

NOVEL HETEROAROMATIC COMPOUNDS EXHIBITING ANTIFUNGAL ACTIVITY AND THEIR METHOD OF USE STATEMENT OF FEDERALLY FUNDED RESEARCH [0001] This invention was made with Government support under grant number R44AI106270 awarded by the National Institutes of Health, and grant number W81XWH1810638 awarded by the US Department of Defense. The Government has certain rights in the invention. FIELD OF INVENTION [0002] The present invention describes compounds that are antifungal agents, useful for the treatment of fungal infections and related conditions. The present invention further describes a novel chemotype useful for the treatment of fungal infections and other diseases that involve fungal infection. BACKGROUND OF THE INVENTION [0003] Fungal infections are a growing problem in numerous medical settings. Modern medical practices including anticancer chemotherapies, immunosuppressive drugs, broad spectrum antibiotics that disrupt the microbiome and indwelling medical devices that disrupt and breach the protective immune system. This creates an opening for infection by opportunistic fungal pathogens. Fungal infections are most common in immunocompromised patients afflicted with HIV or undergoing cancer therapies, hematological stem cell replacement, or organ transplants. Fungal infections can also occur in immunocompetent individuals and the most common cause is from skin and soft tissue wounds resulting from traumatic injury. Significant morbidity is evident with these types of injuries as the local invasive infections often require frequent and extensive surgical debridement in conjunction with systemic antifungal therapy. Nevertheless, amputations are still needed in many of the cases and mortality can be as high as 25%. In both immunosuppressed and immunocompetent patients the most common fungal pathogens are Candida, Aspergillus, Cryptococcus, Mucorales and Fusarium spp. and infections are associated with a significant incidence of treatment failure and high mortality. Invasive Candidiasis (IC) is the fourth leading healthcare associated bloodstream infection in the US and is associated with a 47% mortality rate. Invasive Aspergillosis (IA) is becoming a dominant invasive fungal disease in hematological oncology, organ transplant and exacerbated chronic obstructive pulmonary disease. The incidence of IA in hematopoietic stem cell transplants has been reported to be as high as 15% with mortality rates ranging from 20% to 50%. [0004] Pathogenic fungi include the genus Candida (examples include C. albicans, C. glabrata, C. krusei, C. tropicalis, C. guilliermondii, C. parapsilosis, C. dubliniensis and C. auri), the genus Cryptococcus (examples include C. neoformans and C. gatti), the genus Trichosporon (examples include T. asahii, T. asteroides, T. cutaneum, T. dermatis, T. dohaense, T. inkin, T. loubieri, T. mucoides, and T. ovoides), the genus Malassezia (examples include M. globose and M. restricta), the genus Aspergillus (examples include A. fumigatus. A. flavis, A. terreu and A. niger), the genus Fusarium (examples include F. solani, F. falciforme, F. oxysporum, F. verticillioides, and F. proliferatum), the genus Mucor (examples include M. circinelloides, M, ramosissimus, M. indicus, M. rasemosus, and M. piriformis), the genus Blastomyces (examples include B. dermatitidis and B. brasiliensis), the genus Coccidioides (examples include C. immitis, C. and posadasii), the genus Pneumocystis (examples include P. carinii and P. jiroveci), the genus Histoplasma (examples include H. capsulatum), the genus Trichophyton (examples include T. schoenleinii, T. mentagrophytes, T. verrucosum, and T. rubrum), the genus Rhizopus (examples include R. oryzae and R. stolonifera), the genus Apophysomyces (examples include A. variabilis), the genus Rhizomucor (examples include R. pusillus, R. regularior, and R. chlamydosporus), the genus Lichtheimia (examples include L. ramose and L. corymbifera), the genus Scedosporium (examples include S. apiospermum), and the genus Lomentospora (examples include L. prolificans). [0005] The compounds of the disclosure have excellent activity against pathogenic fungi of the genera Candida, Aspergillus, Fusarium, Cryptococcus and Mucor. They can be used to treat fungal diseases, caused by these and other susceptible fungal pathogens, such as Candidemia, Oral Candidiasis, Vulvovaginal Candidiasis (VVC) and Recurrent VVC, Aspergillosis (including Allergic Bronchopulmonary Aspergillosis, Allergic Aspergillus Sinusitis and Invasive and Disseminated Aspergillosis), Cryptococcosis (including Pulmonary Cryptococcosis and Meningeal Cryptococcosis), Mucomycosis, Blastomycosis, Superficial infections (including Skin Keratitis, Athletes Foot, Ringworm, Ocular Keratitis and Onychomycosis) and other Invasive Infections (including Sinusitis, Endophthalmitis, Otitis, Endocarditis, Pneumonia, Osteomyelitis, Meningitis and Ventriculitis). [0006] Compounds of the disclosure can also be used to treat fungal infections in agricultural crops including Wilt disease in tomato and cotton caused by Fusarium oxysporus, Wilt of Gram caused by Fusarium orthacereas, Downy Mildew of cereals caused by Sclerospora graminicola, Damping of Seedling caused by Phythium spp., Rot of Ginger caused by Phythium debaryaum, Late Blight of Potato caused by Phytophthora infestans, Early Blight of Potato caused by Alternaria solani, Blast Disease of Rice caused by Phyricularia oryzae, Powdery Mildews caused by Erysiphe spp., Tikka Disease of Groundnut caused by Cerecospora personata, Haemelia vastatrix and Cellectotrichum falcatum, Brown Rot in Pear, Plum and Peach caused by Sclerotinia fruiticola, Leaf Spot of Oats caused by Helminthosporium avenae, Leaf Rust of Coffee caused by Haemelia vastatrix, Red Rot of Sugarcane caused by Collectotrichum falcatum, Black Wart Disease of Potato caused by Synchytrium endobioticum, Yellow Rust of Wheat caused by Puccinia striiformis, Maize Smut caused by Ustilago maydis, Loose Smut of Wheat caused by Ustilago tritici, Covered Smut of Oat caused by Ustilago avenae, Flag Smut of Wheat caused by Urocystis tritici, Covered Smut of Barley caused by Ustilago hordei, Black Rust of Wheat caused  
by Puccinia graminis tritici, Bankanese Disease and Foot Rot of Rice caused by Gibberealla fujikuri, and Ergot Disease of Rye caused by Claviceps purpurea. [0007] Compounds of the disclosure can also be used, for example, to treat or prevent fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs. [0008] Compounds of the disclosure can also be used, for example, to treat or prevent diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, , pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax. [0009] Compounds of the disclosure can also be used, for example, to treat or prevent aspergillosis infections in horses, cattle, sheep, goats, dogs and cats. [0010] Compounds of the disclosure can also be used, for example, to treat or prevent diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis. [0011] Compounds of the disclosure can also be used, for example, to treat or prevent mucormycosis infections in horses, cattle, sheep, goats, dogs and cats. [0012] Compounds of the disclosure can also be used, for example, to treat or prevent diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis. [0013] Compounds of the disclosure can also be used, for example, to treat or prevent coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii. [0014] Compounds of the disclosure can also be used, for example, to treat or prevent blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, [0015] Compounds of the disclosure can also be used, for example, to treat or prevent Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, [0016] Compounds of the disclosure can also be used, for example, to treat or prevent dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes  
[0017] Compounds of the disclosure can also be used, for example, to treat or prevent cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, [0018] Compounds of the disclosure can also be used, for example, to treat or prevent histoplasmosis in dogs caused by infection with Histoplasma capsulatum. BRIEF SUMMARY OF THE INVENTION [0019] The present invention is directed toward novel heteroaromatic compounds of formula (I),
Figure imgf000005_0001
Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:
Figure imgf000005_0002
X1 is selected from the group consisting of N and CR2a; X2 is selected from the group consisting of N and CR2b; X3 is selected from the group consisting of O, and S; X4 is selected from the group consisting of O, S, and NR1a;  
Figure imgf000006_0001
X5 is selected from the group consisting of N and CR2c; X6 is selected from the group consisting of N and CR2d; A3 is selected from the group consisting of
Figure imgf000006_0002
Figure imgf000006_0003
 
Figure imgf000007_0001
m is 0, 1, or 2; n is 1, 2, or 3; A4 is selected from the group consisting o
Figure imgf000007_0002
Figure imgf000007_0003
 
Figure imgf000008_0001
q is 0, 1, 2, or 3; t is 1, 2, or 3; R1 is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl; R1 and R2c may be taken together to form a ring consisting of 5 or 6 members; R1a is selected from the group consisting of H, C1-4 alkyl; R2a is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000008_0002
SR8, SO2R9; Y1 is selected from the group consisting of O, NR7; R2b is selected from the group consisting of H, C1-4 alkyl, C3-C5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000008_0003
SR , and SO2R ; R2c is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000008_0004
SR , and SO2R ; Y2 is selected from the group consisting of O, NR7; R2d is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000008_0005
, , SR , and SO2R ; Y3 is selected from the group consisting of O and NR7; R3a is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000008_0006
SR , and SO2R ; Y4 is selected from the group consisting of O and NR7;   R3b is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8
Figure imgf000009_0001
SR , and SO2R9; R3c is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000009_0002
SR8, and SO2R9; Y5 is selected from the group consisting of O and NR7; R3d is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000009_0003
SR8 and SO2R9; r is 0, 1, 2, or 3; Y6 is selected from the group consisting of O and NR7; R4 is at each occurrence independently selected from the group consisting of H, C1-4 alkyl, CN, - CH2(CH2)gC1-4 alkoxy, and -CH2(CH2)gC3-5 branched alkoxy; g is 1 or 2; R4a is selected from the group consisting of H and C1-4 alkyl; R4b is selected from the group consisting of H and C1-4 alkyl; R4c is selected from the group consisting of H and C1-4 alkyl; R4d is selected from the group consisting of H and C1-4 alkyl; R4e is selected from the group consisting of H and C1-4 alkyl; R5a is selected from the group consisting of H and C1-4 alkyl; R5b is selected from the group consisting of H and C1-4 alkyl; R5c is selected from the group consisting of H and C1-4 alkyl; R5d is selected from the group consisting of H and C1-4 alkyl; R5e is selected from the group consisting of H and C1-4 alkyl; R5f is selected from the group consisting of C1-4 alkyl, C3-5 branched alkyl, and C3-5 cycloalkyl; R6a is selected from the group consisting of hydrogen and C1-4 alkyl; R6b is selected from the group consisting of hydrogen and C1-4 alkyl; R7 is a C1-4 alkyl; R8 is a C1-4 alkyl; R9 is a C1-4 alkyl; In some embodiments, R3b and R4b are joined to form a heterocyclic ring consisting of five or six members; and  
In some embodiments, R3d and R4c are joined to form a heterocyclic ring consisting of five or six members; [0020] The compounds of the present invention include compounds having formula (II):
Figure imgf000010_0001
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0021] The compounds of the present invention include compounds having formula (III):
Figure imgf000010_0002
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0022] The compounds of the present invention include compounds having formula (IV):
Figure imgf000010_0004
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0023] The compounds of the present invention include compounds having formula (V):
Figure imgf000010_0003
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0024] The compounds of the present invention include compounds having formula (VI):
Figure imgf000010_0005
   
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0025] The compounds of the present invention include compounds having formula (VII):
Figure imgf000011_0001
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0026] The compounds of the present invention include compounds having formula (VIII):
Figure imgf000011_0003
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0027] The compounds of the present invention include compounds having formula (IX):
Figure imgf000011_0004
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0028] The compounds of the present invention include compounds having formula (X):
Figure imgf000011_0002
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.  
[0029] The present invention further relates to compositions comprising: an effective amount of one or more compounds according to the present invention and an excipient. [0030] The present invention also relates to a method for treating or preventing disease or conditions associated with fungal infection. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention. [0031] The present invention yet further relates to a method for treating or preventing disease or conditions associated with fungal infection, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0032] The present invention also relates to a method for treating or preventing fungal infection, including, for example, infection with an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0033] The present invention yet further relates to a method for treating or preventing fungal infection, including, for example, infection with an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0034] The present invention also relates to a method for treating or preventing fungal infection, including, for example, infection with an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii,  
Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0035] The present invention yet further relates to a method for treating or preventing fungal infection, including, for example, infection with an organism such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0036] The present invention also relates to a method for treating or preventing disease or conditions associated with fungal infection, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, and ventriculitis. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention. [0037] The present invention yet further relates to a method for treating or preventing disease or conditions associated with fungal infection, including candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal  
cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, and ventriculitis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0038] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism from a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora. Said methods comprise administering to a subject an effective amount of a compound or composition according to the present invention [0039] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism from a genus selected from the groups consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0040] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism selected from the groups consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.  
[0041] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection, including infection with an organism selected from the groups consisting Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0042] The present invention also relates to a method for treating or preventing fungal infection in plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bankanese disease foot rot of rice, and ergot disease of rye. Said methods comprise administering to a plant an effective amount of a compound or composition according to the present invention. [0043] The present invention also relates to a method for treating or preventing fungal infection in plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bakanese disease, foot rot of rice, and ergot disease of rye wherein said  
method comprises administering to a plant a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0044] The present invention also relates to a method for treating or preventing fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0045] The present invention also relates to a method for treating or preventing fungal infections in domesticated animals, livestock, and companion animals including candidiasis infections in animals selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, said wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0046] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa, keratitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax, wherein said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0047] The present invention also relates to a method for treating or preventing diseases or conditions associated with fungal infection in domesticated animals, livestock, and companion animals such as cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, rabbits, ferrets, and guinea pigs, wherein said diseases or conditions associated with fungal infection is selected from the group consisting of keratitis, arthritis, endocarditis, disseminated, mastitis, otitis externa, peritonitis, dermatitis, otitis externa, keratitis, pneumoniagranulomatous rhinitis, intestinal granuloma, and pyothorax, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0048] The present invention also relates to a method for treating or preventing aspergillosis infections in horses, cattle, sheep, goats, dogs and cats said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0049] The present invention also relates to a method for treating or preventing aspergillosis infections in horses, cattle, sheep, goats, dogs and cats wherein said method comprises administering to a  
subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0050] The present invention also relates to a method for treating or preventing diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats. including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0051] The present invention also relates to a method for treating or preventing diseases or conditions associated with aspergillosis infections in horses, cattle, sheep, goats, dogs and cats. including diseases or conditions such as guttural pouch, keratomycosis, pneumonia, mycotic pneumonia, gastroenteritis, mastitis, and placentitis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0052] The present invention also relates to a method for treating or preventing mucormycosis infections in horses, cattle, sheep, goats, dogs and cats said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0053] The present invention also relates to a method for treating or preventing mucormycosis infections in horses, cattle, sheep, goats, dogs and cats, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0054] The present invention also relates to a method for treating or preventing diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0055] The present invention also relates to a method for treating or preventing diseases or conditions associated with mucormycosis infections in horses, cattle, sheep, goats, dogs and cats including diseases or conditions such as mucormycotic ruminitis, lymphadentitis, and enteritis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0056] The present invention also relates to a method for treating or preventing coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.  
[0057] The present invention also relates to a method for treating or preventing coccidioidomycosis in dogs and cats caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0058] The present invention also relates to a method for treating or preventing blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0059] The present invention also relates to a method for treating or preventing blastomycosis in dogs and cats caused by infection with Blastomyces dermatitidis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0060] The present invention also relates to a method for treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0061] The present invention also relates to a method for treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0062] The present invention also relates to a method for treating or preventing dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0063] The present invention also relates to a method for treating or preventing dermatophytosis (ringworm) in cats and dogs caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0064] The present invention also relates to a method for treating or preventing cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention.  
[0065] The present invention also relates to a method for treating or preventing cryptococcosis in dogs and cats caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0066] The present invention also relates to a method for treating or preventing histoplasmosis in dogs caused by infection with Histoplasma capsulatum, said method comprising administering to a subject an effective amount of a compound or composition according to the present invention. [0067] The present invention also relates to a method for treating or preventing histoplasmosis in dogs caused by infection with Histoplasma capsulatum, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient. [0068] The present invention further relates to a process for preparing the antifungal agents of the present invention. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein said method comprises: selecting a subject in need of treating and preventing disease or conditions associated with fungal infection; and administering to said subject an effective amount of at least one compound as disclosed herein, thereby treating or preventing disease or conditions associated with fungal infection in the subject. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject wherein the fungal infection is an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the fungal infection is an organism selected from the group consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia  
restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the fungal infection is selected from the group consisting of candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, ventriculitis, COVID-19 Associated Pulmonary Aspergillosis (CAPA), Influenza Associated Pulmonary Aspergillosis (IAPA), and combinations thereof, wherein said method comprises: selecting a subject in need of treating or preventing disease or conditions associated with fungal infection; and administering to a subject an effective amount of at least one compound as disclosed herein, thereby treating or preventing disease or conditions associated with fungal infection in the subject. The disclosure provides a method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing fungal infection in a plant or plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag smut of wheat, covered smut of barley, black rust of wheat, bakanese disease, foot rot of rice, and ergot disease of rye wherein said method comprises: selecting a plant or plants in need of treating or preventing said fungal infection; and administering to the plant or plants an effective amount of a compound as disclosed herein, thereby treating or preventing said fungal infection in the plant or plants. The disclosure provides a method of treating or preventing fungal infection in a plant or plants, wherein the at least one  
compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing fungal infections in an animal selected from the group consisting of domesticated animals, livestock, and companion animals, wherein said domesticated animals, livestock and companion animals are selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs, further wherein said fungal infection includes candidiasis infections, wherein said method comprises: selecting said domesticated animal, livestock, or companion animal in need of treating or preventing fungal infections; and administering to said domesticated animal, livestock, or companion animal an effective amount of a compound as disclosed herein, thereby treating or preventing said fungal infections and said domesticated animal, livestock, or companion animal. The disclosure provides a method of treating or preventing fungal infections in an animal wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing aspergillosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats, wherein said method comprises: selecting said animal in need of treating or preventing aspergillosis infections; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing aspergillosis infections in said animal. The disclosure provides a method of treating or preventing aspergillosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing mucormycosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats wherein said method comprises: selecting said animal in need of treating or preventing mucormycosis infections; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing mucormycosis infections in said animal. The disclosure provides a method of treating or preventing mucormycosis infections in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing coccidioidomycosis in an animal selected from the group consisting of dogs and cats, wherein said coccidioidomycosis infection is caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, wherein said method comprises: selecting an animal in need of treating or preventing coccidioidomycosis; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing coccidioidomycosis in said animal. The disclosure provides a method of treating or preventing coccidioidomycosis in an animal wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing blastomycosis in an animal selected from the group consisting of dogs and cats, wherein said blastomycosis is caused by infection with  
Blastomyces dermatitidis, wherein said method comprises: selecting said animal in need of treating or preventing blastomycosis; and administering to said animal an effective amount of a compound as disclosed herein, thereby treating or preventing blastomycosis in said animal. The disclosure provides a method of treating or preventing blastomycosis in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, wherein said method comprises: selecting a dog in need of treating or preventing Paracoccidioidomycosis; and administering to said dog an effective amount of a compound as disclosed herein, thereby treating or preventing Paracoccidioidomycosis in said dog. The disclosure provides a method of treating or preventing Paracoccidioidomycosis in dogs wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing dermatophytosis (ringworm) in an animal selected from the group consisting of cats and dogs, wherein said dermatophytosis (ringworm) is caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, wherein said method comprises: selecting a dog or cat in need of treating or preventing dermatophytosis (ringworm); and administering to said dog or cat an effective amount of a compound as disclosed herein, thereby treating or preventing dermatophytosis (ringworm) in the dog or cat. The disclosure provides a method of treating or preventing dermatophytosis (ringworm) in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing cryptococcosis in an animal selected from the group consisting of dogs and cats, wherein said cryptococcosis is caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, wherein said method comprises: selecting a dog or cat in need of treating or preventing cryptococcosis; and administering to the dog or cat an effective amount of a compound as disclosed herein, thereby treating or preventing cryptococcosis in the dog or cat. The disclosure provides a method of treating or preventing cryptococcosis in an animal, wherein the at least one compound is administered in a composition further comprising at least one excipient. The disclosure provides a method of treating or preventing histoplasmosis in dogs, wherein said histoplasmosis is caused by infection with Histoplasma capsulatum, wherein said method comprises: selecting a dog in need of treating or preventing histoplasmosis caused by infection with Histoplasma capsulatum; and administering to said dog an effective amount of a compound as disclosed herein, thereby treating or preventing histoplasmosis caused by infection with Histoplasma capsulatum in the dog. The disclosure provides a method of treating or preventing histoplasmosis in dogs, wherein the at least one compound is administered in a composition further comprising at least one excipient.  
The disclosure provides for the use of the compositions of the disclosure for the production of a medicament for preventing and/or treating the indications as set forth herein. In accordance with a further embodiment, the present disclosure provides a use of the pharmaceutical compositions described above, in an amount effective for use in a medicament, and most preferably for use as a medicament for treating a disease or disorder, for example, as set forth in herein, in a subject. In accordance with yet another embodiment, the present disclosure provides a use of the pharmaceutical compositions described above, and at least one additional therapeutic agent, in an amount effective for use in a medicament, and most preferably for use as a medicament for treating a disease or disorder associated with disease, for example, as set forth herein, in a subject. The disclosure provides a method for treating and/or preventing a disease or condition as set forth herein in a patient, wherein said method comprises: selecting a patient in need of treating and/or preventing said disease or condition as set forth herein; administering to the patient a composition of the disclosure in a therapeutically effective amount, thereby treating and/or preventing said disease in said patient. [0069] These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (o C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. DETAILED DESCRIPTION OF THE INVENTION [0070] The compounds of the disclosure act on pathogenic fungi to suppress their growth. The compounds of the disclosure can also kill fungi. As antifungal agents, the compounds of the disclosure can be used to treat local, topical and disseminated infections in animals including humans and can be used to prevent disseminated fungal infections developing from local or topical fungal infections. In another aspect of this invention, the compounds can be applied to agricultural plants, shrubs and trees to cure and prevent fungal infections and fungal diseases. [0071] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.  
[0072] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components. [0073] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. [0074] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously [0075] As used herein, the term "halogen" shall mean chlorine, bromine, fluorine and iodine. [0076] As used herein, unless otherwise noted, “alkyl” and/or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C1-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3- carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as (C1-6alkyl)2amino, the alkyl groups may be the same or different. [0077] As used herein, the terms “alkenyl” and “alkynyl” groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methyloct-4-en-2-yl, 7- hydroxy-7-methyloct-3,5-dien-2-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl. Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl, 5- hydroxy-5-ethylhept-3-ynyl, and the like. [0078] As used herein, “cycloalkyl,” whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alkynyl groups, e.g., having  
from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2- methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5- dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term “cycloalkyl” also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. [0079] “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF3, -CF2CF3). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups. [0080] The term “alkoxy” refers to the group –O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted. The term C3-C6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C3-C6 cyclic alkoxy groups optionally may be substituted. [0081] The term “aryl,” wherein used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, phenyl or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-1-yl, naphthylen-2-yl, 4-fluorophenyl, 2- hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl, and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one  
or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings. [0082] The term “arylalkyl” or “aralkyl” refers to the group –alkyl-aryl, where the alkyl and aryl groups are as defined herein. Aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2- phenylpropyl, fluorenylmethyl and the like. [0083] The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted. [0084] Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4- tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro- 1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl. [0085] The term “heteroaryl,” whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O), or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non- heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-  
limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H- indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl. [0086] One non-limiting example of a heteroaryl group as described above is C1-C5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C1-C5 heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4- yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2- yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4- yl. [0087] Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2 and R3 taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted. [0088] For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula:
Figure imgf000027_0001
is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro-5H- cyclopentapyrimidine having the formula:
Figure imgf000027_0002
is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:
Figure imgf000027_0003
 
is, for the purposes of the present invention, considered a heteroaryl unit. [0089] Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.” [0090] The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below. The substituents are capable of replacing one or two hydrogen atoms of a single moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term “substituted” is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted C1 alkyl; trifluoromethyl is a substituted C1 alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octanyl is a substituted C8 alkyl; 3-guanidinopropyl is a substituted C3 alkyl; and 2-carboxypyridinyl is a substituted heteroaryl. [0091] The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally substituted groups will be so indicated. [0092] The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine(I)), –CN, –NO2, oxo (=O), –OR10, –SR10, –N(R10)2, –NR10C(O)R10, –SO2R10, –SO2OR10, –SO2N(R10)2, –C(O)R10, –C(O)OR10, – C(O)N(R10)2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selected independently from halogen, –CN, –NO2, oxo, and R10; wherein R10, at each occurrence, independently is hydrogen, –OR11, –SR11, –C(O)R11, –C(O)OR11, –C(O)N(R11)2, –SO2R11, -S(O)2OR11, –N(R11)2, – NR11C(O)R11, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, cycloalkyl (e.g., C3-6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R10 units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R11, at each occurrence, independently is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, cycloalkyl (e.g., C3-6 cycloalkyl), aryl, heterocycle, or heteroaryl, or two R11 units taken  
together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms. [0093] In some embodiments, the substituents are selected from i) –OR12; for example, –OH, –OCH3, –OCH2CH3, –OCH2CH2CH3; ii) –C(O)R12; for example, –COCH3, –COCH2CH3, –COCH2CH2CH3; iii) –C(O)OR12; for example, –CO2CH3, –CO2CH2CH3, –CO2CH2CH2CH3; iv) –C(O)N(R12)2; for example, –CONH2, –CONHCH3, –CON(CH3)2; v) –N(R12)2; for example, –NH2, –NHCH3, –N(CH3)2, –NH(CH2CH3); vi) halogen: –F, –Cl, –Br, and –I; vii) –CHeXg; wherein X is halogen, m is from 0 to 2, e+g =3; for example, –CH2F, –CHF2, –CF3, –CCl3, or –CBr3; viii) –SO2R12; for example, –SO2H; –SO2CH3; –SO2C6H5; ix) C1-C6 linear, branched, or cyclic alkyl; x) Cyano xi) Nitro; xii) N(R12)C(O)R12; xiii) Oxo (=O); xiv) Heterocycle; and xv) Heteroaryl. wherein each R12 is independently hydrogen, optionally substituted C1-C6 linear or branched alkyl (e.g., optionally substituted C1-C4 linear or branched alkyl), or optionally substituted C3-C6 cycloalkyl (e.g optionally substituted C3-C4 cycloalkyl); or two R12 units can be taken together to form a ring comprising 3-7 ring atoms. In certain aspects, each R12 is independently hydrogen, C1-C6 linear or branched alkyl optionally substituted with halogen or C3-C6 cycloalkyl or C3-C6 cycloalkyl. [0094] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2- C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6, alkyl. [0095] For the purposes of the present invention the terms “compound,” “analog,” and “composition of matter” stand equally well for the antifungal agent described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.  
[0096] Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography. [0097] Pharmaceutically acceptable salts of compounds of the present teachings, which can have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert- butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids. [0098] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(R9)2, each R9 may be the same or different than the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.   [0099] The terms “treat” and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer. [0100] As used herein, “therapeutically effective” and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect. [0101] Except when noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. As used herein, the term “subject” or "patient" refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human), and most preferably a human. In some embodiments, the subject is a non-human animal such as a farm animal (e.g., horse, cattle, sheep, goats, pig, or cow) or a pet (e.g., a dog or cat). In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention. The antifungal agents [0102] The antifungal agents of the present invention are heteroaromatic compounds, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):
Figure imgf000031_0001
Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: A1 is selected from the group consisting of
Figure imgf000031_0002
Figure imgf000031_0003
 
Figure imgf000032_0001
; X1 is selected from the group consisting of N and CR2a; X2 is selected from the group consisting of N and CR2b; When X1 is N, X2 is CR2b; When X2 is N, X1 is CR2a; X3 is selected from the group consisting of O, and S; X4 is selected from the group consisting A2 is selected from the group consisting
Figure imgf000032_0002
Figure imgf000032_0003
X5 is selected from the group consisting of N and CR2c;  
X6 is selected from the group consisting of N and CR2d;
Figure imgf000033_0004
R R
Figure imgf000033_0001
m is 0, 1, or 2; n is 1, 2, or 3; A4 is selected from the group consisting o
Figure imgf000033_0002
Figure imgf000033_0003
  a
Figure imgf000034_0001
q is 0, 1, 2, or 3; t is 1, 2, or 3; R1 is selected from the group consisting of H, C1-4 alkyl, and C3-5 branched alkyl; R1 and R2c may be taken together to form a ring consisting of 5 or 6 members; R1a is selected from the group consisting of H and C1-4 alkyl; R2a is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000034_0002
SR8, and SO2R9; Y1 is selected from the group consisting of O, NR7; R2b is selected from the group consisting of H, C1-4 alkyl, C3-C5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000034_0003
SR , and SO2R ; R2c is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000034_0004
SR , and SO2R ; Y2 is selected from the group consisting of O and NR7; R2d is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000034_0005
SR8, and SO2R9; Y3 is selected from the group consisting of O and NR7;   R3a is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000035_0001
SR , and SO2R ; Y4 is selected from the group consisting of O and NR7; R3b is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000035_0002
, , SR8, and SO2R9; R3c is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000035_0003
, , SR , and SO2R ; Y5 is selected from the group consisting of O and NR7; R3d is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 8 9
Figure imgf000035_0004
SR , and SO2R ; r is 0, 1, 2, or 3; Y6 is selected from the group consisting of O and NR7; R4 is at each occurrence independently selected from the group consisting of H, C1-4 alkyl, CN, - CH2(CH2)gC1-4 alkoxy, and -CH2(CH2)gC3-5 branched alkoxy; g is 1 or 2; R4a is selected from the group consisting of H and C1-4 alkyl; R4b is selected from the group consisting of H and C1-4 alkyl; R4c is selected from the group consisting of H amd C1-4 alkyl; R4d is selected from the group consisting of H and C1-4 alkyl; R4e is selected from the group consisting of H and C1-4 alkyl; R5a is selected from the group consisting of H and C1-4 alkyl; R5b is selected from the group consisting of H and C1-4 alkyl; R5c is selected from the group consisting of H and C1-4 alkyl; R5d is selected from the group consisting of H and C1-4 alkyl; R5e is selected from the group consisting of H and C1-4 alkyl; R5f is selected from the group consisting of C1-4 alkyl, C3-5 branched alkyl, and C3-5 cycloalkyl; R6a is selected from the group consisting of hydrogen and C1-4 alkyl; R6b is selected from the group consisting of hydrogen and C1-4 alkyl; R7 is a C1-4 alkyl;  
R8 is a C1-4 alkyl; R9 is a C1-4 alkyl; In some embodiments, R3b and R4b are joined to form a heterocyclic ring consisting of five or six members; and In some embodiments, R3d and R4c are joined to form a heterocyclic ring consisting of five or six members. [0103] The compounds of the present invention include compounds having formula (II):
Figure imgf000036_0001
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0104] The compounds of the present invention include compounds having formula (III):
Figure imgf000036_0002
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0105] The compounds of the present invention include compounds having formula (IV):
Figure imgf000036_0003
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0106] The compounds of the present invention include compounds having formula (V):
Figure imgf000036_0004
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0107] The compounds of the present invention include compounds having formula (VI):  
Figure imgf000037_0001
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0108] The compounds of the present invention include compounds having formula (VII):
Figure imgf000037_0002
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0109] The compounds of the present invention include compounds having formula (VIII):
Figure imgf000037_0004
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0110] The compounds of the present invention include compounds having formula (IX):
Figure imgf000037_0003
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0111] The compounds of the present invention include compounds having formula (X):  
Figure imgf000038_0001
  including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. [0112] In some embodiments
Figure imgf000038_0002
[0113] In some embodiments
Figure imgf000038_0003
[0114] In some embodiments
Figure imgf000038_0004
S N [0115] In some embodiments A1 is R2b . [0116] In some embodiments
Figure imgf000038_0005
[0117] In some embodiments
Figure imgf000038_0006
[0118] In some embodiments
Figure imgf000038_0007
[0119] In some embodiments
Figure imgf000038_0008
  [0120] In some embodiments
Figure imgf000039_0001
[0121] In some embodiments
Figure imgf000039_0002
N R3b N [0122] In some embodiments A1 is R2b . [0123] In some embodiments
Figure imgf000039_0003
[0124] In some embodiments A
Figure imgf000039_0004
[0125] In some embodiments A
Figure imgf000039_0005
[0126] In some embodiments A
Figure imgf000039_0006
[0127] In some embodiments A1 is
Figure imgf000039_0009
. [0128] In some embodiments A
Figure imgf000039_0007
[0129] In some embodiments A
Figure imgf000039_0008
 
[0130] In some embodiments
Figure imgf000040_0001
[0131] In some embodiments
Figure imgf000040_0002
[0132] In some embodiments
Figure imgf000040_0003
[0133] In some embodiments
Figure imgf000040_0004
[0134] In some embodiments
Figure imgf000040_0005
[0135] In some embodiments X1 is N. [0136] In some embodiments X1 is CR2a. [0137] In some embodiments X2 is N. [0138] In some embodiments X2 is CR2a. [0139] In some embodiments X3 is O. [0140] In some embodiments X3 is S. [0141] In some embodiments X4 is O. [0142] In some embodiments X4 is S. [0143] In some embodiments X4 is NR1a. [0144] In some embodiments A2 is .  
[0145] In some embodiments A [0146] In some embodiments A [0147] In some embodiments A
Figure imgf000041_0001
[0148] In some embodiments A
Figure imgf000041_0002
[0149] In some embodiments A [0150] In some embodiments A
Figure imgf000041_0003
[0151] In some embodiments [0152] In some embodiments [0153] In some embodiments
Figure imgf000041_0004
[0154] In some embodiments
Figure imgf000041_0005
[0155] In some embodiments
Figure imgf000041_0006
  [0156] In some embodiments A 2 is
Figure imgf000042_0007
[0157] In some embodiments A [0158] In some embodiments A [0159] In some embodiments A [0160] In some embodiments A [0161] In some embodiments A
Figure imgf000042_0001
R1a [0162] In some embodiments A
Figure imgf000042_0002
[0163] In some embodiments A
Figure imgf000042_0003
[0164] In some embodiments
Figure imgf000042_0004
[0165] In some embodiments
Figure imgf000042_0005
[0166] In some embodiments
Figure imgf000042_0006
 
[0167] In some embodiments
Figure imgf000043_0001
[0168] In some embodiments
Figure imgf000043_0002
[0169] In some embodiments
Figure imgf000043_0003
[0170] In some embodiments X5 is N. [0171] In some embodiments X5 is CR2c. [0172] In some embodiments X6 is N. [0173] In some embodiments X6 is CR2d. [0174] In some embodiments
Figure imgf000043_0004
H N R4 [0175] In some embodiments A3 is m NH .  [0176] In some embodiments
Figure imgf000043_0005
H N O R4 [0177] In some embodiments A3 n is NH . [0178] In some embodiments
Figure imgf000043_0006
[0179] In some embodiments
Figure imgf000043_0007
[0180] In some embodiments
Figure imgf000043_0008
 
[0181] In some embodiments
Figure imgf000044_0001
NH N [0182] In some embodiments A3 is HN R4 . [0183] In some embodiments
Figure imgf000044_0002
[0184] In some embodiments
Figure imgf000044_0003
[0185] In some embodiments
Figure imgf000044_0004
[0186] In some embodiments
Figure imgf000044_0005
[0187] In some embodiments
Figure imgf000044_0006
[0188] In some embodiments
Figure imgf000044_0007
[0189] In some embodiments
Figure imgf000044_0008
  R [0190] In some embodiments A3 is [0191] In some embodiments A3 is R [0192] In some embodiments A3 is R [0193] In some embodiments A3 is
Figure imgf000045_0006
[0194] In some embodiments
Figure imgf000045_0001
[0195] In some embodiments
Figure imgf000045_0002
[0196] In some embodiments
Figure imgf000045_0003
[0197] In some embodiments
Figure imgf000045_0004
[0198] In some embodiments
Figure imgf000045_0005
 
[0199] In some embodiments
Figure imgf000046_0001
[0200] In some embodiments
Figure imgf000046_0002
[0201] In some embodiments
Figure imgf000046_0003
[0202] In some embodiments
Figure imgf000046_0004
[0203] In some embodiments
Figure imgf000046_0005
[0204] In some embodiments
Figure imgf000046_0006
[0205] In some embodiments
Figure imgf000046_0007
[0206] In some embodiments
Figure imgf000046_0008
[0207] In some embodiments
Figure imgf000046_0009
[0208] In some embodiments
Figure imgf000046_0010
[0209] In some embodiments
Figure imgf000046_0011
  [0210] In some embodiments
Figure imgf000047_0001
[0211] In some embodiments
Figure imgf000047_0002
[0212] In some embodiments A4 is [0213] In some embodiments A4 is [0214] In some embodiments A4 is [0215] In some embodiments A4 is
Figure imgf000047_0004
[0216] In some embodiments
Figure imgf000047_0003
[0217] In some embodiments m is 0. [0218] In some embodiments m is 1. [0219] In some embodiments m is 2. [0220] In some embodiments n is 1.   [0221] In some embodiments n is 2. [0222] In some embodiments n is 3. [0223] In some embodiments q is 0. [0224] In some embodiments q is 1. [0225] In some embodiments q is 2. [0226] In some embodiments q is 3. [0227] In some embodiments t is 1. [0228] In some embodiments t is 2. [0229] In some embodiments t is 3. [0230] In some embodiments R1 is H. [0231] In some embodiments R1 is C1-4 alkyl. [0232] In some embodiments R1 is C3-5 branched alkyl. [0233] In some embodiments R1 and R2c are taken together to form a carbocyclic ring consisting of 5 members. [0234] In some embodiments R1 and R2c are taken together to form a carbocyclic ring consisting of 6 members. [0235] In some embodiments R1a is H. [0236] In some embodiments R1a is C1-4 alkyl. [0237] In some embodiments R2a is H. [0238] In some embodiments R2a is C1-4 alkyl. [0239] In some embodiments R2a is C3-5 branched alkyl. [0240] In some embodiments R2a is C1-4 alkoxy. [0241] In some embodiments R2a is C3-5 branched alkoxy. [0242] In some embodiments R2a is F. [0243] In some embodiments R2a is Cl. [0244] In some embodiments R2a is CN. [0245] In some embodiments R2a is OCF3. [0246] In some embodiments R2a is CHF2. [0247] In some embodiments R2a is CF3. [0248] In some embodiments R2a is N(R6a)(R6b). r [0249] In some embodiments R2a is
Figure imgf000048_0001
. [0250] In some embodiments R2a is
Figure imgf000048_0002
  [0251] In some embodiments R2a is SR8. [0252] In some embodiments R2a is SO2R9. [0253] In some embodiments Y1 is O. [0254] In some embodiments Y1 is NR7. [0255] In some embodiments R2b is H. [0256] In some embodiments R2b is C1-4 alkyl. [0257] In some embodiments R2b is C3-C5 branched alkyl. [0258] In some embodiments R2b is C1-4 alkoxy. [0259] In some embodiments R2b is C3-5 branched alkoxy. [0260] In some embodiments R2b is F. [0261] In some embodiments R2b is Cl. [0262] In some embodiments R2b is CN. [0263] In some embodiments R2b is OCF3. [0264] In some embodiments R2b is CHF2. [0265] In some embodiments R2b is CF3. [0266] In some embodiments R2b is N(R6a)(R6b). r [0267] In some embodiments R2b is
Figure imgf000049_0001
. [0268] In some embodiments R2b is
Figure imgf000049_0002
[0269] In some embodiments R2b is SR8. [0270] In some embodiments R2b is SO2R9. [0271] In some embodiments R2c is H. [0272] In some embodiments R2c is C1-4 alkyl. [0273] In some embodiments R2c is C3-5 branched alkyl. [0274] In some embodiments R2c is C1-4 alkoxy. [0275] In some embodiments R2c is C3-5 branched alkoxy. [0276] In some embodiments R2c is F. [0277] In some embodiments R2c is Cl. [0278] In some embodiments R2c is CN. [0279] In some embodiments R2c is OCF3. [0280] In some embodiments R2c is CHF2. [0281] In some embodiments R2c is CF3. [0282] In some embodiments R2c is N(R6a)(R6b)/   [0283] In some embodiments
Figure imgf000050_0001
[0284] In some embodiments
Figure imgf000050_0002
[0285] In some embodiments R2c is SR8. [0286] In some embodiments R2c is SO2R9. [0287] In some embodiments Y2 is O. [0288] In some embodiments Y2 is NR7. [0289] In some embodiments R2d is H. [0290] In some embodiments R2d is C1-4 alkyl. [0291] In some embodiments R2d is C3-5 branched alkyl. [0292] In some embodiments R2d is C1-4 alkoxy. [0293] In some embodiments R2d is C3-5 branched alkoxy. [0294] In some embodiments R2d is F. [0295] In some embodiments R2d is Cl. [0296] In some embodiments R2d is CN. [0297] In some embodiments R2d is OCF3. [0298] In some embodiments R2d is CHF2. [0299] In some embodiments R2d is CF3. [0300] In some embodiments R2d is N(R6a)(R6b). r [0301] In some embodiments R2d is
Figure imgf000050_0003
. [0302] In some embodiments R2d is
Figure imgf000050_0004
[0303] In some embodiments R2d is SR8. [0304] In some embodiments R2d is SO2R9. [0305] In some embodiments Y3 is O. [0306] In some embodiments Y3 is NR7. [0307] In some embodiments R3a is H. [0308] In some embodiments R3a is C1-4 alkyl. [0309] In some embodiments R3a is C3-5 branched alkyl, [0310] In some embodiments R3a is C1-4 alkoxy. [0311] In some embodiments R3a is C3-5 branched alkoxy,   [0312] In some embodiments R3a is F. [0313] In some embodiments R3a is Cl. [0314] In some embodiments R3a is CN. [0315] In some embodiments R3a is OCF3. [0316] In some embodiments R3a is CHF2. [0317] In some embodiments R3a is CF3. [0318] In some embodiments R3a is N(R6a)(R6b). r [0319] In some embodiments R3a is
Figure imgf000051_0001
. [0320] In some embodiments R3a is
Figure imgf000051_0003
[0321] In some embodiments R3a is SR8. [0322] In some embodiments R3a is, SO2R9. [0323] In some embodiments Y4 is O. [0324] In some embodiments Y4 is NR7. [0325] In some embodiments R3b is H. [0326] In some embodiments R3b is C1-4 alkyl. [0327] In some embodiments R3b is C3-5 branched alkyl. [0328] In some embodiments R3b is C1-4 alkoxy. [0329] In some embodiments R3b is C3-5 branched alkoxy. [0330] In some embodiments R3b is F. [0331] In some embodiments R3b is Cl. [0332] In some embodiments R3b is CN. [0333] In some embodiments R3b is OCF3. [0334] In some embodiments R3b is CHF2. [0335] In some embodiments R3b is CF3. [0336] In some embodiments R3b is N(R6a)(R6b). r [0337] In some embodiments R3b is
Figure imgf000051_0002
. [0338] In some embodiments R3b is
Figure imgf000051_0004
[0339] In some embodiments R3b is SR8. [0340] In some embodiments R3b is SO2R9.  
[0341] In some embodiments R3c is H. [0342] In some embodiments R3c is C1-4 alkyl. [0343] In some embodiments R3c is C3-5 branched alkyl, [0344] In some embodiments R3c is C1-4 alkoxy. [0345] In some embodiments R3c is C3-5 branched alkoxy, [0346] In some embodiments R3c is F. [0347] In some embodiments R3c is Cl. [0348] In some embodiments R3c is CN. [0349] In some embodiments R3c is OCF3. [0350] In some embodiments R3c is CHF2. [0351] In some embodiments R3c is CF3. [0352] In some embodiments R3c is N(R6a)(R6b). [0353] In some embodiments R3c is
Figure imgf000052_0001
[0354] In some embodiments
Figure imgf000052_0002
[0355] In some embodiments R3ca is SR8. [0356] In some embodiments R3c is, SO2R9. [0357] In some embodiments Y5 is O. [0358] In some embodiments Y5 is NR7. [0359] In some embodiments R3d is H. [0360] In some embodiments R3d is C1-4 alkyl. [0361] In some embodiments R3d is C3-5 branched alkyl, [0362] In some embodiments R3d is C1-4 alkoxy. [0363] In some embodiments R3d is C3-5 branched alkoxy, [0364] In some embodiments R3d is F. [0365] In some embodiments R3d is Cl. [0366] In some embodiments R3d is CN. [0367] In some embodiments R3d is OCF3. [0368] In some embodiments R3d is CHF2. [0369] In some embodiments R3d is CF3. [0370] In some embodiments R3d is N(R6a)(R6b). r [0371] In some embodiments R3d is
Figure imgf000052_0003
.   [0372] In some embodiments R3d is
Figure imgf000053_0001
[0373] In some embodiments R3d is SR8. [0374] In some embodiments R3d is, SO2R9. [0375] In some embodiments Y6 is O. [0376] In some embodiments Y6 is NR7. [0377] In some embodiments r is 0. [0378] In some embodiments r is 1. [0379] In some embodiments r is 2. [0380] In some embodiments r is 3. [0381] In some embodiments R4 is H. [0382] In some embodiments R4 is, C1-4 alkyl. [0383] In some embodiments R4 is CN. [0384] In some embodiments R4 is CH2(CH2)gC1-4 alkoxy.. [0385] In some embodiments R4 is -CH2(CH2)gC3-5 branched alkoxy.. [0386] In some embodiments g is 1. [0387] In some embodiments g is 2. [0388] In some embodiments R4a is H. [0389] In some embodiments R4a is C1-4 alkyl. [0390] In some embodiments R4b is H. [0391] In some embodiments R4b is C1-4 alkyl. [0392] In some embodiments R4c is H. [0393] In some embodiments R4c is C1-4 alkyl. [0394] In some embodiments R4d is H. [0395] In some embodiments R4d is C1-4 alkyl. [0396] In some embodiments R4e is H. [0397] In some embodiments R4e is C1-4 alkyl. [0398] In some embodiments R5a is H. [0399] In some embodiments R5a is C1-4 alkyl. [0400] In some embodiments R5b is H. [0401] In some embodiments R5b is C1-4 alkyl. [0402] In some embodiments R5c is H. [0403] In some embodiments R5c is C1-4 alkyl. [0404] In some embodiments R5d is H.  
[0405] In some embodiments R5d is C1-4 alkyl. [0406] In some embodiments R5e is H. [0407] In some embodiments R5e is C1-4 alkyl. [0408] In some embodiments R5f is C1-4 alkyl. [0409] In some embodiments R5f is C3-5 branched alkyl. [0410] In some embodiments R5f is C3-5 cycloalkyl. [0411] In some embodiments R6a is hydrogren. [0412] In some embodiments R6a is C1-4 alkyl. [0413] In some embodiments R6b is hydrogen. [0414] In some embodiments R6b is C1-4 alkyl. [0415] In some embodiments R7 is C1-4 alkyl. [0416] In some embodiments R9 is C1-4 alkyl. [0417] In some embodiments R9 is C1-4 alkyl. [0418] In some embodiments R3b and R4b are joined to form a heterocyclic ring consisting of five members. [0419] In some embodiments R3b and R4b are joined to form a heterocyclic ring consisting of six members. [0420] In some embodiments R3d and R4c are joined to form a heterocyclic ring consisting of five members. [0421] In some embodiments R3d and R4c are joined to form a heterocyclic ring consisting of six members. [0422] Compounds of the present invention include compounds having the formula (XI) or a pharmaceutically acceptable salt form thereof:
Figure imgf000054_0001
wherein non-limiting examples of R2b, R2d, R3a, R3c and R3d are defined herein below in Table 1. Table 1: Exemplary compounds of the formula (XI)
Figure imgf000054_0002
 
Figure imgf000055_0001
[0423] Compounds of the present invention include compounds having the formula (XII) or a pharmaceutically acceptable salt form thereof:  
Figure imgf000056_0001
  wherein non-limiting examples of R2b, R2c, R2d, R3a, R3c, and R3d are defined herein below in Table 2. Table 2: Exemplary compounds of the formula (XII)
Figure imgf000056_0002
 
Figure imgf000057_0002
[0424] Compounds of the present invention include compounds having the formula (XIII) or a pharmaceutically acceptable salt form thereof:
Figure imgf000057_0001
  wherein non-limiting examples of R2a, R2b, R2d, R3a, R3b, R3c, and R3d are defined herein below in Table 3. Table 3: Exemplary compounds of the formula (XIII)
Figure imgf000057_0003
 
Figure imgf000058_0001
 
Figure imgf000059_0002
[0425] Compounds of the present invention include compounds having the formula (XIV) or a pharmaceutically acceptable salt form thereof:
Figure imgf000059_0001
  wherein non-limiting examples of R2a, R2b, R2c, R2d, R3a, R3b, R3c, and R3dare defined herein below in Table 4. Table 4: Exemplary compounds of the formula (XIV)
Figure imgf000059_0003
 
Figure imgf000060_0002
[0426] Compounds of the present invention include compounds having the formula (XV) or a pharmaceutically acceptable salt form thereof:
Figure imgf000060_0001
  wherein non-limiting examples of R2a, R2b, R3a, R3b, R3c,, and R3d are defined herein below in Table 5. Table 5: Exemplary compounds of the formula (XV)
Figure imgf000060_0003
 
Figure imgf000061_0002
[0427] Compounds of the present invention include compounds having the formula (XVI) or a pharmaceutically acceptable salt form thereof:
Figure imgf000061_0001
  wherein non-limiting examples of R2a, R2b, R2c, R2d, R3c,, and R3d are defined herein below in Table 6. Table 6: Exemplary compounds of the formula (XVI)
Figure imgf000061_0003
 
Figure imgf000062_0001
 
Figure imgf000063_0004
[0428] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:
Figure imgf000063_0001
[0429] has the chemical name N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamide. [0430] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:
Figure imgf000063_0002
[0431] has the chemical name 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide. [0432] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:
Figure imgf000063_0003
[0433] has the chemical name 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-N-methylbenzamide [0434] For the purposes of the present invention, a compound depicted by the racemic formula will stand equally well for either of the two enantiomers or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.  
[0435] In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein. PROCESS [0436] The present invention further relates to a process for preparing the antifungal effect agents of the present invention. [0437] Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein. [0438] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC). [0439] Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes. [0440] The reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than  
one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. [0441] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes. GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS. [0442] The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes. [0443] Compounds of formula (I) may be prepared according to the process outlined in schemes 1-216. 
Figure imgf000065_0001
  [0444] A compounds of the formula (1), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (2), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). Alternatively, a compound of the formula (4), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (2), a known compound or a compound made by known methods, in the presence of a base such  
as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). A compound of the formula (3) is reacted with a compound of the formula (5), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (6). A compound of the formula (6) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (7).  
Figure imgf000067_0001
  [0445] A compounds of the formula (7) is reacted with a compound of the formula (8) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9). A compound of the formula (9) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (9).
Figure imgf000067_0002
[0446] A compounds of the formula (10), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (11), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the  
presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12). Alternatively, a compound of the formula (13), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (11), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (12). A compound of the formula (12) is reacted with a compound of the formula (14), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′- (N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (15). A compound of the formula (15) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16).  
Figure imgf000069_0001
  [0447] A compounds of the formula (16) is reacted with a compound of the formula (17) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (18). A compound of the formula (18) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (19).
Figure imgf000069_0002
  [0448] A compounds of the formula (20), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (21), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a  
solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (22). Alternatively, a compound of the formula (20a), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (21), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (22). A compound of the formula (22) is reacted with a compound of the formula (23), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (24). A compound of the formula (24) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (25).  
Figure imgf000071_0001
  [0449] A compounds of the formula (25) is reacted with a compound of the formula (26) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (27). A compound of the formula (27) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).
Figure imgf000071_0002
  [0450] A compounds of the formula (29), a known compound of a compound prepared by known methods in which Z1 is a C1-6 alkyl, is reacted with a compound of the formula (30), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-  
butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (31). A compound of the formula (31) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (32).
Figure imgf000072_0001
[0451] A compounds of the formula (33), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (34), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-  
(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (35). A compounds of the formula (35) is reacted with a compound of the formula (32), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (36).
Figure imgf000073_0001
    [0452] A compound of the formula (37), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (38), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (39). A compounds of the formula (39), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (40), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on  
carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalla dium-tri(1,3-dibenzylidene)acetone,and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (41).
Figure imgf000074_0001
  [0453] A compound of the formula (42), a known compound or a compound prepared by known methods where in Z2 is selected from the group consisting of bromine and iodine, is reacted with a compound of the formula (43), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (44). A compound of the formula (44) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (45). A compounds of the formula (45) is  
reacted with a compound of the formula (46), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (47).
Figure imgf000075_0001
  [0454] A compounds of the formula (48), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (49), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (50).  
A compound of the formula (50) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (51).
Figure imgf000076_0002
  [0455] A compounds of the formula (51) is reacted with a compound of the formula (52) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (53). A compound of the formula (53) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (54).
Figure imgf000076_0001
  [0456] A compounds of the formula (55), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (56), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-  
dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (57). A compound of the formula (57) is reacted with a compound of the formula (58) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7- ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (59).
Figure imgf000077_0001
  [0457] A compound of the formula (59) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (60). A compounds of the formula (60) is reacted with a compound of the formula (61) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (62). A compound of the formula (62) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of  
methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (63).
Figure imgf000078_0001
  [0458] A compound of the formula (63), a known compound or a compound prepared by known methods wherein Z3 is selected from the group consisting of iodine, bromine and chlorine, is reacted with a compound of the formula (64), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (65). A compound of the formula (65) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (66). A compound of the formula (66) is reacted with a compound of the formula (67), a known compound of a compound prepared by known methods, in the presence of a solvent such as a methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (68). Scheme 16
Figure imgf000078_0002
  [0459] A compound of the formula (68) is reacted with iodomethane in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (69). A compound of the formula (69) is reacted with a compound of the formula (70), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-  
dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (71). 
Figure imgf000079_0001
  [0460] A compound of the formula (72), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (73) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (74). A compound of the formula (74) is reacted with a compound of the formula (75) in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (76). A compound of the formula (76) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (77).  
Figure imgf000080_0001
[0461] A compound of the formula (78), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (79), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide, and the like, in the presence of a solvent such as such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, toluene, benzene and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (80). A compound of the formula (80) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (81).
Figure imgf000080_0002
   
[0462] A compounds of the formula (81) is reacted with a compound of the formula (82) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (83).
Figure imgf000081_0001
[0463] A compound of the formula (83) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (84).
Figure imgf000081_0002
[0464] A compound of the formula (85) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86). Alternatively, a compound of the formula (85) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-  
dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (86). A compounds of the formula (86) is reacted with a compound of the formula (87) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (88). A compound of the formula (88) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (89).
Figure imgf000082_0001
  [0465] A compound of the formula (90), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (91) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (92). A compound of the formula (92) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (93).
Figure imgf000082_0002
  [0466] A compound of the formula (94), a known compound or a compound prepared by known methods in which Z4 is a C1-6 alkyl, is reacted with a compound of the formula (95), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II),  
palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (96). A compound of the formula (96) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (97).
Figure imgf000083_0001
  [0467] A compounds of the formula (97) is reacted with a compound of the formula (93) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (98). A compound of the formula (98) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent  
such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (99).
Figure imgf000084_0001
  [0468] A compounds of the formula (99) is reacted with a compound of the formula (100) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (101). A compound of the formula (101) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (102).
Figure imgf000084_0002
  [0469] A compound of the formula (103) is reacted with a compounds of the formula (104) in the presence of a base such as base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (105). A compound of the formula (105) is  
reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (106). A compounds of the formula (106) is reacted with a compound of the formula (107) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (108).
Figure imgf000085_0001
  [0470] A compound of the formula (108) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (109). A compounds of the formula (109) is reacted with a compound of the formula (110) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (111). A compound of the formula (111) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-  
dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (112).
Figure imgf000086_0001
  [0471] A compound of the formula (113), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (114) in the presence of in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (115). A compound of the formula (115) is reacted with a compound of the formula (116), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (117). A compound of the formula (117) is reacted with a compound of the formula (118), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-  
dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (119). A compound of the formula (119) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (120). A compound of the formula (120) is reacted with a compound of the formula (121) in the presence of in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (122). A compound of the formula (122) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (123).
Figure imgf000087_0001
  [0472] A compound of the formula (124), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (125), a known compound or a compound prepared by  
known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (126). A compound of the formula (126) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (127). A compound of the formula (127) is reacted with a compound of the formula (128), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (129).
Figure imgf000088_0001
   
[0473] A compounds of the formula (129), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (130), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (131). A compound of the formula (131) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (132).
Figure imgf000089_0001
 
[0474] A compounds of the formula (132) is reacted with a compound of the formula (133) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (134). A compound of the formula (134) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (135).
Figure imgf000090_0001
  [0475] A compound of the formula (136), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (137), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (138). A compounds of the formula (138) is reacted with a compound of the formula (139), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-  
methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (140).
Figure imgf000091_0001
  [0476] A compound of the formula (140) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (141). A compounds of the formula (141) is reacted with a compound of the formula (142) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (143). A compound of the formula (143) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (144).  
Figure imgf000092_0001
  [0477] A compound of the formula (145), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (146), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (147). A compounds of the formula (147) is reacted with a compound of the formula (148), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (149).  
Figure imgf000093_0002
  [0478] A compound of the formula (150), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (151), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (152).  
Figure imgf000093_0001
  [0479] A compound of the formula (153), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (154), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (155). A compounds of the formula (155) is reacted with a compound of the formula (156), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-  
biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (157).
Figure imgf000094_0001
  [0480] A compound of the formula (157) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (158). A compounds of the formula (158) is reacted with a compound of the formula (159) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (160). A compound of the formula (160) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (161).  
Figure imgf000095_0001
  [0481] A compound of the formula (162), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (163), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (164).
Figure imgf000095_0002
  [0482] A compounds of the formula (165), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (166), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-  
tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (167)
Figure imgf000096_0001
  [0483] A compounds of the formula (168), a known compound or a comopound prepred by known methods, is reacted with a compound of the formula (169), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (170). A compound   of the formula (170) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (171). A compounds of the formula (171) is reacted with a compound of the formula (172) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (173). A compound of the formula (173) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (174).
Figure imgf000097_0002
[0484] A compound of the formula (175), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (176), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (177).
Figure imgf000097_0001
  [0485] A compounds of the formula (178), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (179), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-  
tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (180). Alternatively, a compound of the formula (181), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (179), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (180). A compound of the formula (180) is reacted with a compound of the formula (181), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (182). A compound of the formula (182) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like,   optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (183).
Figure imgf000099_0002
[0486] A compounds of the formula (183) is reacted with a compound of the formula (184) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (185). A compound of the formula (185) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (186).
Figure imgf000099_0001
[0487] A compounds of the formula (187), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (188), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like,  
optionally with heating, optionally with microwave irradiation to provide a compound of the formula (189). Alternatively, a compound of the formula (190), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (188), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (189). A compound of the formula (189) is reacted with a compound of the formula (191), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′- (N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (192). A compound of the formula (192) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (193).  
Figure imgf000101_0001
  [0488] A compounds of the formula (193) is reacted with a compound of the formula (194) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (195). A compound of the formula (195) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (196).
Figure imgf000101_0002
[0489] A compounds of the formula (197), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (198), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (199).  
Alternatively, a compound of the formula (200), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (198), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (199). A compound of the formula (199) is reacted with a compound of the formula (201), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’- dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (202). A compound of the formula (202) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (203).  
Figure imgf000103_0001
  [0490] A compounds of the formula (203) is reacted with a compound of the formula (204) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (205). A compound of the formula (205) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (206).
Figure imgf000103_0002
  [0491] A compounds of the formula (207), a known compound of a compound prepared by known methods in which Z1 is a C1-6 alkyl, is reacted with a compound of the formula (208), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-  
biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (209). A compound of the formula (209) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (210).
Figure imgf000104_0001
[0492] A compounds of the formula (211), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (212), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such  
as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (213). A compounds of the formula (213) is reacted with a compound of the formula (210), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (214).
Figure imgf000105_0001
    [0493] A compound of the formula (215), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (216), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (217). A compounds of the formula (217), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (218), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalla dium-tri(1,3-dibenzylidene)acetone,and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-  
dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (219).
Figure imgf000106_0001
[0494] A compounds of the formula (220), a known compound of a compound prepared by known methods where in Z2 is selected from the group consisting of bromine and iodine, is reacted with a compound of the formula (221), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-  
dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (223).
Figure imgf000107_0001
[0495] A compounds of the formula (224), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (225), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (226). A compound of the formula (226) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (227).
Figure imgf000107_0002
  [0496] A compounds of the formula (227) is reacted with a compound of the formula (228) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave  
irradiation to provide a compound of the formula (229). A compound of the formula (229) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (230).
Figure imgf000108_0001
  [0497] A compound of the formula (231), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (232) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (233). A compound of the formula (233) is reacted with a compound of the formula (234) wherein Z3 is selected from the group consisting of iodine, bromine and chlorine, in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence os a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (235). A compound of the formula (235) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-  
dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (236).
Figure imgf000109_0001
[0498] A compound of the formula (237) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (238). Alternatively, a compound of the formula (237) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (238). A compounds of the formula (238) is reacted with a compound of the formula (239) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (240). A compound of the formula (240) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (241).  
Figure imgf000110_0001
  [0499] A compound of the formula (242), a known compound or a compound prepared by known methods in which Z4 is a C1-6 alkyl, is reacted with a compound of the formula (243), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (244). A compound of the formula (244) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (245).
Figure imgf000110_0002
 
[0500] A compounds of the formula (245) is reacted with a compound of the formula (246) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (247). A compound of the formula (247) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (248).
Figure imgf000111_0001
  [0501] A compounds of the formula (248) is reacted with a compound of the formula (249) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (250). A compound of the formula (250) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (251).
Figure imgf000111_0002
 
[0502] A compounds of the formula (252) is reacted with a compound of the formula (253) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (254).
Figure imgf000112_0001
[0503] A compound of the formula (254) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (255). A compounds of the formula (255) is reacted with a compound of the formula (256) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (257). A compound of the formula (257) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (258).  
Figure imgf000113_0001
Figure imgf000113_0002
[0504] A compound of the formula (259) is reacted with a compound of the formula (260), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (261). A compound of the formula (261) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (262). A compound of the formula (262) is reacted with a compound of the formula (263) in the presence of in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as  
N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (264). A compound of the formula (264) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (265).
Figure imgf000114_0001
  [0505] A compounds of the formula (260), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (261), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (262). A compound of the formula (262) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid,  
and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (263).
Figure imgf000115_0001
[0506] A compounds of the formula (263) is reacted with a compound of the formula (264) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (265). A compound of the formula (265) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (266).
Figure imgf000115_0002
  [0507] A compounds of the formula (267) is reacted with a compound of the formula (268), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-  
2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (269).
Figure imgf000116_0001
  [0508] A compound of the formula (269) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (270). A compounds of the formula (270) is reacted with a compound of the formula (271) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (272). A compound of the formula (272) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-  
dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (273).
Figure imgf000117_0001
  [0509] A compounds of the formula (274) is reacted with a compound of the formula (275), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (276).
Figure imgf000117_0002
  [0510] A compounds of the formula (277) is reacted with a compound of the formula (278), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and  
the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (279).
Figure imgf000118_0001
  [0511] A compound of the formula (279) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (280). A compounds of the formula (280) is reacted with a compound of the formula (281) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (282). A compound of the formula (282) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-  
dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (283).
Figure imgf000119_0001
  [0512] A compounds of the formula (284), a known compound or a comopound prepred by known methods, is reacted with a compound of the formula (285), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (286). A compound of the formula (286) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (287). A compounds of the formula (287) is reacted with a compound  
of the formula (288) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (289). A compound of the formula (289) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (290).
Figure imgf000120_0001
  [0513] A compound of the formula (291) is reacted with a compound of the formula (292), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with  
microwave irradiation to provide a compound of the formula (293). A compound of the formula (293) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (294). Alternatively, a compound of the formula (293) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (294). 
Figure imgf000121_0001
  [0514] A compound of the formula (295), a known compound or a compound prepared by known methods in which Z5 is a C1-6 alkyl,is reacted with a compound of the formula (296), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-  
dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (297). A compound of the formula (297) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (298). A compounds of the formula (298) is reacted with a compound of the formula (299) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (300). A compound of the formula (300) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (301). Alternatively, a compound of the formula (300) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent   such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (301). A compound of the formula (301) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (302). A compounds of the formula (302) is reacted with a compound of the formula (303) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (304). A compound of the formula (304) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (305).
Figure imgf000123_0001
[0515] A compounds of the formula (306) is reacted with a compound of the formula (307) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium  
hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (308). A compound of the formula (308) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (309). Alternatively, a compound of the formula (308) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (309). A compound of the formula (309) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (310). A compounds of the formula (310) is reacted with a compound of the formula (311) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (312). A compound of the formula (312) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (313).  
Figure imgf000125_0001
  [0516] A compound of the formula (314) wherein Z6 is selected from the group consisting of iodine, bromine and chlorine, is reacted with a compound of the formula (315) in the presence of in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (316). A compound of the formula (316) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (317). Alternatively, a compound of the formula (316) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (317).  
Figure imgf000126_0001
[0517] A compound of the formula (318) is reacted with a compound of the formula (319), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (320). A compound of the formula (320) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave  
irradiation to provide a compound of the formula (321). Alternatively, a compound of the formula (320) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (321). A compound of the formula (321) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (322). A compounds of the formula (322) is reacted with a compound of the formula (323) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (324). A compound of the formula (324) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (325). 
Figure imgf000127_0001
  [0518] A compound of the formula (326) is reacted with a compound of the formula (327), a known  
compound or a compound prepared by known methods, in the presence of a palladium catalyst 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-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (328). A compound of the formula (328) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (329). Alternatively, a compound of the formula (328) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (329). A compound of the formula (329) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol,  
N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (330).
Figure imgf000129_0001
  [0519] A compounds of the formula (331), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (332), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with  
heating, optionally with microwave irradiation to provide a compound of the formula (333). A compound of the formula (333) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (334). Alternatively, a compound of the formula (333) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (334). A compound of the formula (334) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (335). A compounds of the formula (335) is reacted with a compound of the formula (336) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (337). A compound of the formula (337) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (338).  
Figure imgf000131_0001
  [0520] A compounds of the formula (339) is reacted with a compound of the formula (340), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (341). A compound of the formula (341) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-  
dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (342). Alternatively, a compound of the formula (341) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (342). A compound of the formula (342) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (343). A compounds of the formula (343) is reacted with a compound of the formula (344) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (345). A compound of the formula (345) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (346).  
Figure imgf000133_0001
  [0521] A compounds of the formula (347) is reacted with a compound of the formula (348), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (349). A compound of the formula (349) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (350). Alternatively, a compound of the formula (349) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,  
tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (350). A compound of the formula (350) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (351). A compounds of the formula (351) is reacted with a compound of the formula (352) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (353). A compound of the formula (353) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (354).  
Figure imgf000135_0001
  [0522] A compounds of the formula (355), a known compound or a comopound prepred by known methods, is reacted with a compound of the formula (356), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (357). A compound of the formula (357) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-  
dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (358). Alternatively, a compound of the formula (357) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (358). A compound of the formula (358) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (359). A compounds of the formula (359) is reacted with a compound of the formula (360) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (361). A compound of the formula (361) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (362).
Figure imgf000136_0001
  [0523] A compound of the formula (363) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),  
dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (364). Alternatively, a compound of the formula (363) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (364). A compound of the formula (364) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (365). Alternatively, a compound of the formula (364) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (365).
Figure imgf000137_0001
  [0524] A compound of the formula (366) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),  
dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (367). Alternatively, a compound of the formula (366) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (367). A compound of the formula (367) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (368). Alternatively, a compound of the formula (367) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (368). A compound of the formula (368) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (369). A compounds of the formula (369) is reacted with a compound of the formula (370) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (371). A compound of the formula (371) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,   methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (372). 5d
Figure imgf000139_0001
[0525] A compound of the formula (373) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (374). Alternatively, a compound of the formula (373) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (374). A compound of the formula (374) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (375). Alternatively, a compound of the formula (374) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating,  
optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (375). A compound of the formula (375) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (376). A compounds of the formula (376) is reacted with a compound of the formula (377) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (378). A compound of the formula (378) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (379).
Figure imgf000140_0001
  [0526] A compound of the formula (380) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (381). Alternatively, a compound of the formula (380) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-  
dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (381). A compound of the formula (381) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (382). Alternatively, a compound of the formula (381) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (382).
Figure imgf000141_0001
  [0527] A compound of the formula (383) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (384). Alternatively, a compound of the formula (383) is reacted with hydrogen in the presence of platinum on  
carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (384). A compound of the formula (384) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (385). Alternatively, a compound of the formula (384) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (385). A compound of the formula (385) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (386). A compounds of the formula (386) is reacted with a compound of the formula (387) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (388). A compound of the formula (388) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (389).  
Figure imgf000143_0001
  [0528] A compound of the formula (390) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (391). Alternatively, a compound of the formula (390) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (391). A compound of the formula (391) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (392). Alternatively, a compound of the formula (391) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (392). A compound of the formula (392) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol,  
N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (393).
Figure imgf000144_0001
  [0529] A compound of the formula (394) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (395). Alternatively, a compound of the formula (394) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (395). A compound of the formula (395) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (396). Alternatively, a compound of the formula (395) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating,  
optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (396). A compound of the formula (396) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (397). A compounds of the formula (397) is reacted with a compound of the formula (398) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (399). A compound of the formula (399) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (400).  
Figure imgf000146_0001
A compound of the formula (401) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (402). Alternatively, a compound of the formula (401) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (402). A compound of the formula (402) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (403). Alternatively, a compound of the formula (402) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent  
such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (403). A compound of the formula (403) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (404). A compounds of the formula (404) is reacted with a compound of the formula (405) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (406). A compound of the formula (406) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (407).
Figure imgf000147_0001
  [0531] A compound of the formula (408) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (409).  
Alternatively, a compound of the formula (408) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (409). A compound of the formula (409) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (410). Alternatively, a compound of the formula (409) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (410). A compound of the formula (410) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (411). A compounds of the formula (411) is reacted with a compound of the formula (412) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (413). A compound of the formula (413) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (414).  
Figure imgf000149_0001
  [0532] A compound of the formula (415) is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (416). Alternatively, a compound of the formula (415) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (416). A compound of the formula (416) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (417). Alternatively, a compound of the formula (416) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave  
irradiation.to provide a compound of the formula (417). A compound of the formula (417) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (418). A compounds of the formula (418) is reacted with a compound of the formula (419) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (420). A compound of the formula (420) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (421).
Figure imgf000150_0001
  [0533] A compound of the formula (422) is reacted with a compound of the formula (423), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),  
dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (424). A compound of the formula (424) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (425). A compounds of the formula (425) is reacted with a compound of the formula (426) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (427). A compound of the formula (427) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (428).  
Figure imgf000152_0001
  [0534] A compound of the formula (429), a known compound or a compound prepared by known methods in which Z7 is a C1-6 alkyl, is reacted with a compound of the formula (430), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (431). A compound of the formula (431) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a  
solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (432). A compounds of the formula (432) is reacted with a compound of the formula (433) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (434). A compound of the formula (434) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (435). A compounds of the formula (435) is reacted with a compound of the formula (436) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (437). A compound of the formula (437) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (438).
Figure imgf000153_0001
   
[0535] A compounds of the formula (439) is reacted with a compound of the formula (440) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (441). A compound of the formula (441) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (442). A compounds of the formula (442) is reacted with a compound of the formula (443) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (444). A compound of the formula (444) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (445).
Figure imgf000154_0001
  [0536] A compound of the formula (446) wherein Z8 is selected from the group consisting of iodine, bromine and chlorine, is reacted with a compound of the formula (447) in the presence of in the presence  
of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and the like, in the prescence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (448). A compound of the formula (448) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (449). A compounds of the formula (449) is reacted with a compound of the formula (450) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (451). A compound of the formula (451) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (452).
Figure imgf000155_0001
  [0537] A compound of the formula (453) is reacted with a compound of the formula (454), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0),  
dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (455). A compound of the formula (455) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (456). A compounds of the formula (456) is reacted with a compound of the formula (457) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (458). A compound of the formula (458) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (459).  
Figure imgf000157_0001
    [0538] A compound of the formula (460) is reacted with a compound of the formula (461), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (462). A compound of the formula (462) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (463). A compounds of the formula (463) is reacted with a compound  
of the formula (464) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (465). A compound of the formula (465) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (466).
Figure imgf000158_0001
  [0539] A compounds of the formula (467), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (468), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate,  
lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (469). A compound of the formula (469) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (470). A compounds of the formula (470) is reacted with a compound of the formula (471) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (472). A compound of the formula (472) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (473).
Figure imgf000159_0001
    [0540] A compounds of the formula (474) is reacted with a compound of the formula (475), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-  
bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (476). A compound of the formula (476) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (477). A compounds of the formula (477) is reacted with a compound of the formula (478) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (479). A compound of the formula (479) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (480).  
Figure imgf000161_0001
    [0541] A compounds of the formula (481) is reacted with a compound of the formula (482), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (483). A compound of the formula (483) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (484). A compounds of the formula (484) is reacted with a compound of the formula (485) in the presence of a base such as triethylamine, N,N-  
diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (486). A compound of the formula (486) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (487).
Figure imgf000162_0001
    [0542] A compounds of the formula (488), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (489), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide,  
potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (490). A compound of the formula (490) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (491). A compounds of the formula (491) is reacted with a compound of the formula (492) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (493). A compound of the formula (493) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (494).
Figure imgf000163_0001
  [0543] A compounds of the formula (495), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (496), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (497).  
A compound of the formula (497) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (498).
Figure imgf000164_0001
  [0544] A compounds of the formula (498) is reacted with a compound of the formula (499) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (500). A compound of the formula (500) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (501).
Figure imgf000164_0002
  [0545] A compound of the formula (502) is reacted with a compound of the formula (503) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-  
triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (59).
Figure imgf000165_0001
  [0546] A compound of the formula (504) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (505). A compounds of the formula (505) is reacted with a compound of the formula (506) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (507). A compound of the formula (507) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (508).
Figure imgf000165_0002
 
[0547] A compound of the formula (509), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (510), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide, and the like, in the presence of a solvent such as such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, toluene, benzene and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (511). A compound of the formula (511) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (512).
Figure imgf000166_0001
  [0548] A compounds of the formula (512) is reacted with a compound of the formula (513) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,  
acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (514).
Figure imgf000167_0001
[0549] A compound of the formula (514) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (515).
Figure imgf000167_0002
  [0550] A compound of the formula (516), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (517), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide,  
potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (518). A compound of the formula (518) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (519). A compound of the formula (519) is reacted with a compound of the formula (520), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (521).
Figure imgf000168_0001
  [0551] A compounds of the formula (521), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (522), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-  
methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (523). A compound of the formula (523) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (524).
Figure imgf000169_0001
[0552] A compounds of the formula (524) is reacted with a compound of the formula (525) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (526). A compound of the formula (526) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (527).  
Figure imgf000170_0001
  [0553] A compound of the formula (528), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (529), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (530). A compounds of the formula (530) is reacted with a compound of the formula (531), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (532).  
Figure imgf000171_0001
  [0554] A compound of the formula (532) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (533). A compounds of the formula (533) is reacted with a compound of the formula (534) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (535). A compound of the formula (535) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (536).
Figure imgf000171_0002
  [0555] A compound of the formula (537), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (538), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-  
dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (539). A compounds of the formula (539) is reacted with a compound of the formula (540), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (541).
Figure imgf000172_0001
  [0556] A compound of the formula (542), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (543), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone,  
dimethylsulfoxide, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (544).  
Figure imgf000173_0002
  [0557] A compound of the formula (545), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (546), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (547).
Figure imgf000173_0001
   
[0558] A compounds of the formula (548), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (549), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (550)
Figure imgf000174_0001
[0559] A compounds of the formula (551), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (552), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (553). A compound of the formula (553) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (554).  
Figure imgf000175_0001
  [0560] A compounds of the formula (554) is reacted with a compound of the formula (555) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (556). A compound of the formula (556) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (557).
Figure imgf000175_0002
  [0561] A compounds of the formula (558), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (559), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-  
butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (560). A compound of the formula (560) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (561).
Figure imgf000176_0001
[0562] A compounds of the formula (562) is reacted with a compound of the formula (563) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (564). A compound of the formula (564) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (565).  
Figure imgf000177_0001
  [0563] A compounds of the formula (566) is reacted with a compound of the formula (567), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (568).
Figure imgf000177_0002
  [0564] A compound of the formula (568) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane,  
tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (569). A compounds of the formula (569) is reacted with a compound of the formula (570) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (571). A compound of the formula (571) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (572).
Figure imgf000178_0001
  [0565] A compounds of the formula (573) is reacted with a compound of the formula (574), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-  
dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (575).
Figure imgf000179_0001
  [0566] A compounds of the formula (576), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (577), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (578). A compound of the formula (578) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (579). Alternatively, a compound of the formula (578) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (579).  
A compound of the formula (579) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (580). A compounds of the formula (580) is reacted with a compound of the formula (581) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (582). Scheme 124
Figure imgf000180_0001
[0567] A compound of the formula (582) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (583).
Figure imgf000180_0002
  [0568] A compound of the formula (584) is reacted with a compound of the formula (585) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like,  
optionally with heating, optionally with microwave irradiation to provide a compound of the formula (586). A compound of the formula (586) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (587). Alternatively, a compound of the formula (586) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (587). A compound of the formula (587) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (588). A compounds of the formula (588) is reacted with a compound of the formula (589) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (590).
Figure imgf000181_0001
  [0569] A compound of the formula (590) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (591).  
Figure imgf000182_0001
[0570] A compound of the formula (592), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (593), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide, and the like, in the presence of a solvent such as such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, toluene, benzene and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (594). A compound of the formula (594) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (595). Alternatively, a compound of the formula (594) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent  
such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (595).
Figure imgf000183_0001
  [0571] A compound of the formula (596), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (597), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (598). A compound of the formula (598) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a  
compound of the formula (599). A compound of the formula (599) is reacted with a compound of the formula (600), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (601).
Figure imgf000184_0001
  [0572] A compounds of the formula (601), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (602), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-  
dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (603). A compound of the formula (603) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (604). Alternatively, a compound of the formula (603) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (604). A compound of the formula (604) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (605). A compounds of the formula (605) is reacted with a compound of the formula (606) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (607).
Figure imgf000185_0001
[0573] A compound of the formula (607) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (608).
Figure imgf000186_0001
  [0574] A compound of the formula (609), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (610), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (611). A compounds of the formula (611) is reacted with a compound of the formula (612), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-  
dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (613). A compound of the formula (613) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (614). Alternatively, a compound of the formula (613) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (614). A compound of the formula (614) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (615).
Figure imgf000187_0001
  [0575] A compounds of the formula (615) is reacted with a compound of the formula (616) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave  
irradiation to provide a compound of the formula (617). A compound of the formula (617) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (618).
Figure imgf000188_0001
  [0576] A compound of the formula (619), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (620), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (621). A compounds of the formula (621) is reacted with a compound of the formula (622), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-  
(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (623). A compound of the formula (623) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (624). Alternatively, a compound of the formula (623) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (624). A compound of the formula (624) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (625).
Figure imgf000189_0001
 
[0577] A compounds of the formula (625) is reacted with a compound of the formula (626) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (627). A compound of the formula (627) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (628).
Figure imgf000190_0001
  [0578] A compound of the formula (629), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (630), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (631).  
Figure imgf000190_0002
  [0579] A compound of the formula (632), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (633), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-  
bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (634).
Figure imgf000191_0001
  [0580] A compounds of the formula (635), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (636), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (637)  
Figure imgf000192_0001
[0581] A compounds of the formula (638), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (639), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (640). A compound of the formula (640) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (641). Alternatively, a compound of the formula (640) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (641). A compound of the formula (641) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the  
like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (642). A compounds of the formula (642) is reacted with a compound of the formula (643) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (644).
Figure imgf000193_0001
  [0582] A compound of the formula (644) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (645).
Figure imgf000193_0002
  [0583] A compounds of the formula (646), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (647), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-  
dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (648). A compound of the formula (648) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (649). Alternatively, a compound of the formula (648) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (649). A compound of the formula (649) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (650). A compounds of the formula (650) is reacted with a compound of the formula (651) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane,  
tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (652).
Figure imgf000195_0001
[0584] A compound of the formula (652) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (653).
Figure imgf000195_0002
  [0585] A compounds of the formula (654) is reacted with a compound of the formula (655), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with  
heating, optionally with microwave irradiation to provide a compound of the formula (656). A compound of the formula (656) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (657). Alternatively, a compound of the formula (656) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (657). Scheme 143 NBoc 4
Figure imgf000196_0001
  [0586] A compound of the formula (657) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (658). A compounds of the formula (658) is reacted with a compound of the formula (659) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (660). A compound of the formula (660) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,  
tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (661).
Figure imgf000197_0001
  [0587] A compounds of the formula (662) is reacted with a compound of the formula (663), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (664).  
Figure imgf000198_0001
  [0588] A compounds of the formula (665), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (666), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (667). A compound of the formula (667) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (668). Alternatively, a compound of the formula (667) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (668). A compound of the formula (668) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-  
dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (669). A compounds of the formula (669) is reacted with a compound of the formula (670) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (671).
Figure imgf000199_0002
[0589] A compound of the formula (671) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (672).
Figure imgf000199_0001
  [0590] A compound of the formula (673) is reacted with a compound of the formula (674) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like,  
optionally with heating, optionally with microwave irradiation to provide a compound of the formula (675). A compound of the formula (675) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (676). Alternatively, a compound of the formula (675) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (676). A compound of the formula (676) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (677). A compounds of the formula (677) is reacted with a compound of the formula (678) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (679).
Figure imgf000200_0001
  [0591] A compound of the formula (679) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (680).
Figure imgf000201_0001
[0592] A compound of the formula (681), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (682), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide, and the like, in the presence of a solvent such as such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, toluene, benzene and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (683). A compound of the formula (683) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (684). Alternatively, a compound of the formula (683) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-  
dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (684).
Figure imgf000202_0001
  [0593] A compound of the formula (665), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (666), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (667). A compound of the formula (667) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane,  
methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (668). A compound of the formula (668) is reacted with a compound of the formula (669), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (670).
Figure imgf000203_0001
  [0594] A compounds of the formula (670), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (671), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-  
dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (672). A compound of the formula (672) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (673). Alternatively, a compound of the formula (672) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (673). A compound of the formula (673) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (674). A compounds of the formula (674) is reacted with a compound of the formula (675) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (676).
Figure imgf000204_0001
[0595] A compound of the formula (676) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (677).
Figure imgf000205_0001
  [0596] A compound of the formula (678), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (679), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (680). A compounds of the formula (680) is reacted with a compound of the formula (681), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with  
heating, optionally with microwave irradiation to provide a compound of the formula (682). A compound of the formula (682) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (683). Alternatively, a compound of the formula (682) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (683). A compound of the formula (683) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (684).
Figure imgf000206_0001
  [0597] A compounds of the formula (684) is reacted with a compound of the formula (685) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (686). A compound of the formula (686) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as  
methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (687).
Figure imgf000207_0001
  [0598] A compound of the formula (688), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (689), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (690). A compounds of the formula (690) is reacted with a compound of the formula (691), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-  
biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (692). A compound of the formula (692) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (693). Alternatively, a compound of the formula (692) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (693). A compound of the formula (693) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (694).
Figure imgf000208_0001
 
[0599] A compounds of the formula (694) is reacted with a compound of the formula (695) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (696). A compound of the formula (696) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (697).
Figure imgf000209_0001
  [0600] A compound of the formula (698), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (699), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (700).  
Figure imgf000209_0002
  [0601] A compound of the formula (701), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (702), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-  
bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (703).
Figure imgf000210_0001
  [0602] A compounds of the formula (704), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (705), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (706)  
Figure imgf000211_0001
[0603] A compounds of the formula (707), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (708), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (709). A compound of the formula (709) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (710). Alternatively, a compound of the formula (709) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (710). A compound of the formula (710) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the  
like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (711). A compounds of the formula (711) is reacted with a compound of the formula (712) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (713).
Figure imgf000212_0001
  [0604] A compound of the formula (713) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (714).
Figure imgf000212_0002
  [0605] A compounds of the formula (715), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (716), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-  
butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (717). A compound of the formula (717) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (718). Alternatively, a compound of the formula (717) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (718). A compound of the formula (718) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (719). A compounds of the formula (719) is reacted with a compound of the formula (720) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (721).  
Figure imgf000214_0001
[0606] A compound of the formula (721) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (722).
Figure imgf000214_0002
  [0607] A compounds of the formula (723) is reacted with a compound of the formula (724), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (725). A compound of the formula (725) is reacted with ammonium chloride, in the presence of trimethylaluminum, in the  
presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane, benzene, toluene, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (726). Alternatively, a compound of the formula (725) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation. The resulting material is then reacted with ammonia in a solvent such as as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4- dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation.to provide a compound of the formula (726).
Figure imgf000215_0001
  [0608] A compound of the formula (726) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of anisol, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (727). A compounds of the formula (727) is reacted with a compound of the formula (728) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (729). A compound of the formula (729) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-  
dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (730).
Figure imgf000216_0001
  [0609] A compounds of the formula (731) is reacted with a compound of the formula (732), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (733).
Figure imgf000216_0002
  [0610] A compounds of the formula (734), a known compound or a compound prepared by known methods in which PG1 is selected from the group consisting of tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, and carboxybenzyl, is reacted with a compound of the formula (735), a known compound or a compound prepared by kmown methods, in the presence of an azodicarboxylate such as  
diethyl azodicarboxylate, diisopropyl azodicaboxylate, and the like in the presence of triphenylphosphine, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (736).
Figure imgf000217_0001
  [0611] A compounds of the formula (737), a known compound or a compound prepared by known methods in which PG1 is selected from the group consisting of tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, and carboxybenzyl, is reacted with a compound of the formula (738), a known compound or a compound prepared by kmown methods wherein X7 is selected from the group consisting of iodine, chlorine and bromine, in the presence of base such as sodium hydride, potassium hydride, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (736).
Figure imgf000217_0002
  [0612] A compound of the formula (737) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (738). A compound of the formula (738) is reacted with a compound of the formula (739), a known compound or a  
compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (740).
Figure imgf000218_0001
  [0613] A compound of the formula (741) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (742). A compound of the formula (742) is reacted with a compound of the formula (743), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (744).
Figure imgf000218_0002
  [0614] A compound of the formula (745) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as  
methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (746). A compound of the formula (746) is reacted with a compound of the formula (747), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (748).
Figure imgf000219_0001
  [0615] A compound of the formula (749) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (750). A compound of the formula (750) is reacted with a compound of the formula (751), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (752).  
Figure imgf000220_0001
[0616] A compound of the formula (753) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (754). A compound of the formula (754) is reacted with a compound of the formula (755), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (756).
Figure imgf000220_0002
[0617] A compound of the formula (757) is reacted ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (758). A  
compound of the formula (758) is reacted with a compound of the formula (759), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (760).
Figure imgf000221_0001
  [0618] A compounds of the formula (761) is reacted with a compound of the formula (762), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (763). A compound of the formula (763) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (764). A compound of the formula (764) is reacted with a compound of the formula (765), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,  
tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (766). A compound of the formula (766) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (767). Alternatively, a compound of the formula (766) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (767). A compounds of the formula (767) is reacted with a compound of the formula (768) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (769). A compound of the formula (769) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (770).  
Figure imgf000223_0001
  [0619] A compounds of the formula (771) is reacted with a compound of the formula (772), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′- dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (773). A compound of the formula (773) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (774). A compound of the formula (774) is reacted with a compound of the formula (775), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (776). A compound of the formula (776) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on  
carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (777). Alternatively, a compound of the formula (776) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (777). A compounds of the formula (777) is reacted with a compound of the formula (778) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (779). A compound of the formula (779) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (780).
Figure imgf000224_0001
  [0620] A compounds of the formula (781), a known compound or a compounds prepared by known methods, is reacted with a compound of the formula (782), a known compound or a compound made by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a coupling agent such as O-(benzotriazol- 1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a  
solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (783). Alternatively, a compound of the formula (784), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (782), a a known compound or a compound made by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (784). A compound of the formula (784) is reacted with a compound of the formula (785), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (786).  
Figure imgf000226_0001
[0621] A compound of the formula (786) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (787). A compound of the formula (787) is reacted with a compound of the formula (788), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (789). A compound of the formula (789) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (790). Alternatively, a compound of the formula (789) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (790). A compounds of the formula (790) is reacted with a compound of the formula (791) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (792). A compound of the formula (792) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (793).
Figure imgf000227_0001
[0622] A compound of the formula (794), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, is reacted with a compound of the formula (795) in the presence of in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (796). A compound of the formula (796) is reacted with a compound of the formula (797), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (798). A compound of the formula (798) is reacted with  
a compound of the formula (799), a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’- dimethoxybiphenyl-2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2- dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2- biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 2-di-tert- butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′-(di-tert- butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′-biphenyl)- 2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (800). A compound of the formula (800) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (801). A compound of the formula (801) is reacted with a compound of the formula (802), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (803). A compound of the formula (803) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (804). Alternatively, a compound of the formula (803) is  
reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (804).
Figure imgf000229_0001
  [0623] A compound of the formula (805), a known compound or a compound prepared by known methods is reacted with a compound of the formula (806) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, a known compound or a compound prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’, 6’-dimethoxybiphenyl- 2-yl) phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (807). A compound of the formula (807) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane,  
methanol, ethanol, and the like, optionally in the presence of an acid such as acetic acid, formic acid, trifluoroactic acid and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (808). A compound of the formula (808) is reacted with a compound of the formula (809), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (810).
Figure imgf000230_0001
  [0624] A compounds of the formula (810), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (811), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-  
methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (812). A compound of the formula (812) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (813). A compound of the formula (813) is reacted with a compound of the formula (814), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (815). A compound of the formula (815) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (816). Alternatively, a compound of the formula (815) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (816). A compounds of the formula (816) is reacted with a compound of the formula (817) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (818). A compound of the formula (818) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane,  
methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (819).
Figure imgf000232_0001
  [0625] A compound of the formula (820), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (821), a known compound or a compound made by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, N-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (822). A compounds of the formula (822) is reacted with a compound of the formula (823), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-  
methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (824). A compound of the formula (824) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (825). A compound of the formula (825) is reacted with a compound of the formula (826), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (827).
Figure imgf000233_0001
  [0626] A compound of the formula (827) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (828). Alternatively, a compound of the formula (827) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene  
chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (828). A compounds of the formula (828) is reacted with a compound of the formula (829) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (830). A compound of the formula (830) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (831).
Figure imgf000234_0001
  [0627] A compound of the formula (832), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (833), a known compound or a compound made by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (834). A compounds of the formula (834) is reacted with a compound of the  
formula (835), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (836). A compound of the formula (836) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (837). A compound of the formula (837) is reacted with a compound of the formula (838), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (839). A compound of the formula (839) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (840). Alternatively, a compound of the formula (839) is  
reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (840). A compounds of the formula (840) is reacted with a compound of the formula (841) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (842). A compound of the formula (842) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (843).
Figure imgf000236_0001
[0628] A compounds of the formula (844), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, is reacted with a compound of the formula (845), a known compound or a compound made by known methods, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (846).  
A compounds of the formula (846) is reacted with a compound of the formula (847), a known compound or a compounds prepared by known methods, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (848). A compound of the formula (848) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (849). A compound of the formula (849) is reacted with a compound of the formula (850), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (851).  
Figure imgf000238_0001
    [0629] A compound of the formula (851) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (852). Alternatively, a compound of the formula (851) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (852). A compounds of the formula (852) is reacted with a compound of the formula (853) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (854). A compound of the formula (854) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (855).  
Figure imgf000239_0001
  [0630] A compound of the formula (856), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (857), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (858). A compound of the formula (858) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, methanol, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (859). A compounds of the formula (859) is reacted with a compound of the formula (860) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (861). A compound of the formula (861) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-  
dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (862). A compound of the formula (862) is reacted with a compound of the formula (863), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (864).
Figure imgf000240_0001
[0631] A compound of the formula (864) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (865). Alternatively, a compound of the formula (865) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (865). A compounds of the formula (865) is reacted with a compound of the formula (866) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (867). A compound of the formula (867) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (869).
Figure imgf000241_0001
  [0632] A compound of the formula (870), a known compound or a compound prepared by known methods, is reacted with a compounds of the formula (871), a known compound or a compound prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a base such as base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (872). A compound of the formula (872) is reacted with zinc in the presence of ammonium chloride, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (873). A compounds of the formula (873) is reacted with a compound of the formula (874) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (875). A compound of the formula (875) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride,  
chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (876). A compound of the formula (876) is reacted with a compound of the formula (877), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (878).
Figure imgf000242_0001
[0633] A compound of the formula (878) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (879). Alternatively, a compound of the formula (878) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (879). A compounds of the formula (879) is reacted with a compound of the formula (880) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (881). A compound of the formula (881) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (882).
Figure imgf000243_0001
[0634] A compound of the formula (883) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (884). Alternatively, a compound of the formula (883) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (884). A compound of the formula (884) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (885). A compound of the formula (885) is reacted with a compound of the formula (886), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with  
microwave irradiation to provide a compound of the formula (887). A compound of the formula (887) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (888). Alternatively, a compound of the formula (887) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (888). A compounds of the formula (888) is reacted with a compound of the formula (889) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (890). A compound of the formula (890) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (891).
Figure imgf000244_0001
  [0635] A compound of the formula (892) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-  
dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (893). Alternatively, a compound of the formula (892) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (893). A compound of the formula (893) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (894). A compound of the formula (894) is reacted with a compound of the formula (894), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (896). A compound of the formula (896) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (897). Alternatively, a compound of the formula (896) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (897).  
Figure imgf000246_0001
  [0636] A compound of the formula (898) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (899). Alternatively, a compound of the formula (898) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (899). A compound of the formula (899) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (900). A compound of the formula (900) is reacted with a compound of the formula (901), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (902). A compound of the formula (902) is  
reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (903). Alternatively, a compound of the formula (902) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (903). A compounds of the formula (903) is reacted with a compound of the formula (904) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (905). A compound of the formula (905) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (906).
Figure imgf000247_0001
   
  [0637] A compound of the formula (907) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (908). Alternatively, a compound of the formula (907) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (908). A compound of the formula (908) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (909). A compound of the formula (909) is reacted with a compound of the formula (910), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (911). A compound of the formula (911) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (912). Alternatively, a compound of the formula (911) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (912). A compounds of the formula (912) is reacted with a compound of the formula (913) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide,  
dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (914). A compound of the formula (914) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (915).
Figure imgf000249_0001
  [0638] A compound of the formula (916) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (917). Alternatively, a compound of the formula (916) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (917). A compound of the formula (917) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-  
dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (918). A compound of the formula (918) is reacted with a compound of the formula (919), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (920). A compound of the formula (920) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (921). Alternatively, a compound of the formula (920) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (921). A compounds of the formula (921) is reacted with a compound of the formula (922) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (923). A compound of the formula (923) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (924).  
Figure imgf000251_0001
  [0639] A compound of the formula (925) wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl is reacted with hydrogen in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (926). Alternatively, a compound of the formula (925) is reacted with hydrogen in the presence of platinum on carbon, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (926). A compound of the formula (926) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (927). A compound of the formula (927) is reacted with a compound of the formula (928), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (929). A compound of the formula (929) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate,  
tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (930). Alternatively, a compound of the formula (929) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (930). A compounds of the formula (930) is reacted with a compound of the formula (931) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (932). A compound of the formula (932) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (933).
Figure imgf000252_0001
  [0640] A compounds of the formula (934), a known compound of a compound prepared by known methods in which Z9 is a C1-6 alkyl, is reacted with a compound of the formula (935), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-  
butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (936). A compound of the formula (31) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (937).
Figure imgf000253_0001
  [0641] A compounds of the formula (937) is reacted with a compound of the formula (938), a known compound or a compound made by known methods, in the presence of a coupling agent such as O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and  
the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (939). A compound of the formula (939) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (940). A compound of the formula (940) is reacted with a compound of the formula (941), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (942). A compound of the formula (942) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (943). Alternatively, a compound of the formula (942) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (943). A compounds of the formula (943) is reacted with a compound of the formula (944) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (945). A compound of the formula (945) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (946).  
Figure imgf000255_0001
[0642] A compound of the formula (947) is reacted with a compound of the formula (948) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7- triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (949). A compound of the formula (949) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (950). A compound of the formula (950) is reacted with a compound of the formula (951), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (952). A compound of the formula (952) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (953). Alternatively, a compound of the formula (952) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like,  
in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (953). A compounds of the formula (953) is reacted with a compound of the formula (954) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (955). A compound of the formula (955) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (956).
Figure imgf000256_0001
  [0643] A compounds of the formula (957), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (958), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenyzl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-  
bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (959). A compound of the formula (959) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (960). A compound of the formula (960) is reacted with a compound of the formula (961), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (962). A compound of the formula (962) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (963). Alternatively, a compound of the formula (962) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide  
a compound of the formula (963). A compounds of the formula (963) is reacted with a compound of the formula (964) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (965). A compound of the formula (965) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (966).
Figure imgf000258_0001
  [0644] A compound of the formula (967), a known compound or a compound prepared by known methods, is reacted with a compound of the formula (968), a known compound or a compound made by known methods, in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (969). A compounds of the formula (969) is reacted with a compound of the formula (970), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-  
dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (971). A compound of the formula (971) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (972). A compound of the formula (972) is reacted with a compound of the formula (973), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (974).
Figure imgf000259_0001
  [0645] A compound of the formula (974) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis  
(triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (975). Alternatively, a compound of the formula (974) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (975). A compounds of the formula (975) is reacted with a compound of the formula (976) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (977). A compound of the formula (977) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (978).
Figure imgf000260_0001
  [0646] A compounds of the formula (979) is reacted with a compound of the formula (980), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as  
dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (981). A compound of the formula (981) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (982). A compound of the formula (982) is reacted with a compound of the formula (983), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (984). A compound of the formula (984) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (985). Alternatively, a compound of the formula (984) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (985).  
Figure imgf000262_0002
[0647] A compounds of the formula (985) is reacted with a compound of the formula (986) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (987). A compound of the formula (987) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (988).
Figure imgf000262_0001
[0648] A compounds of the formula (989), a known compound of a compound prepared by known methods in which Z10 is a C1-6 alkyl, is reacted with a compound of the formula (990), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-  
butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (991). A compound of the formula (991) is reacted with a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and the like, in the presence of a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (992).
Figure imgf000263_0001
[0649] A compounds of the formula (992) is reacted with a compound of the formula (993) in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1- hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with  
microwave irradiation to provide a compound of the formula (994). A compound of the formula (994) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (995). A compound of the formula (995) is reacted with a compound of the formula (996), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (997). A compound of the formula (997) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (998). Alternatively, a compound of the formula (997) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (998). A compounds of the formula (998) is reacted with a compound of the formula (999) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1000). A compound of the formula (1000) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1001).  
Figure imgf000265_0001
  [0650] A compounds of the formula (1002) is reacted with a compound of the formula (1003), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1004). A compound of the formula (1004) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane,  
tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1005). A compound of the formula (1005) is reacted with a compound of the formula (1006), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1007). A compound of the formula (1007) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1008). Alternatively, a compound of the formula (1007) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1008). A compounds of the formula (1008) is reacted with a compound of the formula (1009) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1010). A compound of the formula (1010) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1011).
Figure imgf000266_0001
  [0651] A compounds of the formula (1012) is reacted with a compound of the formula (1013), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected   from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1014). A compound of the formula (1014) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1015).
Figure imgf000267_0001
 
[0652] A compound of the formula (1015) is reacted with a compound of the formula (1016), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1017). A compound of the formula (1017) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1018). Alternatively, a compound of the formula (1017) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1018). A compounds of the formula (1018) is reacted with a compound of the formula (1019) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1020). A compound of the formula (1020) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1021).  
Figure imgf000269_0001
  [0653] A compounds of the formula (1022), a known compound or a compounds prepared by known methods methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, is reacted with a compound of the formula (1023), a known compound or a compound made by known methods, in the presence of a coupling agent such as O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1024). A compound of the formula (1024) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1025). A compound of the formula (1025) is reacted with a compound of the formula (1026), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1027). A compound of the  
formula (1027) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1028). Alternatively, a compound of the formula (1027) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1028). A compounds of the formula (1028) is reacted with a compound of the formula (1029) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1030). A compound of the formula (1030) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1031).
Figure imgf000270_0001
  [0654] A compound of the formula (1032) a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl  
and carboxybenzyl, is reacted with a compound of the formula (1033) a known compound or a compound prepared by known methods, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5,7-triazabicyclo4.4.0dec-5-ene, and the like, in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1034). A compound of the formula (1034) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1035). A compound of the formula (1035) is reacted with a compound of the formula (1036), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1037). A compound of the formula (1037) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1038). Alternatively, a compound of the formula (1037) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1038). A compounds of the formula (1038) is reacted with a compound of the formula (1039) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1040). A compound of the formula (1040) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like,  
optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1041).
Figure imgf000272_0001
  [0655] A compounds of the formula (1042), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (1043), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1044). A compound  
of the formula (1044) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1045). A compound of the formula (1045) is reacted with a compound of the formula (1046), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1047). A compound of the formula (1047) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1048). Alternatively, a compound of the formula (1047) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1048). A compounds of the formula (1048) is reacted with a compound of the formula (1049) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1050). A compound of the formula (1050) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1051).  
Figure imgf000274_0001
  [0656] A compounds of the formula (1052) is reacted with a compound of the formula (1053), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1054). A compound of the formula (1054) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1055). A compound of the formula (1045) is  
reacted with a compound of the formula (1056), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1057). A compound of the formula (1057) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1058). Alternatively, a compound of the formula (1057) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1058).
Figure imgf000275_0001
  [0657] A compounds of the formula (1058) is reacted with a compound of the formula (1059) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1060). A compound of the formula (1060) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the  
presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1061).
Figure imgf000276_0001
  [0658] A compounds of the formula (1062) is reacted with a compound of the formula (1063), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1064). A compound of the formula (1064) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid,  
and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1065). A compound of the formula (1065) is reacted with a compound of the formula (1066), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1067). A compound of the formula (1067) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1068). Alternatively, a compound of the formula (1067) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1068).
Figure imgf000277_0001
[0659] A compounds of the formula (1068) is reacted with a compound of the formula (1069) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave  
irradiation to provide a compound of the formula (1070). A compound of the formula (1070) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1071).
Figure imgf000278_0001
[0660] A compounds of the formula (1072), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, is reacted with a compound of the formula (1073), a known compound or a compound made by known methods, in the presence of a coupling agent such as O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, N,N′-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-hydroxy-7-azabenzotriazole and the like, optionally in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1074). A compound of the formula (1074) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1075). A compound of the formula (1075) is reacted with a compound of the formula (1076), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating,  
optionally with microwave irradiation to provide a compound of the formula (1077). A compound of the formula (1077) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1078). Alternatively, a compound of the formula (1077) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1078). A compounds of the formula (1078) is reacted with a compound of the formula (1079) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1080).
Figure imgf000279_0001
  [0661] A compound of the formula (1080) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1081).  
Figure imgf000280_0001
  [0662] A compounds of the formula (1082), a known compound of a compound prepared by known methods, is reacted with a compound of the formula (1083), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3-dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl- 2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N- dimethylamino) biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert- butylphosphino-2′,4′,6′-triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert- butylphosphine, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6- tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′- biphenyl-3-sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′- methylbiphenyl, 2′-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)- N,N′-dimethyl-(1,1′-biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2- dichloroethane, 1,2-dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1084). A compound of the formula (1084) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid,  
hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1085). A compound of the formula (1085) is reacted with a compound of the formula (1086), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1087). A compound of the formula (1087) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1088). Alternatively, a compound of the formula (1087) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1088). A compounds of the formula (1088) is reacted with a compound of the formula (1089) in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1090). A compound of the formula (1090) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1091).
Figure imgf000281_0001
   
[0663] A compounds of the formula (1092) is reacted with a compound of the formula (1093), a known compound or a compounds prepared by known methods wherein PG is a protecting group selected from the group consisting of fluorenylmethoxycarbonyl and carboxybenzyl, in the presence of a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitrile)dichloro palladium(II), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bispalladium-tri(1,3- dibenzylidene)acetone, and the like, optionally in the presence of an organophosphine such as dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl)phosphine, 2-dicyclo hexylphosphino-2′,6′- dimethoxybiphenyl, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl, (2-biphenyl)dicyclohexylphosphine, (2-biphenyl)di-tert-butylphosphine, 2- dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′- triisopropyl-1,1′-biphenyl, Sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3- sulfonate, 2-di-tert-butylphosphino-2′-methylbiphenyl, 2-dicyclohexylphosphino-2′-methylbiphenyl, 2′- (di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2′-(diphenylphosphino)-N,N′-dimethyl-(1,1′- biphenyl)-2-amine, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in a solvent such as tetrahydrofuran, 1,4-dioxane, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, 1,2- dimethoxyethane, and the like, optionally in the presence of water, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1094). A compound of the formula (1094) is reacted with ethanol in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1095).
Figure imgf000282_0001
   
[0664] A compound of the formula (1095) is reacted with a compound of the formula (1096), a known compound or a compound prepared by known methods, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1097). A compound of the formula (1097) is reacted with hydrogen in the presence of a catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine)palladium(II), palladium on carbon, bis(acetonitrile)dichloropalladium(II), and the like, in the presence of a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, and the like, optionally with heating, optionally with microwave irradiation to give a compound of the formula (1098). Alternatively, a compound of the formula (1097) is reacted with a base such as piperidine, pyridine, triethylamine, N,N-diisopropylethyl amine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1098). A compounds of the formula (1098) is reacted with a compound of the formula (1099) in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1100). A compound of the formula (1100) is reacted with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, in a solvent such as methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally in the presence of methylphenyl ether, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (1101). [0665] The Examples provided below provide representative methods for preparing exemplary compounds of the present invention. The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds of the present invention. [0666] The following LC/MS procedure was used for the analysis of the examples described herein. LC/MS data were determined with a Waters Alliance 2695 HPLC/MS (Waters Symmetry C18, 4.6 × 75 mm, 3.5 μm) with a 2996 diode array detector from 210−400 nm; the solvent system is 5−95% acetonitrile in water (with 0.1% TFA) over nine minutes using a linear gradient, and retention times are in minutes. Mass spectrometry was performed on a Waters ZQ using electrospray in positive mode.  
[0667] 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 with 0.1% TFA as buffer using 214 and 254 nm as detection wavelengths. Injection and fraction collection were performed with a Gilson 215 liquid handling apparatus using Trilution LC software. [0668] 1H-NMR’s were taken on a Varian 300 MHz NMR using tetramethylsilane (TMS) as internal standard ( ^ = 0.00) with peaks reported downfield from TMS. [0669] The examples provides methods for preparing representative compounds of formulas (I) through (XVI). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds of the present invention. [0670] General experimental procedures: The general experimental procedures described herein can be used by one skilled in the art to prepare the compounds of the disclosure and the intermediates necessary for preparation of the compounds of the disclosure. [0671] Example 1: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamide
Figure imgf000284_0001
[0672] Step 1: Synthesis of tert-butyl N-{2-[4-(4-bromo-3-fluorobenzamido) phenyl]ethyl}carbamate: To a stirred, ice-cold solution of tert-butyl N-[2-(4-aminophenyl) ethyl]carbamate (900 mg, 3.8 mmol) and N,N-diisopropylethyl amin (0.36 mL, 2.0 mmol) in CH2Cl2 (15 mL) was added dropwise over 10 min a solution of 4-bromo-3-fluorobenzoyl chloride (905 mg, 3.8 mmol) in CH2Cl2 (5 mL). After stirring for 18 hours, the mixture was diluted with ethyl acetate and 1 M aqueous HCl. The mixture was filtered and the pale yellow solid collected was dried in vacuo to give tert-butyl N-{2-[4-(4- bromo-3-fluorobenzamido)phenyl]ethyl}carbamate (1.14 g, 68%). LC-MS tR 5.73 min, m/z 459 [M+Na+].
Figure imgf000284_0002
[0673] Step 2: Synthesis of tert-butyl 4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}ethyl) phenyl]carbamoyl}-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate: A flask equipped with a magnetic stir bar was charged with tert-butyl N-{2-[4-(4-bromo-3-fluorobenzamido)phenyl]ethyl}  
carbamate (1.14 g, 2.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro pyridine-1-carboxylate (970 mg, 3.1 mmol), Pd(OAc)2 (23 mg, 0.1 mmol), 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (107 mg, 0.26 mmol) and K2CO3 (1.33 g, 9.7 mmol). The flask was sealed with a septum and flushed with N2 for 10 minutes. N2-sparged 3:11,4-dioxane/H2O (20 mL) was introduced by syringe and the mixture was stirred at 100 ⁰C under N2 for 4 hours. The mixture was concentrated. The residue was taken up in ethyl acetate (80 mL), washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left a dark solid (1.46 g) which was chromatographed on silica gel, eluted with an ethyl acetate/hexanes gradient to provide tert-butyl 4-(4-{[4- (2-{[(tert-butoxy)carbonyl]amino}ethyl)phenyl]carbamoyl}-2-fluorophenyl)-1,2,3,6-tetrahydropyridine- 1-carboxylate (1.05 g, 75%) as a grey solid. LC-MS tR 6.23 min, m/z 562 [M+Na+].
Figure imgf000285_0001
[0674] Step 3: Synthesis of N-[4-(2-aminoethyl)phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro pyridin-4- yl)benzamide: tert-butyl 4-(4-{[4-(2-{[(tert-butoxy)carbonyl]amino}ethyl)phenyl] carbamoyl}-2- fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (1.05 g, 1.95 mmol) was dissolved in 1:1 CH2Cl2/trifluoroacetic acid (10 mL), stirred for 18 hours and concentrated. The residue was taken up in 3:1 MeCN/10% aqueous HCl (8 mL) and concentrated to provide N-[4-(2-aminoethyl)phenyl]-3-fluoro-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide 2HCl salt (810 mg, 100%) as an off-white solid. LC-MS tR 2.47 min, m/z 340 [M+H+].
Figure imgf000285_0002
[0675] Step 4: Synthesis of tert-butyl N-[(Z)-({2-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido) phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a stirred suspension of N-[4- (2-aminoethyl)phenyl]-3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide 2HCl salt (810 mg, 1.96 mmol) in 3:1 N,N-dimethylformamide/CH2Cl2 (10 mL) were added Et3N (1.8 mL, 12.8 mmol) and tert- butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (1.53 g, 4.91 mmol). The mixture was stirred at 20 oC for 3 days and 4-amino-N-methylpiperidine (500 mg, 4.4 mmol) was added. The mixture was stirred for 18 hours at 20oC and concentrated. The residue was taken up in ethyl acetate  
(90 mL), washed with water (2 x 10 mL), 10% aqueous NaHSO4 (10 mL) and 9:1 brine/saturated aqueous NaHCO3 (10 mL), and dried over Na2SO4. Removal of the solvent left a solid (710 mg) which was purified by chromatography on a 40 g silica cartridge, eluted with a 0-100% ethyl acetate/hexanes gradient to provide tert-butyl N-[(Z)-({2-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorobenzamido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (1.67 g, 100%) as a solid. LC-MS tR 4.83 min, m/z 824 [M+H+].
Figure imgf000286_0001
[0676] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-N-[4-(2- guanidino-ethyl)-phenyl]-benzamide: A solution of tert-butyl N-[(Z)-({2-[4-(4-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorobenzamido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (250 mg, mmol) in 1:1 CH2Cl2/trifluoacetic acid (4 mL) was stirred at 20oC for 18 hours and concentrated. The residue was purified by prep HPLC to afford 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide di-trifluoacetic acid salt (107 mg, 54%) as a white solid. LC-MS tR 2.88 min, m/z 424 [M+H+]. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1 H), 7.74 - 7.87 (m, 1H), 7.64 - 7.73 (m, 2H), 7.50 - 7.63 (m, 2H), 7.24 (d, J=8.79 Hz, 2H), 6.07 - 6.24 (m, 1H), 4.05- 4.15 (m, 2H), 3.62 (t, J=5.49 Hz, 2H), 3.21 - 3.43 (m, 2H), 2.75 (t, J=7.25 Hz, 2H), 2.59 (br s, 2H). [0677] Example 2: Synthesis of 4-(carbamimidamidomethyl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydro pyridin-4-yl)-3-fluorophenyl]benzamide
Figure imgf000286_0002
[0678] Step 1: Synthesis of tert-butyl N-({4-[(4-bromo-3-fluorophenyl)carbamoyl] phenyl}methyl)carbamate: To a stirred solution of 4-bromo-3-fluoroaniline (208 mg, 1.1 mmol), 4-({[(tert- butoxy)carbonyl]amino}methyl)benzoic acid (250 mg, 1.0 mmol) and i-Pr2NEt (0.4 mL, 2.2 mmol) in 1,2- dichloroethane (10 mL) was added solid N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (460 mg, 1.2 mmol). The mixture was stirred at 20oC for 2 hours and at 50 ⁰C for 18 hours. The mixture was diluted with ethyl acetate (90  
mL), washed with 1 M aqueous HCl (15 mL) and 4:1 brine/saturated aqueous NaHCO3 (15 mL), and dried over Na2SO4. Removal of the solvent left a dark oil (1.10 g) which was chromatographed on a 12 g silica cartridge, eluted with a 0-100% ethyl acetate in hexanes gradient to give tert-butyl N-({4-[(4-bromo-3- fluorophenyl)carbamoyl]phenyl}methyl)carbamate (380 mg, 90%). LC-MS tR 5.49 min, m/z 447, 445 [
Figure imgf000287_0001
[0679] Step 2: Synthesis of tert-butyl 4-{4-[4-({[(tert-butoxy)carbonyl]amino} methyl)benzamido]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate: A flask equipped with a magnetic stir bar was charged with tert-butyl N-({4-[(4-bromo-3-fluorophenyl)carbamoyl] phenyl}methyl)carbamate (380 mg, 0.90 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (333 mg, 1.1 mmol), Pd(OAc)2 (8 mg, 0.04 mmol), 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (37 mg, 0.09 mmol) and K2CO3 (460 mg, 3.3 mmol). The flask was sealed with a septum and flushed with N2 for 10 minutes. N2-sparged 3:11,4-dioxane/H2O (20 mL) was introduced by syringe and the mixture was stirred at 100 ⁰C under N2 for 4 hours. The mixture was concentrated. The residue was taken up in ethyl acetate (80 mL), washed with water (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left a dark solid (640 mg) which was chromatographed on silica gel, eluted with an ethyl acetate/hexanes gradient to provide tert-butyl 4-{4-[4- ({[(tert-butoxy)carbonyl]amino}methyl)benzamido]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate (370 mg, 78%). LC-MS tR 6.17 min, m/z 548 [M+Na+], 526 [M+H+].
Figure imgf000287_0002
[0680] Step 3: Synthesis of tert-butyl 4-{4-[4-({[(tert-butoxy)carbonyl]amino} methyl)benzamido]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate: To a solution of tert-butyl 4-{4-[4-({[(tert-butoxy)carbonyl]amino}methyl)benzamido]-2-fluorophenyl}-1,2,3,6-tetrahydro pyridine- 1-carboxylate (370 mg, 0.70 mmol) in CH2Cl2 (10 mL) was added CF3CO2H (5 mL). The mixture was stirred at 20oC for 18 hours and concentrated. The residue was taken up in MeCN and aqueous HCl and concentrated to give 4-(aminomethyl)-N-[3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]benzamide 2HCl salt (280 mg, 100%). LC-MS tR 2.40 min, m/z 326.  
Figure imgf000288_0002
[0681] Step 4: Synthesis of tert-butyl N-[(Z)-[({4-[(4-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorophenyl)carbamoyl]phenyl}methyl)amino]({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a stirred suspension of 4-(aminomethyl)-N-[3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]benzamide 2HCl salt (280 mg, 0.70 mmol) in 3:1 N,N-dimethylformamide /CH2Cl2 (8 mL) were added Et3N (0.65 mL, 4.6 mmol) and tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (545 mg, 1.76 mmol). The mixture was stirred at 20oC for 3 days and 4-amino-N-methylpiperidine (0.12 mL, 1.0 mmol) was added. The mixture was stirred for 18 hours at 20oC and concentrated. The residue was taken up in ethyl acetate (90 mL), washed with water (2 x 10 mL), 10% aqueous NaHSO4 (10 mL) and 9:1 brine/saturated aqueous NaHCO3 (10 mL), and dried over Na2SO4. Removal of the solvent left a solid (710 mg) which was purified by chromatography on silica gel, eluted with an ethyl acetate/hexanes gradient to provide tert-butyl N-[(Z)-[({4-[(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorophenyl)carbamoyl]phenyl}methyl)amino]({[(tert-butoxy)carbonyl]imino})methyl] carbamate (520 mg, 91%) as a solid. LC-MS tR 5.15 min, m/z 832 [M+Na+], 810 [M+H+].
Figure imgf000288_0001
[0682] Step 5: Synthesis of 4-(carbamimidamidomethyl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl]benzamide: A solution of tert-butyl N-[(Z)-[({4-[(4-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorophenyl)carbamoyl]phenyl}methyl)amino]({[(tert-butoxy)carbonyl]imino})methyl] carbamate (520 mg, mmol) in 1:1 CH2Cl2/trifluoroacetic acid (6 mL) was stirred at 20oC for 18 hours and concentrated to leave an oil (630 mg) which was purified by prep HPLC to give 4-(carbamimidamidomethyl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl] benzamide di-CF3CO2H salt (231 mg, 56%) as a white solid. LC-MS tR 2.78 min, m/z 410 [M+H+]. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.48  
(s, 1 H), 8.30 (t, J=6.15 Hz, 1H), 7.96 (d, J=8.35 Hz, 2H), 7.76 (dd, J=14.28, 1.98 Hz, 1H), 7.29 - 7.46 (m, 3H), 5.98 - 6.11 (m, 1H), 4.47 (d, J=6.59 Hz, 2H), 4.07 (br d, J=2.64 Hz, 2H), 3.60 (t, J=5.49 Hz, 2H), 2.55 (br s, 2H). [0683] Example 3: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-2-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide.
Figure imgf000289_0001
[0684] Step 1: Synthesis of tert-butyl N-{[4-(2-bromo-1,3-thiazole-5-amido)phenyl] methyl}carbamate: To a stirred, ice-cold suspension of 2-bromo-1,3-thiazole-5-carboxylic acid (600 mg, 2.9 mmol) in CH2Cl2 (5 mL) were added N,N-dimethylforamide (2 drops) and oxalyl chloride (0.37 mL, 4.3 mmol). The mixture was stirred for 3 hours during which time it reached 20oC. The mixture was concentrated under reduced pressure, chasing with CH2Cl2, to afford a solid. An ice-cold solution of this solid in CH2Cl2 (20 mL) was cooled in an ice bath and tert-butyl N-[(4-aminophenyl)methyl]carbamate (610 mg, 2.7 mmol) and i-Pr2NEt (1 mL, 5.5 mmol) were added. The mixture was stirred for 18 hours at 20oC and concentrated. The residue was taken up in ethyl acetate (80 mL), washed with 5% aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left a yellow solid (940 mg) which was chromatographed on a 40 g silica cartridge, eluted with a 0- 100% ethyl acetate in hexanes gradient, to give tert-butyl N-{[4-(2-bromo-1,3-thiazole-5- amido)phenyl]methyl}carbamate (790 mg, 66%) as a solid. LC-MS tR 5.0 min, m/z 434.
Figure imgf000289_0002
[0685] Step 2: Synthesis of tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate: A flask was charged with tert-butyl N-{[4-(2-bromo-1,3-thiazole-5-amido)phenyl] methyl}carbamate (790 mg, 1.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (711 mg, 2.3 mmol), 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, (118 mg, 0.29 mmol), Pd(OAc)2 (20 mg, 0.11 mmol) and K2CO3 (980 mg, 7.1 mmol), and sealed with a septum. The flask was flushed with N2 for 10 minutes and N2-sparged 3:1 1,4-  
dioxane/H2O (20 mL) was introduced by syringe. The mixture was stirred at 100 ⁰C for 1 day, cooled to 20oC, diluted with ethyl acetate (90 mL) and washed with water (2 x 15 mL) and brine (15 mL). The combined aqueous washes were back extracted with ethyl acetate (20 mL). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated to leave a brown oil (1.91 g) which was chromatographed on a 0-100% ethyl acetate in hexanes gradient to afford tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (220 mg, 22%). LC-MS tR 5.56 min, m/z 515.
Figure imgf000290_0001
[0686] Step 3: Synthesis of N-[4-(aminomethyl)phenyl]-2-(1,2,3,6-tetrahydropyridin-4-yl)-1,3- thiazole-5-carboxamide: A solution of tert-butyl 4-(5-{[4-({[(tert-butoxy)carbonyl]amino} methyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (220 mg, 0.43 mmol) in 1:1 CH2Cl2/CF3CO2H (6 mL) was stirred at rt for 4 hours and concentrated. The residue was taken up in MeCN/10% aqueous HCl and concentrated to leave N-[4-(aminomethyl)phenyl]-2-(1,2,3,6- tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide.2HCl salt (220 mg, quant). LC-MS tR 2.28 min, 315. N
Figure imgf000290_0002
[0687] Step 4: Synthesis of tert-butyl N-[(E)-({[4-(2-{1-[(E)-{[(tert-butoxy)carbonyl]amino} ({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5-amido) phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a stirred slurry of N-[4- (aminomethyl)phenyl]-2-(1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide.2HCl salt (220 mg, 0.43 mmol), Et3N (0.52 mL, 3.7 mmol), CH2Cl2 (2.5 mL) and N,N-dimethylformamide (7.5 mL) was added tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (440 mg, 1.4 mmol). The mixture was stirred at 20oC for 1 day and 4-amino-1-methylpiperidine (0.2 mL, 1.6 mmol) was added. The mixture was stirred at 20oC for 2 hours and concentrated. The residue was taken up in ethyl acetate  
(90 mL), washed with water (15 mL), 10% aqueous NaHSO4 (15 mL) and 4:1 brine/saturated aqueous NaHCO3 (15 mL), and dried over Na2SO4. Removal of the solvent left a residue (380 mg) which was chromatographed on a 40 g silica cartridge, eluted with a 0-100% ethyl acetate in hexanes gradient, to afford tert-butyl N-[(E)-({[4-(2-{1-[(E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5- amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (66 mg, 20%). 1H NMR (300 MHz, CDCl3-d) 8.58 - 8.77 (m, 2 H), 8.28 - 8.40 (m, 1 H), 7.46 (d, J=8.35 Hz, 2 H), 7.06 (d, J=8.79 Hz, 2 H), 6.64 (s, 1 H), 4.52 (br d, J=5.71 Hz, 2 H), 4.21 - 4.33 (m, 2 H), 3.61 - 3.86 (m, 2 H), 2.73 - 2.91 (m, 2 H), 1.46 - 1.52 (m, 27 H), 1.39 - 1.45 (m, 9 H). LC-MS tR 4.99 min, m/z 799.
Figure imgf000291_0001
[0688] Step 5: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-2-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide. A solution of tert-butyl N-[(E)-({[4-(2-{1-[(E)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}- 1,3-thiazole-5-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino}) methyl]carbamate (66 mg, 83 μmol) in 1:1 CF3CO2H/CH2Cl2 (2 mL) was stirred at 20oC for 18 hours and concentrated. The residue was purified by prep HPLC to give the di-CF3CO2H salt of the title compound (22 mg, 42%) as a pale yellow solid. 1H NMR (300 MHz, Methanol-d4) 8.44 (s, 1 H), 7.71 (d, J=8.79 Hz, 2 H), 7.34 (d, J=8.35 Hz, 2 H), 6.78 (s, 1 H), 4.39 (s, 2 H), 4.13 - 4.28 (m, 2 H), 3.66-3.77 (m, 2 H), 2.79 - 2.87 (m, 2 H). LC- MS tR 2.53 min, m/z 399. [0689] Example 4: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl - 1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide:
Figure imgf000291_0002
[0690] Step 1: Synthesis of Synthesis of tert-butyl 4-aminophenethylcarbamate: To a solution of 4- (2-aminoethyl)benzenamine (2.50 g, 18.4 mmol) in ethyl acetate (46 mL) at 0 °C under N2 was added di- tert-butyl dicarbonate (4.01 g, 18.4 mmol). The reaction warmed to 20 oC as it was stirred for 18 hours. The mixture was concentrated. The residue was partitioned between dichloromethane (200 mL) and saturated  
NaHCO3 solution (50 mL) and separated. The aqueous layer was re-extracted with dichloromethane (100 mL). The organic layers were combined and washed with saturated NaHCO3 solution (30 mL), then brine (25 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl 4- aminophenethylcarbamate (3.87 g, 89%) as a light yellow foam.
Figure imgf000292_0001
[0691] Step 2: Synthesis of tert-butyl 4-(4-bromothiophene-2-carboxamido) phenethylcarbamate: To a solution of 4-bromo-2-thiophenecarboxylic acid (0.105 g, 0.508 mmol) and N,N- diisopropylethylamine (0.219 g, 0.295 mL, 1.69 mmol) in N,N-dimethylformamide in a 2-dram vial at 20 oC under nitrogen was added N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (0.201 g, 0.529 mmol) followed by tert-butyl 4- aminophenethylcarbamate (0.100 g, 0.423 mmol). The reaction was stirred at 20 oC for 18 hours. The mixture was diluted with CHCl3 (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, and injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of CHCl3. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-(4-bromothiophene-2-carboxamido)phenethylcarbamate (0.166 g, 92%) as a light yellow solid.
Figure imgf000292_0002
[0692] Step 3: Synthesis of tert-butyl 4-(5-{[4-(2-{[(tert-butoxy)carbonyl]amino} ethyl)phenyl]carbamoyl}thiophen-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of tert-butyl 4-(4-bromothiophene-2-carboxamido)phenethylcarbamate (0.0800 g, 0.188 mmol), tert-butyl 5,6-dihydro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.0698 g, 0.226 mmol), 2 M Na2CO3 solution (0.282 mL, 0.564 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0154 g, 0.0188 mmol) in 1,4-dioxane (1.5 mL) in a 2-dram vial was degassed by bubbling nitrogen through the mixture for 2-3 minutes. The reaction was heated at 80 °C for 16 hours. The mixture was diluted with CHCl3 (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, and injected directly onto a silica gel cartridge. The  
extraction was repeated with 2 x 2 mL portions of CHCl3. Elution with 0 to 60% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-(5-{[4-(2-{[(tert- butoxy)carbonyl]amino}ethyl)phenyl]carbamoyl}thiophen-3-yl)-1,2,3,6- tetrahydropyridine-1- carboxylate (0.0974 g, 98%) as a tan foam.
Figure imgf000293_0001
[0693] Step 4: Synthesis of N-(4-(2-aminoethyl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxamide: To a solution of tert-butyl 4-(5-{[4-(2-{[(tert-butoxy)carbonyl] amino}ethyl)phenyl]carbamoyl}thiophen-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0974 g, 0.185 mmol) in dichloromethane (2 mL) at 20 oC was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was partitioned between dichloromethane (35 mL) and saturated NaHCO3 solution (30 mL) and separated. The aqueous layer was re-extracted with dichloromethane (35 mL). The organic layers were combined and washed with saturated NaHCO3 solution (20 mL), then brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield N-(4-(2-aminoethyl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide (0.0617 g, quantitative) as an off-white solid.
Figure imgf000293_0002
[0694] Step 5: Synthesis of tert-butyl N-[(E)-({2-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2- amido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of N-(4-(2- aminoethyl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide (0.185 mmol) in dichloromethane (3 mL) was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol -1- yl)methyl]carbamate (0.144g, 0.463 mmol). The reaction was stirred at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and 10% KHSO4 solution (15 mL) and separated. The organic layer was washed with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(E)-({2-[4-(4-{1-[(Z)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}thiophene-2-amido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0621 g, 41%) as a flocculent, white solid.  
Figure imgf000294_0001
[0695] Step 6: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl -1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide trifluoroacetate: To a solution of tert-butyl: N-[(E)-({2- [4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]ethyl}amino)({[(tert-butoxy) carbonyl]imino})methyl]carbamate (0.0621 g, 0.0765 mmol) in dichloromethane (3 mL) at 20 oC was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for 4 hours, then placed in the refrigerator for 18 hours. The mixture was concentrated without heating. The residue was suspended in 3:1 water/acetonitrile, frozen at -78 °C, then lyophilized to yield N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide trifluoroacetate (0.0492 g, 100%) as a flocculent, white solid. 1H NMR (DMSO-d6) δ: 10.23 (s, 1H), 8.27 (d, J=1.4 Hz, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.50 (s, 4H), 7.24 (d, J=8.4 Hz, 2H), 6.94 (br s, 2H), 6.21 (s, 1H), 4.09 (s, 2H), 3.56-3.67 (m, 2H), 3.32-3.40 (m, J=8.2 Hz, 1H), 2.75 (t, J=7.3 Hz, 2H), 2.57 (br s, 2H). LC/MS (M + H)+ = 412. [0696] Example 5: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-5-(1-carbamimidoyl - 1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide.
Figure imgf000294_0002
[0697] Step 1: Synthesis of tert-butyl 4-(5-bromofuran-2-carboxamido)phenethylcarbamate: To a solution of 5-bromofuran-2-carboxylic acid (0.145 g, 0.762 mmol) and N-[(dimethylamino)-1H-1,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.314 g, 0.825 mmol) in N,N-dimethylformamide at 20 oC under nitrogen was added N,N-diisopropylethylamine (0.328 g, 0.442 mL, 0.442 mmol). The mixture was stirred for 15 minutes before adding tert-butyl 4- aminophenethylcarbamate (0.150 g, 0.635 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed twice with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl 4-(5-bromofuran-2- carboxamido)phenethylcarbamate (0.209 g, 81%) as an off-white solid.  
Figure imgf000295_0003
[0698] Step 2: Synthesis of tert-butyl 4-(5-{[4-(2-{[(tert-butoxy)carbonyl] amino}ethyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of tert- butyl 4-(5-bromofuran-2-carboxamido)phenethylcarbamate (0.0800 g, 0.195 mmol), tert-butyl 5,6- dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.0725 g, 0.235 mmol), 2 M Na2CO3 solution (0.293 mL, 0.586 mmol), and 1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), dichloromethane adduct (0.0160 g, 0.0195 mmol) in 1,4-dioxane (1.5 mL) in a 2-dram vial was degassed by bubbling nitrogen through the mixture for 2 - 3 minutes. The reaction was heated at 80 °C for 18 hours. The mixture was diluted with CHCl3 (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, and injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of CHCl3. Elution with 0 to 50% ethyl acetate/hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-(5-{[4-(2-{[(tert- butoxy)carbonyl]amino}ethyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0902 g, 90%) as an off-white foam.
Figure imgf000295_0001
[0699] Step 3: Synthesis of N-(4-(2-aminoethyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)furan-2- carboxamide trifluoroacetate: To a solution of tert-butyl 4-(5-{[4-(2-{[(tert-butoxy) carbonyl]amino}ethyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.172 mmol) in dichloromethane (2 mL) at 20 oC was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved in acetonitrile (1 mL), then diluted with water (3 mL), frozen at -78 °C, and lyophilized to yield N-(4-(2- aminoethyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide trifluoroacetate (0.0946 g, quantitative) as a flocculent, light yellow solid.
Figure imgf000295_0002
[0700] Step 4: Synthesis of tert-butyl N-[(E)-({2-[4-(5-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}furan-2-  
amido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of N-(4-(2- aminoethyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide trifluoroacetate (0.172 mmol) and N,N-diisopropylethylamine (0.156 g, 0.210 mL, 1.20 mmol) in a mixture of dichloromethane (1.5 mL) and N,N-dimethylformamide (1.5 mL) was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H- pyrazol-1-yl)methyl]carbamate (0.139 g, 0.447 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0517 g, 0.0572 mL, 0.516 mmol) was added, and the reaction was stirred for 30 minutes. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(E)-({2-[4-(5-{1-[(Z)-{[(tert- butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}furan- 2-amido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0817 g, 60%) as an off-white solid.
Figure imgf000296_0001
[0701] Step 4: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-5-(1-carbamimidoyl -1,2,3,6- tetrahydropyridin-4-yl)furan-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(E)-({2-[4-(5- {1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy) carbonyl]imino}) methyl]-1,2,3,6- tetrahydropyridin-4-yl}furan-2-amido)phenyl]ethyl}amino)({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0817 g, 0.103 mmol) in dichloromethane (2 mL) at 20 oC was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was suspended in 3 /1 water/acetonitrile, frozen at -78 °C, then lyophilized to yield N-[4-(2-carbamimidamidoethyl)phenyl]-5-(1-carbamimidoyl-1,2,3,6-tetra hydropyridin-4-yl)furan-2-carboxamide trifluoroacetate (0.0645 g, 100%) as a flocculent, off-white solid. 1H NMR (METHANOL-d4) δ: 7.61-7.70 (m, 2H), 7.23-7.32 (m, 3H), 6.58-6.66 (m, J=3.7 Hz, 2H), 4.19 (d, J=3.3 Hz, 2H), 3.69 (t, J=5.7 Hz, 2H), 3.45 (t, J=7.1 Hz, 2H), 2.88 (t, J=7.1 Hz, 2H), 2.59-2.70 (m, 2H). LC/MS (M + H)+ = 396. [0702] Example 6: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-2- (1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide trifluoroacetate  
Figure imgf000297_0001
[0703] Step 1: Synthesis of (2-{4-[(2-bromo-thiazole-5-carbonyl)-amino]-phenyl}-ethyl)- carbamic acid tert-butyl ester: A mixture of 2-bromo-thiazole-5-carboxylic acid (0.158 g, 0.762 mmol), N,N-diisopropylethylamine (0.328 g, 0.442 mL, 2.54 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.314 g, 0.825 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was stirred for 20 minutes, before adding tert- butyl 4-aminophenethylcarbamate (0.150 g, 0.635 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded (2-{4-[(2-bromo-thiazole-5- carbonyl)-amino]-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.1262 g, 47%) as an off-white solid.
Figure imgf000297_0002
[0704] Step 2: Synthesis of 4-{5-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]- thiazol-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of (2-{4-[(2-bromo- thiazole-5-carbonyl)-amino]-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.0400 g, 0.0938 mmol), tert- butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.0348 g, 0.113 mmol), 2 M Na2CO3 solution (0.141 mL, 0.281 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.00766 g, 0.00938 mmol) in 1,4-dioxane (1.5 mL) in a 2-dram vial was degassed by bubbling nitrogen through the mixture for 2 - 3 minutes. The reaction was heated at 80 °C for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 75% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded 4-{5-[4-(2-tert- butoxycarbonylamino-ethyl)-phenylcarbamoyl]-thiazol-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0185 g, 37%) as an off-white solid.  
Figure imgf000298_0001
[0705] Step 3: Synthesis of 2-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(2- amino-ethyl)-phenyl]-amide trifluoroacetate: To a solution of 4-{5-[4-(2-tert-butoxycarbonylamino-ethyl)- phenylcarbamoyl]-thiazol-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0185 g, 0.0350 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for 2 - 3 hours, then concentrated without heating. The residue was dissolved / suspended in dichloromethane and concentrated again, then dried under vacuum to yield 2- (1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide trifluoroacetate as a yellowish solid / oil that was used immediately in the next reaction.
Figure imgf000298_0002
[0706] Step 4: Synthesis of tert-butyl N-[(E)-({2-[4-(2-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5- amido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 2- (1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(2-amino-ethyl)-phenyl]-amide trifluoroacetate (0.0350 mmol) and N,N-diisopropylethylamine (0.0317 g, 0.0427 mL, 0.245 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.0282 g, 0.0910 mmol). The reaction was stirred at 20 oC for 18 hours. An additional 20 mg (0.0644 mmol) of tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate was added to the reaction, and it was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0140 g, 0.0155 mL, 0.140 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 100% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(E)-({2-[4-(2-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]- 1,2,3,6-tetrahydropyridin-4-yl}-1,3- thiazole-5-amido)phenyl]ethyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0134 g, 47% over two steps) as an off-white solid.  
Figure imgf000299_0001
[0707] Step 5: Synthesis of N-[4-(2-carbamimidamidoethyl)phenyl]-2-(1-carbamimidoyl -1,2,3,6- tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(E)-({2- [4-(2-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}-1,3-thiazole-5-amido)phenyl]ethyl}amino)({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0134 g, 0.0165 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield N-[4-(2-carbamimidamidoethyl) phenyl]-2-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-5-carboxamide trifluoroacetate (0.0099 g, 94%) as a flocculent, off-white solid. 1H NMR (METHANOL-d4) δ: 8.46 (s, 1H), 7.59-7.67 (m, 2H), 7.23-7.32 (m, J=8.5 Hz, 2H), 6.78 (dt, J=3.3, 2.0 Hz, 1H), 4.20 (q, J=2.8 Hz, 2H), 3.72 (t, J=5.7 Hz, 2H), 3.45 (t, J=7.1 Hz, 2H), 2.81-2.91 (m, 4H). LC/MS (M + H)+ = 413. [0708] Example 7: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-5-(3-carbamimid amidopropyl)furan-2-carboxamide trifluoroacetate.
Figure imgf000299_0002
[0709] Synthesis of {4-[(5-bromo-furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester: A mixture of 5-bromofuran-2-carboxylic acid (0.516 g, 2.70 mmol), N,N-diisopropylethyl amine (1.16 g, 1.57 mL, 9.00 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.11 g, 2.93 mmol) in N,N-dimethylformamide (5.6 mL) at 25 oC under N2 was stirred for 20 minutes, before adding tert-butyl 4-aminobenzylcarbamate (0.500 g, 2.25 mmol) and stirring at 25 oC for 18 hours. The mixture was partitioned between ethyl acetate (300 mL) and saturated NH4Cl solution (50 mL) and separated. The organic layer was washed with water (2 x 30 mL), saturated NaHCO3 solution (30 mL), then brine (30 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {4-[(5-bromo-furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester (0.7797 g, 88%) as an off-white solid.  
Figure imgf000300_0001
[0710] Synthesis of (3-{5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-furan-2-yl}- prop-2-ynyl)-carbamic acid tert-butyl ester: A solution of {4-[(5-bromo-furan-2-carbonyl)-amino]- benzyl}-carbamic acid tert-butyl ester (0.250 g, 0.633 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (0.147 g, 0.949 mmol) in a mixture of tetrahydrofuran (3 mL) and triethylamine (1 mL) was degassed with nitrogen for 5 minutes. Copper(I) iodide (0.00602 g, 0.0316 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.0222 g 0.0316 mmol) were added, and the mixture was heated at 60 °C for 18 hours. The reaction was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed again with saturated NH4Cl solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded (3-{5-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-furan-2-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (0.1849 g, 62%) as a light brown foam.
Figure imgf000300_0002
[0711] Synthesis of 5-(3-amino-prop-1-ynyl)-furan-2-carboxylic acid (4-aminomethyl-phenyl)- amide trifluoroacetate: To a solution of (3-{5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- furan-2-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (0.0600 g, 0.128 mmol) in dichloromethane (2 mL) at 25 oC was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 25 oC for two hours, then concentrated without heating. The residue was suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 5-(3-amino-prop-1-ynyl)-furan-2-carboxylic acid (4-aminomethyl-phenyl)- amide trifluoroacetate (0.0602 g, 95%) as a yellow solid.
Figure imgf000300_0003
[0712] Step 1: Synthesis of (3-{5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-furan- 2-yl}-propyl)-carbamic acid tert-butyl ester: A solution of (3-{5-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-furan-2-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (0.0600 g, 0.128 mmol) in ethanol (4 mL) at 20 oC was purged with nitrogen. After adding 10% palladium on carbon (0.0200 g), the  
mixture was purged again with nitrogen, then hydrogen, then stirred under hydrogen for 90 minutes. The reaction was purged with nitrogen and filtered through a Celite pad, which was washed with ethyl acetate. Concentration and drying under vacuum yielded (3-{5-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-furan-2-yl}-propyl)-carbamic acid tert-butyl ester (0.0556 g, 92%) as a tan foam.
Figure imgf000301_0001
[0713] Step 2: Synthesis of 5-(3-amino-propyl)-furan-2-carboxylic acid (4-aminomethyl-phenyl)- amide trifluoroacetate: To a solution of (3-{5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- furan-2-yl}-propyl)-carbamic acid tert-butyl ester (0.0556 g, 0.117 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 5-(3-amino-propyl)-furan-2-carboxylic acid (4-aminomethyl- phenyl)-amide trifluoroacetate (0.0574 g, 98%) as a brown solid / oil.
Figure imgf000301_0002
[0714] Step 3: Synthesis of tert-butyl N-[(E)-{[3-(5-{[4-({[(E)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl}furan-2- yl)propyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 5-(3-amino-propyl)- furan-2-carboxylic acid (4-aminomethyl-phenyl)-amide trifluoroacetate (0.0574 g, 0.114 mmol) and N,N- diisopropylethylamine (0.106 g, 0.143 mL, 0.819 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.109 g, 0.351 mmol). The reaction was stirred at 20 oC for six hours, then placed in the refrigerator over the weekend. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0352 g, 0.0389 mL, 0.351 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(E)-{[3-(5-{[4-({[(E)- {[(tert-butoxy) carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl}furan-2-yl)propyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0562 g, 63%) as a white solid.  
Figure imgf000302_0001
[0715] Step 4: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-5-(3-carbamimidamido propyl)furan-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(E)-{[3-(5-{[4-({[(E)-{[(tert- butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl}furan-2-yl)propyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0540 g, 0.0713 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield N-[4-(carbamimidamidomethyl)phenyl]-5-(3- carbamimidamidopropyl)furan-2-carboxamide trifluoroacetate (0.0448 g, quantitative) as a flocculent, off- white solid. 1H NMR (DMSO-d6) δ: 10.05 (s, 1H), 7.96 (t, J=6.0 Hz, 1H), 7.67-7.76 (m, J=8.6 Hz, 3H), 7.08-7.43 (m, 9H), 6.37 (d, J=3.4 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.16 (q, J=6.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.84 (quin, J=7.0 Hz, 2H). LC/MS (M + H)+ = 358. [0716] Example 8: Synthesis of 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate.
Figure imgf000302_0002
[0717] Synthesis of 2-bromo-thiazole-5-carboxylic acid (4-bromo-phenyl)-amide: A mixture of 2- bromo-thiazole-5-carboxylic acid (0.300 g, 1.44 mmol), N,N-diisopropylethylamine (0.932 g, 1.26 mL, 7.21 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (0.713 g, 1.87 mmol) in N,N-dimethylformamide (3.6 mL) at 20 oC under N2 was stirred for five minutes before adding 4-bromo-phenylamine (0.347 g, 2.02 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed twice with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 2-bromo-thiazole-5-carboxylic acid (4-bromo-phenyl)-amide (0.137 g, 26%) as a tan solid.  
Figure imgf000303_0001
[0718] Synthesis of tert-butyl 4-[4-(2-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin -4-yl}- 1,3-thiazole-5-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of 2-bromo-thiazole-5- carboxylic acid (4-bromo-phenyl)-amide (0.0625 g, 0.173 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.133 g, 0.432 mmol), 2 M Na2CO3 solution (0.518 mL, 1.04 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0141 g, 0.0173 mmol) in 1,4-dioxane (2.5 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (80 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 100% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(2-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5- amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0689 g, 70%) as a yellow solid.
Figure imgf000303_0002
[0719] Synthesis of 2-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(2-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5-amido)phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0689 g, 0.122 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 2-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.123 g, quantitative) as a flocculent, yellow solid.
Figure imgf000303_0003
 
[0720] Synthesis of tert-butyl N-[(Z)-{4-[4-(2-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert - butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5-amido)phenyl]-1,2,3,6- tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamatee: To a solution of 2-(1,2,3,6- tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0690 g, 0.116 mmol) and N,N-diisopropylethytlamine (0.105 g, 0.142 mL, 0.812 mmol) in dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.108 g, 0.348 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0349 g, 0.0386 mL, 0.348 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 75% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N- [(Z)-{4-[4-(2-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}-1,3-thiazole-5-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0472 g, 48%) as a yellowish solid.
Figure imgf000304_0001
[0721] Synthesis of 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl N-[(Z)-{4-[4-(2-{1-[(Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-5-amido)phenyl]-1,2,3,6- tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0450 g, 0.0529 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was purified by reverse phase HPLC (Waters Sunfire Prep C18 OBD, 10 µm, 30 x 150 mm column; 5 to 50% MeCN – water (both with 0.1% TFA) over 18 min.) to yield 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0218 g, 61%) as a flocculent, off-white solid. 1H NMR (DMSO-d6) δ: 10.50 (s, 1H), 8.58 (s, 1H), 7.70 (br d, J=8.3 Hz, 2H), 7.38-7.54 (m, 10H), 6.79 (s, 1H), 6.19 (br s, 1H), 4.14 (br s, 2H), 4.06 (br s, 2H), 3.61 (br s, 4H), 2.70 (br d, J=3.1 Hz, 2H), 2.57 (s, 2H). LC/MS (M + H)+ = 451.  
[0722] Example 9: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl) -N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]thiophene-2-carboxamide trifluoroacetate:
Figure imgf000305_0001
[0723] Step 1: Synthesis of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl ester: A mixture of 4-bromobenzenamine (0.500 g, 2.91 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (1.08 g, 3.49 mmol), 2 M Na2CO3 solution (4.36 mL, 8.72 mmol), and 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), dichloromethane adduct (0.119 g, 0.145 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (100 mL) and saturated NaHCO3 solution (50 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (30 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-(4-amino- phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.6043 g, 76%) as an off-white solid.
Figure imgf000305_0002
[0724] Step 2: Synthesis of 4-{4-[(4-bromo-thiophene-2-carbonyl)-amino]-phenyl}-3,6-dihydro- 2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of 4-bromo-thiophene-2-carboxylic acid (0.0634 g, 0.306 mmol), N,N-diisopropylethylamine (0.132 g, 0.178 mL, 1.02 mmol), and N-[(dimethylamino)-1H- 1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.126 g, 0.332 mmol) in N,N-dimethylformamide (1.5 mL) in a 2-dram vial at 20 oC under N2 was stirred for 15 minutes, before adding 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0700 g, 0.255 mmol) and stirring at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded 4-{4-[(4-bromo-thiophene- 2-carbonyl)-amino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.106 g, 90%) as an off-white solid.  
Figure imgf000306_0001
[0725] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}thiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of 4-{4-[(4- bromo-thiophene-2-carbonyl)-amino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.100 g, 0.216 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- 1(2H)-carboxylate (0.0867 g, 0.281 mmol), 2 M Na2CO3 solution (0.324 mL, 0.647 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0176 g, 0.0216 mmol) in 1,4-dioxane (2.5 mL) in a 20 mL vial was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for six hours, then stirred at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 60% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (0.0987 g, 81%) as an off-white solid. B
Figure imgf000306_0002
[0726] Step 4: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0987 g, 0.174 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.106 g, quantitative) as a flocculent, light yellow solid.  
Figure imgf000307_0002
[0727] Step 4: Synthesis of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2- amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin- 4-yl)-phenyl]-amide trifluoroacetate (0.0600 g, 0.101 mmol) and N,N-diisopropylethylamine (0.0915 g, 0.123 mL, 0.708 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)- {[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.0941 g, 0.303 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0303 g, 0.0336 mL, 0.303 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N- [(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0588 g, 69%) as an off-white foam.
Figure imgf000307_0001
[0728] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]thiophene-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]-1,2,3,6- tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0588 g, 0.0692 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (1 mL) dropwise. The reaction was stirred at 20 oC for two hours, then placed in the refrigerator for 18 hours. The mixture was concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-  
tetrahydropyridin-4-yl)phenyl]thiophene-2-carboxamide trifluoroacetate (0.0459 g, 98%) as a flocculent, white solid.1H NMR (METHANOL-d4) δ: 8.14 (d, J=1.4 Hz, 1H), 7.64-7.75 (m, 3H), 7.42-7.51 (m, J=4.5, 4.5, 4.5 Hz, 2H), 6.24 (dt, J=3.3, 2.0 Hz, 1H), 6.14 (dt, J=3.2, 1.9 Hz, 1H), 4.14 (dd, J=5.3, 2.9 Hz, 4H), 3.70 (td, J=5.8, 1.5 Hz, 4H), 2.66-2.75 (m, 4H). LC/MS (M + H)+ = 450. [0729] Example 10: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-4-(1- carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide trifluoroacetate,
Figure imgf000308_0001
[0730] Step 1: Synthesis of {4-[(4-bromo-thiophene-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester: A mixture of 4-bromo-thiophene-2-carboxylic acid (0.224 g, 1.08 mmol), N,N- diisopropylethylamine (0.465 g, 0.627 mL, 3.60 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.445 g, 1.17 mmol) in dimethylformamide (3 mL) at 20 oC under N2 was stirred for 15 minutes, before adding (4-amino-benzyl)- carbamic acid tert-butyl ester (0.200 g, 0.900 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed twice with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {4-[(4-bromo-thiophene-2- carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester (0.356 g, 96%) as an off-white solid.
Figure imgf000308_0002
[0731] Step 2: Synthesis of 4-{5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- thiophen-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of {4-[(4-bromo- thiophene-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester (0.0800 g, 0.195 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.0722 g, 0.233 mmol), 2 M Na2CO3 solution (0.291 mL, 0.584 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0159 g, 0.0195 mmol) in 1,4-dioxane (1.5 mL) in a 2-dram vial was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for seven hours, then stirred at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected  
directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 100% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded 4-{5-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-thiophen-3-yl}-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (0.0766 g, 77%) as a tan foam.
Figure imgf000309_0001
[0732] Step 3: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid (4- aminomethyl-phenyl)-amide hydrochloride: To a solution of 4-{5-[4-(tert-butoxycarbonylamino-methyl)- phenylcarbamoyl]-thiophen-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0723 g, 0.141 mmol) in dichloromethane (3.2 mL) at 20 oC under N2 was added 4 N HCl – dioxane solution (0.800 mL, 3.20 mmol) dropwise. The reaction was stirred at 20 oC for 18 hours, then concentrated. The residue was dissolved / suspended in dichloromethane, concentrated again, then dried under vacuum to yield 4- (1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid (4-aminomethyl-phenyl)-amide hydrochloride (0.0559 g, quantitative) as an off-white solid.
Figure imgf000309_0002
[0733] Step 4: Synthesis of tert-butyl N-[(E)-({[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2- amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 4- (1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid (4-aminomethyl-phenyl)-amide hydrochloride (0.0536 g, 0.139 mmol) and N,N-diisopropylethylamie (0.126 g, 0.169 mL, 0.971 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy) carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.129 g, 0.416 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0417 g, 0.0462 mL, 0.416 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(E)-({[4-(4- {1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy) carbonyl]imino})methyl]-1,2,3,6-  
tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]methyl}amino)({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0566 g, 51%) as a white solid.
Figure imgf000310_0001
[0734] Step 5: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-4-(1-carbamimidoyl- 1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(E)-({[4- (4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]methyl}amino)({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0550 g, 0.0689 mmol) in dichloromethane (3.2 mL) at 20 oC under N2 was added 4 N HCl – dioxane solution (0.800 mL, 3.20 mmol) dropwise. The reaction was stirred at 20 oC for 18 hours, then concentrated. The residue was dissolved / suspended in dichloromethane and concentrated again, then purified by reverse phase HPLC (Waters Sunfire Prep C18 OBD, 10 µm, 30 x 150 mm column; 7 to 44% MeCN – water (both with 0.1% TFA) over 22 min.). The good fractions were lyophilized to yield N-[4-(carbamimidamidomethyl)phenyl]- 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide trifluoroacetate (0.0265 g, 62%) as a flocculent, white solid. 1H NMR (DMSO-d6) δ: 10.29 (s, 1H), 8.27 (d, J=1.5 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.45 (s, 4H), 6.93-7.35 (m, J=8.4 Hz, 5H), 6.21 (s, 1H), 4.32 (d, J=5.9 Hz, 2H), 4.08 (br d, J=1.2 Hz, 2H), 3.61 (t, J=5.6 Hz, 2H), 2.56 (br s, 2H). LC/MS (M + H)+ = 398. [0735] Example 11: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]thiophene-2-carboxamide trifluoroacetate.
Figure imgf000310_0002
[0736] Step 1: Synthesis of 4-bromo-thiophene-2-carboxylic acid (4-bromo-3-fluoro-phenyl)- amide: A mixture of 4-bromo-thiophene-2-carboxylic acid (0.327 g, 1.58 mmol), N,N- diisopropylethylamine (0.850 g, 1.15 mL, 6.58 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.650 g, 1.71 mmol) in N,N-dimethylformamide (4 mL) at 20 oC under N2 was stirred for 30 minutes, before adding 4-bromo-3- fluoro-phenylamine (0.250 g, 1.32 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 20% ethyl acetate - hexanes), followed  
by concentration and drying under vacuum, yielded 4-bromo-thiophene-2-carboxylic acid (4-bromo-3- fluoro-phenyl)-amide (0.484 g, 97%) as an off-white solid.
Figure imgf000311_0001
[0737] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of 4-bromo-thiophene-2-carboxylic acid (4-bromo-3-fluoro-phenyl)-amide (0.0800 g, 0.211 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.150 g, 0.485 mmol), 2 M Na2CO3 solution (0.633 mL, 1.27 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0172 g, 0.0211 mmol) in 1,4-dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (100 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (30 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.104 g, 84%) as an off-white foam. B
Figure imgf000311_0002
[0738] Step 3: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4- (4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)-2- fluorophenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (0.100 g, 0.171 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [3-fluoro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.109 g, quantitative) as a flocculent, yellowish solid.  
Figure imgf000312_0001
[0739] Step 4: Synthesis of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2- amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate: To a solution of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)- thiophene-2-carboxylic acid [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.102 g, 0.167 mmol) and N,N-diisopropylethyleamine (0.151 g, 0.203 mL, 1.17 mmol) in N,N- dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.155 g, 0.500 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0501 g, 0.0555 mL, 0.500 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N- [(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.1057 g, 73%) as an off-white solid.
Figure imgf000312_0002
[0740] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N- [4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]thiophene-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)-2-fluorophenyl]- 1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.102 g, 0.118 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-  
1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-3- fluorophenyl]thiophene-2-carboxamide trifluoroacetate (0.0809 g, 99%) as a flocculent, white solid. 1H NMR (DMSO-d6) δ: 10.48 (s, 1H), 8.27 (d, J=1.4 Hz, 1H), 7.84 (d, J=1.3 Hz, 1H), 7.69 (dd, J=14.0, 2.0 Hz, 1H), 7.43-7.54 (m, 9H), 7.36-7.43 (m, 1H), 6.22 (s, 1H), 6.03 (s, 1H), 4.03-4.12 (m, 4H), 3.60 (q, J=6.1 Hz, 4H), 2.56 (br d, J=6.2 Hz, 4H).19F NMR (DMSO-d6) δ: -73.66 (s, 1F), -113.85--113.73 (m, 1F). LC/MS (M + H)+ = 468. [0741] Example 12: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl]thiophene-2-carboxamide trifluoroacetate.
Figure imgf000313_0001
[0742] Step 1: Synthesis of 4-bromo-thiophene-2-carboxylic acid (4-bromo-3-methoxy-phenyl)- amide: A mixture of 4-bromo-thiophene-2-carboxylic acid (0.307 g, 1.48 mmol), N,N- diisopropylethyleamine (0.800 g, 1.08 mL, 6.19 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.612 g, 1.61 mmol) in dimethylformamide (4 mL) at 20 oC under N2 was stirred for 30 minutes, before adding 4-bromo-3- methoxy-phenylamine (0.250 g, 1.24 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed twice with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 20% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-bromo-thiophene-2-carboxylic acid (4-bromo-3- methoxy-phenyl)-amide (0.4112 g, 85%) as an off-white solid. B
Figure imgf000313_0002
[0743] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}thiophene-2-amido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of 4-bromo-thiophene-2-carboxylic acid (4-bromo-3-methoxy-phenyl)-amide (0.0800 g, 0.205 mmol), tert- butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.145 g, 0.470 mmol), 2 M Na2CO3 solution (0.614 mL, 1.23 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0167 g, 0.0205 mmol)  
in 1,4-dioxane (3 mL) in a scintillation vial was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for six hours, then stirred at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2- amido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0989 g, 81%) as an off-white foam.
Figure imgf000314_0001
[0744] Step 3: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [3- methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4- [4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)-2- methoxyphenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (0.0960 g, 0.161 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [3- methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.1138 g, quantitative) as a flocculent, yellow solid.
Figure imgf000314_0002
[0745] Step 4: Synthesis of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)-2- methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [3-methoxy-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.161 mmol) and N,N-diisopropylethylamine (0.146 g, 0.196 mL, 1.13 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.150 g, 0.483 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1- methylpiperazine (0.0484 g, 0.0536 mL, 0.483 mmol) was added, and the reaction was stirred for two hours.  
The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2-amido)-2-methoxyphenyl]- 1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.1000 g, 71%) as an off-white solid.
Figure imgf000315_0001
[0746] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl]thiophene-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophene-2- amido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0980 g, 0.111 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl) -N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl]thiophene-2-carboxamide trifluoroacetate (0.0784 g, 100%) as a flocculent, off-white solid. 1H NMR (DMSO-d6) δ: 10.29 (s, 1H), 8.28 (d, J=1.4 Hz, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.49 (br s, 4H), 7.46 (d, J=2.1 Hz, 1H), 7.43 (br s, 4H), 7.33 (dd, J=8.3, 1.9 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.22 (t, J=3.1 Hz, 1H), 5.79-5.87 (m, 1H), 4.05-4.14 (m, 2H), 4.01 (br d, J=3.5 Hz, 2H), 3.76 (s, 3H), 3.61 (t, J=5.6 Hz, 2H), 3.54 (t, J=5.6 Hz, 2H), 2.57 (br s, 2H), 2.51 (br s, 2H). LC/MS (M + H)+ = 480. [0747] Example 13: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4yl)phenyl]-3-methylthiophene-2-carboxamide trifluoroacetate,
Figure imgf000315_0002
 
[0748] Step 1: Synthesis of 4-bromo-3-methyl-thiophene-2-carboxylic acid (4-bromo-phenyl)- amide: A mixture of 4-bromo-3-methyl-thiophene-2-carboxylic acid (0.386 g, 1.74 mmol), N,N- diisopropylethylamine (0.939 g, 1.27 mL, 7.27 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.718 g, 1.89 mmol) in N,N-dimethylformamide (3.6 mL) at 20 oC under N2 was stirred for 20 minutes, before adding 4-bromo- phenylamine (0.250 g, 1.45 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed twice with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 20% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-bromo-3-methyl-thiophene-2-carboxylic acid (4-bromo- phenyl)-amide (0.4124 g, 76%) as a white solid.
Figure imgf000316_0001
[0749] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6 - tetrahydropyridin-4-yl}-3-methylthiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of 4-bromo-3-methyl-thiophene-2-carboxylic acid (4-bromo-phenyl)-amide (0.0750 g, 0.200 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.142 g, 0.460 mmol), 2 M Na2CO3 solution (0.600 mL, 1.20 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0163 g, 0.0200 mmol) in 1,4-dioxane (2.5 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (80 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylthiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0638 g, 55%) as a white solid.
Figure imgf000316_0002
[0750] Step 3: Synthesis of 3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4-  
{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylthiophene-2- amido)phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0610 g, 0.105 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0762 g, quantitative) as a flocculent, yellow solid.
Figure imgf000317_0001
[0751] Step 4: Synthesis of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylthiophene-2- amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0705 g, 0.116 mmol) and N,N- diisopropylethylamine (0.105 g, 0.141 mL, 0.812 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl] carbamate (0.108 g, 0.348 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0349 g, 0.0386 mL, 0.348 mmol) was added, and the reaction was stirred for 30 minutes. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylthiophene-2-amido)phenyl]- 1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0729 g, 63%) as a white solid.
Figure imgf000317_0002
[0752] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4yl)phenyl]-3-methylthiophene-2-carboxamide trifluoroacetate:  
To a solution of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylthiophene-2-amido)phenyl]- 1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.0600 g, 0.0694 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for 60 minutes, then placed in the refrigerator for 18 hours. The mixture was concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4yl)phenyl]-3-methylthiophene-2-carboxamide trifluoroacetate (0.0514 g, quantitative) as an off-white solid.1H NMR (DMSO-d6) δ: 10.16 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.59 (s, 1H), 7.40-7.49 (m, 10H), 6.17 (t, J=3.1 Hz, 1H), 5.79 (t, J=3.1 Hz, 1H), 4.06 (br s, 4H), 3.58-3.64 (m, 4H), 2.57 (br s, 2H), 2.37 (s, 3H). LC/MS (M + H)+ = 464. [0753] Example 14: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-5-methylthiophene-2-carboxamide trifluoroacetate.
Figure imgf000318_0001
[0754] Step 1: Synthesis of 4-bromo-5-methyl-thiophene-2-carboxylic acid (4-bromo-phenyl)- amide: A mixture of 4-bromo-5-methyl-thiophene-2-carboxylic acid (0.308 g, 1.40 mmol), N,N=diisopropylethylamine (0.751 g, 1.01 mL, 5.81 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.575 g, 1.51 mmol) in N,N-dimethylformamide (2.9 mL) at 20 oC under N2 was stirred for 20 minutes, before adding 4- bromo-phenylamine (0.200 g, 1.16 mmol) and stirring at 20 oC for 18 hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed twice with water (15 mL), saturated NaHCO3 solution (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 15% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-bromo-5-methyl-thiophene-2-carboxylic acid (4- bromo-phenyl)-amide (0.4044 g, 93%) as a white solid.
Figure imgf000318_0002
 
[0755] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-5-methylthiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of 4-bromo-5-methyl-thiophene-2-carboxylic acid (4-bromo-phenyl)-amide (0.0750 g, 0.200 mmol), tert- butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.142 g, 0.460 mmol), 2 M Na2CO3 solution (0.600 mL, 1.20 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0163 g, 0.0200 mmol) in 1,4-dioxane (2.5 mL) in a scintillation vial was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin- 4-yl}-5-methylthiophene-2-amido)phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0991 g, 86%) as an off-white foam.
Figure imgf000319_0001
[0756] Step 3: Synthesis of 5-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4- {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-5-methylthiophene-2- amido)phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0970 g, 0.167 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 5-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.1025 g, quantitative) as a flocculent, yellow solid.
Figure imgf000319_0002
[0757] Step 4: Synthesis of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-5-methylthiophene-2-  
amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a solution of 5-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0979 g, 0.161 mmol) and N,N- diisopropylethylamine (0.146 g, 0.196 mL, 1.13 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.150 g, 0.483 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0484 g, 0.0536 mL, 0.483 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (140 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-5-methylthiophene-2-amido)phenyl]- 1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl]carbamate (0.1012 g, 73%) as a white solid. B
Figure imgf000320_0001
[0758] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-5-methylthiophene-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-5- methylthiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0980 g, 0.113 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin -4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-5-methylthiophene-2-carboxamide trifluoroacetate (0.0701 g, 90%) as a flocculent, off-white solid.1H NMR (DMSO-d6) δ: 10.17 (s, 1H), 7.92 (s, 1H), 7.67- 7.73 (m, 2H), 7.41-7.52 (m, 10H), 6.17 (t, J=3.1 Hz, 1H), 5.84 (s, 1H), 4.06 (br d, J=3.5 Hz, 4H), 3.61 (td, J=5.7, 2.2 Hz, 4H), 2.57 (br s, 2H). LC/MS (M + H)+ = 464.  
[0759] Example 15: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N- [4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3-methoxythiophene-2-carboxamide trifluoroacetate.
Figure imgf000321_0001
[0760] Step 1: Synthesis of 4-(4-methoxy-5-methoxycarbonyl-thiophen-3-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester: A mixture of 4-bromo-3-methoxy-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.796 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-1(2H)-carboxylate (0.295 g, 0.956 mmol), 2 M Na2CO3 solution (1.19 mL, 2.39 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0650 g, 0.0796 mmol) in 1,4-dioxane (4 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 20% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-(4-methoxy-5-methoxycarbonyl-thiophen-3-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.1790 g, 64%) as an off-white solid.
Figure imgf000321_0002
[0761] Step 2: Synthesis of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methoxy-thiophene-2-carboxylate: To a solution of 4-(4-methoxy-5-methoxycarbonyl-thiophen-3-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.176 g, 0.498 mmol) in a mixture of methanol (1.25 mL) and tetrahydrofuran (1.25 mL) at 20 oC under N2 was added 1 N NaOH solution (0.523 mL, 0.523 mmol) dropwise. The mixture was stirred at 20 oC for 18 hours. LC-MS analysis still showed a small amount of starting material. The reaction was heated at 40 °C for three hours, then concentrated and dried under vacuum to yield sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- thiophene-2-carboxylate (0.1852 g, quantitative) as an off-white solid.
Figure imgf000321_0003
 
[0762] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methoxythiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-thiophene-2- carboxylate (0.0724 g, 0.200 mmol), N,N-diisopropylethylamine (0.118 g, 0.159 mL, 0.911 mmol), and N- [(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl methanaminium hexafluorophosphate N-oxide (0.0901 g, 0.237 mmol) in dimethylformamide (1.5 mL) in a 2-dram vial at 20 oC under N2 was stirred for 10 minutes, before adding 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (0.0500 g, 0.182 mmol) and stirring at 20 oC for three days. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxythiophene-2- amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0917 g, 85%) as an off-white foam.
Figure imgf000322_0001
[0763] Step 4: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methoxythiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: To a solution of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxy thiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0900 g, 0.151 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 3 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 3-methoxy-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.1069 g, quantitative) as a flocculent, light yellow solid.
Figure imgf000322_0002
[0764] Step 5: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-4-methoxy-thiophen-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 3-  
methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-amide trifluoroacetate (0.151 mmol) and N,N-diisopropylethylamine (0.137 g, 0.184 mL, 1.057 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.141 g, 0.453 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0454 g, 0.0502 mL, 0.453 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {[4-(5-{4- [1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]- phenylcarbamoyl}-4-methoxy-thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (0.0943 g, 71%) as a white solid.
Figure imgf000323_0001
[0765] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3-methoxythiophene-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxy carbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-4-methoxy-thiophen-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0910 g, 0.103 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3- methoxythiophene-2-carboxamide trifluoroacetate (0.0696 g, 96%) as a flocculent, white solid. 1H NMR (DMSO-d6) δ: 9.73 (d, J=3.0 Hz, 1H), 7.74 (d, J=3.0 Hz, 1H), 7.69 (dd, J=8.7, 3.0 Hz, 2H), 7.48 (br d, J=8.2 Hz, 10H), 6.23 (br s, 1H), 6.18 (br s, 1H), 4.07 (br s, 4H), 3.85 (d, J=2.9 Hz, 3H), 3.58-3.66 (m, 4H), 2.56 (br s, 4H). LC/MS (M + H)+ = 480. [0766] Example 16: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3-fluorothiophene-2-carboxamide trifluoroacetate.  
Figure imgf000324_0001
[0767] Step 1: Synthesis of 4-(4-fluoro-5-methoxycarbonyl-thiophen-3-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester: A mixture of 4-bromo-3-fluoro-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.418 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-1(2H)-carboxylate (0.155 g, 0.502 mmol), 2 M Na2CO3 solution (0.627 mL, 1.25 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0342 g, 0.0418 mmol) in 1,4-dioxane (2 mL) in a scintillation vial was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 50 °C for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 20% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded 4-(4-fluoro-5- methoxycarbonyl-thiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.1265 g, 89%) as an off-white solid.
Figure imgf000324_0002
[0768] Step 2: Synthesis of sodium 4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin- 4-yl}- 3-fluorothiophene-2-carboxylate: To a solution of 4-(4-fluoro-5-methoxycarbonyl-thiophen-3-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.124 g, 0.363 mmol) in a mixture of methanol (1.5 mL) and tetrahydrofuran (1.5 mL) at 20 oC under N2 was added 1 N NaOH solution (0.381 mL, 0.381 mmol) dropwise. The reaction was stirred at 20 oC for six hours, heated at 40 °C for two hours, then stirred at 20 oC for 18 hours. The mixture was concentrated and dried under vacuum to yield sodium 4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorothiophene -2-carboxylate (0.0806 g, 64%) as an off-white solid.
Figure imgf000324_0003
[0769] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluoro thiophene-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of  
sodium 4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorothiophene- 2-carboxylate (0.0770 g, 0.221 mmol), N,N=diisopropylethylamine (0.130 g, 0.175 mL, 1.00 mmol), and N- [(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0991 g, 0.261 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was stirred for 10 minutes, before adding 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0550 g, 0.200 mmol) and stirring at 20 oC over the weekend. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 35% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4- (4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-fluorothiophene-2-amido)phenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (0.0966 g, 83%) as an off-white foam.
Figure imgf000325_0001
[0770] Step 4: Synthesis of 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4- {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorothiophene-2- amido)phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0950 g, 0.163 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0986 g, 99%) as a flocculent, light yellow solid.
Figure imgf000325_0002
[0771] Step 5: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-4-fluoro-thiophen-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 3-fluoro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-  
phenyl]-amide trifluoroacetate (0.0920 g, 0.150 mmol) and N,N-diisopropylethylamine (0.136 g, 0.183 mL, 1.05 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl] carbamate (0.140 g, 0.451 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0451 g, 0.0499 mL, 0.450 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {[4-(5-{4- [1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenyl carbamoyl}-4-fluoro-thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (0.0957 g, 74%) as a white solid.
Figure imgf000326_0001
[0772] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3-fluorothiophene-2-carboxamide trifluoroacetate : To a solution of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-4-fluoro-thiophen-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0930 g, 0.107 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3-fluorothiophene-2-carboxamide trifluoroacetate (0.0705 g, 95%) as a flocculent, off-white solid. 1H NMR (DMSO-d6) δ: 10.04 (d, J=2.2 Hz, 1H), 7.85 (d, J=4.8 Hz, 1H), 7.62-7.70 (m, J=8.8 Hz, 2H), 7.48 (br s, 5H), 7.45 (br d, J=2.1 Hz, 5H), 6.21-6.27 (m, 1H), 6.15-6.21 (m, 1H), 4.02-4.13 (m, J=3.8 Hz, 4H), 3.61 (t, J=5.6 Hz, 4H), 2.52-2.62 (m, 4H).19F NMR (DMSO-d6) δ: -73.57 (s, 1F), -117.59 (br d, J=5.9 Hz, 1F). LC/MS (M + H)+ = 468. [0773] Example 17: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]furan-2-carboxamide trifluoroacetate.  
Figure imgf000327_0001
[0774] Step 1: Synthesis of 4-(5-methoxycarbonyl-furan-3-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester: A mixture of 4-bromo-furan-2-carboxylic acid methyl ester (0.250 g, 1.22 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.415 g, 1.34 mmol), 2 M Na2CO3 solution (1.83 mL, 3.66 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0996 g, 0.122 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (80 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. After adsorption onto Florisil, silica gel chromatography (0 to 20% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-(5- methoxycarbonyl-furan-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.2278 g, 61%) as an off-white solid.
Figure imgf000327_0002
[0775] Step 2: Synthesis of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- furan-2-carboxylate: To a solution of 4-(5-methoxycarbonyl-furan-3-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (0.2116 g, 0.688 mmol) in a mixture of methanol (1.8 mL) and tetrahydrofuran (1.8 mL) at 20 oC under N2 was added 6 N NaOH solution (0.120 mL, 0.723 mmol) dropwise. The mixture was heated at 40 °C for 18 hours, then concentrated. The residue was suspended in dichloromethane and concentrated again, then dried under vacuum to yield sodium 4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.2120 g, 98%) as an off-white solid.
Figure imgf000327_0003
[0776] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}furan-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of sodium 4-(1-  
tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.0695 g, 0.221 mmol), N,N=diisopropylethylamine (0.130 g, 0.175 mL, 1.00 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0991 g, 0.261 mmol) in N,N-dimethylformamide (2 mL) in a scintillation vial at 20 oC under N2 was stirred for 20 minutes, before adding 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0550 g, 0.200 mmol) and stirring at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl} furan-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0543 g, 49%) as an off-white solid.
Figure imgf000328_0001
[0777] Step 4: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}furan-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate (0.0520 g, 0.946 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-amide trifluoroacetate (0.0570 g, quantitative) as a flocculent, light yellow solid.
Figure imgf000328_0002
[0778] Step 5: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 4-(1,2,3,6-tetrahydro- pyridin-4-yl)-furan-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0527 g, 0.0913 mmol) and N,N-diisopropylethylamine (0.0826 g, 0.111 mL, 0.639 mmol) in dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-  
butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.0850 g, 0.274 mmol). The reaction was stirred at 20 oC over the weekend. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0274 g, 0.0304 mL, 0.274 mmol) was added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {[4-(5-{4- [1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]- phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0540 g, 71%) as a white solid.
Figure imgf000329_0001
[0779] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]furan-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin- 4-yl]-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (0.0540 g, 0.0648 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]furan-2-carboxamide trifluoroacetate (0.0410 g, 96%) as a flocculent, light yellow solid.1H NMR (DMSO-d6) δ: 10.30 (s, 1H), 8.07 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.61 (d, J=0.9 Hz, 1H), 7.39-7.52 (m, 10H), 6.11-6.26 (m, 2H), 4.06 (br s, 4H), 3.57-3.64 (m, 4H), 2.57 (br s, 2H). LC/MS (M + H)+ = 434. [0780] Example 18: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]furan-2-carboxamide trifluoroacetate.
Figure imgf000329_0002
 
[0781] Step 1: Synthesis of 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of 4-bromo-3-fluoro-phenylamine (0.500 g, 2.63 mmol), tert-butyl 5,6- dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.895 g, 2.89 mmol), 2 M Na2CO3 solution (3.95 mL, 7.89 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.107 g, 0.132 mmol) in 1,4-dioxane (6 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 35% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester (0.6912 g, 90%) as an off-white solid.
Figure imgf000330_0001
[0782] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}furan-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.0679 g, 0.215 mmol), N,N-diisopropylethylamine (0.129 g, 0.173 mL, 1.03 mmol), and N-[(dimethylamino)-1H- 1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0975 g, 0.257 mmol) in dimethylformamide (1.5 mL) in a scintillation vial at 20 oC under N2 was stirred for 20 minutes, before adding 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0600 g, 0.205 mmol) and stirring at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded tert-butyl 4-[4- (4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}furan-2-amido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0676 g, 58%) as an off-white solid.
Figure imgf000330_0002
 
[0783] Step 3: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [3-fluoro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}furan-2-amido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0676 g, 0.119 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [3-fluoro-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0797 g, quantitative) as a flocculent, off-white solid.
Figure imgf000331_0001
[0784] Step 4: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl iminomethyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 4-(1,2,3,6- tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- amide trifluoroacetate (0.0743 g, 0.125 mmol) and N,N-diisopropylethylamine (0.113 g, 0.152 mL, 0.873 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.116 g, 0.374 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0375 g, 0.0415 mL, 0.374 mmol) was added, and the reaction was stirred for four hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {[4-(5-{4- [1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3- fluoro-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (0.0762 g, 72%) as a white solid.
Figure imgf000331_0002
 
[0785] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]furan-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0762 g, 0.0894 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-3-fluorophenyl]furan-2- carboxamide trifluoroacetate (0.0640 g, quantitative) as a flocculent, off-white solid.1H NMR (DMSO-d6) δ: 10.50 (s, 1H), 8.10 (s, 1H), 7.72 (dd, J=14.0, 2.0 Hz, 1H), 7.63 (s, 1H), 7.57 (dd, J=8.7, 2.1 Hz, 1H), 7.45 (br s, 8H), 7.33-7.41 (m, 1H), 6.20 (s, 1H), 6.02 (s, 1H), 4.05 (br s, 4H), 3.59 (br t, J=5.3 Hz, 4H), 2.54 (br s, 2H), 2.48 (br s, 2H).19F NMR (DMSO-d6) δ: -73.86 (s, 1F), -113.98--113.82 (m, 1F). LC/MS (M + H)+ = 452. [0786] Example 19: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl]- 4-(4-carbamimidoylpiperazin-1-yl)thiophene-2-carboxamide trifluoroacetate.
Figure imgf000332_0001
[0787] Step 1: Synthesis of 4-bromo-thiophene-2-carboxylic acid methyl ester: To a solution of 4- bromo-thiophene-2-carboxylic acid (0.500 g, 2.42 mmol) in methanol (12 mL) in a small pressure tube in a bath of cool tap water under N2 was added concentrated H2SO4 (0.600 mL, 10.8 mmol) dropwise. The mixture was stirred at 20 oC for 3 days. LC-MS analysis showed only a small amount of the desired product. The reaction was heated at 60 °C for 18 hours. After cooling to 0 °C, the mixture was carefully quenched with cold (0 °C) saturated NaHCO3 solution (~40 mL), then extracted with three portions (80, 25, and 25 mL) of dichloromethane. The organic layers were combined and washed with saturated NaHCO3 solution (20 mL), then brine, then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield 4-bromo- thiophene-2-carboxylic acid methyl ester (0.4749 g, 89%) as a clear, yellowish oil.
Figure imgf000332_0002
[0788] Step 2: Synthesis of 4-(5-methoxycarbonyl-thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester: A suspension of 4-bromo-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.905 mmol)  
and Cs2CO3 (0.590 g, 1.81 mmol) in anhydrous toluene (6 mL) in a scintillation vial was degassed by bubbling nitrogen through the mixture for several minutes. Piperazine-1-carboxylic acid tert-butyl ester (0.337 g, 1.81 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (0.0422 g, 0.0905 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.0828 g, 0.0905 mmol) were added, the suspension was degassed for two more minutes, then heated at 95 °C for 18 hours. The mixture was partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min.). The good fractions were partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (30 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield 4-(5-methoxycarbonyl-thiophen-3-yl)-piperazine-1-carboxylic acid tert- butyl ester (0.1844 g, 62%) as a brown oil.
Figure imgf000333_0001
[0789] Step 3: Synthesis of sodium 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-thiophene-2- carboxylate: To a solution of 4-(5-methoxycarbonyl-thiophen-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.1805 g, 0.553 mmol) in a mixture of methanol (1.4 mL) and tetrahydrofuran (1.4 mL) at 20 oC under N2 was added 6 N NaOH solution (0.0968 mL, 0.581 mmol) dropwise. The mixture was stirred at 20 oC for 18 hours. LC-MS analysis still showed a small amount of starting material. The reaction was heated at 50 °C for several hours and progressed very slowly. Added 10 µL of 6 N NaOH, then continued heating at 50 °C for 18 hours. The mixture was concentrated. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield sodium 4-(4-tert-butoxycarbonyl-piperazin-1-yl)- thiophene-2-carboxylate (0.1841 g, 100%) as a flocculent, brownish solid.
Figure imgf000333_0002
[0790] Step 4: Synthesis of 4-{5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenylcarbamoyl]-thiophen-3-yl}-piperazine-1-carboxylic acid tert-butyl ester: A mixture of sodium 4-(4- tert-butoxycarbonyl-piperazin-1-yl)-thiophene-2-carboxylate (0.0804 g, 0.241 mmol), N,N- diisopropylethylamine (0.130 g, 0.175 mL, 1.00 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-  
[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0991 g, 0.261 mmol) in N,N-dimethylformamide (1.5 mL) in a scintillation vial at 20 oC under N2 was stirred for 15 minutes, before adding 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0550 g, 0.200 mmol) and stirring at 20 oC over the weekend. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 40% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded 4-{5-[4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl carbamoyl]-thiophen-3-yl}-piperazine-1- carboxylic acid tert-butyl ester (0.1047 g, 92%) as a clear, yellowish oil.
Figure imgf000334_0001
[0791] Step 5: Synthesis of 4-piperazin-1-yl-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of 4-{5-[4-(1-tert-butoxycarbonyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenylcarbamoyl]-thiophen-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.102 g, 0.179 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized. Due to retention of excess TFA, the lyophilization was repeated to yield 4-piperazin-1-yl-thiophene-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0914 g, 72%) as a tan solid.
Figure imgf000334_0002
[0792] Step 6: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-thiophen-3-yl)-piperazin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 4-piperazin-1-yl-thiophene- 2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0848 g, 0.119 mmol) and N,N-diisopropylethylamine (0.154 g, 0.208 mL, 1.19 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1- yl)methyl]carbamate (0.111 g, 0.358 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0359 g, 0.0397 mL, 0.358 mmol) was  
added, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NaHCO3 solution (20 mL) and separated. The organic layer was washed with water (2 x 15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes) yielded an impure, off-white solid, which was further purified by reverse- phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min.). The good fractions were partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (30 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-thiophen-3-yl)-piperazin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0374 g, 37%) as a tan solid.
Figure imgf000335_0001
[0793] Step 7: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-4- (4- carbamimidoylpiperazin-1-yl)thiophene-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[1- (tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]- phenylcarbamoyl}-thiophen-3-yl)-piperazin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert- butyl ester (0.0374 g, 0.0438 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)phenyl]-4-(4- carbamimidoylpiperazin-1-yl)thiophene-2-carboxamide trifluoroacetate (0.0333 g, 96%) as a flocculent, tan solid.1H NMR (DMSO-d6) δ: 10.16 (s, 1H), 7.91 (d, J=1.7 Hz, 1H), 7.67-7.73 (m, J=8.7 Hz, 2H), 7.51 (br s, 4H), 7.45-7.49 (m, J=8.8 Hz, 2H), 7.44 (br s, 4H), 6.81 (d, J=1.6 Hz, 1H), 6.12-6.23 (m, 1H), 4.06 (br d, J=3.5 Hz, 2H), 3.54-3.64 (m, 6H), 3.10-3.18 (m, 4H), 2.53-2.62 (m, 2H). LC/MS (M + H)+ = 453. [0794] Example 20: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide trifluoroacetate.  
Figure imgf000336_0001
[0795] Step 1: Synthesis of 4-(5-methoxycarbonyl-1-methyl-1H-pyrrol-3-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester: A mixture of 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (0.250 g, 1.15 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-1(2H)-carboxylate (0.390 g, 1.26 mmol), 2 M Na2CO3 solution (1.72 mL, 3.44 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0937 g, 0.115 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours. The mixture was partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 25% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-(5-methoxycarbonyl-1-methyl-1H-pyrrol-3-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.1630 g, 44%) as a clear, yellowish oil.
Figure imgf000336_0002
[0796] Step 2: Synthesis of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1- methyl-1H-pyrrole-2-carboxylate: To a solution of 4-(5-methoxycarbonyl-1-methyl-1H-pyrrol-3-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.160 g, 0.499 mmol) in a mixture of methanol (1.25 mL) and tetrahydrofuran (1.25 mL) at 20 oC under N2 was added 6 N NaOH solution (0.0874 mL, 0.524 mmol) dropwise. The mixture was stirred at 20 oC for 18 hours. LC-MS analysis showed primarily the starting material. The reaction was heated at 50 °C for four hours and progressed very slowly. The temperature was increased to 60 °C, and heating was continued for 18 hours. LC-MS analysis still showed a small amount of possible starting material. Added 10 µL of 6 N NaOH, then continued heating at 60 °C for four hours. The mixture was concentrated, then dried under vacuum to yield sodium 4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxylate (0.1603 g, 98%) as an off-white solid.
Figure imgf000336_0003
 
[0797] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-1-methyl-1H-pyrrole-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxylate (0.0790 g, 0.241 mmol), N,N-diisoproylethylamine (0.130 g, 0.175 mL, 1.00 mmol), and N- [(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexa fluorophosphate N-oxide (0.0991 g, 0.261 mmol) in N,N-dimethylformamide (1.5 mL) in a scintillation vial at 20 oC under N2 was stirred for 20 minutes, before adding 4-(4-amino-phenyl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (0.0550 g, 0.200 mmol) and stirring at 20 oC for 18 hours. The reaction mixture was injected directly onto the column and purified by reverse-phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}- 1-methyl-1H-pyrrole-2-amido)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0727 g, 65%) as an off- white foam.
Figure imgf000337_0001
[0798] Step 4: Synthesis of 1-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4-[4-(4- {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1-methyl-1H-pyrrole-2- amido)phenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (0.0727 g, 0.129 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise, which immediately caused the mixture to become darker in color. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 1-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid [4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0759 g, 100%) as a flocculent, light brown solid.  
Figure imgf000338_0001
[0799] Step 5: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-1-methyl-1H-pyrrol-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 1-methyl- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid [4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-amide trifluoroacetate (0.0697 g, 0.118 mmol) and N,N-diisopropylethylamine (0.107 g, 0.144 mL, 0.826 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.110 g, 0.354 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0355 g, 0.0393 mL, 0.354 mmol) was added, and the reaction was stirred for four hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with saturated NaHCO3 solution (15 mL), water (2 x 15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes) yielded an impure, off-white solid, which was further purified by reverse-phase chromatography (Silicycle SiliaSep C18; 12 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 15 min.). The good fractions were partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (30 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-1-methyl-1H-pyrrol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0532 g, 45%) as an off-white solid.
Figure imgf000338_0002
[0800] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-1-methyl-1H-pyrrol-3-yl)-3,6-dihydro-2H-  
pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0451 g, 0.0532 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for four hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-methyl- 1H-pyrrole-2-carboxamide trifluoroacetate (0.0369 g, quantitative) as a flocculent, off-white solid. 1H NMR (DMSO-d6) δ: 9.86 (s, 1H), 7.66-7.75 (m, J=8.7 Hz, 2H), 7.35-7.50 (m, 10H), 7.19 (s, 2H), 6.09-6.21 (m, 1H), 5.82-5.95 (m, 1H), 4.04-4.10 (m, 2H), 3.97-4.03 (m, 2H), 3.84 (s, 3H), 3.54-3.64 (m, 4H), 2.53- 2.61 (m, 2H), 2.39-2.47 (m, 2H). LC/MS (M + H)+ = 447. [0801] Example 21: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (4- carbamimidoylpiperazin-1-yl)phenyl]furan-2-carboxamide trifluoroacetate.
Figure imgf000339_0001
[0802] Step 1: Synthesis of 4-(4-{[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- furan-2-carbonyl]-amino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester: A mixture of sodium 4-(1- tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.0688 g, 0.218 mmol), N,N- diisopropylethylamine (0.128 g, 0.173 mL, 0.991 mmol), and N-[(dimethylamino) -1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0980 g, 0.258 mmol) in N,N-dimethylformamide (1.5 mL) in a scintillation vial at 20 oC under N2 was stirred for 20 minutes, before adding 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.0550 g, 0.198 mmol) and stirring at 20 oC for 18 hours. The reaction mixture was injected directly onto the column and purified by reverse-phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield 4-(4-{[4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carbonyl]-amino}-phenyl)-piperazine-1- carboxylic acid tert-butyl ester (0.0836 g, 76%) as an off-white solid.
Figure imgf000339_0002
 
[0803] Step 2: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid (4- piperazin-1-yl-phenyl)-amide trifluoroacetate: To a solution of 4-(4-{[4-(1-tert-butoxycarbonyl-1,2,3,6- tetrahydro-pyridin-4-yl)-furan-2-carbonyl]-amino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.0836 g, 0.151 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise, which immediately caused the mixture to become darker in color. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized. Due to retention of excess trifluoroacetic acid, the lyophilization procedure was repeated to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide trifluoroacetate (0.0915 g, 87%) as a flocculent, tan solid.
Figure imgf000340_0001
[0804] Step 3: Synthesis of {[4-(5-{4-[4-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-piperazin-1-yl]-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 4-(1,2,3,6-tetrahydro- pyridin-4-yl)-furan-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide trifluoroacetate (0.0866 g, 0.125 mmol) and N,N-diisopropylethylamine (0.129 g, 0.174 mL, 0.998 mmol) in N,N-dimethylformamide (1.5 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1- yl)methyl]carbamate (0.116 g, 0.374 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0375 g, 0.0415 mL, 0.374 mmol) was added, and the reaction was stirred for two hours. The reaction mixture was injected directly onto the column and purified by reverse-phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 100% acetonitrile – 95 to 0% water (both with 0.1% formic acid) over 25 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield {[4-(5-{4-[4-(tert- Butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-phenylcarbamoyl}-furan-3-yl)- 3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0929 g, 89%) as a tan solid.  
Figure imgf000341_0001
[0805] Step 3: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(4- carbamimidoylpiperazin-1-yl)phenyl]furan-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[4- (tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-phenylcarbamoyl}-furan-3- yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0929 g, 0.111 mmol) in dichloromethane (2.5 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- N-[4-(4-carbamimidoylpiperazin-1-yl)phenyl]furan-2- carboxamide trifluoroacetate (0.0765 g, 89%) as a flocculent, off-white solid.1H NMR (300MHz, DMSO- d6) δ = 10.09 (s, 1H), 8.03 (s, 1H), 7.64 - 7.57 (m, J=9.1 Hz, 2H), 7.54 (d, J=1.0 Hz, 1H), 7.48 (br d, J=6.4 Hz, 8H), 7.00 - 6.92 (m, J=9.2 Hz, 2H), 6.24 - 6.10 (m, 1H), 4.04 (br d, J=3.4 Hz, 2H), 3.61 - 3.54 (m, 6H), 3.16 (br t, J=5.1 Hz, 4H), 2.47 - 2.43 (m, 2H). LC/MS (M + H)+ = 437. [0806] Example 22: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]-1-methyl-1H-pyrrole-2-carboxamide trifluoroacetate.
Figure imgf000341_0002
[0807] Step 1: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-1-methyl-1H-pyrrole-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1 -carboxylate: A mixture of sodium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-pyrrole-2- carboxylate (0.0741 g, 0.226 mmol), N,N-diisopropylethylamine (0.133 g, 0.179 mL, 1.03 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene] -N-methylmethanaminium hexafluorophosphate N-oxide (0.101 g, 0.267 mmol) in N,N-dimethyl formamide (2 mL) in a scintillation vial at 20 oC under N2 was stirred for 15 minutes, before adding 4-(4-amino-2-fluoro-phenyl)-3,6-dihydro- 2H-pyridine-1-carboxylic acid tert-butyl ester (0.0600 g, 0.205 mmol) and stirring at 20 oC over the weekend. LC-MS analysis appeared to show some desired product and several impurities. The reaction mixture was injected directly onto a Silicycle SiliaSep C18 40-gram column and eluted with 5 to 95%  
acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min. Separation was poor, and fractions containing the desired product were not very pure (these were concentrated and set aside). Closer analysis of other fractions showed that the two major components appeared to be the unreacted aniline starting material and the N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide adduct of the carboxylate starting material (neither of which appeared to ionize well). These fractions were combined and concentrated. The residue was dissolved in dimethylformamide (2 mL). After adding N,N-diisopropylethylamine (0.179 mL, 1.03 mmol), the mixture was stirred at 20 oC for 18 hours. This time, LC-MS analysis showed primarily the desired product, but also some possible unreacted starting materials. Heating the reaction to 50 °C and adding additional N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide both resulted in no obvious change to the reaction mixture. The reaction mixture was combined with the earlier impure desired product, injected directly onto a (new) Silicycle SiliaSep C1840-gram column, and eluted with 5 to 100% acetonitrile – 95 to 0% water (both with 0.1% formic acid) over 25 min. The good fractions were combined, concentrated, and dried under vacuum to yield tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1- methyl-1H-pyrrole-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0466 g, 39%) as an off-white solid.
Figure imgf000342_0001
[0808] Step 2: Synthesis of 1-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert- butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1-methyl-1H -pyrrole-2-amido)- 2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (0.0466 g, 0.0802 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 1-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H- pyrrole-2-carboxylic acid [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0518 g, quantitative) as a flocculent, yellow solid.
Figure imgf000342_0002
 
[0809] Step 3: Synthesis of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy)carbonyl] amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1-methyl-1H-pyrrole-2- amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert-butoxy)carbonyl]imino})methyl] carbamate: To a solution of 1-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid [3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0490 g, 0.0805 mmol) and N,N-diisoproylethylamine (0.0729 g, 0.0982 mL, 0.564 mmol) in N,N-dimethyl formamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1- yl)methyl]carbamate (0.0750 g, 0.242 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0484 g, 0.0536 mL, 0.483 mmol) was added, and the reaction was stirred for two hours. The reaction mixture was injected directly onto a Silicycle SiliaSep C1840 gram column, and eluted with 5 to 100% acetonitrile – 95 to 0% water (both with 0.1% formic acid) over 25 min. The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (25 mL) and separated. The aqueous layer was re-extracted with dichloromethane (35 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1- methyl-1H-pyrrole-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0314 g, 45%) as a tan solid.
Figure imgf000343_0001
[0810] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]-1-methyl-1H-pyrrole-2-carboxamide trifluoroacetate: To a solution of tert-butyl N-[(Z)-{4-[4-(4-{1-[(Z)-{[(tert-butoxy) carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1-methyl-1H- pyrrole-2-amido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl}({[(tert- butoxy)carbonyl]imino})methyl]carbamate (0.0314 g, 0.0363 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl]-1-methyl-1H-pyrrole-2- carboxamide  
trifluoroacetate (0.0253 g, quantitative) as a flocculent, off-white solid.1H NMR (300MHz, DMSO-d6) δ = 10.02 (s, 1H), 7.69 (dd, J=2.1, 14.3 Hz, 1H), 7.51 - 7.38 (m, 9H), 7.38 - 7.31 (m, 1H), 7.24 - 7.18 (m, J=1.9, 1.9, 1.9 Hz, 2H), 6.07 - 5.95 (m, 1H), 5.94 - 5.84 (m, 1H), 4.10 - 4.04 (m, J=3.2 Hz, 2H), 4.03 - 3.98 (m, 2H), 3.84 (s, 3H), 3.63 - 3.54 (m, 4H), 2.57 - 2.51 (m, 2H), 2.47 - 2.38 (m, 2H).19F NMR (282MHz, DMSO- d6) δ = -73.56 (s, 1F), -113.98 - -114.14 (m, 1F). LC/MS (M + H)+ = 465. [0811] Example 23: Synthesis of N-{1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4'-bipyridin]- 6- yl}-4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide trifluoroacetate.
Figure imgf000344_0001
[0812] Step 1: Synthesis of lithium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- furan-2-carboxylate: To a solution of 4-(5-methoxycarbonyl-furan-3-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (0.533 g, 1.73 mmol) in a mixture of methanol (2 mL) and tetrahydrofuran (2 mL) at 20 oC under N2 was added 1 N LiOH solution (1.82 mL, 1.82 mmol) dropwise. The mixture was heated at 40 °C for 18 hours. LC-MS analysis still showed a small amount of starting material. Additional 1 N LiOH solution (100 µL) was added, the reaction was heated at 40 °C for six hours, then stirred at 20 oC over the weekend. The mixture was concentrated and dried under vacuum to yield lithium 4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.5058 g, 98%) as an off-white solid.
Figure imgf000344_0002
[0813] Step 2: Synthesis of 6-amino-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert- butyl ester: A mixture of 5-bromo-pyridin-2-ylamine (0.250 g, 1.44 mmol), tert-butyl 5,6-dihydro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.491 g, 1.59 mmol), 2 M Na2CO3 solution (2.17 mL, 4.33 mmol), and 1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), dichloromethane adduct (0.118 g, 0.144 mmol) in 1,4-dioxane (6 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 80 °C for 18 hours, then stirred at 20 oC over the weekend. The mixture was partitioned between 4 : 1 chloroform - isopropanol (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform - isopropanol (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 100% (10% methanol – 90%  
ethyl acetate); 100 to 0% hexanes), followed by concentration and drying under vacuum, yielded 6-amino- 3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (0.3060 g, 77%) as an off-white solid.
Figure imgf000345_0001
[0814] Step 3: Synthesis of 6-{[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2- carbonyl]-amino}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: A mixture of lithium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.0658 g, 0.220 mmol), N,N=diisorpoylethylamine (0.129 g, 0.174 mL, 0.999 mmol), and N-[(dimethylamino)- 1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0987 g, 0.259 mmol) in N,N-dimethylformamide (1.0 mL) in a scintillation vial at 20 oC under N2 was stirred for 15 minutes, before adding 6-amino-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert- butyl ester (0.0550 g, 0.200 mmol) and stirring at 20 oC for 18 hours. LC-MS analysis showed some desired product, but also possible starting materials. The reaction was heated at 50 °C for three hours, but LC-MS analysis still showed possible unreacted aniline. Added additional N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (30 mg), heated at 40 °C for 90 minutes, then stirred at 20 oC for 18 hours. Added additional dimethylformamide (1 mL) for better solubility, heated at 50 °C for six hours, then stirred at 20 oC for 18 hours. The mixture was partitioned between 4 : 1 chloroform – isopropanol (80 mL) and saturated NaHCO3 solution (15 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (40 mL). The organic layers were combined and washed with water (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 6-{[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2- carbonyl]-amino}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (0.0507 g, 46%) as an off-white solid.
Figure imgf000345_0002
[0815] Step 4: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid (1',2',3',6'- tetrahydro-[3,4']bipyridinyl-6-yl)-amide trifluoroacetate: To a solution of 6-{[4-(1-tert-butoxycarbonyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carbonyl]-amino}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'- carboxylic acid tert-butyl ester (0.0507 g, 0.0921 mmol) in dichloromethane (2 mL) at 20 oC under N2 was  
added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid (1',2',3',6'- tetrahydro-[3,4']bipyridinyl-6-yl)-amide trifluoroacetate (0.0731 g, quantitative) as a tan solid.
Figure imgf000346_0001
[0816] Step 5: Synthesis of [(4-{5-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-furan-3-yl}-3,6-dihydro-2H-pyridin-1-yl)- tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: To a suspension of 4-(1,2,3,6-tetrahydro- pyridin-4-yl)-furan-2-carboxylic acid (1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-amide trifluoroacetate (0.0675 g, 0.0975 mmol) and N,N-diisopropylethylamine (0.0882 g, 0.119 mL, 0.682 mmol) in N,N- dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.0908 g, 0.292 mmol). The reaction was stirred at 20 oC for 18 hours. LC-MS analysis showed some desired product, but also some starting material. The suspension was heated at 40 °C for seven hours, then stirred at 20 oC over the weekend. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0586 g, 0.0649 mL, 0.585 mmol) was added, and the reaction was stirred for two hours. The reaction mixture was injected directly onto a reverse- phase column, and elution of the desired product was attempted (Silicycle SiliaSep C18; 40 g column; 5 to 100% acetonitrile – 95 to 0% water (both with 0.1% formic acid) over 25 min.). However, only a small amount of the desired product eluted. The gradient was repeated with 0.1% TFA as buffer, and the desired product eluted (along with some minor impurities). The fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between 4 : 1 chloroform – isopropanol (90 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re- extracted with 4 : 1 chloroform – isopropanol (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. The residue was adsorbed onto Florisil and further purified by silica gel chromatography (0 to 60% ethyl acetate - dichloromethane), followed by concentration and drying under vacuum, to yield [(4-{5-[1'-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-furan-3-yl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (0.0302 g, 31%) as an off-white solid.  
Figure imgf000347_0001
[0817] Step 6: Synthesis of N-{1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl}- 4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide trifluoroacetate: To a solution of [(4- {5-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-ylcarbamoyl]-furan-3-yl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxy carbonylimino- methyl]-carbamic acid tert-butyl ester (0.0252 g, 0.0302 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield N-{1'-carbamimidoyl-1',2',3',6' -tetrahydro-[3,4'-bipyridin]-6-yl}-4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide trifluoroacetate (0.0286 g, 95%) as a flocculent, off-white solid. 1H NMR (300MHz, DMSO-d6) δ = 10.60 (s, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.15 - 8.05 (m, 2H), 7.94 (dd, J=2.5, 8.7 Hz, 1H), 7.85 (s, 1H), 7.46 (br d, J=4.2 Hz, 8H), 6.34 - 6.23 (m, 1H), 6.16 - 6.06 (m, 1H), 4.13 - 4.00 (m, 4H), 3.63 - 3.58 (m, 4H), 2.65 - 2.55 (m, 2H), 2.47 - 2.42 (m, 2H). LC/MS (M + H)+ = 435. [0818] Example 24: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[5- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)thiophen-2-yl]benzamide trifluoroacetate.
Figure imgf000347_0002
[0819] Step 1: Synthesis of N-(5-bromo-thiophen-2-yl)-4-iodo-benzamide: To a solution of N-(5- bromo-thiophen-2-yl)-acetamide (0.125 g, 0.568 mmol) in anhydrous dichloromethane (4.2 mL) at 20 oC under N2 was added N,N-diisopropylethylamine (0.220 g, 0.297 mL, 1.70 mmol), 4-iodo-benzoyl chloride (0.227 g, 0.852 mmol), and DMAP (0.00694 g, 0.0568 mmol). The dark mixture was stirred at 20 oC for 18 hours. LC-MS analysis showed possible desired product and no more of the thiophene starting material. The reaction was quenched with saturated NaHCO3 solution (5 mL) and stirred for five minutes, then partitioned between 4 : 1 chloroform – isopropanol (80 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated to yield a brown oil / solid (0.3776 g). To remove the acetyl protecting group, the compound was dissolved in  
a mixture of methanol (2 mL) and tetrahydrofuran (2 mL) at 20 oC under N2, and 1 N NaOH solution (2.0 mL, 2.0 mmol) was added. The mixture was stirred at 20 oC for two hours. LC-MS analysis showed no obvious change in the reaction mixture, indicating that the acetyl group had probably been removed in the initial reaction. The reaction was concentrated, then partitioned between 4 : 1 chloroform – isopropanol (80 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 25% ethyl acetate - dichloromethane), followed by concentration and drying under vacuum, yielded N-(5-bromo-thiophen-2- yl)-4-iodo-benzamide (0.0922 g, 40%) as a brownish solid.
Figure imgf000348_0001
[0820] Step 2: Synthesis of tert-butyl 4-{4-[(5-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}thiophen-2-yl)carbamoyl]phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate: A solution of N- (5-bromo-thiophen-2-yl)-4-iodo-benzamide (0.0900 g, 0.221 mmol) in 1,4-dioxane (2 mL) in a scintillation vial was degassed by bubbling nitrogen through the mixture for several minutes. Added 2 M Na2CO3 solution (0.551 mL, 1.10 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-1(2H)-carboxylate (0.150 g, 0.485 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0272 g, 0.0662 mmol), and Pd(OAc)2 (0.00495 g, 0.0221 mmol), degassed for 2 – 3 more minutes, then heated at 60 °C for 18 hours. The mixture was partitioned between 4 : 1 chloroform – isopropanol (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (30 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded tert-butyl 4-{4-[(5-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl} thiophen-2-yl)carbamoyl]phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (0.1113 g, 89%) as a red – orange foam.
Figure imgf000348_0002
[0821] Step 3: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1,2,3,6-tetrahydro-pyridin-4- yl)-thiophen-2-yl]-benzamide trifluoroacetate: To a solution of tert-butyl 4-{4-[(5-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}thiophen-2-yl)carbamoyl]phenyl}-1,2,3,6-  
tetrahydropyridine-1-carboxylate (0.108 g, 0.191 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1,2,3,6-tetrahydro-pyridin-4-yl)- thiophen-2-yl]-benzamide trifluoroacetate (0.0897 g, 79%) as an orange – red solid.
Figure imgf000349_0002
[0822] Step 4: Synthesis of {[4-(4-{5-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophen-2-ylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 4-(1,2,3,6-tetrahydro- pyridin-4-yl)-N-[5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophen-2-yl]-benzamide trifluoroacetate (0.0855 g, 0.144 mmol) and N,N-diisopropylethylamine (0.130 g, 0.176 mL, 1.01 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1- yl)methyl]carbamate (0.134 g, 0.432 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0866 g, 0.0959 mL, 0.864 mmol) was added, and the reaction was stirred for two hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 55% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {[4-(4-{5-[1-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-thiophen-2-ylcarbamoyl}-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0525 g, 43%) as a light yellow solid.
Figure imgf000349_0001
[0823] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)thiophen-2-yl]benzamide trifluoroacetate: To a solution of {[4-(4-{5-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4- yl]-thiophen-2-ylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-  
carbamic acid tert-butyl ester (0.0525 g, 0.0618 mmol) in dichloromethane (2.5 mL) at 0 °C under N2 was added trifluoroacetic acid (0.250 mL) dropwise. The reaction was stirred at 0 °C for 90 minutes and warmed to 20 oC for two hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield a flocculent, tan solid. Purification by reverse-phase chromatography (Silicycle SiliaSep C18; 12 g column; 5 to 40% acetonitrile – 95 to 60% water (both with 0.1% TFA) over 15 min.), followed by lyophilization of the good fractions, yielded 4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)thiophen-2-yl]benzamide trifluoroacetate (0.0064 g, 15%) as a flocculent, light yellow solid. 1H NMR (300MHz, DMSO-d6) δ = 11.60 (s, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.67 - 7.62 (m, J=8.1 Hz, 2H), 7.46 (br s, 4H), 7.42 (br s, 4H), 6.94 (d, J=3.9 Hz, 1H), 6.82 (d, J=4.0 Hz, 1H), 6.42 - 6.33 (m, 1H), 6.01 - 5.92 (m, 1H), 4.14 - 4.07 (m, 2H), 4.07 - 4.00 (m, 2H), 3.66 - 3.56 (m, 4H), 2.67 - 2.59 (m, 2H), 2.59 - 2.53 (m, 2H). LC/MS (M + H)+ = 450. [0824] Example 25: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4- (1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]furan-2-carboxamide trifluoroacetate,
Figure imgf000350_0001
[0825] Step 1: Synthesis of 4-(4-amino-2,6-difluoro-phenyl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester: A mixture of 4-bromo-3,5-difluoro-phenylamine (0.250 g, 1.20 mmol), tert- butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.409 g, 1.32 mmol), 2 M Na2CO3 solution (1.80 mL, 3.61 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0981 g, 0.120 mmol) in 1,4-dioxane (6 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was stirred at 20 oC for 18 hours. LC-MS analysis showed primarily the desired product, but also a small amount of the aniline starting material. The reaction was heated at 50 °C for seven hours, then stirred at 20 oC over the weekend. The mixture was partitioned between dichloromethane (90 mL) and saturated NaHCO3 solution (20 mL) and separated. The aqueous layer was re-extracted with dichloromethane (35 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 30% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-(4-amino-2,6-difluoro-phenyl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (0.3036 g, 82%) as an off-white solid.  
Figure imgf000351_0001
[0826] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}furan-2-amido)-2,6-difluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A mixture of lithium 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylate (0.0607 g, 0.203 mmol), N,N-diisoproylethylamine (0.125 g, 0.168 mL, 0.967 mmol), and N-[(dimethylamino)-1H- 1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.0919 g, 0.242 mmol) in dimethylformamide (1.0 mL) in a scintillation vial at 20 oC under N2 was stirred for 15 minutes, before adding 4-(4-amino-2,6-difluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0600 g, 0.193 mmol) and stirring at 20 oC for 18 hours. LC-MS analysis showed a small amount of both starting materials. Added some additional N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (20 mg) and stirred at 20 oC for 3 days. The reaction mixture was injected directly onto a reverse-phase chromatography column (Silicycle SiliaSep C18; 12 g column; 5 to 100% acetonitrile – 95 to 0% water (both with 0.1% formic acid) over 25 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between 4 : 1 chloroform – isopropanol (90 mL) and saturated NaHCO3 solution (30 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (35 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}furan-2-amido)-2,6-difluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (0.0774 g, 69%) as an off-white solid.
Figure imgf000351_0002
[0827] Step 2: Synthesis of 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [3,5- difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate: To a solution of tert-butyl 4- [4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}furan-2-amido)-2,6-difluorophenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (0.0774 g, 0.132 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for two hours, then  
concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [3,5-difluoro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide trifluoroacetate (0.0872 g, quantitative) as a flocculent, tan solid.
Figure imgf000352_0001
[0828] Step 3: Synthesis of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a solution of 4-(1,2,3,6- tetrahydro-pyridin-4-yl)-furan-2-carboxylic acid [3,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- amide trifluoroacetate (0.0819 g, 0.134 mmol) and N,N-diisopropylethylamine (0.121 g, 0.163 mL, 0.935 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl] carbamate (0.124 g, 0.401 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0669 g, 0.0740 mL, 0.668 mmol) was added, and the reaction was stirred for two hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 5% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 50% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {[4-(5-{4- [1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3,5- difluoro-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (0.0825 g, 71%) as a white solid.
Figure imgf000352_0002
[0829] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]furan-2-carboxamide trifluoroacetate: To a solution of {[4-(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-  
tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-furan-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.0825 g, 0.0948 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]furan-2-carboxamide trifluoroacetate (0.0688 g, quantitative) as a white solid.1H NMR (300MHz, DMSO-d6) δ = 10.65 (s, 1H), 8.12 (s, 1H), 7.66 (s, 1H), 7.63 - 7.53 (m, 2H), 7.46 (br s, 8H), 6.27 - 6.16 (m, 1H), 5.96 - 5.86 (m, 1H), 4.11 - 3.99 (m, 4H), 3.59 (br t, J=5.6 Hz, 4H), 2.47 - 2.39 (m, 4H). 19F NMR (282MHz, DMSO-d6) δ = - 73.70 (s, 1F), -112.67 - -112.83 (m, 1F). LC/MS (M + H)+ = 470. [0830] Example 26: Synthesis of 2-(4-carbamimidoyl-piperazin-1-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide hydrochloride.
Figure imgf000353_0001
[0831] Step 1: Synthesis of 4-{5-[4-(2-tert-butoxycarbonylamino-ethyl)-benzoylamino]-thiazol-2- yl}-piperazine-1-carboxylic acid tert-butyl ester: To a solution of {2-[4-(2-bromo-thiazol-5-ylcarbamoyl)- phenyl]-ethyl}-carbamic acid tert-butyl ester (0.0400 g, 0.0938 mmol) in anhydrous tetrahydrofuran (3 mL) in a scintillation vial at 20 oC under N2 was added piperazine-1-carboxylic acid tert-butyl ester (0.0262 g, 0.141 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0300 g, 0.0295 mL, 0.197 mmol). The reaction was heated at 75 °C for 18 hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NaHCO3 solution (15 mL) and separated. The organic layer was washed twice with water (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 60% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded 4-{5-[4-(2-tert- butoxycarbonylamino-ethyl)-benzoylamino]-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.0323 g, 65%) as an off-white solid.
Figure imgf000353_0002
[0832] Step 2: Synthesis of 4-(2-amino-ethyl)-N-(2-piperazin-1-yl-thiazol-5-yl)-benzamide hydrochloride: To a solution of 4-{5-[4-(2-tert-butoxycarbonylamino-ethyl)-benzoylamino]-thiazol-2-yl}- piperazine-1-carboxylic acid tert-butyl ester (0.0323 g, 0.0608 mmol) in dichloromethane (2 mL) at 20 oC  
under N2 was added 4 N HCl – dioxane solution (0.800 mL, 3.20 mmol) dropwise. The reaction was stirred at 20 oC for 48 hours, then concentrated. The residue was dissolved / suspended in dichloromethane, concentrated again, then dried under vacuum to yield 4-(2-amino-ethyl)-N-(2-piperazin-1-yl-thiazol-5-yl)- benzamide hydrochloride (0.0272 g, quantitative) as an off-white solid.
Figure imgf000354_0001
[0833] Step 3: Synthesis of ({4-[4-({2-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-piperazin-1-yl]-thiazole-5-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-tert- butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester: To a solution of 4-(2-amino-ethyl)-N-(2- piperazin-1-yl-thiazol-5-yl)-benzamide hydrochloride (0.0243 g, 0.0601 mmol) and N,N-diisopropylethyl aminde (0.0466 g, 0.0628 mL, 0.361 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.0513 g, 0.165 mmol). The reaction was stirred at 20 oC for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0181 g, 0.0200 mL, 0.180 mmol) was added, and the reaction was stirred for three hours. What was initially thought to be a significant impurity (before addition of the 1- methylpiperazine) was subsequently identified as mono-guanylated thiazole starting material. Added an additional 0.102 g (0.329 mmol) of the pyrazole guanylating reagent, stirred at 20 oC for three hours, then placed the reaction in the refrigerator over the weekend. LC-MS now showed that all of the mono- guanylated material had been converted to the desired product. Additional 1-methylpiperazine (0.040 mL, 0.360 mmol) was then added, and the reaction was stirred at 20 oC for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (20 mL) and separated. The organic layer was washed again with saturated NH4Cl solution (20 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 75% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded ({4-[4-({2-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]- thiazole-5-carbonyl}-amino)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-tert-butoxycarbonylimino-methyl)- carbamic acid tert-butyl ester (0.0286 g, 58%) as an off-white foam.
Figure imgf000354_0002
[0834] Step 4: Synthesis of 2-(4-carbamimidoyl-piperazin-1-yl)-thiazole-5-carboxylic acid [4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide hydrochloride: To a solution of ({4-[4-({2-  
[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-thiazole-5-carbonyl}- amino)-phenyl]-3,6-dihydro-2H-pyridin-1-yl}-tert-butoxycarbonylimino-methyl)-carbamic acid tert-butyl ester (0.0260 g, 0.0319 mmol) in dichloromethane (2 mL) in a bath of cool tap water under N2 was added 4 N HCl – dioxane solution (0.800 mL, 3.20 mmol) dropwise. The reaction was stirred at 20 oC for two hours, then placed in the refrigerator for 18 hours. The reaction was then stirred at 20 oC for three hours— LC-MS analysis still showed some mono-BOC material. The gel-like reaction mixture was stirred at 20 oC for 18 hours, and LC-MS analysis showed only the desired product. The mixture was concentrated. The residue was dissolved / suspended in dichloromethane, concentrated again, then dried under vacuum to yield 2-(4-carbamimidoyl-piperazin-1-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide hydrochloride (0.0193 g, quantitative) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1 H) 8.19 (s, 1 H) 7.52 - 7.93 (m, 8 H) 7.21 (m, J=8.80 Hz, 5 H) 3.60 (s, 8 H) 3.32 (q, J=6.64 Hz, 2 H) 2.72 (br t, J=7.33 Hz, 2 H). LC/MS (M + H)+ = 416. [0835] Example 27: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N- (4-{2- [(Z)-N',N',N''-trimethylcarbamimidamido]ethyl}phenyl)benzamide trifluoroacetate.
Figure imgf000355_0001
[0836] Step 1: Synthesis of {2-[4-(4-iodo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester: To a solution of tert-butyl 4-aminophenethylcarbamate (0.600 g, 2.54 mmol) in anhydrous dichloromethane (12.7 mL) at 0 °C under N2 was added N,N-diisopropylethylamine (0.985 g, 1.33 mL, 7.62 mmol) followed by 4-iodo-benzoyl chloride (0.812 g, 3.05 mmol). An off-white, gelantinous mass formed almost immediately, and additional dichloromethane (12.7 mL) was added to aid mixing. The ice bath was removed after 10 minutes, and the suspension was stirred at 20 oC for 18 hours. The mixture was partitioned between 4 : 1 chloroform – isopropanol (100 mL) and saturated NaHCO3 solution (25 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (50 mL). The organic layers were combined and washed with saturated NaHCO3 solution (25 mL), then brine (15 mL), but not dried or filtered because of the apparent low solubility of the desired product. Concentration and drying under vacuum yielded {2-[4-(4-iodo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.33 g, quantitative) as an off-white solid, which was used without further purification in the next reaction.
Figure imgf000355_0002
 
[0837] Step 2: Synthesis of N-[4-(2-amino-ethyl)-phenyl]-4-iodo-benzamide: To a suspension of {2-[4-(4-iodo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2.54 mmol) in dichloromethane (20 mL) at 0 °C under N2 was added trifluoroacetic acid (5.79 g, 3.89 mL, 50.8 mmol) dropwise. The reaction warmed to 20 oC as it was stirred for 18 hours. The reaction was concentrated without heating. The residue was diluted with water (25 mL) and washed with ether (50 mL). The aqueous layer was diluted with 4 : 1 chloroform – isopropanol (40 mL) and basified to pH ~12 with 6 N NaOH solution. The layers were separated, and the aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (3 x 40 mL). The organic layers were combined and washed with brine, then dried (Na2SO4), filtered, and concentrated to yield N-[4-(2-amino-ethyl)-phenyl]-4-iodo-benzamide (0.75 g, 81% over two steps) as an off-white solid.
Figure imgf000356_0001
[0838] Step 3: Synthesis of 4-iodo-N-{4-[2-(3-methyl-thioureido)-ethyl]-phenyl}-benzamide: To a suspension of N-[4-(2-amino-ethyl)-phenyl]-4-iodo-benzamide (0.300 g, 0.819 mmol) in anhydrous dichloromethane (10 mL) at 20 oC under N2 was added methyl isothiocyanate (0.0899 g, 0.0841 mL, 1.23 mmol) dropwise. The reaction was stirred for 18 hours. LC-MS analysis showed primarily the desired product, but also some amine starting material. Over several hours, added three 0.0841 mL aliquots of methyl isothiocyanate and additional dimethylformamide (10 mL), then heated to 50 °C. A minute amount of starting material still appeared to be present, and some possible minor decomposition was observed. The mixture was concentrated. The residue was suspended in dichloromethane and concentrated again, then suspended in ether (25 mL) and stirred vigorously for 15 minutes. The resulting solid was collected by filtration, washed with ether, then dried under vacuum to yield 4-iodo-N-{4-[2-(3-methyl-thioureido)- ethyl]-phenyl}-benzamide (0.3569 g, 99%) as an off-white solid.
Figure imgf000356_0002
[0839] Step 4: Synthesis of N-{4-[2-(2,3-dimethyl-isothioureido)-ethyl]-phenyl}-4-iodo- benzamide hydroiodide: To a suspension of 4-iodo-N-{4-[2-(3-methyl-thioureido)-ethyl]-phenyl}- benzamide (0.245 g, 0.558 mmol) in a mixture of tetrahydrofuran (2.8 mL) and dichloromethane (2.8 mL) in a scintillation vial at 20 oC under N2 was added iodomethane (0.119 g, 0.0521 mL, 0.837 mmol) dropwise. The reaction was stirred for 18 hours. LC-MS analysis showed primarily the desired product, but also some  
starting material. Additional iodomethane (0.0521 mL) was added, and the reaction was heated to 60 °C for 2.5 hours. The mixture was concentrated. The residue was suspended in dichloromethane and concentrated again, then dried under vacuum to yield N-{4-[2-(2,3-dimethyl-isothioureido)-ethyl]-phenyl}-4-iodo- benzamide hydroiodide (0.3045 g, 94%) as an off-white solid.
Figure imgf000357_0001
[0840] Step 5: Synthesis of 4-iodo-N-(4-{2-[(Z)-N',N',N''-trimethylcarbamimidamido]ethyl} phenyl)benzamide: N-{4-[2-(2,3-dimethyl-isothioureido)-ethyl]-phenyl}-4-iodo-benzamide hydroiodide (0.300 g, 0.516 mmol) was dissolved in 2.0 M solution of dimethylamine in tetrahydrofuran (5.16 mL, 10.3 mmol) in a scintillation vial at 20 oC under N2. As a precipitate began to form, the vial was capped, and the reaction was stirred for 18 hours. LC-MS analysis showed both the desired product and starting material. The mixture was heated at 50 °C for 18 hours. The reaction mixture was partitioned between 4 : 1 chloroform – isopropanol (80 mL) and saturated NaHCO3 solution (15 mL) and separated. The aqueous layer was re-extracted with 4 : 1 chloroform – isopropanol (2 x 20 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse-phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between 4 : 1 chloroform – isopropanol (90 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re- extracted with 4 : 1 chloroform – isopropanol (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield 4-iodo-N-(4- {2-[(Z)-N',N',N''-trimethylcarbamimidamido]ethyl}phenyl)benzamide (0.1306 g, 56%) as an off-white solid.
Figure imgf000357_0002
[0841] Step 6: Synthesis of {tert-butoxycarbonylimino-[4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methyl}-carbamic acid tert-butyl ester: To a suspension of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine hydrochloride (1.00 g, 4.07 mmol) in N,N-dimethylformamide (10 mL) at 0 °C under N2 was added DIPEA (1.58 g, 2.13 mL, 12.2 mmol) dropwise, followed by tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1- yl)methyl]carbamate (1.64 g, 5.29 mmol). The reaction warmed to 20 oC and was stirred for 18 hours. In  
order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.611 g, 0.677 mL, 6.11 mmol) was added, and the reaction was stirred for 30 minutes. The mixture was partitioned between ethyl acetate (300 mL) and saturated NH4Cl solution (30 mL) and separated. The organic layer was washed with 10% KHSO4 solution (30 mL), water (2 x 30 mL), saturated NaHCO3 solution (30 mL), and brine (30 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 100% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded {tert-butoxycarbonylimino-[4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methyl}-carbamic acid tert-butyl ester (1.40 g, 76%) as a white foam.
Figure imgf000358_0001
[0842] Step 7: Synthesis of tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(4- {4-[(4-{2-[(Z)- N',N',N''-trimethylcarbamimidamido]ethyl}phenyl)carbamoyl]phenyl}-1,2,3,6-tetrahydropyridin-1- yl)methyl]carbamate:
Figure imgf000358_0002
mixture of 4-iodo-N-(4-{2-[(Z)-N',N',N''-trimethyl carbamimidamido]ethyl}phenyl)benzamide (0.121 g, 0.269 mmol), {tert-butoxycarbonylimino-[4- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-methyl}-carbamic acid tert- butyl ester (0.146 g, 0.322 mmol), 2 M Na2CO3 solution (0.537 mL, 1.07 mmol), and 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (0.0219 g, 0.0269 mmol) in 1,4-dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for several minutes. The reaction was heated at 40 °C for 18 hours. The mixture was partitioned between 4 : 1 chloroform – isopropanol (80 mL) and saturated NaHCO3 solution (15 mL) and separated. The aqueous layer was re- extracted with 4 : 1 chloroform – isopropanol (2 x 25 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum. The residue was purified by reverse-phase chromatography (Silicycle SiliaSep C18; 40 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 25 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between 4 : 1 chloroform – isopropanol (90 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re- extracted with 4 : 1 chloroform – isopropanol (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum. Further purification by silica gel chromatography (0 to 100% (50% (20 : 1 : 1 EtOH : NH4OH : H2O)) – 50% ethyl acetate); 100 to 0% hexanes), followed by concentration and drying under vacuum, yielded tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(4-{4-[(4-{2-[(Z)-N',N',N''-  
trimethylcarbamimidamido]ethyl}phenyl)carbamoyl]phenyl}-1,2,3,6-tetrahydropyridin-1- yl)methyl]carbamate (0.0236 g, 14%) as an off-white solid.
Figure imgf000359_0001
              [0001] Step 8: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ (4‐{2‐[(Z)‐ N',N',N''‐trimethylcarbamimidamido]ethyl}phenyl)benzamide trifluoroacetate: To a suspension of tert‐ butyl N‐[(Z)‐{[(tert‐butoxy)carbonyl]imino}(4‐{4‐[(4‐{2‐[(Z)‐N',N',N''‐ trimethylcarbamimidamido]ethyl}phenyl)carbamoyl]phenyl}‐1,2,3,6‐tetrahydropyridin‐1‐ yl)methyl]carbamate (0.0227 g, 0.0350 mmol) in dichloromethane (3 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was purified by reverse-phase chromatography (Silicycle SiliaSep C18; 12 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% TFA) over 15 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then lyophilized to yield 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl) ‐N‐(4‐{2‐ [(Z)‐N',N',N''‐trimethylcarbamimidamido]ethyl}phenyl)benzamide trifluoroacetate (0.00947 g, 27%) as an off-white solid.1H NMR (DMSO-d6) δ: 10.22 (s, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.40-7.53 (m, 6H), 7.22 (d, J=8.4 Hz, 2H), 6.32-6.41 (m, 1H), 4.11 (br d, J=3.5 Hz, 2H), 3.64 (br t, J=5.6 Hz, 2H), 2.79-2.85 (m, 8H), 2.69 (d, J=4.6 Hz, 3H), 2.63 (br s, 2H). LC/MS (M + H)+ = 448. [0002] Example 28:: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4 ‐yl)‐N‐{4‐ [2‐(N‐methylcarbamimidamido)ethyl]phenyl}benzamide trifluoroacetate.
Figure imgf000360_0001
o)-ethyl]- phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of 4- (4-carboxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester; sodium salt (0.0936 g, 0.288 mmol), N,N-diisopropylethylamine (0.169 g, 0.228 mL, 1.31 mmol), and N-[(dimethyl amino)- 1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluoro phosphate N- oxide (0.129 g, 0.340 mmol) in N,N-dimethylformamide (1.5 mL) in a 2-dram vial at 20 oC under N2 was stirred for 20 minutes, before adding [2-(4-amino-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (0.0750 g, 0.262 mmol) and stirring at 20 oC for 18 hours. The mixture was diluted with chloroform (3 mL) and saturated NaHCO3 solution (3 mL), then the vial was shaken and let stand for     the layers to separate. The organic layer was removed with a needle and syringe, then injected directly onto a silica gel cartridge. The extraction was repeated with 2 x 2 mL portions of chloroform. Elution with 0 to 50% ethyl acetate - hexanes, followed by concentration and drying under vacuum, yielded 4- (4-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (0.0724 g, 52%) as a clear, colorless oil.
Figure imgf000361_0001
[0004] Step 2: Synthesis of N-[4-(2-methylamino-ethyl)-phenyl]-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide trifluoroacetate: To a solution of 4-(4-{4-[2-(tert-butoxycarbonyl-methyl- amino)-ethyl]-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.0724 g, 0.135 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added 4 N HCl – dioxane solution (0.500 mL, 2.0 mmol) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield N-[4-(2-methylamino-ethyl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide trifluoroacetate (0.0501 g, 91%) as a flocculent, light yellow solid.
Figure imgf000361_0002
[0005] Step 3: Synthesis of tert‐butyl N‐[(Z)‐({2‐[4‐(4‐{1‐[(Z)‐{[(tert‐butoxy)carbonyl] amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐ yl}benzamido)phenyl]ethyl}(methyl)amino)({[(tert‐butoxy)carbonyl]imino})methyl]carbamate: To a solution of N-[4-(2-methylamino-ethyl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide trifluoroacetate (0.0501 g, 0.123 mmol) and N,N-diisopropylethylamine (0.111 g, 0.150 mL, 0.859 mmol) in N,N-dimethylformamide (2 mL) at 20 oC under N2 was added tert-butyl N-[(Z)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.114 g, 0.368 mmol). The reaction was stirred at 20 oC for 18 hours. LC-MS analysis showed the desired product and a significant amount of     mono-guanylated starting material. The mixture was heated at 40 °C for three hours, but still showed some of the intermediate. Additional N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1- yl)methyl]carbamate (0.076 g, 0.245 mmol) was added, and the heating was continued for 18 hours. In order to scavenge unreacted guanylating reagent, 1-methylpiperazine (0.0738 g, 0.0816 mL, 0.736 mmol) was added at 20 oC, and the reaction was stirred for three hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NH4Cl solution (15 mL) and separated. The organic layer was washed with 10% KHSO4 solution (15 mL), water (15 mL), saturated NaHCO3 solution (15 mL), and brine (15 mL), then dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse- phase chromatography (Silicycle SiliaSep C18; 12 g column; 5 to 95% acetonitrile – 95 to 5% water (both with 0.1% formic acid) over 15 min.). The good fractions were combined and partially concentrated (without heating) to remove most of the acetonitrile, then partitioned between dichloromethane (80 mL) and saturated NaHCO3 solution (35 mL) and separated. The aqueous layer was re-extracted with dichloromethane (40 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, concentrated, and dried under vacuum to yield tert‐butylN‐ [(Z)‐({2‐[4‐(4‐{1‐[(Z)‐{[(tert‐butoxy)carbonyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐ 1,2,3,6‐tetrahydropyridin‐4‐yl}benzamido)phenyl]ethyl}(methyl)amino)({[(tert‐ butoxy)carbonyl]imino})methyl]carbamate (0.0221 g, 22%) as a white solid.
Figure imgf000362_0001
[0006] Step 4: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐{4‐[2‐(N‐ methylcarbamimidamido)ethyl]phenyl}benzamide trifluoroacetate: To a solution of tert‐butyl N‐[(Z)‐ ({2‐[4‐(4‐{1‐[(Z)‐{[(tert‐butoxy)carbonyl]amino}({[(tert‐butoxy)carbonyl]imino}) methyl]‐1,2,3,6‐ tetrahydropyridin‐4‐yl}benzamido)phenyl]ethyl}(methyl)amino)({[(tert‐butoxy) carbonyl]imino})methyl]carbamate (0.0221 g, 0.0270 mmol) in dichloromethane (2 mL) at 20 oC under N2 was added trifluoroacetic acid (0.5 mL) dropwise. The reaction was stirred at 20 oC for three hours, then concentrated without heating. The residue was dissolved / suspended in 4 : 1 water – acetonitrile, frozen at -78 °C, then lyophilized to yield 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydro pyridin‐4‐yl)‐N‐{4‐     [2‐(N‐methylcarbamimidamido)ethyl]phenyl}benzamide trifluoroacetate (0.0187 g, quantitative) as a flocculent, white solid. 1H NMR (DMSO-d6) δ: 10.22 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.47 (s, 4H), 7.26 (d, J=8.6 Hz, 2H), 7.21 (s, 4H), 6.37 (t, J=3.0 Hz, 1H), 4.11 (br d, J=3.5 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 3.50-3.56 (m, 3H), 2.88 (s, 2H), 2.79 (br t, J=7.4 Hz, 2H), 2.63 (br s, 2H). LC/MS (M + H)+ = 420. [0007] Example 29: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ [4‐ (1‐ carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)phenyl]benzamide: Br
Figure imgf000363_0001
[0008] Step 1: Synthesis of 4-bromo-N-(4-bromophenyl)benzamide: A solution of 4- bromobenzoic acid (1.0 g, 5.0 mmol), 4-bromoaniline (0.89 g, 5.2 mmol) and N,N- diisopropylethylamine (0.65 g, 5.0 mmol, 0.90 ml) in N,N-dimethylformamide (10 ml) was treated with N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (1.9 g, 5.0 mmol) and the mixture stirred for 20 hours. The reaction mixture was diluted with water (10 ml) and stirred for 5 minutes. The precipitate was filtered, washed with water and dried under vacuum to leave a beige powder (1.6 g, 92%).1H-NMR (DMSO-d6) ^ 10.4 (bs, 1H), 7.80 (d, 2H, J = 8.5 Hz), 7.73 (d, 2H, J = 8.5 Hz, 7.72 (d, J = 8.8 Hz), 7.52 (d, 2H, J = 8.8 Hz). LC/MS Rt = 5.66 min., purity > 95%, (M+H)+ = 356.
Figure imgf000363_0002
[0009] Step 2: Synthesis of 4‐(1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐(1,2,3,6‐tetrahydropyridin ‐4‐yl)phenyl]benzamide: A mixture of 4-bromo-N-(4-bromophenyl)benzamide (100 mg, 0.28 mmol), tert‐butyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1,2,3,6‐tetrahydropyridine‐1‐carboxylate (261 mg, 0.85 mmol), dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl) phosphine (8 mg, 20 ^mol), Palladium acetate (4.5 mg, 20 ^mol), potassium carbonate (306 mg, 2.2 mmol), water (0.8 ml) and 1,4- dioxane (2 ml) was purged with nitrogen, stirred and heated to 90 oC for 20 hours. The mixture was     diluted with dichloromethane (20 ml) and water (20 ml) and the aqueous layer was extracted with dichloromethane (20 ml). The combined dichloromethane layers were dried (Na2SO4) and evaporated. The crude product mixture was purified by reversed phase HPLC and the combined product fractions were treated with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (2 X 20 ml), combined, dried (Na2SO4) and evaporated in vacuo to leave a white solid that was dissolved in trifluoroacetic acid and dichloromethane (1:1, 2 ml), allowed to stand for 18 h then evaporated and lyophilized to leave a beige solid bistrifluoroacetate salt (171 mg, 100%).1H-NMR (CD3OD) ^ 7.97 (d, 2H, J = 8.5 Hz), 7.74 (d, 2H, J = 8.8 Hz), 7.64 (d, 2H, J = 8.5 Hz), 7.50 (d, 2H, J = 8.8 Hz), 6.32 (m, 1H), 6.17 (m, 1H), 4.3 (m, 2H), 3.50 (m, 2H), 2.82 (m, 2H). LC/MS Rt = 6.51 min., purity > 95%, (M+H)+ = 356.
Figure imgf000364_0001
[0010] Step 3: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐(1‐ carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)phenyl]benzamide: A solution of 4‐(1,2,3,6‐ tetrahydropyridin‐4‐yl)‐N‐[4‐(1,2,3,6‐tetrahydropyridin‐4‐yl)phenyl]benzamide (85 mg, 0.14 mmol), N-((N’, N”-bis-tert-butyloxycarbonyl)amidino)pyrrazole (135 mg, 0.43 mmol) and N,N- (diisopropyl)ethylamine (181 mg, 1.4 mmol, 251 ^l) in methanol (2.5 ml) was stirred for 18 hours then purified by reverse phase HPLC and the combined product fractions were lyophilized to leave a white solid (76 mg). The product was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and stirred for 3 hours. The solvents were evaporated and the product was lyophilized to leave a white solid (67 mg, 71% for two steps). 1H-NMR (CD3OD) ^ 7.95 (d, 2H, J = 8.5 Hz), 7.72 (d, 2H, J = 8.5 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.48 (d, 2H, J = 8.8 Hz), 6.30 (m, 1H), 6.15 (m, 1H), 4.15 (m, 4H), 3.71 (m, 4H), 2.82 (m, 4H). LC/MS Rt = 2.81 min., purity > 95%, (M+H)+ = 444. [0011] Example 30:: Synthesis of Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin ‐4‐yl)‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)phenyl]‐N‐methylbenzamide.    
Figure imgf000365_0001
[0012] Step 1: Synthesis of 4‐bromo‐N‐(4‐bromophenyl)‐N‐methylbenzamide: A solution of 4-bromobenzoic acid (0.26 g, 2.6 mmol), 4-bromo-N-methylaniline (0.50 g, 2.7 mmol, 0.34 ml) and N,N-diisopropylethylamine (0.34 g, 2.6 mmol, 0.47 ml) in N,N-dimethylformamide (6 ml) was treated with N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl methanaminium hexafluorophosphate N-oxide (0.99 g, 2.6 mmol) and the mixture stirred for 20 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (2 X 30 ml). The organic extracts were washed with water (2 X 50 ml), 1N HCl (50 ml) and brine (20 ml). The mixture was dried (MgSO4) and evaporated and the crude product was purified by chromatography on silica gel eluted with a gradient of 25% methylene chloride in hexanes to 100% methylene chloride to leave the pure product as a gum (0.61 g, 64%).1H-NMR (DMSO-d6) ^ 7.44 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.5 Hz), 7.18 (d, 2H, J = 8.5 Hz), 7.15 (d, 2H, J = 8.8 Hz), 3.29 (s, 3H). LC/MS Rt = 5.49 min., purity > 95%, (M+H)+ = 370. B
Figure imgf000365_0002
[0013] Step 2: Synthesis of N‐methyl‐4‐(1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐(1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]benzamide: A mixture of 4-Bromo-N-(4-bromophenyl)-N-methyl benzamide (100 mg, 0.27 mmol), tert‐butyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1,2,3,6‐ tetrahydropyridine‐1‐carboxylate (251 mg, 0.81 mmol), dicyclohexyl(2’, 6’-dimethoxybiphenyl-2-yl) phosphine (8 mg, 20 ^mol), Palladium acetate (4.5 mg, 20 ^mol), potassium carbonate (306 mg, 2.2 mmol), water (0.8 ml) and 1,4-dioxane (2 ml) was purged with nitrogen, stirred and heated to 90 oC for 20 hours. The mixture was diluted with dichloromethane (20 ml) and water (20 ml) and the aqueous layer was extracted with dichloromethane (20 ml). The combined dichloromethane layers were dried (Na2SO4) and evaporated. The crude product mixture was purified by reversed phase PHPLC and the combined product fractions were treated with saturated sodium bicarbonate solution. The product was     extracted with methylene chloride (2 X 20 ml), combined, dried (Na2SO4) and evaporated in vacuo to leave a white solid that was dissolved in trifluoroacetic acid and methylene chloride (1:1, 2 ml), allowed to stand for 18 hours then evaporated and lyophilized to leave a beige solid bistrifluoroacetate salt (172 mg, 100%).1H-NMR (CD3OD) ^ 7.40 (d, 2H, J = 8.8 Hz), 7.35 (s, 4H), 7.18 (d, 2H, J = 8.8 Hz), 6.17 (m, 2H), 3.81 (m, 4H), 3.44 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H). LC/MS Rt = 2.45 min., purity > 95%, (M+H)+ = 374.
Figure imgf000366_0001
[0014] Step 3: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐(1‐ carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)phenyl]‐N‐methylbenzamide: A solution of N‐methyl‐ 4‐(1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐(1,2,3,6‐tetrahydropyridin‐4‐yl)phenyl]benzamide (85 mg, 0.14 mmol), N-((N’, N”-bis-tert-butyloxycarbonyl)amidino)pyrrazole (132 mg, 0.42 mmol) and N,N- (diisopropyl)ethylamine (181 mg, 1.4 mmol, 251 ^l) in methanol (2.5 ml) was stirred for 18 hours then purified by reverse phase HPLC and the combined product fractions were lyophilized to leave a white solid (72 mg). The product was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and stirred for 2 hours. The solvents were evaporated and the product was lyophilized to leave a white solid (48 mg, 59% for two steps).1H-NMR (CD3OD) ^ 7.38 (d, 2H, J = 8.5 Hz), 7.33 (s, 4H), 7.15 (d, 2H, J = 8.5 Hz), 6.15 (m, 2H), 4.09 (m, 4H), 3.65 (m, 4H), 3.45 (s, 3H), 2.62 (m, 4H). LC/MS Rt = 2.81 min., purity > 95%, (M+H)+ = 458. [0015] Example 31: Synthesis of 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]‐N‐methylbenzamide    
Figure imgf000367_0001
[0016] Step 1: Synthesis of N‐methyl‐4‐(piperazin‐1‐yl)‐N‐[4‐(piperazin‐1‐yl)phenyl] benzamide: A mixture of 4-bromo-N-(4-bromophenyl)-N-methylbenzamide (100 mg, 0.27 mmol), N- (tert-butyloxcarbonyl)piperazine (150 mg, 0.81 mmol), dicyclohexyl(2’,6’-dimethoxybiphenyl-2-yl) phosphine (8.6 mg, 21 ^mol), bispalladium-tri(1,3-dibenzylidene) acetone (6.4 mg, 7.0 ^mol), sodium tert-butoxide (81 mg, 0.84 mmol) and toluene (2 ml) was purged with nitrogen, stirred and heated to 100 oC for 18 hours. The reaction mixture was cooled to 20 oC, diluted with water (25 ml) and extracted with dichloromethane (2 X 25 ml). The combined extracts were dried (MgSO4) and evaporated to leave a crude product which was purified by reverse phase HPLC. The combined product fractions were treated with sodium bicarbonate solution and extracted with dichloromethane (2 X 40 ml), dried (Na2SO4) and evaporated to a gum which was dissolved in trifluoroacetic acid (1 ml) and dichloromethane (1 ml) and stood for 18 hours. The solvents were evaporated and the product was lyophilized to leave the white powdery product as a bistrifluoroacetate salt (15 mg, 95% overall).1H- NMR (CD3OD) ^ 7.26 (d, 2H, J = 9.1 Hz), 7.06 (d, 2H, J = 8.8 Hz), 6.93 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 9.1 Hz), 3.41 (s, 3H), 3.39 (m, 8H). LC/MS Rt = 2.28 min., purity > 95%, (M+H)+ = 380.
Figure imgf000367_0002
[0017] Step 2: Synthesis of 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]‐N‐methylbenzamide: A solution of N‐methyl‐4‐(piperazin‐1‐yl)‐ N‐[4‐ (piperazin‐1‐yl)phenyl]benzamide (77 mg, 0.13 mmol), N-((N’, N”-bis-tert-butyloxycarbonyl) amidino)pyrrazole (118 mg, 0.38 mmol) and N,N-(diisopropyl)ethylamine (168 mg, 1.3 mmol, 233 ^l) in methanol (2.5 ml) was stirred for 18 hours then purified by reverse phase HPLC and the     combinedproduct fractions were lyophilized to leave a white solid. The product was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and stirred for 2 hours. The solvents were evaporated and the product was lyophilized to leave a white solid (61 mg, 68% for two steps).1H-NMR (CD3OD) ^ 7.24 (d, 2H, J = 8.8 Hz), 7.04 (d, 2H, J = 9.1 Hz), 6.88 (d, 2H, J = 8.8 Hz), 6.76 (d, 2H, J = 8.8 Hz), 3.60 (m, 4H), 3.39 (s, 3H), 3.25 (m, 4H). LC/MS Rt = 2.55 min., purity > 95%, (M+H)+ = 464. [0018] Example 32: Synthesis of 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]benzamide
Figure imgf000368_0001
[0019] Step 1: Synthesis of N‐methyl‐4‐(piperidin‐4‐yl)‐N‐[4‐(piperidin‐4‐yl)phenyl] benzamide: A solution of 4‐(1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐(1,2,3,6‐tetrahydropyridin‐4‐yl) phenyl]benzamide (50 mg, 87 ^mol) in methanol (2 ml) was hydrogenated at 1 atmosphere hydrogen pressure over platimun on carbon (15 mg) for 3 hours. The catalyst was filtered and washed (MeOH) and the filtrate was evaporated to leave a white solid (47 mg, 94%).1H-NMR (CD3OD) ^ 7.93 (d, 2H, J = 8.8 Hz), 7.66 (d, 2H, J = 9.1 Hz), 7.42 (d, 2H, J = 8.8 Hz), 7.28 (d, 2H, J = 8.8 Hz), 3.50 (m, 4H), 3.10 (m, 6H), 2.0 (m, 8H). LC/MS Rt = 2.42 min., purity > 95%, (M+H)+ = 364.
Figure imgf000368_0002
[0020] Step 2: Synthesis of 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]benzamide: A solution of N‐methyl‐4‐(piperidin‐4‐yl)‐N‐[4‐ (piperidin‐4‐ yl)phenyl]benzamide (41 mg, 69 ^mol), N-((N’, N”-bis-tert-butyloxycarbonyl)amidino) pyrrazole (65 mg, 0.21 mmol) and N,N-(diisopropyl)ethylamine (89 mg, 0.69 mmol, 124 ^l) in methanol (1 ml) was stirred for 18 hours then purified by reverse phase HPLC and the combined product fractions were     neutralized with sodium bicarbonate solution, extracted with dichloromethane (2 X), dried (Na2SO4) and evaporated to leave a white solid. The product was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and stirred for 2 hours. The solvents were evaporated and the product was lyophilized to leave a white solid (39 mg, 60% for two steps).1H-NMR (CD3OD) ^ 7.90 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H, J = 9.1 Hz), 7.42 (d, 2H, J = 8.8 Hz), 7.26 (d, 2H, J = 8.8 Hz), 4.02 (m, 4H), 3.22 (m, 4H), 2.98 (m, 2H), 2.00 (m, 4H), 1.77 (m, 4H). LC/MS Rt = 2.81 min., purity > 95%, (M+H)+ = 448. [0021] Example 33: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)furan-2-carboxamide
Figure imgf000369_0001
[0022] Step 1: Synthesis of 5-bromo-N-(4-bromo-3-fluorophenyl)furan-2-carboxamide. A flask was charged with 1030 mg (4.9 mmol) of 5-bromofuran-2-carbonyl chloride and 20 mL of chloroform and reaction cooled in an ice water bath. Then 4-bromo-3-fluoroaniline (978 mg, 5.15 mmol) was added in small portions over ten minutes. Next, (822 mg, 6.87 mmol) of N,N- diisopropylethylamine was added over 20 minutes. The reaction was stirred at room temp for two hours and chloroform was removed under vacuum, 40 mL ethyl acetate and 25 mL of water added. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 1.71 g of 5-bromo-N-(4-bromo-3-fluorophenyl)furan-2-carboxamide. (96%).
Figure imgf000369_0002
[0023] Step 2: Synthesis of tert-butyl 4-(5-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenylcarbamoyl)furan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 445 mg (1.23 mmol) of 5-bromo-N-(4-bromo-3-fluorophenyl)furan-2- carboxamide, 22 mg (.0984 mmol) of palladium acetate, 101 mg (0.246mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 871 mg (2.82 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 10 mL of dioxane and 4.5 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five     minutes and heated at 95oC for 18 hours. The reaction was then to cool and diluted with 20 mL water and 40 mL of ethyl acetate added over two minutes. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield the products as a solid in quantitative yield.
Figure imgf000370_0001
[0024] Step 3: Synthesis of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)furan-2-carboxamide bis trifluoroacetic acid salt. The tert-butyl 4-(5-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenylcarbamoyl) furan-2-yl)-5,6- dihydropyridine-1(2H)-carboxylate was slurried with 4 mL dichloromethane. Then 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum and triturated with two 20 mL portions of ether and ether decanted away to yield the product as a solid in quantitative yield.
Figure imgf000370_0002
[0025] Step 4 :Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)carbamoyl)furan-2-yl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 480 mg (0.80 mmol) of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)furan-2-carboxamide bis trifluoroacetic acid salt , 4 mL dichloromethane and 3 mL N,N-dimethylformamide. Then 485 mg (4.80 mmol) of triethylamine added over two minutes. Then 570 mg (1.84 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction stirred at room temperature over weekend. The reaction was heated at 40 oC for two hours. The reaction was charged with an additional 300 mg (0.97 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate and reaction heated at 40 oC for 18 hours. The reaction was concentrated under vacuum and then placed on vacuum pump for two hours and the dimethylformamide solution directly reacted.
Figure imgf000370_0003
    [0026] Step 5: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)furan-2-carboxamide. A flask was charged with 680 mg (0.800 mmol) of tert-butyl (4,4'-(4,4'-(4-methyl-4H-1,2,4-triazole-3,5-diyl)bis(3- fluoro-4,1-phenylene))bis(5,6-dihydropyridine-4,1(2H)-diyl)) bis(methane-1-yl-1,1- diylidene)tetracarbamate in 3 mL N,N-dimethylformamide. Then added 3 mL of dichloromethane, followed by addition of 7 mL (91 mmol) of trifluoroacetic acid added over two minutes with stirring and stirred for 18 hours. The next day LCMS indicted the reaction was complete and reaction concentrated under vacuum. Liquid was diluted with 6 mL dimethylformamide and one third was purified by prep HPLC. Yield of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)furan-2-carboxamide was 123 mg (68 %). 1H NMR (300 MHz, METHANOL-d4) δ ppm 7.67 (dd, J=13.48, 1.76 Hz, 1 H) 7.49 (dd, J=8.50, 2.05 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 6.63 (d, J=3.52 Hz, 1 H) 6.04 (t, J=3.52 Hz, 2 H) 4.10 - 4.23 (m, 4 H) 3.69 (q, J=5.86 Hz, 4 H) 2.66 (br d, J=4.10 Hz, 4 H). LC/MS method A: Rt = 2.9 mins., (M+H)+ =452 purity > 95%. [0027] Example 34: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl)thiophene-2-carboxamide
Figure imgf000371_0001
[0028] Step 1: Synthesis of 5-bromo-N-(4-bromo-3-methoxyphenyl)thiophene-2- carboxamide. A flask was charged with 10 mL of chloroform, 4-bromo-3-methoxyaniline (586 mg, 2.90 mmol). and (822 mg, 6.87 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 655 mg (2.90 mmol) of 5-bromothiophene-2-carbonyl chloride in 15 mL chloroform was added over 20 minutes. The reaction was stirred at room temp for 18 hours, chloroform was removed under vacuum, 40 mL ethyl acetate and 20 mL of water added. The organic phase was dried and concentrated under vacuum to yield 1050 mg of 5-bromo-N-(4-bromo-3- methoxyphenyl)thiophene-2-carboxamide (93%).    
Figure imgf000372_0001
[0029] Step 2: Synthesis of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-methoxyphenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 548 mg (1.23 mmol) of 5-bromo-N-(4-bromo-3- methoxyphenyl)thiophene-2-carboxamide, 26 mg (0.11 mmol) of palladium acetate, 116 mg (0.284mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 1050 mg (3.41 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 10 mL of 1,4- dioxane and 5.3 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was then allowed to cool and diluted with 40 mL water and 40 mL of ethyl acetate added over two minutes. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 1050 mg of tert-butyl 4- (5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- methoxyphenyl)carbamoyl)thiophen-2-yl)-3,6-dihydro pyridine-1(2H)-carboxylate as a solid in nearly quantitative yield.
Figure imgf000372_0002
[0030] Step 4: Synthesis of N-(3-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5- (1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide. A flask was charged with tert-butyl 4-(5- ((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl)carbamoyl) thiophen- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1050 mg ,11.4 mmol) was dissolved with 4 mL dichloromethane. Then 500 mg of anisole (4.63 mmol) was added followed by dropwise addition of 9 mL (117 mmol) of trifluoroacetic acid added over five minutes with stirring. The next day the reaction was concentrated under vacuum and triturated with two 30 mL portions of ether and ether decanted away to yield a solid in quantitative yield.    
Figure imgf000373_0001
[0031] Step 5: Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl)carbamoyl) thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate. A flask was charged with 620 mg (1.00 mmol) of N-(3-methoxy-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide bis trifluoroacetic acid salt and 6 mL of N,N-dimethylformamide. Then 758 mg (7.50 mmol) of triethylamine was added over two minutes. Then 744 mg (2.40 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was diluted with 30 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum. Oil was chromatographed on silica using an ethyl acetate/dichloromethane step gradient from 0 to 100 %. Similar fractions were combined and concentrated under vacuum to yield 540 mg of tert-butyl ((E)-(4- (5-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- methoxyphenyl) carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino) methylene)carbamate (61 %).
Figure imgf000373_0002
[0032] Step 6: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxyphenyl)thiophene-2-carboxamide. A flask was charged with 540 mg (0.610 mmol)of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methoxy phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 4 mL dichloromethane and 4000 mg (37.0 mmol) of anisole. Then added 8 mL (104 mmol) of trifluoroacetic acid over two minutes with stirring and stirred for 18 hours. The next day LCMS indicted reaction complete and reaction concentrated under vacuum. Liquid was diluted with dimethylformamide and was purified by prep HPLC. Yield of 5-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-     methoxyphenyl)thiophene-2-carboxamide was 94 mg (22 %).1H NMR (300 MHz, DMSO-d6) δ ppm 7.94 (d, J=4.10 Hz, 1 H) 7.47 (s, 3 H) 7.45 (d, J=1.76 Hz, 1 H) 7.41 (s, 3 H) 7.36 (d, J=1.76 Hz, 1 H) 7.33 (d, J=1.76 Hz, 1 H) 7.28 (d, J=4.10 Hz, 1 H) 6.31 (s, 1 H) 5.83 (s, 1 H) 4.05 (br dd, J=19.93, 1.76 Hz, 4 H) 3.76 (s, 3 H) 3.52 - 3.65 (m, 4 H) 2.61 (br s, 4 H). LC/MS method A: Rt = 2.8 mins., (M+H)+ =480, purity > 95%. [0033] Example 35: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)thiophene-2-carboxamide
Figure imgf000374_0001
[0034] Step 1: Synthesis of 5-bromo-N-(4-bromo-3-fluorophenyl)thiophene-2-carboxamide. A flask was charged with 10 mL of dichloromethane, 4-bromo-3-fluoroaniline (820 mg, 4.18mmol) and (7400 mg, 10.9 mmol) of diisopropylethylamine and cooled in an ice water bath. Then a solution of 902 mg (4.01 mmol) of 5-bromothiophene-2-carbonyl chloride in 10 mL of dichloromethane was added over 20 minutes. The reaction stirred at room temp for 18 hours and dichloromethane was removed under vacuum; 30 mL ethyl acetate and 20 mL of water added. The organic phase was dried and concentrated under vacuum to yield 1150 mg of 5-bromo-N-(4-bromo-3-fluorophenyl)thiophene-2- carboxamide (82 %).
Figure imgf000374_0002
[0035] Step 2: Synthesis of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 400 mg (1.23 mmol) of 5-bromo-N-(4-bromo-3- fluorophenyl)thiophene-2-carboxamide, 16 mg ( 0.074 mmol) of palladium acetate, 76 mg ( 0.185 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 950 mg (3.07 mmol) of tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 8 mL of 1,4- dioxane and 4.3 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The was then allowed to cool and diluted     with 10 mL water and 4 mL of ethyl acetate added over two minutes. After a two hour age the solids were collected and rinsed with 3 mL of ethyl acetate, air dried for 18 hours to yield 430 mg of a solid, 73 % yield.
Figure imgf000375_0001
[0036] Step 3: Synthesis of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide. The tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (430 mg ,0.74 mmol) was dissolved with 4 mL dichloromethane. Then 500 mg of anisole (4.63 mmol) was added followed by dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum and triturated with two 30 mL portions of ether and ether decanted away to yield a solid in quantitative yield.
Figure imgf000375_0002
[0037] Step 3: Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)carbamoyl)thiophen-2-yl)- 3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate. A flask was charged with 450 mg (0.74 mmol) of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide bis trifluoroacetic acid salt and 5 mL of N,N- dimethylformamide. Then 425 mg (4.20 mmol) of triethylamine was added over two minutes. Then 520 mg (1.68 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was diluted with 20 mL of ethyl acetate and washed with two 10 mL portions of water. The organic phase was dried and concentrated under vacuum to yield of tert-butyl ((E)-(4-(5-((4-(1- ((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- fluorophenyl)carbamoyl) thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.    
Figure imgf000376_0001
[0038] Step 4: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)thiophene-2-carboxamide. A flask was charged with 610 mg (0.700 mmol)of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl) carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 4 mL dichloromethane and 6 mL (98 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred over the weekend. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and was purified by prep HPLC. Yield of 5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)-3-fluorophenyl)thiophene-2-carboxamide was 155 mg (26 %).1H NMR (300 MHz, METHANOL- d4) δ ppm 7.82 (d, J=4.10 Hz, 1 H) 7.61 - 7.68 (m, 1 H) 7.42 - 7.48 (m, 1 H) 7.30 - 7.38 (m, 1 H) 7.20 (d, J=4.10 Hz, 1 H) 6.30 - 6.34 (m, 1 H) 6.04 (br s, 1 H) 4.10 - 4.17 (m, 4 H) 3.69 (dt, J=9.82, 5.64 Hz, 4 H) 2.63 - 2.76 (m, 4 H). LC/MS method A: Rt = 2.7 mins., (M+H)+ =468, purity > 95%. [0039] Example 36: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-difluorophenyl)thiophene-2-carboxamide
Figure imgf000376_0002
[0040] Step 1: Synthesis of 5-bromo-N-(4-bromo-2,5-difluorophenyl)thiophene-2- carboxamide. A flask was charged with 20 mL of chloroform, 4-bromo-2,5-difluoroaniline (1340 mg, 6.43 mmol) and (1300 mg, 10.1 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 1420 mg (6.30 mmol) of 5-bromothiophene-2-carbonyl chloride in 12 mL of chloroform was added over 20 minutes. The reaction stirred at room temp for 18 hours and chloroform was removed under vacuum and 30 mL ethyl acetate and 20 mL of water added. The organic phase was dried and concentrated under vacuum to yield 2100 mg of 5-bromo-N-(4-bromo-2,5- difluorophenyl)thiophene-2-carboxamide (87 %).    
Figure imgf000377_0001
[0041] Step 2: Synthesis of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2,5-difluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 510 mg (1.28 mmol) of N-(2,5-difluoro-4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide, 23 mg ( 0.102 mmol) of palladium acetate, 105 mg ( 0.256 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 996 mg (3.21 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5,6-dihydropyridine-1(2H)-carboxylate, 12 mL of 1.4-dioxane and 4.5 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC over for 72 hours. The reaction was allowed to cool and diluted with 10 mL water and 25 mL of ethyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum to yield the tert- butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,5- difluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000377_0002
[0042] Step 2: Synthesis of N-(2,5-difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5- (1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide. A flask was charged with tert-butyl 4-(5- ((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,5-difluorophenyl) carbamoyl)thiophen- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (770 mg ,1.28 mmol) and dissolved with 6 mL dichloromethane. Then 500 mg of anisole (4.63 mmol) was added followed by dropwise addition of 8 mL (104 mmol) of trifluoroacetic acid over five minutes with stirring. The next day the reaction was concentrated under vacuum and triturated with two 30 mL portions of ether and ether decanted away to yield a solid in quantitative yield.    
Figure imgf000378_0001
  [0043] Step 3: Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,5-difluorophenyl)carbamoyl) thiophen-2- yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate. A flask was charged with 620 mg (1.00 mmol) of N-(2,5-difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5- (1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide bis trifluoroacetic acid salt and 8 mL of N,N- dimethylformamide. Then 606 mg (6.00 mmol) of triethylamine was added over two minutes. Then 744 mg (2.40 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was charged with 210 mg (2.08 mmol) of triethylamine and 200 mg (0.67 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate. The next day the reaction was heated at 40oC for 72 hours. Then the reaction was diluted with 50 mL of ethyl acetate and washed with three 30 mL portions of water. The organic phase was dried and concentrated under vacuum and concentrate was chromatographed on silica using a step gradient with ethyl acetate/dichloromethane from 0 to 80% to yield 540 mg of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2,5-difluoro phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridin- 1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate in a 61 % yield.
Figure imgf000378_0002
  [0044] Step 4: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-difluorophenyl)thiophene-2-carboxamide. A flask was charged with 540 mg (0.610 mmol) of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,5- difluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxy carbonyl)amino)methylene)carbamate, 500 mg (4.63 mmol)of anisole, 6 mL dichloromethane and 8 mL (124 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and was     purified by prep HPLC. Yield of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2,5-difluorophenyl)thiophene-2-carboxamide was 130 mg (19%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1 H) 7.96 (d, J=4.10 Hz, 1 H) 7.90 - 7.93 (m, 1 H) 7.54 - 7.60 (m, 1 H) 7.47 - 7.53 (m, 6 H) 7.38 (dd, J=11.43, 7.33 Hz, 1 H) 6.33 (br s, 1 H) 6.13 (br s, 1 H) 4.07 (br s, 4 H) 3.60 (q, J=5.86 Hz, 4 H) 2.52 - 2.62 (m, 4 H). LC/MS method A: Rt = 3.3 mins., (M+H)+ =486, purity > 95%. [0045] Example 37: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)thiophene-2-carboxamide.
Figure imgf000379_0001
[0046] Step 1: Synthesis of 5-bromo-N-(4-bromophenyl)thiophene-2-carboxamide. A flask was charged with 10 mL of dichloromethane, 4-bromoaniline (720 mg, 4.18 mmol), (810 mg, 6.27 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 896 mg (3.98 mmol) of 5-bromothiophene-2-carbonyl chloride in 10 mL of dichloromethane was added over 20 minutes. The reaction stirred at room temp for 18 hours and dichloromethane was removed under vacuum; 30 mL ethyl acetate and 20 mL of water were added. The organic phase was dried and concentrated under vacuum to yield 1370 mg of 5-bromo-N-(4-bromophenyl)thiophene-2-carboxamide (95 %).
Figure imgf000379_0002
[0047] Step 1: Synthesis of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 340 mg (0.944 mmol) of 5-bromo-N-(4-bromophenyl)thiophene-2- carboxamide, 13 mg (0.057) of palladium acetate, 58 mg ( 0.142 mmol) of 2-dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl, 730 mg (2.36 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 6 mL of 1,4-dioxane and 3.3 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 15 mL water and 8 mL of ethyl acetate     added over five minutes. After stirring for two hours the solids were collected and rinsed with 3 mL of ether and air dried for several hours to yield 200 mg of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (38%).
Figure imgf000380_0001
[0048] Step 2: Synthesis of 5-(1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)thiophene-2-carboxamide. The tert-butyl 4-(5-((4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)carbamoyl)thiophen-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (200 mg, 0.35 mmol) was dissolved with 4 mL dichloromethane. Then 500 mg of anisole (4.63 mmol) was added followed by dropwise addition over five minutes of 6 mL (78 mmol) of trifluoroacetic acid. The next day the reaction was concentrated under vacuum to yield a solid in nearly quantitative yield.
Figure imgf000380_0002
[0049] Step 3: Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)carbamoyl)thiophen-2-yl)- 3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 240 mg (0.35 mmol) of 5-(1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)thiophene-2-carboxamide bis trifluoroacetic acid salt and 6 mL of N, N-dimethylformamide. Then 412 mg (4.08 mmol) of triethylamine was added over two minutes. Then 527 mg (1.70 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidene dicarbamate was added. The next day the reaction was charged with 350 mg (3.47 mmol) of triethylamine and the reaction was heated at 40oC for 18 hours. The next day the reaction was diluted with 20 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum and concentrate was chromatographed on silica using a step gradient with ethyl acetate/dichloromethane from 0 to 80% to yield 140 mg of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate in 47 % yield.    
Figure imgf000381_0001
[0050] Step 4: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)thiophene-2-carboxamide. A flask was charged with 140 mg (0.165 mmol)of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)carbamoyl) thiophen-2-yl)- 3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate, 500 mg ( 4.63 mmol) of anisole, 6 mL dichloromethane and 8 mL (124 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. The concentrate was diluted with dimethylformamide and was purified by prep HPLC. Yield of 5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)thiophene-2-carboxamide was 130 mg (19 %).1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (s, 1 H) 7.94 (d, J=4.10 Hz, 1 H) 7.71 (d, J=8.79 Hz, 2 H) 7.41 - 7.49 (m, 6 H) 7.27 (d, J=3.52 Hz, 2 H) 6.31 (s, 1 H) 6.17 (s, 1 H) 4.07 (br s, 4 H) 3.61 (br t, J=4.98 Hz, 4 H) 2.54 - 2.62 (m, 4 H).LC/MS method A: Rt = 2.6 mins., (M+H)+ =450, purity > 95%. [0051] Example 38: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4- ((2-guanidinoethyl)thio)phenyl)thiophene-2-carboxamide.
Figure imgf000381_0002
[0052] Step 1: Synthesis of tert-butyl (2-((4-nitrophenyl)thio)ethyl)carbamate. A flask was charged with 2830 mg (20.1 mmol) of 1-fluoro-4-nitrobenzene, 10 mL of N,N-dimethylformamide and 3490 mg (19.7 mmol) of tert-butyl (2-mercaptoethyl)carbamate. The N,N-diisopropylethylamine (3180 mg, 24.6 mmol) was added over two minutes and 30 minutes later the reaction was heated at 65oC for 18 hours. The next day the reaction was diluted with 40 mL of ethyl acetate, washed with three 20 mL portions of water, dried and concentrated under vacuum to yield 5.7 grams of a yellow solid in quantitative yield.
Figure imgf000381_0003
    [0053] Step 2: Synthesis of tert-butyl (2-((4-aminophenyl)thio)ethyl)carbamate. A flask was charged with 5700 mg (19.7 mmol) of tert-butyl (2-((4-nitrophenyl)thio)ethyl)carbamate, 50 mL of tetrahydrofuran, 20 mL of methanol and 12400 mg (229 mmol) of ammonium chloride. Then 7460 mg (115 mmol) of zinc dust was added in two roughly equal portions over 30 minutes and reaction was warmed to 40oC for 18 hours. The reaction was allowed to cool, filtered thru Celite, rinsed with ethyl acetate and methanol. The filtrate was concentrated under vacuum, concentrate partitioned between 40 mL ethyl acetate and 20 mL of water, dried and concentrated under vacuum to yield the tert-butyl (2- ((4-aminophenyl)thio)ethyl)carbamate in quantitative yield.
Figure imgf000382_0001
[0054] Step 3: Synthesis of tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate. A flask was charged with 4240 mg (18.2 mmol) of methyl 5- bromothiophene-2-carboxylate, 162 mg (0.72 mmol) of palladium acetate, 740 mg ( 1.80 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 700 mg (2.25 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 50 mL of 1,4-dioxane and 27 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 20 mL of ethyl acetate added. The organic phase was dried and concentrated under vacuum. Then 30 mL toluene added and removed under vacuum to yield 6100 mg of tert-butyl 4-(5- (methoxycarbonyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000382_0002
[0055] Step 4: Synthesis of 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxylic acid. A flask was charged with 6100 mg (18.2 mmol) of tert-butyl 4-(5- (methoxycarbonyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, 50 mL of 1/1 methanol/tetrahydrofuran, a solution of LiOH (450 mg, 10.4 mmol) in 10 mL of water. After stirring     for one hour 10 mL more water added. After stirring for 18 hours, the organic solvents were removed under vacuum and then aqueous phase extracted with two 30 mL portions of 2/1 ether/ethyl acetate. The aqueous phase was cooled in an ice/water bath and made acidic with 20 mL of 2.0 N HCl and 40 mL ethyl acetate added. The solid was collected on a filter to yield 800 mg of 5-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic acid after drying over the weekend. The ethyl acetate extract was dried and concentrated under vacuum to yield 1500 mg of 5- (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxylic acid. Total yield was 2300 mg (41 %).
Figure imgf000383_0001
[0056] Step 4: Synthesis of tert-butyl 4-(5-((4-((2-((tert-butoxycarbonyl)amino) ethyl)thio)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 350 mg (1.13 mmol) of 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxylic acid, 10 mL of dry N,N-dimethylformamide and (387 mg, 3.00 mmol) of N,N-diisopropylethylamine. Then 560 mg (1.47 mmol) of 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate was added. After 30 minutes of stirring a solution of tert-butyl (2-((4-aminophenyl)thio)ethyl)carbamate (318 mg, 1.18 mmol) in 2mL of dry N,N-dimethylformamide was added over one minute. The reaction was stirred at room temp for 18 hours and reaction diluted with 30 mL of ethyl acetate and washed with four 20 mL portions of water. The organic phase was dried and concentrated under vacuum. The concentrate was chromatographed on silica with ethyl acetate/dichloromethane from 0 to 70 % to yield 340 mg of tert-butyl 4-(5-((4-((2- ((tert-butoxycarbonyl)amino)ethyl)thio)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (54%).
Figure imgf000383_0002
[0057] Step 5: Synthesis of N-(4-((2-aminoethyl)thio)phenyl)-5-(1,2,3,6-tetrahydro pyridin-4- yl)thiophene-2-carboxamide. A flask was charged tert-butyl 4-(5-((4-((2-((tert-     butoxycarbonyl)amino)ethyl)thio)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H) - carboxylate (340 mg , 0.607 mmol) was dissolved with 5 mL of dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was conducted over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000384_0001
  [0058] Step 6: Synthesis of tert‐butyl N‐[(Z)‐[(2‐{[4‐(5‐{1‐[(E)‐{[(tert‐butoxy) carbonyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl} thiophene‐ 2‐amido)phenyl]sulfanyl}ethyl)amino]({[(tert‐butoxy)carbonyl]imino})methyl]carbamate. A flask was charged with 340 mg (0.58 mmol) of N-(4-((2-aminoethyl)thio)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide bis trifluoroacetic acid salt, 3mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 351 mg (3.48 mmol) of triethylamine was added over two minutes. Then 410 mg (1.30 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was concentrated under vacuum and diluted with 20 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum and concentrate was chromatographed on silica using a step gradient with ethyl acetate/dichloromethane from 0 to 60% to yield 450 mg of tert‐butyl N‐[(Z)‐[(2‐{[4‐(5‐{1‐[(E)‐{[(tert‐ butoxy)carbonyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐ yl}thiophene‐2‐amido)phenyl]sulfanyl}ethyl)amino]({[(tert‐ butoxy)carbonyl]imino})methyl]carbamate in a 92 % yield.
Figure imgf000384_0002
[0059] Step 6: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((2- guanidinoethyl)thio)phenyl)thiophene-2-carboxamide. A flask was charged with 450 mg (0.53 mmol) of tert‐butyl N‐[(Z)‐[(2‐{[4‐(5‐{1‐[(E)‐{[(tert‐butoxy) carbonyl]amino} ({[(tert‐ butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}thiophene‐2‐ amido)phenyl]sulfanyl}ethyl)amino]({[(tert‐butoxy)carbonyl]imino})methyl]carbamate, 4 mL     dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid was added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and was purified by prep HPLC. Yield of 5-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-((2-guanidinoethyl)thio)phenyl)thiophene -2-carboxamide was 228 mg (59 %). 1H NMR (300 MHz, METHANOL-d4) δ ppm 7.80 (d, J=4.10 Hz, 1 H) 7.64 - 7.70 (m, 2 H) 7.41 - 7.48 (m, 2 H) 7.19 (d, J=4.10 Hz, 1 H) 6.31 (t, J=3.52 Hz, 1 H) 4.14 (br d, J=2.93 Hz, 2 H) 3.71 (t, J=5.57 Hz, 2 H) 3.34 - 3.41 (m, 2 H) 3.08 - 3.14 (m, 2 H) 2.72 (br d, J=1.76 Hz, 2 H). LC/MS method A: Rt = 2.6 mins., (M+H)+ =372,497,429, purity > 95%. [0060] Example 39: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2- guanidinoethoxy)phenyl)thiophene-2-carboxamide
Figure imgf000385_0001
[0061] Step 1: Synthesis of tert-butyl (2-(4-nitrophenoxy)ethyl)carbamate. A dry flask was charged with 2270 mg (16.3 mmol) of 4-nitrophenol, 15 mL of N,N-dimethylformamide and 11800 mg (36.2 mmol) of cesium carbonate. The reaction was heated to 40 oC and a solution of tert-butyl (2- bromoethyl)carbamate (4800 mg, 21.2 mmol) in 7 mL of dry N,N;dimethylformamide was added dropwise over several minutes and reaction heated at 80oC for 18 hours. The next day the reaction was cooled, diluted with 60 mL of ethyl acetate, washed with three 30 mL portion of water, dried and concentrated under vacuum to yield 4.4 grams.( 95%).
Figure imgf000385_0002
[0062] Step 2: Synthesis of tert-butyl (2-(4-aminophenoxy)ethyl)carbamate. A flask was charged with 4400 mg (15.6 mmol) of tert-butyl (2-(4-nitrophenoxy)ethyl)carbamate, 40 mL of tetrahydrofuran, 20 mL of methanol and 10100 mg (187 mmol) of ammonium chloride. Then 6080 mg (93.6 mmol) of zinc dust was added in two roughly equal portions over 30 minutes and reaction was warmed to 55oC for two hours and then room temp for 18 hours. The next day the reaction was filtered thru Celite and rinsed with ethyl acetate and methanol. The filtrate was concentrated under vacuum, concentrate partitioned between 60 mL ethyl acetate and 30 mL of water, dried and concentrated under vacuum to yield 3200 mg of tert-butyl (2-(4-aminophenoxy)ethyl)carbamate in 81% yield.    
Figure imgf000386_0001
[0063] Step 3: Synthesis of tert-butyl 4-(5-((4-(2-((tert-butoxycarbonyl)amino) ethoxy)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 350 mg (1.13 mmol) of 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2- carboxylic acid, 2 mL of N,N-dimethylformamide and (437 mg, 3.39 mmol) of N,N- diisopropylethylamine. Then 560 mg (1.47 mmol) of 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate was added. After 30 minutes of stirring a solution of tert-butyl (2-(4-aminophenoxy)ethyl)carbamate (300 mg, 1.19 mmol) in 2mL of dry dimethylformamide was added over one minute. The reaction was stirred at room temp for 18 hours and reaction diluted with 30 mL of ethyl acetate and washed with four 20 mL portions of water. The organic phase was dried and concentrated under vacuum. The concentrate was chromatographed on silica with ethyl acetate/dichloromethane from 0 to 70 % to yield 350 mg of tert-butyl 4-(5-((4-(2-((tert- butoxycarbonyl)amino)ethoxy)phenyl) carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (57%).
Figure imgf000386_0002
[0064] Step 4: Synthesis of N-(4-(2-aminoethoxy)phenyl)-5-(1,2,3,6-tetrahydro pyridin-4- yl)thiophene-2-carboxamide. A flask was charged with tert-butyl 4-(5-((4-(2-((tert- butoxycarbonyl)amino)ethoxy)phenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (350 mg, 0.607 mmol) was dissolved with 5 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in nearly quantitative yield.    
Figure imgf000387_0001
[0065] Step 5: Synthesis of tert‐butyl N‐[(Z)‐({2‐[4‐(5‐{1‐[(E)‐{[(tert‐butoxy) carbonyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}thiophene‐ 2‐amido)phenoxy]ethyl}amino)({[(tert‐butoxy)carbonyl]imino})methyl]carbamate. A flask was charged with 280 mg (0.48 mmol) of N-(4-(2-aminoethoxy)phenyl)-5-(1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxamide bistrifluoroacetic acid salt, 3mL dichloromethane and 2 mL of dimethylformamide. Then 333 mg (3.30 mmol) of triethylamine was added over two minutes. Then 390 mg (1.19 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was concentrated under vacuum and diluted with 20 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum and concentrate was chromatographed on silica using a step gradient with ethyl acetate/dichloromethane from 0 to 60% to yield 285 mg of tert‐butyl N‐[(Z)‐({2‐[4‐(5‐{1‐[(E)‐{[(tert‐butoxy)carbonyl] amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}thiophene‐2‐ amido)phenoxy]ethyl}amino)({[(tert‐butoxy)carbonyl]imino})methyl]carbamatein a 72 % yield.
Figure imgf000387_0002
[0066] Step 6: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2- guanidinoethoxy)phenyl)thiophene-2-carboxamide: A flask was charged with 285 mg (0.35 mmol) of tert‐butyl N‐[(Z)‐({2‐[4‐(5‐{1‐[(E)‐{[(tert‐butoxy)carbonyl]amino} ({[(tert‐butoxy)carbonyl]imino}) methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}thiophene‐2‐amido) phenoxy]ethyl}amino)({[(tert‐butoxy) carbonyl]imino})methyl]carbamate, 4 mL dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid was added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and was purified by prep HPLC. Yield of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-guanidinoethoxy)phenyl) thiophene-2- carboxamide was 147 mg (63 %).1H NMR (300 MHz, METHANOL-d4) δ ppm 10.03 (s, 1 H) 7.79 (d, J=4.10 Hz, 1 H) 7.55 - 7.60 (m, 2 H) 7.35 (br s, 1 H) 7.16 - 7.26 (m, 2 H) 6.31 (t, J=3.52 Hz, 1 H) 4.14     (br d, J=3.52 Hz, 2 H) 3.71 (t, J=5.57 Hz, 2 H) 3.15 - 3.24 (m, 2 H) 2.64 - 2.76 (m, 2 H) 1.90 (quin, J=7.33 Hz, 2 H). LC/MS method A: Rt = 2.6 mins., (M+H)+ =428, purity > 95%. [0067] Example 40: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)thiophene-2-carboxamide
Figure imgf000388_0001
[0068] Step 1: Synthesis of 5-bromo-N-(4-bromo-3-chlorophenyl)thiophene-2- carboxamideophenylthiophene. A flask was charged with 5 mL of chloroform, 4-bromo-3- chloroaniline (511 mg, 2.48 mmol) and (396 mg, 3.07 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 529 mg (2.36 mmol) of 5-bromothiophene-2-carbonyl chloride in 5 mL of chloroform was added over 5 minutes. The reaction stirred at room temp for four hours and solvent was removed under vacuum and 10 mL ethyl acetate and 20 mL of water added. The solid was collected, rinsed with 5 mL of ethyl acetate and air dried for 18 hours. Yield of 5-bromo-N-(4-bromo- 3-chlorophenyl)thiophene-2-carboxamideophenyl thiophene was 560 mg (60 %)
Figure imgf000388_0002
[0069] Step 2: Synthesis of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 307 mg (0.781 mmol) of 5-bromo-N-(4-bromo-3- chlorophenyl)thiophene-2-carboxamide, 44 mg ( 0.062) of bis(triphenylphosphine)palladium chloride, 555 mg (1.80 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 3.0 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 55oC for 2.5 hours and then 70oC for 18 hours. The reaction was allowed to cool and diluted with 25 mL water and 30 mL of ethyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum to yield a brown solid in quantitative yield.    
Figure imgf000389_0001
[0070] Step 3: Synthesis of N-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide. The tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (467 mg, 0.78 mmol) was dissolved with 5 mL dichloromethane. Then 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum to yield a solid in quantitative yield.
Figure imgf000389_0002
[0071] Step 4: Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl) thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate. A flask was charged with 440 mg (0.70 mmol) of N-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)- 5-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide bis trifluoroacetic acid salt, 3mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 424 mg (4.20 mmol) of triethylamine was added over two minutes. Then 564 mg (1.820 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. After three hours an additional 150 mg (0.48 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. After four more hours the reaction was concentrated under vacuum and was diluted with 40 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum to yield 590 mg of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl) carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)- yl)((tert-butoxycarbonyl)amino) methylene)carbamate in a 95 % yield.
Figure imgf000389_0003
    [0072] Step 4: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)thiophene-2-carboxamide. A flask was charged with 590 mg (0.65 mmol)of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)thiophen- 2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 8 mL dichloromethane and 8 mL (124 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N- dimethylformamide and was purified by prep HPLC. Yield of 5-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3- chlorophenyl)thiophene-2-carboxamide was 89 mg (19 %). 1H NMR (300 MHz, METHANOL-d4) δ ppm 10.03 (s, 1 H) 7.79 (d, J=4.10 Hz, 1 H) 7.55 - 7.60 (m, 2 H) 7.35 (br s, 1 H) 7.16 - 7.26 (m, 2 H) 6.31 (t, J=3.52 Hz, 2 H) 4.14 (br d, J=3.52 Hz, 4 H) 3.71 (t, J=5.57 Hz, 4 H) 2.64 - 2.76 (m, 4 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ =484, purity > 95%. [0073] Example 41: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)thiophene-2-carboxamide
Figure imgf000390_0001
[0074] Step 1: Synthesis of 5-bromo-N-(4-bromo-2-fluorophenyl)thiophene-2-carboxamide. A flask was charged with 10 mL of dichloromethane, 4-bromo-2-fluoroaniline (740 mg, 3.89 mmol) and (810 mg, 6.27 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 902mg (4.01 mmol) of 5-bromothiophene-2-carbonyl chloride in 10 mL of dichloromethane was added over 20 minutes. The reaction was stirred at room temp for 18 hours and dichloromethane was removed under vacuum; 30 mL ethyl acetate and 20 mL of water added. The organic phase was dried and concentrated under vacuum to yield 1370 mg of 5-bromo-N-(4-bromo-2-fluorophenyl)thiophene- 2-carboxamide (93%).
Figure imgf000390_0002
    [0075] Step 2: Synthesis of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 300 mg (0.792 mmol) of 5-bromo-N-(4-bromo-2- fluorophenyl)thiophene-2-carboxamide, 11 mg (0.048) of palladium acetate, 49mg ( 0.119 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 611 mg (1.97 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 5 mL of 1,4-dioxane and 2.8 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 3 mL water and 3 mL of ethyl acetate added over five minutes. After stirring for two hours the solids were collected and air dried for several hours to yield 500 mg of tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate in quantitative yield.
Figure imgf000391_0001
[0076] Step 3: Synthesis of N-(2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-(1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide. The tert-butyl 4-(5-((4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)carbamoyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (500 mg, 0.715 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 8 mL (104 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum to yield a solid in nearly quantitative yield.
Figure imgf000391_0002
[0077] Step 4: Synthesis of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)carbamoyl) thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate. A flask was charged with 415 mg (0.68 mmol) of N-(2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)- 5-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide bis trifluoroacetic acid salt and 6 mL of N,N-dimethylformamide. Then 412 mg (4.08 mmol) of triethylamine was added over two minutes.     Then 527 mg (1.70 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was charged with 350 mg (3.47 mmol) of triethylamine and the reaction was heated at 40oC for 18 hours. The next day the reaction was diluted with 20 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum and concentrate was chromatographed on silica using a step gradient with ethyl acetate/dichloromethane from 0 to 80% to yield 140 mg of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'- bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl) carbamoyl)thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate in a 47 % yield.
Figure imgf000392_0001
[0078] Step 5: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)thiophene-2-carboxamide. A flask was charged with 140 mg (0.165 mmol)of tert-butyl ((E)-(4-(5-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl) carbamoyl) thiophen-2-yl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 500 mg (4.63 mmol)of anisole ,3 mL dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and was purified by prep HPLC. Yield of 5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)-2-fluoro phenyl)thiophene-2-carboxamide was 26 mg (23 %). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.17 (s, 1 H) 7.93 (d, J=4.10 Hz, 1 H) 7.56 (t, J=8.21 Hz, 1 H) 7.39 - 7.48 (m, 6 H) 7.32 (dd, J=8.79, 1.76 Hz, 1 H) 7.24 - 7.29 (m, 1 H) 7.09 (s, 1 H) 6.31 (br d, J=3.52 Hz, 2 H) 4.07 (br s, 4 H) 3.61 (t, J=5.57 Hz, 4 H) 2.53 - 2.64 (m, 4 H). LC/MS method A: Rt = 2.8 mins., (M+H)+ =468, purity > 95%. [0079] Example 42: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-2-fluorobenzamide.    
Figure imgf000393_0001
[0080] Step 1: Synthesis of 4-bromo-N-(4-bromo-5-fluoro-2-methylphenyl)-2- fluorobenzamide. A flask was charged with 5 mL of chloroform, 4-bromo-5-fluoro-2-methylaniline (407 mg, 2.00 mmol) and (355 mg, 2.76 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 448 mg (1.90 mmol) of 4-bromo-2-fluorobenzoyl chloride in 10 mL of chloroform was added over 20 minutes. The reaction stirred at room temp for 18 hours and then solvent was removed under vacuum; 15 mL ethyl acetate and 10 mL of water added. The solid was collected on a filter after one hour of stirring and was air dried for two hours to yield 836 mg of 4-bromo-N-(4- bromo-5-fluoro-2-methylphenyl)-2-fluorobenzamide in quantitative yield.
Figure imgf000393_0002
[0081] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 178 mg (0.442 mmol) of -bromo-N-(4-bromo-5-fluoro-2- methylphenyl)-2-fluorobenzamide, 8 mg ( 0.035) of palladium acetate, 36 mg (0.087 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 314 mg (1.02 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.65 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 5 mL water and 5 mL of ethyl acetate added over five minutes. After stirring for 30 minutes the solids were collected, rinsed with 2 mL of ethyl acetate and air dried for several hours to yield 170 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-fluoro-5- methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate in 86 % yield.    
Figure imgf000394_0001
[0082] Step 4: Synthesis of 2-fluoro-N-(5-fluoro-2-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6- dihydropyridine-1(2H)-carboxylate (170 mg , 0.345 mmol) was dissolved with 3 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was done over five minutes with stirring. The next day the reaction was concentrated under vacuum to yield a solid in quantitative yield.
Figure imgf000394_0002
[0083] Step 5: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-fluoro-5- methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate. A flask was charged with 215 mg (0.34 mmol) of 2-fluoro-N-(5-fluoro-2-methyl-4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL of dichloromethane and 2 mL of N,N-dimethylformamide. Then 283 mg (2.80 mmol) of triethylamine was added over two minutes. Then 322 mg (1.04 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. The next day the reaction was concentrated under vacuum and the reaction was diluted with 20 mL of ethyl acetate and washed with three 15 mL portions of water. The organic phase was dried and concentrated under vacuum to yield the tert-butyl ((E)-(4-(4- (4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene) carbamate in quantitative yield.
Figure imgf000394_0003
    [0084] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro benzamide. A flask was charged with 300 mg (0.340 mmol)of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-fluoro-5- methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate ,3 mL dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and one half was purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2- methylphenyl)-2-fluorobenzamide was 26 mg (22%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.78 - 9.81 (m, 1 H) 7.72 - 7.75 (m, 1 H) 7.47 - 7.52 (m, 2 H) 7.44 (br d, J=8.79 Hz, 7 H) 7.26 (d, J=8.79 Hz, 1 H) 6.42 (br s, 1 H) 6.02 (br s, 1 H) 4.07 (br d, J=10.55 Hz, 4 H) 3.56 - 3.64 (m, 4 H) 2.45 - 2.49 (m, 4 H) 2.23 (s, 3 H). LC/MS method A: Rt = 3.1 mins., (M+H)+ =423, 494, purity > 95%. [0085] Example 43: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)-2-fluorobenzamide.
Figure imgf000395_0001
[0086] Step 1: Synthesis of 4-bromo-N-(4-bromo-2-fluorophenyl)-2-fluorobenzamide. A flask was charged with 10 mL of chloroform, 4-bromo-2-fluoroaniline (404 mg, 2.20 mmol) and (382 mg, 2.97 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 516 mg (2.19 mmol) of 4-bromo-2-fluorobenzoyl chloride in 3 mL of chloroform was added over three minutes. The reaction stirred at room temp for three hours and solvent was removed under vacuum. Then 5 mL ethyl acetate and 10 mL of water added. The solid was collected on a filter after one hour of stirring and was air dried for two hours to yield 480 mg of 4-bromo-N-(4-bromo-2-fluorophenyl)-2- fluorobenzamide in 58 % yield.
Figure imgf000395_0002
    [0087] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorobenzamido)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 348 mg (0.895 mmol) of 4-bromo-N-(4-bromo-2-fluorophenyl)-2- fluorobenzamide, 16 mg ( 0.072) of palladium acetate, 74mg (0.179 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 635 mg (2.06 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 8 mL of 1,4-dioxane and 3.4 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for three hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of ethyl acetate added over five minutes. After stirring for two hours the solids were collected and air dried for several hours to yield 620 mg of tert-butyl 4-(4-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-3-fluorophenyl)-3,6- dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000396_0001
[0088] Step 3: Synthesis of 2-fluoro-N-(2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorobenzamido)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (620 mg, 0.880 mmol) was dissolved with 6 mL dichloromethane. Then dropwise addition of 9 mL (117 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in nealy quantitative yield.
Figure imgf000396_0002
[0089] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-3- fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 470 mg (0.75 mmol) 2-fluoro-N-(2-fluoro-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL     dichloromethane and 2 mL of N,N-dimethylformamide. Then 455 mg (4.50 mmol) of triethylamine was added over two minutes. Then 560 mg (1.80 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. The reaction was heated at 40oC for 18 hours. The next day 2 mL dimethylformamide added and the reaction was charged with 180 mg (0.58 mmol) of tert- butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate and heated at 40oC for 18 hours. The next day, dichloromethane was removed under vacuum the reaction was heated at 55oC for 18 hours. Then 350 mg (3.47 mmol) of triethylamine and 300 mg (0.97 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate were added and reaction heated at 60oC for five days. The reaction was diluted with 5 mL of ethyl acetate and 10 mL of water. After one hour of stirring the solid was collected, rinsed with 3 mL of ether and air dried for two hours to yield 460 mg (70%).
Figure imgf000397_0001
[0090] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)-2-fluorobenzamide. A flask was charged with 140 mg (0.165 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-3- fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in dichloromethane 9 mL, and 9 mL (117 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and one half of material was purified by prep HPLC. Yield of 4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)-2-fluorophenyl)-2-fluorobenzamide was 45 mg (14%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.04 (d, J=2.34 Hz, 1 H) 7.75 (br t, J=8.21 Hz, 1 H) 7.65 (t, J=7.91 Hz, 1 H) 7.35 - 7.45 (m, 9 H) 7.25 - 7.30 (m, 1 H) 6.38 (br s, 1 H) 6.24 (br s, 1 H) 4.03 (br d, J=5.86 Hz, 4 H) 3.52 - 3.60 (m, 4 H) 2.53 (br d, J=4.69 Hz, 4 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ =438, 472, 502 purity > 95%. [0091] Example 44: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4- guanidinophenyl)-2-methylbenzamide.     [0092] Step 1: Synthesis of tert‐butyl N‐[(Z)‐[(4‐aminophenyl)amino]({[(tert‐butoxy) carbonyl]imino})methyl]carbamate. A flask was charged with 578 mg (3.19 mmol) of benzene-1,4- diamine dihydrochloride salt, 6 mL of N,N-dimethylformamide and 1240 (9.38 mmol) of N,N- diisopropylethylamine. The reaction was cooled in an ice water bath and tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate (989 mg, 3.19 mmol) was added at once and reaction slowly allowed to warm to room temp and stir for two days. Then 15 mL of water added and after 15 minutes of stirring the solid was collected and rinsed with 4 mL of water and dried for two hours to yield 800 mg of tert‐ butyl N‐[(Z)‐[(4‐aminophenyl)amino]({[(tert‐butoxy)carbonyl]imino})methyl]carbamate (72%).
Figure imgf000398_0001
[0093] Step 2: Synthesis of tert‐butyl N‐[(Z)‐{[4‐(4‐bromo‐2‐methylbenzamido) phenyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]carbamate. A flask was charged with 10 mL of chloroform, tert‐butyl N‐[(Z)‐[(4‐aminophenyl)amino]({[(tert‐butoxy)carbonyl] imino})methyl]carbamate (462 mg, 1.32 mmol) and (277 mg, 1.91 mmol) of N,N- diisopropylethylamine and cooled in an ice water bath. Then a solution of 280 mg (1.32 mmol) of 4- bromo-2-methylbenzoyl chloride in 5 mL of chloroform was added over three minutes. The reaction stirred at room temp for 18 hours and then solvent was removed under vacuum. Then 40 mL ethyl acetate and 20 mL of water added. The organic phase was dried and concentrated under vacuum to yield 610 mg of tert‐butyl N‐[(Z)‐{[4‐(4‐bromo‐2‐methylbenzamido)phenyl]amino}({[(tert‐ butoxy)carbonyl]imino})methyl]carbamate in 93 % yield.
Figure imgf000398_0002
[0094] Step 3: Synthesis of tert-butyl (Z)-4-(4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)phenyl)carbamoyl)-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 272 mg (0.498 mmol) of tert‐butyl N‐[(Z)‐{[4‐(4‐bromo‐ 2‐ methylbenzamido)phenyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]carbamate, 4.5 mg (0.020) of palladium acetate, 21mg (0.05 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 182     mg (0.588 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate, 2.5 mL of 1,4-dioxane and 1.0 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 5 mL of ethyl acetate and 750 mg of boc anhydride (3.44 mmol) added over one minute. After stirring for three hours, 20 mL of ethyl acetate and 15 mL of water were added; the organic phase washed with 20 mL of water, dried and concentrated under vacuum to yield tert-butyl (Z)-4-(4-((4-(2,3-bis(tert-butoxycarbonyl)guanidino)phenyl)carbamoyl)-3- methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000399_0001
[0095] Step 4: Synthesis of N-(4-guanidinophenyl)-2-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)benzamide. The tert-butyl (Z)-4-(4-((4-(2,3-bis(tert-butoxycarbonyl) guanidino)phenyl)carbamoyl)- 3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (320 mg, 0.48 mmol) was dissolved with 3 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum, concentrate triturated with 30 mL of ether to yield a solid in quantitative yield.
Figure imgf000399_0002
[0096] Step 5: Synthesis of tert-butyl (E)-(((tert-butoxycarbonyl)amino)(4-(4-((4- guanidinophenyl)carbamoyl)-3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)methylene) carbamate. A flask was charged with 310mg (0.48 mmol) of N-(4-guanidinophenyl)-2-methyl-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide mono trifluoroacetic acid salt, 2 mL of dichloromethane and 2 mL of N,N-dimethylformamide. Then 273 mg (2.7 mmol) of triethylamine was added over two minutes. Then 190 mg (0.63 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The next day the reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portions of water. The organic phase was dried and concentrated under vacuum to yield the tert-butyl (E)-(((tert-butoxycarbonyl)amino)(4-(4-((4-     guanidinophenyl)carbamoyl)-3-methyl phenyl)-3,6-dihydropyridin-1(2H)-yl)methylene)carbamate in quantitative yield.
Figure imgf000400_0001
[0097] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4- guanidinophenyl)-2-methylbenzamide. A flask was charged with 290 mg (0.480 mmol)of tert-butyl (E)-(((tert-butoxycarbonyl)amino)(4-(4-((4-guanidinophenyl)carbamoyl)-3-methylphenyl)-3,6- dihydropyridin-1(2H)-yl)methylene)carbamate, 3 mL dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and was purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-guanidinophenyl)-2- methylbenzamide was 58 mg (20 %). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.11 (s, 1 H) 9.28 (s, 1 H) 7.48 (d, J=8.79 Hz, 2 H) 6.98 - 7.16 (m, 6 H) 6.89 (d, J=8.79 Hz, 2 H) 5.96 (br s, 1 H) 3.78 (br s, 2 H) 2.20 - 2.32 (m, 2 H) 2.07 (s, 3 H). LC/MS method A: Rt = 2.5 mins., (M+H)+ =392, purity > 95%. [0098] Example 45: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)benzamide
Figure imgf000400_0002
[0099] Step 1: Synthesis of tert-butyl 4-(2-methyl-4-nitrophenyl)piperazine-1-carboxylate. A flask was charged with 3290 mg (15.3 mmol) of 1-bromo-2-methyl-4-nitrobenzene, 5690 mg (38.3 mmol) of tert-butyl piperazine-1-carboxylate, 68 mg (0.30 mmol) of palladium acetate, 316 mg (0.77mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 12400 mg (38.3 mmol) of cesium carbonate and 30 mL of 1,4-dioxane. The reaction was swept with nitrogen for 15 minutes and heated at 95oC for 18 hours. The reaction was cooled and 75 mL of ethyl acetate and 100 mL of water added. The organic phase was washed with two 75 mL portions of 10 % citric acid, two 50 mL portions of water, dried and concentrated under vacuum to yield tert-butyl 4-(2-methyl-4-nitrophenyl)piperazine- 1-carboxylate in quantitative yield.    
Figure imgf000401_0001
[0100] Step 2: Synthesis of tert-butyl 4-(4-amino-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 5120 mg (15.3 mmol) of tert-butyl 4-(2-methyl-4-nitrophenyl)piperazine-1- carboxylate, 30 mL of tetrahydrofuran, 30 mL of methanol, 2300 mg (38.3 mmol) of acetic acid and 8000 mg (157 mmol) of ammonium chloride. Then 5000 mg of zinc dust was added in three roughly equal portions over 30 minutes and reaction was warmed to 41oC over the weekend. The reaction was allowed to cool, filtered thru Celite, rinsed with ethyl acetate and methanol. The filtrate was concentrated under vacuum to yield 4.8 grams of a black oil in nearly quantitative yield.
Figure imgf000401_0002
[0101] Step 3: Synthesis of tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine- 1-carboxylate. A flask was charged with 15 mL of chloroform, tert-butyl 4-(4-amino-2- methylphenyl)piperazine-1-carboxylate (2200 mg, 7.77 mmol) and (1240 mg, 9.62 mmol) of N,N- diisopropylethylamine. Then a solution of 1610 mg (7.40 mmol) of 4-bromobenzoyl chloride in 13 mL of chloroform was added over ten minutes. The reaction stirred at room temp for two hours and solvent was removed under vacuum. Then 40 mL ethyl acetate and 20 mL of water added. The organic phase was dried and concentrated under vacuum to yield 3.4 grams (97%) of a brown solid.
Figure imgf000401_0003
[0102] Step 4: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)benzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 525 mg (1.11 mmol) of tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine-1- carboxylate, 10 mg (0.044) of palladium acetate, 45 mg ( 0.11 mmol) of 2-dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl, 418 mg (1.35 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 5 mL of 1,4-dioxane and 2.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 93oC for     three hours. The reaction was allowed to cool and diluted with 30 mL of ethyl acetate and washed with two 20 mL portions of water, dried and concentrated under vacuum to yield 740 mg of pro tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-2- methylphenyl)piperazine-1-carboxylate duct in quantitative yield.
Figure imgf000402_0001
[0103] Step 5: Synthesis of N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)benzamido)-2-methylphenyl)piperazine-1-carboxylate (740 mg , 1.11 mmol) was dissolved with 5 mL dichloromethane. Then dropwise addition of 7 mL (91 mmol) of trifluoroacetic acid was added over five minutes with stirring. Three hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000402_0002
[0104] Step 6: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-2-methylphenyl) piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 573 mg (0.95 mmol) of N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 6 mL dichloromethane and 7 mL of N,N-dimethylformamide. Then 537 mg (5.32 mmol) of triethylamine was added over two minutes. Then 677 mg (2.19 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was heated at 37oC for 18 hours. The next day the reaction was charged with 170 mg (0.55 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate and stirred at room temperature over the weekend. The reaction was concentrated under vacuum and 40 mL of ethyl acetate added. The organic washed with three 20 mL portions of water. The concentrate was dissolved with 10 mL of dichloromethane and 240 µl of 1- methylpiperidin-4-amine was added and stirred for two hours, concentrated under vacuum, dissolved with 30 mL ethyl acetate. Organic phase washed with 20 mL of water, 20 mL of 10% citric acid, 20     mL of water, dried and concentrated under vacuum. The concentrate dissolved with dichloromethane and chromatographed on silica with a step gradient from 0 to 100 % (20% acetonitrile/dichloromethane)/dichloromethane. Yield of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate was 570 mg (70%).
Figure imgf000403_0001
[0105] Step 7: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)benzamide. A flask was charged with 570 mg (0.67 mmol)of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)benzamido)-2-methylphenyl) piperazin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 9 mL (117 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum, slurried with 20% acetonitrile/water, frozen and freeze dried. Yield of 4- (1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide was 256 mg (57%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.07 (br s, 1 H) 7.97 (d, J=8.35 Hz, 2 H) 7.60 - 7.65 (m, 4 H) 7.05 (br d, J=9.23 Hz, 1 H) 6.36 (br s, 1 H) 3.65 - 3.70 (m, 2 H) 3.56 - 3.62 (m, 2 H) 3.15 - 3.18 (m, 2 H) 2.88 - 2.93 (m, 4 H) 2.76 (br d, J=2.20 Hz, 2 H) 2.67 (br s, 2 H) 2.31 (s, 3 H).LC/MS method A: Rt = 2.8 mins., (M+H)+ =461, purity > 95%. [0106] Example 46: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3- fluoro-N-(4-(guanidinomethyl)henyl)benzamide
Figure imgf000403_0002
[0107] Step 1: Synthesis of tert-butyl (4-(4-bromo-3-fluorobenzamido)benzyl) carbamate. A flask was charged with 5 mL of chloroform, tert-butyl (4-aminobenzyl)carbamate (357 mg, 1.61 mmol) and (323 mg, 2.50 mmol) of N,N-diisopropylethylamine. Then a solution of 424 mg (1.79 mmol) of 4- bromo-3-fluorobenzoyl chloride in 5 mL of chloroform was added over three minutes. The reaction was stirred at room temp for 18 hours. The next day the solvent was removed under vacuum. Then 5     mL of ethyl acetate and 10 mL of water were added and solids formed. After one hour of stirring the solids were collected, rinsed with 3 mL of ethyl acetate and air dried to yield 530 mg (70%).
Figure imgf000404_0001
[0108] Step 2: Synthesis of tert-butyl 4-(4-((4-(((tert-butoxycarbonyl)amino)methyl) phenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 320 mg (0.758 mmol) of tert-butyl (4-(4-bromo-3-fluorobenzamido)benzyl) carbamate, 7 mg (0.030) of palladium acetate, 31 mg (0.076 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 281 mg (0.91 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate, 4 mL of 1,4-dioxane and 1.4 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for three hours. The reaction was allowed to cool and diluted with 25 mL of ethyl acetate and washed with 15 mL of water, dried and concentrated under vacuum to yield 520 mg of of tert-butyl 4-(4-((4-(((tert-butoxycarbonyl) amino)methyl)phenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000404_0002
[0109] Step 3: Synthesis of 3-fluoro-N-(4-((methylamino)methyl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-((4-(((tert-butoxycarbonyl)amino) methyl)phenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (530 mg, 0.75mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 5 mL (65mmol) of trifluoroacetic acid was done over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in nearly quantitative yield.    
Figure imgf000405_0001
[0110] Step 4: Synthesis of tert‐butyl N‐[(E)‐({[4‐(4‐{1‐[(E)‐{[(tert‐butoxy)carbonyl] amino}({[(tert‐butoxy)-carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}‐3‐fluorobenzamido) phenyl]methyl}amino)({[(tert‐butoxy)carbonyl]imino})methyl]carbamate. A flask was charged with 382 mg (0.60 mmol) of 3-fluoro-N-(4-((methylamino)methyl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4- yl)benzamide bis trifluoroacetic acid salt, 2 mL dichloromethane and 2 mL of NN-dimethylformamide. Then 364 mg (3.60 mmol) of triethylamine was added over two minutes. Then 484 mg (1.56 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added and the reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and 40 mL of ethyl acetate added. The organic phase was washed with three 20 mL portions of water The concentrate was dissolved with 10 mL of dichloromethane and 240 ul of 1-methylpiperidin-4-amine added and stirred for two hours, concentrated under vacuum, dissolved with 30 mL ethyl acetate Organic phase washed with 20 mL water, 20 mL 10% citric acid, 20 mL of water, dried and concentrated under vacuum to yield the tert‐butyl N‐[(E)‐({[4‐(4‐{1‐[(E)‐{[(tert‐butoxy) carbonyl]amino}({[(tert‐butoxy)- carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}‐3‐fluoro benzamido)phenyl]methyl}amino)({[(tert‐butoxy)carbonyl]imino})methyl]carbamate in quantitative yield.
Figure imgf000405_0002
[0111] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N- (4-(guanidinomethyl)henyl)benzamide. A flask was charged with 533 mg (0.60 mmol) of tert‐butyl N‐ [(E)‐({[4‐(4‐{1‐[(E)‐{[(tert‐butoxy)carbonyl]amino}({[(tert‐ butoxy)carbonyl]imino}) methyl]‐     1,2,3,6‐tetrahydropyridin‐4‐yl}‐3‐fluorobenzamido)phenyl]methyl}amino)({[(tert‐ butoxy)carbonyl]imino})methyl]carbamate, 6 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum, dissolved with dimethylformamide and purified by reverse phase prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-(4- (guanidinomethyl)henyl) benzamide was 163 mg (43%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.02 (s, 1 H) 7.62 (br t, J=5.86 Hz, 1 H) 7.41 - 7.51 (m, 6 H) 7.23 (br t, J=7.91 Hz, 2 H) 7.16 (s, 3 H) 6.96 (d, J=8.79 Hz, 1 H) 5.84 (br s, 1 H) 4.00 (d, J=5.86 Hz, 2 H) 3.78 (br s, 2 H) 2.18 - 2.30 (m, 4 H).LC/MS method A: Rt = 2.6 mins., (M+H)+ = 410, 432 purity > 95%. [0112] Example 47: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-3-(trifluoromethyl)benzamide
Figure imgf000406_0001
[0113] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluorophenyl)-3-(trifluoromethyl) benzamide. A flask was charged with 10 mL of chloroform, 4-bromo-3-fluoroaniline (410 mg, 2.22 mmol) and (360 mg, 2.79 mmol) of N,N-diisopropylethylamine and cooled in an ice water bath. Then a solution of 340 mg (1.19 mmol) of 4-bromo-3-(trifluoromethyl)benzoyl chloride in 6 mL of chloroform was added over five minutes. The reaction stirred at room temp for 18 hours. The next day the solvent was removed under vacuum. Then 30 mL ethyl acetate and 20 mL of water were added. The organic phase was dried and concentrated under vacuum to yield 480 mg of 4-bromo-N-(4-bromo- 3-fluorophenyl)-3-(trifluoromethyl)benzamide in nearly quantitative yield.
Figure imgf000406_0002
[0114] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 332 mg (0.732 mmol) of 4-bromo-N-(4-bromo-3-fluorophenyl)-3- (trifluoromethyl)benzamide, 13 mg (0.059) of palladium acetate, 60 mg (0.146 mmol) of 2-     dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 521 mg (1.69 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 6 mL of 1,4-dioxane and 2.8 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 30 mL of ethyl acetate added over five minutes. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 500 mg of tert-butyl 4-(4-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6- dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000407_0001
[0115] Step 3: Synthesis of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6-dihydropyridine- 1(2H)-carboxylate (500 mg , 0.732 mmol) was dissolved with 3 mL dichloromethane. Then of 5 mL (650 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000407_0002
[0116] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 470 mg (0.70 mmol) of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 364 mg (3.60mmol) of triethylamine was added over two minutes. Then 520 mg (168 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three     20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000408_0001
[0117] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-3-(trifluoromethyl)benzamide. A flask was charged with 580 mg (0.68 mmol)of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl) benzamido)-2- fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate, 3 mL of dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-3- (trifluoromethyl)benzamide was 334 mg (65%).1H NMR (300 MHz, DMSO-d6) δ ppm 11.08 (s, 1 H) 8.68 (s, 1 H) 8.62 (br d, J=8.21 Hz, 1 H) 8.15 (dd, J=14.07, 1.76 Hz, 1 H) 7.92 - 8.02 (m, 2 H) 7.88 (br d, J=13.48 Hz, 6 H) 6.40 - 6.47 (m, 1 H) 6.10 (br s, 1 H) 4.45 (br s, 4 H) 4.00 (br t, J=5.86 Hz, 4 H) 2.95 (br s, 2 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ = 434, 505 purity > 95%. [0118] Example 48: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-fluorobenzamide B
Figure imgf000408_0002
[0119] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-2-fluorobenzamido)-2-methylphenyl) piperazine-1-carboxylate. A flask was charged with 10 mL of chloroform, tert-butyl 4-(4-amino-2- methylphenyl)piperazine-1-carboxylate (520 mg, 1.75mmol) and (420 mg, 3.26 mmol) of diisopropylethylamine and cooled in an ice water bath. Then a solution of 450 mg (1.90 mmol) of 4- bromo-2-fluorobenzoyl chloride in 8 mL of chloroform was added over five minutes. The reaction     stirred at room temp for 18 hours. The next day the solvent was removed under vacuum. Then 30 mL ethyl acetate and 20 mL of water were added. The organic phase was washed with 20 mL water, dried and concentrated under vacuum to yield 850 mg of tert-butyl 4-(4-(4-bromo-2-fluorobenzamido)-2- methylphenyl)piperazine-1-carboxylate. (99%)
Figure imgf000409_0001
[0120] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-fluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 296 mg (0.603 mmol) of tert-butyl 4-(4-(4-bromo-2-fluorobenzamido)-2-methylphenyl) piperazine-1- carboxylate, 5.4 mg (0.024) of palladium acetate, 25 mg (0.061 mmol) of 2-dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl, 243 mg (0.708 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.2 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 25 mL of ethyl acetate added over five minutes. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 380 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000409_0002
[0121] Step 3: Synthesis of 2-fluoro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-fluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate (380 mg , 0.60 mmol) was dissolved with 3 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum to yield a solid in quantitative yield.    
Figure imgf000410_0001
[0122] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-2-methylphenyl) piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 340 mg (0.50 mmol) of 2-fluoro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4- yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 303 mg (3.00mmol) of triethylamine was added over two minutes. Then 420 mg (1.35 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene) carbamate in a quantitative yield.
Figure imgf000410_0002
[0123] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-fluorobenzamide. A flask was charged with 560 mg (0.50 mmol)of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-(trifluoromethyl) benzamido)-2-fluorophenyl)-3,6-dihydropyridin-1(2H)- yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3-methylphenyl)-2-fluorobenzamide was 142 mg (34%).1H NMR (300 MHz, DMSO- d6) δ ppm 9.85 - 9.87 (m, 1 H) 7.11 - 7.20 (m, 11 H) 6.67 (br d, J=8.21 Hz, 1 H) 6.07 (br s, 1 H) 3.75 (br s, 2 H) 3.17 - 3.29 (m, 4 H) 2.51 (br s, 2 H) 2.15 - 2.22 (m, 6 H) 1.91 (br s, 3 H). LC/MS method A: Rt = 2.9 mins., (M+H)+ =479, purity > 95%.     [0124] Example 49: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)-3-fluorobenzamide.
Figure imgf000411_0001
[0125] Step 1: Synthesis of 4-bromo-N-(4-bromo-2-chlorophenyl)-3-fluorobenzamide. A flask was charged with 10 mL of chloroform, 4-bromo-2-chloroaniline (618 mg, 3.00 mmol) and (420 mg, 3.25 mmol) of diisopropylethylamine. Then a solution of 661 mg (2.80 mmol) of 4-bromo-3- fluorobenzoyl chloride in 10 mL of chloroform was added over five minutes. Then five mL of chloroform added to help stirring. The reaction stirred at room temp for four hours. Then the solvent was removed under vacuum. Then 8 mL ethyl acetate and 20 mL of water were added and suspension briefly sonicated. The solid was collected, rinsed with 3 mL of ether and was air dried for 18 hours to yield 1200 mg of 4-bromo-N-(4-bromo-2-chlorophenyl)-3-fluorobenzamide in nearly quantitative yield.
Figure imgf000411_0002
[0126] Step 2: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-chlorophenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 310 mg (0.765 mmol) of 4-bromo-N-(4-bromo-2-chlorophenyl)- 3-fluorobenzamide, 43 mg (0.061) of bis(triphenylphosphine)palladium chloride, 544 mg (1.76 mmol) of tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 2.9 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 55oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 5 mL of ethyl acetate added over five minutes. After 30 minutes the solid was collected on a funnel and rinsed with ether and air dried to yield 290 mg of tert-butyl 4-(4- ((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)carbamoyl)-2- fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate in 62% yield.    
Figure imgf000412_0001
[0127] Step 3: Synthesis of N-(2-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-fluoro-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (290 mg , 0.474 mmol) was dissolved with 4 mL dichloromethane. Then 5 mL (65 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000412_0002
[0128] Step 4: Synthesis of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)carbamoyl)-2-fluorophenyl) -3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 340 mg (0.47 mmol) of N-(2-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-fluoro-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 364 mg (3.60 mmol) of triethylamine was added over two minutes. Then 521 mg (1.68 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. The reaction was stirred at 36oC for three hours, then room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)carbamoyl)-2-fluorophenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate in a quantitative yield.
Figure imgf000412_0003
[0129] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)-3-fluorobenzamide. A flask was     charged with 460 mg (0.47 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)carbamoyl)-3-fluoro phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorophenyl)-3-fluoro benzamide was 622 mg (18%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.16 (s, 1 H) 7.75 - 7.84 (m, 2 H) 7.63 (d, J=1.76 Hz, 1 H) 7.51 - 7.59 (m, 3 H) 7.49 (br s, 6 H) 6.30 (br s, 1 H) 6.15 (br s, 1 H) 4.07 (br s, 4 H) 3.60 (br t, J=5.27 Hz, 4 H) 2.58 (br s, 4 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ =496, purity > 95%. [0130] Example 50: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-chlorobenzamide Br
Figure imgf000413_0001
[0131] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-2-chlorobenzamido)-2- methylphenyl)piperazine-1-carboxylate. A flask was charged with 6 mL of chloroform, tert-butyl 4-(4- amino-2-methylphenyl)piperazine-1-carboxylate (491 mg, 1.69 mmol) and (327mg, 2.54 mmol) of diisopropylethylamine. Then a solution of 426 mg (1.69 mmol) of 4-bromo-2-chlorobenzoyl chloride in 5 mL of chloroform was added over five minutes. The reaction stirred at room temp for 18 hours. The next day the solvent was removed under vacuum. Then 30 mL ethyl acetate and 20 mL of water were added, the organic phase was dried and concentrated under vacuum to yield 850 mg of tert-butyl 4-(4-(4-bromo-2-chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000413_0002
[0132] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged     with 302 mg (0.590 mmol) of tert-butyl 4-(4-(4-bromo-2-chlorobenzamido)-2-methylphenyl) piperazine-1-carboxylate, 21 mg (0.03 mmol) of Bis(triphenylphosphine)palladium chloride, 238 mg (0.769 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 55oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 25 mL of ethyl acetate added over five minutes. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 510 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000414_0001
[0133] Step 3: Synthesis of 2-chloro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate (510 mg, 0.769 mmol) was dissolved with 3 mL dichloromethane. Then 5 mL (65 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000414_0002
[0134] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorobenzamido)-2-methylphenyl)piperazin-1-yl) ((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 350 mg (0.48 mmol) of 2-chloro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 291 mg (2.88 mmol) of triethylamine was added over two minutes. Then 402 mg (1.30 mmol) of tert-butyl (1H- pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp over the weekend. Then 100 mg (0.32mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. Two hours later, the reaction was concentrated under vacuum and diluted with 30 mL of ethyl     acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'- bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-chlorobenzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl) amino)methylene)carbamate in a quantitative yield.
Figure imgf000415_0001
[0135] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-chlorobenzamide. A flask was charged with 490 mg (0.47 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-(trifluoromethyl)benzamido)-2-fluorophenyl)-3,6-dihydropyridin-1(2H)- yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin -4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)- 3-methylphenyl)-2-chlorobenzamide was 142 mg (43%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.33 - 7.37 (m, 1 H) 7.26 - 7.31 (m, 5 H) 7.03 - 7.14 (m, 6 H) 6.02 (d, J=8.79 Hz, 1 H) 5.14 (d, J=7.03 Hz, 2 H) 4.06 (br t, J=5.86 Hz, 2 H) 3.65 - 3.73 (m, 2 H) 3.41 - 3.50 (m, 2 H) 3.23 - 3.30 (m, 2 H) 2.51 (s, 3 H) 2.14 - 2.19 (m, 4 H). LC/MS Rt = 3.0 mins., (M+H)+ =496, purity > 95%. [0136] Example 51: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-methoxybenzamide
Figure imgf000415_0002
[0137] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-2-methoxybenzamido)-2-methylphenyl) piperazine-1-carboxylate. A flask was charged with 5 mL of chloroform, tert-butyl 4-(4-amino-2- methylphenyl)piperazine-1-carboxylate (785 mg, 2.70 mmol) and (490 mg, 3.80 mmol) of diisopropylethylamine. Then a solution of 608 mg (2.45 mmol) of 4-bromo-2-methoxybenzoyl chloride in 5 mL of chloroform was added over five minutes. The reaction was stirred at room temp for two hours. The next day the solvent was removed under vacuum. Then 40 mL ethyl acetate and 20 mL of     water were added, and the organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 940 mg of tert-butyl 4-(4-(4-bromo-2-methoxybenzamido)-2- methylphenyl)piperazine-1-carboxylate in 76% yield.
Figure imgf000416_0001
[0138] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methoxybenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 333 mg (0.654 mmol) of tert-butyl 4-(4-(4-bromo-2-methoxybenzamido)-2- methylphenyl)piperazine-1-carboxylate, 6.0 mg (0.026) of palladium acetate, 27 mg (0.65 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 263 mg (0.850 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 4 mL of 1,4-dioxane and 1.2 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 93oC for 18 hours.The reaction was allowed to cool and diluted with 20 mL water and 25 mL of ethyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum to yield 430 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methoxybenzamido)-2-methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000416_0002
[0139] Step 3: Synthesis of 2-methoxy-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methoxybenzamido)-2-methylphenyl)piperazine-1-carboxylate (430 mg, 0.65 mmol) was dissolved with 4 mL dichloromethane. Then 4 mL (65 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.    
Figure imgf000417_0001
[0140] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxybenzamido)-2-methylphenyl)piperazin-1- yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 460 mg (0.48 mmol) of 2-methoxy-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 303 mg (3.0 mmol) of triethylamine was added over two minutes. Then 434 mg (1.40 mmol) of tert-butyl (1H- pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The next day the reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'- bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxybenzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in quantitative yield.
Figure imgf000417_0002
[0141] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-methoxybenzamide. A flask was charged with 460 mg (0.47 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-methoxybenzamido)-2-methylphenyl)piperazin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3-methylphenyl)-2-methoxybenzamide was 97mg (28%).1H NMR (300 MHz, DMSO- d6) δ ppm 10.23 (s, 1 H) 7.95 (d, J=7.91 Hz, 1 H) 7.78 - 7.85 (m, 7 H) 7.48 (s, 1 H) 7.44 (d, J=8.35 Hz, 1 H) 7.28 - 7.34 (m, 1 H) 6.65 (br s, 1 H) 4.40 (br s, 2 H) 4.24 (s, 3 H) 3.93 (br t, J=5.49 Hz, 2 H) 3.85 (br s, 4 H) 3.44 (s, 2 H) 3.15 (br s, 2 H) 2.92 (br s, 2 H) 2.56 (s, 2 H) 2.48 (s, 3 H). LC/MS method A: Rt = mins., (M+H)+ =, purity > 95%.     [0142] Example 52: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-3-fluorobenzamide.
Figure imgf000418_0001
[0143] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-chlorophenyl)-3-fluorobenzamide. A flask was charged with 8 mL of chloroform and 583 mg (2.40 mmol) of 4-bromo-3-fluorobenzoyl chloride. Then a solution of 4-bromo-3-chloroaniline (510 mg, 2.48mmol) in 15 mL of chloroform was added over five minutes and (433mg, 3.36 mmol) of diisopropylethylamine was added dropwise over ten minutes. The reaction was stirred at room temp for four hours. Then the solvent was removed under vacuum. Then 8 mL ethyl acetate and 20 mL of water were added and suspension briefly sonicated. The solid was collected, rinsed with 3 mL of ether and was air dried for 18 hours to yield 940 mg of 4- bromo-N-(4-bromo-3-chlorophenyl)-3-fluorobenzamide in 97 % yield.
Figure imgf000418_0002
[0144] Step 2: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 334 mg (0.825 mmol) of 4-bromo-N-(4-bromo-3-chlorophenyl)- 3-fluorobenzamide, 46 mg (0.066) of bis(triphenylphosphine)palladium chloride, 586 mg (1.90 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,2-dioxane and 3.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 60oC for 18 hours. The reaction was allowed to cool and diluted with 15 mL water and 5 mL of ethyl acetate added over five minutes. After 30 minutes the solid was collected on a funnel and rinsed with ether and air dried to yield 170 mg of tert-butyl 4-(4- ((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)-2- fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate in 34% yield.    
Figure imgf000419_0001
[0145] Step 3: Synthesis of N-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-fluoro-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (290 mg, 0.474 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000419_0002
[0146] Step 4: Synthesis of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)-3-fluorophenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 300 mg (0.47 mmol) of N-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-fluoro-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N- dimethylformamide. Then 333 mg (3.30 mmol) of triethylamine was added over two minutes. Then 465 mg (1.50 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)- (4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- chlorophenyl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl) ((tert- butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000419_0003
[0147] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-3-fluorobenzamide. A flask was     charged with 460 mg (0.47 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)carbamoyl)-3- fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-3- fluorobenzamide was 102 mg (30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.71 - 10.77 (m, 1 H) 8.19 - 8.25 (m, 1 H) 8.03 - 8.11 (m, 1 H) 7.92 - 8.02 (m, 1 H) 7.82 - 7.87 (m, 1 H) 7.71 - 7.82 (m, 6 H) 7.53 - 7.59 (m, 1 H) 6.44 (br s, 1 H) 6.03 - 6.07 (m, 1 H) 4.34 (br d, J=16.41 Hz, 2 H) 3.82 - 3.91 (m, 4 H) 3.57 (br s, 2 H) 2.86 (br s, 2 H) 2.71 (dd, J=3.52, 1.76 Hz, 2 H). LC/MS Rt = 3.1 mins., (M+H)+ =496, purity > 95%. [0148] Example 53: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-3-chlorobenzamide.
Figure imgf000420_0001
[0149] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-3-chlorobenzamido)-2- methylphenyl)piperazine-1-carboxylate. A flask was charged with 5 mL of chloroform, 850 mg (2.92 mmol) of tert-butyl 4-(4-amino-2-methylphenyl)piperazine-1-carboxylate and (700 mg, 5.43 mmol) of diisopropylethylamine. Then the reaction was cooled in an ice water bath. Then a solution of 743 mg (2.95 mmol) of 4-bromo-3-chlorobenzoyl chloride in 10 mL of chloroform was added dropwise over ten minutes. The reaction was stirred at room temp for 18 hours. Then the solvent was removed under vacuum. Then 40 mL ethyl acetate and 20 mL of water were added. The organic phase was washed with 20 mL of water, dried and concentrated under vacuum to yield 1420 mg of tert-butyl 4-(4-(4- bromo-3-chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate in 99% yield.
Figure imgf000420_0002
    [0150] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 350 mg (0.690 mmol) of 4-bromo-N-(4-bromo-3-chlorophenyl)-3-fluorobenzamide, 25 mg (0.035) of bis(triphenylphosphine)palladium chloride, 270 mg (0.863 mmol) of tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 4 mL of 1,4- dioxane and 1.3 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 55oC for four hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of ethyl acetate added over five minutes. After 30 minutes the solid was collected on a funnel and rinsed with ether and air dried to yield 320 mg of tert-butyl 4-(4-(4-(1- (tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-methylphenyl) piperazine-1-carboxylate in 76% yield.
Figure imgf000421_0001
[0151] Step 3: Synthesis of 3-chloro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-3-chlorobenzamido)-2-methylphenyl)piperazine-1-carboxylate (320 mg, 0.530 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000421_0002
[0152] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-methylphenyl)piperazin-1- yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 290 mg (0.40 mmol) of 3-chloro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 280 mg (2.75 mmol) of triethylamine was added over two minutes. Then 434 mg (1.40 mmol) of tert-butyl (1H-     pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-methyl phenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in quantitative yield.
Figure imgf000422_0001
[0153] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-3-chlorobenzamide. A flask was charged with 460 mg (0.47 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-methylphenyl)piperazin-1-yl) ((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3-methylphenyl)-3-chlorobenzamide was 187 mg (65%).1H NMR (300 MHz, DMSO- d6) δ ppm 10.23 (s, 1 H) 7.95 (d, J=7.91 Hz, 1 H) 7.78 - 7.85 (m, 8 H) 7.48 (s, 1 H) 7.44 (d, J=8.35 Hz, 1 H) 7.28 - 7.34 (m, 1 H) 6.65 (br s, 1 H) 4.40 (br s, 2 H) 4.24 (s, 3 H) 3.93 (br t, J=5.49 Hz, 2 H) 3.85 (br s, 4 H) 3.44 (s, 2 H) 3.15 (br s, 2 H) 2.92 (br s, 2 H) 2.51 (s, 3 H).LC/MS method A: Rt = 3.0 mins., (M+H)+ =495, purity > 95%. [0154] Example 54: Synthesis of N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5- fluoro-2-methylphenyl)-4-(4-carbamimidoylpiperazin-1-yl)-3-fluorobenzamide. F F
Figure imgf000422_0002
[0155] Step 1: Synthesis of N-(4-bromo-5-fluoro-2-methylphenyl)-3,4-difluorobenzamide. A flask was charged with 10 mL of chloroform, 829 mg (4.66 mmol) of 4-bromo-5-fluoro-2- methylaniline and (733 mg, 5.68 mmol) of diisopropylethylamine. Then the reaction was cooled in an ice water bath and a solution of 708 mg (4.10 mmol) of 3,4-difluorobenzoyl chloride in 5 mL of     chloroform was added dropwise over 30 minutes. After two hours at room temp the solvent was removed under vacuum. Then 30 mL ethyl acetate and 20 mL of water were added. The organic phase was dried and concentrated under vacuum to yield 1400 mg of N-(4-bromo-5-fluoro-2-methylphenyl)- 3,4-difluorobenzamide in 79% yield.
Figure imgf000423_0001
[0156] Step 2: Synthesis of tert-butyl 4-(4-((4-bromo-5-fluoro-2-methylphenyl)carbamoyl)-2- fluorophenyl)piperazine-1-carboxylate. A pressure flask was charged with 1340 mg (3.90 mmol) of 4- bromo-N-(4-bromo-3-chlorophenyl)-3-fluorobenzamide, 2170 mg (11.7 mmol) of tert-butyl piperazine-1-carboxylate, 750 mg (5.85 mmol) of diisopropylethylamine and 5 mL of N- methylpyrrolidinone. The reaction was heated at 110oC for 18 hours and then 125oC for 18 hours. The reaction was cooled and charged with 1000 mg (2.70 mmol) of tert-butyl piperazine-1-carboxylate and 490 mg (3.80 mmol) of diisopropylethylamine and reaction heated at 130oC for 40 hours. The reaction was allowed to cool and was diluted with 80 mL of ethyl acetate and washed with 40 mL of water, two 40 mL portion of 10% citric acid and 40 mL of water. Then dried and concentrated under vacuum to yield 1600 mg of tert-butyl 4-(4-((4-bromo-5-fluoro-2-methylphenyl)carbamoyl)-2- fluorophenyl)piperazine-1-carboxylate as a yellow solid in 81% yield.
Figure imgf000423_0002
[0157] Step 3: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)carbamoyl)-2-fluorophenyl)piperazine-1- carboxylate. A flask was charged with 365 mg (0.72 mmol) of tert-butyl 4-(4-((4-bromo-5-fluoro-2- methylphenyl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate, 7 mg (0.029) palladium acetate, 30 mg ( 0.072 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 276 mg (0.90 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 4 mL of dioxane and 1.4 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept     with nitrogen for five minutes and heated at 95oC for four hours. The reaction was allowed to cool and diluted with 10 mL water and 4 mL of ethyl acetate added over five minutes. After for 18 hours age the solid was collected on a funnel and rinsed with ether and air dried to yield 260 mg of tert-butyl 4-(4- ((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl) carbamoyl)-2- fluorophenyl)piperazine-1-carboxylate in 56% yield.
Figure imgf000424_0001
[0158] Step 4: Synthesis of 3-fluoro-N-(5-fluoro-2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl) phenyl)-4-(piperazin-1-yl)benzamide. The tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetra hydropyridin-4-yl)-5-fluoro-2-methylphenyl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (260 mg, 0.403) was dissolved with 4 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000424_0002
[0159] Step 5: Synthesis of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)carbamoyl) -2-fluorophenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 260 mg (0.40 mmol) of 3-fluoro-N-(5-fluoro-2-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4-(piperazin-1-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 333 mg (3.30 mmol) of triethylamine was added over two minutes. Then 515 mg (1.65 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the of tert- butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin- 4-yl)-5-fluoro-2-methylphenyl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)((tert-butoxycarbonyl) amino)methylene)carbamate in a quantitative yield.    
Figure imgf000425_0001
[0160] Step 6: Synthesis of N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro- 2-methylphenyl)-4-(4-carbamimidoylpiperazin-1-yl)-3-fluorobenzamide. A flask was charged with 360 mg (0.40 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)carbamoyl) -2-fluorophenyl)piperazin-1- yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-4-(4- carbamimidoylpiperazin-1-yl)-3-fluoro benzamide was 94 mg (33%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.43 - 10.48 (m, 1 H) 8.25 - 8.30 (m, 1 H) 8.12 - 8.18 (m, 1 H) 7.84 (s, 1 H) 7.81 (br d, J=4.69 Hz, 1 H) 7.70 - 7.77 (m, 6 H) 7.26 - 7.31 (m, 1 H) 6.10 - 6.14 (m, 1 H) 4.33 (br s, 2 H) 3.84 - 3.91 (m, 2 H) 3.81 (br s, 2 H) 3.11 (br d, J=3.52 Hz, 2 H) 2.77 - 2.81 (m, 2 H) 2.69 - 2.73 (m, 2 H) 2.53 (s, 3 H) 2.51 (d, J=5.27 Hz, 2 H). LC/MS Rt = 2.9 mins., (M+H)+ =497, purity > 95%. [0161] Example 55: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-fluorophenyl)-2-methylbenzamide..
Figure imgf000425_0002
[0162] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate. A flask was charged with 2500 mg (15.7 mmol) of 1,2-difluoro-4-nitrobenzene, 3510 mg (18.9 mmol) of tert-butyl piperazine-1-carboxylate, 3240 mg (25.1 mmol) of diisopropylethylamine and 20 mL of N- methylpyrrolidinone. The reaction was heated at 70oC for two hours and then cooled and stood for 18 hours. The reaction was diluted with 60 mL water, aged for 30 minutes and the solid was collected, air dried for 30 minutes and directly reacted.
Figure imgf000425_0003
    [0163] Step 2: Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate. A flask was charged with 5040 mg (15.5 mmol) of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1- carboxylate, 30 mL of tetrahydrofuran, 30 mL of methanol, 8370 mg (155 mmol) of ammonium chloride and 2300 mg (39 mmol) of acetic acid. Then 5000 mg (77.5 mmol) of zinc dust was added in two roughly equal portions over 30 minutes and reaction was warmed to 45oC for three hours and room temp for 18 hours. The next day the reaction was filtered thru Celite, rinsed with ethyl acetate and methanol. The filtrate was concentrated under vacuum, concentrate diluted with 80 mL ethyl acetate and washed with 50 mL of water, 50 mL 10% citric and 50 mL of water, dried and concentrated under vacuum to yield 4.90 grams of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate in nearly quantitative yield.
Figure imgf000426_0001
[0164] Step 3: Synthesis of tert-butyl 4-(4-(4-bromo-2-methylbenzamido)-2- fluorophenyl)piperazine-1-carboxylate. A flask was charged with 10 mL of chloroform, 1020 mg (3.43 mmol) of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate and (590 mg, 4.60 mmol) of diisopropylethylamine. Then the reaction was cooled in an ice water bath and a solution of 759 mg (3.27 mmol) of 4-bromo-2-methylbenzoyl chloride in 3 mL of chloroform was added dropwise over five minutes. After four hours at room temp the solvent was removed under vacuum. Then 40 mL ethyl acetate and 30 mL of water were added. The organic phase was dried and concentrated under vacuum to yield 1200 mg of tert-butyl 4-(4-(4-bromo-2-methylbenzamido)-2-fluorophenyl)piperazine-1- carboxylate in 75% yield.
Figure imgf000426_0002
[0165] Step 4: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)piperazine-1-carboxylate. A flask was charged with 349 mg (0.711 mmol) of tert-butyl 4-(4-(4-bromo-2-methylbenzamido)-2- fluorophenyl)piperazine-1-carboxylate, 6 mg (0.029 mmol) palladium acetate, 30 mg ( 0.072 mmol) of     2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 263 mg (0.852 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.3 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 7 mL of ethyl acetate added over five minutes. After a 30-minute age the solid was collected on a funnel and rinsed with ether and air dried to yield 210 mg of tert-butyl 4-(4-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)piperazine-1- carboxylate in 51% yield.
Figure imgf000427_0001
[0166] Step 5: Synthesis of N-(3-fluoro-4-(piperazin-1-yl)phenyl)-2-methyl-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)piperazine-1-carboxylate (210 mg, 0.354) was dissolved with 4 mL dichloromethane. Then 5 mL (65 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000427_0002
[0167] Step 6: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)piperazin-1-yl) ((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 190 mg (0.30 mmol) of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2- fluorophenyl)piperazine-1-carboxylate bis trifluoroacetic acid salt, 3 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 363 mg (3.60 mmol) of triethylamine was added over two minutes. Then 558 mg (1.80 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-     methylbenzamido)-2-fluorophenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene) carbamate in a quantitative yield.
Figure imgf000428_0001
[0168] Step 7: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-fluorophenyl)-2-methylbenzamide. A flask was charged with 260 mg (0.30 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl) carbamoyl)-2-fluorophenyl)piperazin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)- 3-fluorophenyl)-2-methylbenzamide was 113 mg (53%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1 H) 7.69 (d, J=2.20 Hz, 1 H) 7.64 (d, J=2.20 Hz, 1 H) 7.47 (br d, J=5.28 Hz, 6 H) 7.34 - 7.42 (m, 4 H) 7.00 - 7.08 (m, 1 H) 6.26 (br s, 1 H) 4.08 (br s, 2 H) 3.62 (br t, J=5.72 Hz, 2 H) 3.56 (br s, 3 H) 3.42 (br s, 1 H) 3.14 (s, 1 H) 2.98 - 3.03 (m, 4 H) 2.86 (s, 1 H) 2.37 (s, 3H). LC/MS method A: Rt = 2.9 mins., (M+H)+ =479, purity > 95%. [0169] Example 56: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-3-fluorobenzamide
Figure imgf000428_0002
[0170] Step 1: Synthesis of 4-bromo-N-(4-bromo-5-fluoro-2-methylphenyl)-3-fluoro benzamide. A flask was charged with 15 mL of chloroform, 2180 mg (10.7 mmol) of 4-bromo-5-fluoro- 2-methylaniline and (1840 mg, 14.3 mmol) of diisopropylethylamine. Then the reaction was cooled in a cool water bath and a solution of 2410 mg (10.2 mmol) of 4-bromo-3-fluorobenzoyl chloride in 10 mL of chloroform was added dropwise over ten minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 10 mL ethyl acetate and 20 mL of water were added. Solids     formed, slurry sonicated briefly and stirred for 30 minutes and solid collected and air dried. The yield 3410 mg of 4-bromo-N-(4-bromo-5-fluoro-2-methylphenyl)-3-fluorobenzamide in 72% yield.
Figure imgf000429_0001
[0171] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 338 mg (0.83 mmol) of 4-bromo-N-(4-bromo-5-fluoro-2- methylphenyl)-3-fluorobenzamide, 15 mg (0.066 mmol) of palladium acetate, 68 mg ( 0.166 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 546 mg (1.92 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 3.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of ethyl acetate added over five minutes. After a 30-minute age the solid was collected on a funnel and rinsed with ether and air dried to yield 250 mg of tert-butyl 4-(4-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6- dihydropyridine-1(2H)-carboxylate in 49 % yield.
Figure imgf000429_0002
[0172] Step 3: Synthesis of 3-fluoro-N-(5-fluoro-2-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxy carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6-dihydro pyridine-1(2H)-carboxylate (250 mg, 0.41) was dissolved with 4 mL dichloromethane. Then dropwise addition of 6 mL (78 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.    
Figure imgf000430_0001
[0173] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluoro-5-methylphenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 190 mg (0.30 mmol) of 3-fluoro-N-(5-fluoro-2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 363 mg (3.60 mmol) of triethylamine was added over two minutes. Then 558 mg (1.80 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert- butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin- 4-yl)-3-fluorobenzamido)-2-fluoro-5-methyl phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000430_0002
[0174] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-3-fluorobenzamide. A flask was charged with 370 mg (0.41 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluoro-5- methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and purified by prep HPLC twice. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2- methylphenyl)-3-fluorobenzamide was 27 mg (9%).1H NMR (300 MHz, DMSO-d6) δ ppm 9.98 (s, 1 H) 7.74 - 7.82 (m, 2 H) 7.51 - 7.58 (m, 1 H) 7.48 (br d, J=7.62 Hz, 6 H) 7.29 (d, J=4.10 Hz, 1 H) 7.25     (s, 1 H) 6.14 (br s, 1 H) 6.02 (br s, 1 H) 4.06 (br d, J=7.03 Hz, 4 H) 3.59 (q, J=5.27 Hz, 4 H) 2.56 (br d, J=2.93 Hz, 4 H) 2.19 (s, 3 H). LC/MS Rt = 3.0 mins., (M+H)+ =494, purity > 95%. [0175] Example 57: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-3-chlorobenzamide
Figure imgf000431_0001
[0176] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-chlorophenyl)-3-chlorobenzamide. A flask was charged with 20 mL of chloroform, 3610 mg (17.4 mmol) of 4-bromo-3-chloroaniline and (3040 mg, 23.6 mmol) of diisopropylethylamine. Then a solution of 3960 mg (15.7 mmol) of 4-bromo-3- chlorobenzoyl chloride in 20 mL of chloroform was added dropwise over one hour. After stirring for three hours at room temp the solvent was removed under vacuum. Then 30 mL of ethyl acetate and 20 mL of water were added. Solids formed, slurry sonicated briefly and stirred for 18 hours. The next day the solid was collected and air dried for 18 hours. The yield was 3200 mg of 4-bromo-N-(4-bromo-3- chlorophenyl)-3-chlorobenzamide in 37 % yield.
Figure imgf000431_0002
[0177] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-3-chlorobenzamido)-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 289 mg (0.682 mmol) of 4-bromo-N-(4-bromo-3-chlorophenyl)-3-chlorobenzamide, 48 mg (0.068 mmol) of Bis(triphenylphosphine)palladium chloride, 464 mg (1.50 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 5 mL of 1,4- dioxane and 2.6 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 55oC for five hours. The reaction was allowed to cool and diluted with 25 mL water and 30 mL of ethyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum to yield the tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-chlorophenyl)-3,6-dihydro pyridine-1(2H)-carboxylate in quantitative yield.    
Figure imgf000432_0001
[0178] Step 3: Synthesis of 3-chloro-N-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (430 mg, 0.68) was dissolved with 3mL dichloromethane. Then 4 mL (52 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 10 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000432_0002
[0179] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorobenzamido)-2-chlorophenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 370 mg (0.570 mmol) of 3-chloro-N-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 2 mL dichloromethane and 4 mL of N,N- dimethylformamide. Then 630 mg (6.20 mmol) of triethylamine was added over two minutes. Then 600 mg (1.94 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)- (4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- chlorobenzamido)-2-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate in a quantitative yield.
Figure imgf000432_0003
[0180] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-3-chlorobenzamide. A flask was charged with 520 mg (0.57 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluoro-5-     methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 6 mL of dichloromethane and 8 mL (104 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-3- chlorobenzamide was 218 mg (52%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.50 (s, 1 H) 8.03 (d, J=1.76 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.88 - 7.92 (m, 1 H) 7.69 (dd, J=8.50, 2.05 Hz, 1 H) 7.44 - 7.53 (m, 7 H) 7.26 - 7.31 (m, 1 H) 5.85 (s, 1 H) 5.77 (s, 1 H) 4.04 (br d, J=5.86 Hz, 4 H) 3.59 (q, J=5.86 Hz, 4 H) 2.49 - 2.54 (m, 4 H).LC/MS method A: Rt = 3.2 mins., (M+H)+ =512, purity > 95%. [0181] Example 58: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-3-fluorobenzamide.
Figure imgf000433_0001
[0182] Step 1: Synthesis of 4-bromo-N-(4-bromo-2-methylphenyl)-3-fluorobenzamide. A flask was charged with 5 mL of chloroform, 960 mg (5.20 mmol) of 4-bromo-2-methylaniline and (849 mg, 6.60 mmol) of diisopropylethylamine. Then a solution of 1110 mg (4.7 mmol) of 4-bromo-3- fluorobenzoyl chloride in 5 mL of chloroform was added dropwise over ten minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 10 mL of ethyl acetate and 10 mL of water were added. Solids formed, slurry sonicated briefly and stirred for 30 minutes. The solid was collected and air dried for 18 hours. The yield was 2000 mg of 4-bromo-N-(4-bromo-2- methylphenyl)-3-fluorobenzamide in quantitative yield.
Figure imgf000433_0002
[0183] Step 2: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 385 mg (0780 mmol) of 4-bromo-N-(4-bromo-2-methylphenyl)- 3-fluorobenzamide, 14 mg (0.062 mmol) of palladium acetate, 64mg (0.156 mmol) of 2-     dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 578 mg (1.87 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 2.9 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of ethyl acetate added over five minutes. After one hour of stirring, the solids were collected, rinsed with ether and air dried to yield 250 mg (54%).
Figure imgf000434_0001
[0184] Step 3: Synthesis of 3-fluoro-N-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (250 mg, 0.42) was dissolved with 3mL dichloromethane. Then 4 mL (52 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000434_0002
[0185] Step 4: Synthesis of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-fluoro phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 260 mg (0.420 mmol) of 3-fluoro-N-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 2 mL dichloromethane and 4 mL of N,N-dimethylformamide. Then 630 mg (6.20 mmol) of triethylamine was added over two minutes. Then 520 mg (1.68 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water, dried and concentrated under vacuum to give the tert-butyl ((E)-(4-(4-((4-(1-     ((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl phenyl)carbamoyl)-2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate in a quantitative yield.
Figure imgf000435_0001
[0186] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-3-fluorobenzamide. A flask was charged with 370 mg (0.42 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2- fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 3 mL of dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-3- fluorobenzamide was 61 mg (21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.95 (s, 1 H) 7.74 - 7.84 (m, 2 H) 7.54 (br t, J=8.21 Hz, 2 H) 7.45 (br d, J=9.38 Hz, 6 H) 7.36 (s, 1 H) 7.30 (s, 1 H) 6.12 - 6.20 (m, 2 H) 4.03 - 4.11 (m, 4 H) 3.59 (q, J=5.86 Hz, 4 H) 2.57 (br s, 4 H) 2.21 (s, 3 H). LC/MS Rt = 2.9 mins., (M+H)+ =476, purity > 95%. [0187] Example 59: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-3-fluorobenzamide
Figure imgf000435_0002
[0188] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-3-fluorobenzamido)-2-methylphenyl) piperazine-1-carboxylate. A flask was charged with 5 mL of chloroform, 306 mg (1.05 mmol) of tert- butyl 4-(4-amino-2-methylphenyl)piperazine-1-carboxylate and (190 mg, 1.47mmol) of diisopropylethylamine. Then the reaction was cooled in an ice water bath and a solution of 271 mg (1.15 mmol) of 4-bromo-3-fluorobenzoyl chloride in 5 mL of chloroform was added dropwise over five minutes. After stirring for 18 hours at room temp, the solvent was removed under vacuum. Then 30 mL     ethyl acetate and 30 mL of water were added. The organic phase was dried and concentrated under vacuum to yield 420 mg of tert-butyl 4-(4-(4-bromo-3-fluorobenzamido)-2-methylphenyl) piperazine- 1-carboxylate in 82% yield.
Figure imgf000436_0001
[0189] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-3-fluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 270 mg (0.55 mmol) of tert-butyl 4-(4-(4-bromo-3-fluorobenzamido)-2-methylphenyl) piperazine-1- carboxylate, 5 mg (0.022 mmol) palladium acetate, 23 mg (0.055 mmol) of 2-dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl, 221 mg (0.715 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of ethyl acetate added over five minutes. After a 30-minute age the solid was collected on a funnel and rinsed with ether and air dried to yield 180 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate in 56% yield.
Figure imgf000436_0002
[0190] Step 3: Synthesis of 3-fluoro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-bromo-3-fluorobenzamido)-2-methyl phenyl)piperazine-1-carboxylate (180 mg, 0.308) was dissolved with 3 mL dichloromethane. Then dropwise addition of 4 mL (52 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000436_0003
    [0191] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-methylphenyl)piperazin-1-yl) ((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 190 mg (0.30 mmol) of from 3-fluoro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 630 mg (6.24 mmol) of triethylamine was added over two minutes. Then 516 mg (1.68 mmol) of tert-butyl (1H- pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with two 25 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a uantitative yield.
Figure imgf000437_0001
[0192] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-3-fluorobenzamide. A flask was charged with 260 mg (0.30 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)piperazin-1-yl) ((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)- 3-methylphenyl)-3-fluorobenzamide was 39 mg (18%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.16 (s, 1 H), 7.73 - 7.81 (m, 2 H), 7.56 (br s, 3 H), 7.49 - 7.54 (m, 6 H), 7.01 (d, J=8.79 Hz, 1 H), 6.14 (br s, 1 H), 4.08 (br s, 2 H), 3.60 (br t, J=5.57 Hz, 4 H), 3.53 (br d, J=1.76 Hz, 4 H), 2.84 (br s, 2 H), 2.57 (br s, 2 H), 2.25 (s, 3 H). LC/MS method A: Rt = 2.9 mins., (M+H)+ =479, purity > 95%. [0193] Example 60: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)benzamide. O H2N N NBoc O Br Br Cl HN N NBoc DIPEA, CHCl3     [0194] Step 1: Synthesis of tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine- 1-carboxylate. A flask was charged with 5 mL of chloroform, 625 mg (2.14 mmol) of tert-butyl 4-(4- amino-2-methylphenyl)piperazine-1-carboxylate and (352 mg, 2.73 mmol) of diisopropylethylamine. Then the reaction was cooled in an ice water bath and a solution of 424 mg (1.95 mmol) of 4- bromobenzoyl chloride in 5 mL of chloroform was added dropwise over five minutes. After stirring for 18 hours at room temp, the solvent was removed under vacuum. Then 30 mL ethyl acetate and 20 mL of water were added. The organic phase was dried and concentrated under vacuum to yield tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000438_0001
[0195] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)benzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 287mg (0.627 mmol) of tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine-1-carboxylate, 5.5 mg (0.026 mmol) palladium acetate, 25 mg (0.0607 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 220 mg (0.698 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5,6-dihydropyridine-1(2H)-carboxylate, 4 mL of 1,4-dioxane and 1.2 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 25 mL of isopropyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum to yield the tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-2-methyl phenyl)piperazine-1-carboxylate in a quantitative yield.
Figure imgf000438_0002
[0196] Step 3: Synthesis of N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-bromobenzamido)-2- methylphenyl)piperazine-1-carboxylate (390 mg, 0.67 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 4 mL (52 mmol) of trifluoroacetic acid was added over     five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000439_0001
[0197] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-2-methylphenyl) piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 334 mg (0.55 mmol) from N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl) benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 490 mg (3.79 mmol) of diisopropylethylamine was added over two minutes. Then 550 mg (1.77 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 20 mL of isopropyl acetate and organic phase was washed with two 20 mL portion of water to give the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydro pyridin-4-yl)benzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene) carbamate in a quantitative yield.
Figure imgf000439_0002
[0198] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)benzamide. A flask was charged with 470 mg (0.55 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)piperazin-1-yl)((tert-butoxy carbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3- methylphenyl)benzamide was 105 mg (28%).1H NMR (300 MHz, DMSO-d6) δ ppm 9.92 (s, 1 H) 7.72 - 7.78 (m, 2 H) 7.60 (d, J=9.38 Hz, 2 H) 7.50 (br d, J=9.96 Hz, 6 H) 7.08 (d, J=8.79 Hz, 1 H) 6.95 (d,     J=9.38 Hz, 2 H) 4.08 (br s, 2 H), 3.12 - 3.18 (m, 4 H) 2.94 (br s, 4 H) 2.47 (dt, J=3.96, 1.83 Hz, 4 H) 2.32 (s, 3 H). LC/MS Rt = 2.8 mins., (M+H)+ =461, purity > 95%. [0199] Example 61: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-3-fluorobenzamide.
Figure imgf000440_0001
[0200] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluorophenyl)-3-fluorobenzamide. A flask was charged with 7 mL of chloroform, 4-bromo-3-fluoroaniline (1080 mg, 5.30mmol) and (862mg, 6.68 mmol) of diisopropylethylamine and cooled in an ice water bath. Then a solution of 984 mg (4.17 mmol) of 4-bromo-3-fluorobenzoyl chloride in 3 mL of chloroform was added over five minutes. The reaction was stirred at room temp for two hours. Then the solvent was removed under vacuum. Then 20 mL of water were added and suspension briefly sonicated. After 30 minutes of stirring the solid was collected, rinsed with 3 mL of ether and was air dried for 18 hours to yield 1720 mg of 4-bromo-N-(4- bromo-3-fluorophenyl)-3-fluorobenzamide in 89 % yield.
Figure imgf000440_0002
[0201] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 290 mg (0.746 mmol) of 4-bromo-N-(4-bromo-3-fluorophenyl)-3- fluorobenzamide, 13 mg (0.068) of palladium acetate, 61mg (0.149 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 530 mg (1.72 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 2.8 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 25 mL of isopropyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum in quantitative yield.    
Figure imgf000441_0001
[0202] Step 3: Synthesis of 3-fluoro-N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (440 mg, 0.74 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 4 mL (52 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000441_0002
[0203] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluorophenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 420 mg (0.60 mmol) of 3-fluoro-N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 3 mL of N,N- dimethylformamide. Then 420 mg (4.16 mmol) of triethylamine was added over two minutes. Then 560 mg (1.80 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at 37oC for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert-butyl ((E)-(4-(4- (4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- fluorobenzamido)-2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino) methylene)carbamate in a quantitative yield.
Figure imgf000441_0003
[0204] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-3-fluorobenzamide. A flask was     charged with 530 mg (0.60 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorobenzamido)-2-fluorophenyl) -3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-3- fluorobenzamide was 15 mg (4%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H) 7.76 - 7.80 (m, 2 H) 7.72 (d, J=1.76 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 7.44 (br s, 3 H) 7.41 (s, 3 H) 7.39 (br s, 2 H) 6.17 (br s, 1 H) 6.03 (br s, 1 H) 4.04 - 4.11 (m, 4 H) 3.56 - 3.64 (m, 4 H) 3.37 - 3.38 (m, 2 H) 2.47 (s, 3 H) 2.22 - 2.40 (m, 4H).LC/MS Rt = 3.0 mins., (M+H)+ =480, purity > 95%. [0205] Example 62: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-3-methylbenzamide.
Figure imgf000442_0001
[0206] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methylphenyl)-3-methylbenzamide. A flask was charged with 1000 mg (4.31 mmol) of 4-bromo-3-methylbenzoyl chloride and 4 mL of chloroform. Then a solution of 4-bromo-3-methylaniline (833 mg, 4.55 mmol) and (778 mg, 6.03 mmol) of diisopropylethylamine and in 6 mL of chloroform was added over five minutes. The reaction was stirred at room temp for two hours. Then the solvent was removed under vacuum. and 20 mL of water were added and suspension briefly sonicated. After 30 minutes of stirring the solid was collected, rinsed with 3 mL of ether and was air dried for 18 hours to yield 1400 mg of 4-bromo-N-(4-bromo-3- methylphenyl)-3-methylbenzamide in 85 % yield.
Figure imgf000442_0002
[0207] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-     carboxylate. A flask was charged with 315 mg (0.829 mmol) of 4-bromo-N-(4-bromo-3- methylphenyl)-3-methylbenzamide, 19 mg ( 0.083) of palladium acetate, 68 mg (0.166 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 589 mg (1.90 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 3.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 20 mL of isopropyl acetate added over five minutes. The organic phase was dried and concentrated under vacuum in quantitative yield.
Figure imgf000443_0001
[0208] Step 3: Synthesis of 3-methyl-N-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)- 4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate (495 mg, 0.83 mmol) was dissolved with 4 mL dichloromethane. The 4 mL (52 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000443_0002
[0209] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzamido)-2-methylphenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 370 mg (0.60 mmol) of 3-methyl-N-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 3 mL of N,N- dimethylformamide. Then 700 mg (6.93 mmol) of triethylamine was added over two minutes. Then 510 mg (1.65 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at 37oC for 18 hours. The next day the reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water to give the tert- butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-     yl)-3-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000444_0001
[0210] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-3-methylbenzamide. A flask was charged with 530 mg (0.60 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzamido)-2-methyl phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-3-methyl benzamide was 161 mg (38%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.10 (s, 1 H) 7.75 - 7.83 (m, 2 H) 7.58 - 7.64 (m, 1 H) 7.45 - 7.50 (m, 1 H) 7.27 (d, J=7.92 Hz, 1 H) 7.11 (d, J=8.79 Hz, 1 H) 5.62 - 5.73 (m, 2 H) 4.05 - 4.11 (m, 4 H) 3.66 (q, J=5.72 Hz, 4 H) 2.54 (s, 3 H) 2.47 (s, 3 H) 2.22 - 2.40 (m, 4H).LC/MS Rt = 3.0 mins., (M+H)+ =472, purity > 95%. [0211] Example 63: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoylazetidin-3-yl)phenyl)-2-methylbenzamide.
Figure imgf000444_0002
[0212] Step 1: Synthesis of tert-butyl 3-(4-(4-bromo-2-methylbenzamido)phenyl)azetidine-1- carboxylate. A flask was charged with tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (280 mg, 1.13 mmol), (203 mg, 1.58 mmol) of diisopropylethylamine and 8 mL of dichloromethane. Then a solution of 275 mg (1.19 mmol) of 4-bromo-2-methylbenzoyl chloride in 2 mL of dichloromethane was added over three minutes. The reaction was stirred at room temp for 18 hours. Then the solvent was removed under vacuum and 25 mL of isopropyl acetate added. Organic phase was washed with 20 mL of water, 20 mL of 10% citric acid and 20 mL of water and concentrated under vacuum to yield 466 mg of tert-butyl 3-(4-(4-bromo-2-methylbenzamido)phenyl)azetidine-1-carboxylate in 93 % yield.    
Figure imgf000445_0001
[0213] Step 2: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl) carbamoyl)-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 466 mg (1.05 mmol) of tert-butyl 3-(4-(4-bromo-2-methylbenzamido)phenyl)azetidine-1-carboxylate, 10 mg ( 0.042) of palladium acetate, 45 mg (0.110 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 422 mg (1.35 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5,6-dihydropyridine-1(2H)-carboxylate, 5 mL of 1,4-dioxane and 2.1 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 30 mL of isopropyl acetate added over five minutes. The organic phase and concentrated under vacuum in quantitative yield.
Figure imgf000445_0002
[0214] Step 3: Synthesis of N-(4-(azetidin-3-yl)phenyl)-2-methyl-4-(1,2,3,6-tetrahydro pyridin-4-yl)benzamide. The tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl) carbamoyl)-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (570 mg, 1.05 mmol) was dissolved with 4 mL dichloromethane. Then 6 mL (78 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. The next day the solvent was removed under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000445_0003
[0215] Step 4: Synthesis of tert-butyl ((E)-(3-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)phenyl)azetidin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 550 mg (0.95 mmol) of N-(4- (azetidin-3-yl)phenyl)-2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid     salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 700 mg (6.93 mmol) of triethylamine was added over two minutes. Then 910 mg (2.93 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The next day the reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with 20 mL of water, 20 mL of 10% citric acid and 20 mL of water, dried and concentrated under vacuum to give the tert-butyl ((E)-(3-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)phenyl)azetidin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000446_0001
[0216] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoylazetidin-3-yl)phenyl)-2-methylbenzamide. A flask was charged with 790 mg (0.95 mmol) of tert-butyl ((E)-(3-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)phenyl)azetidin-1-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoylazetidin-3-yl)phenyl)-2-methylbenzamide was 120 mg (19%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.74 - 7.79 (m, 1 H) 7.46 - 7.50 (m, 1 H) 7.35 - 7.43 (m, 5 H) 6.25 - 6.29 (m, 1 H) 4.45 - 4.53 (m, 2 H) 4.04 - 4.14 (m, 4 H) 3.65 - 3.70 (m, 2 H) 3.16 - 3.20 (m, 2 H) 2.65 (br s, 3 H). LC/MS method A: Rt = 2.8 mins., (M+H)+ =432, purity > 95%. [0217] Example 64: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4- (1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamide Br
Figure imgf000446_0002
[0218] Step 1: Synthesis of tert-butyl 6-(4-bromo-2-methylbenzamido)-3,4-dihydro isoquinoline-2(1H)-carboxylate. A flask was charged with tert-butyl 6-amino-3,4-dihydroisoquinoline- 2(1H)-carboxylate (170 mg, .685 mmol), (124mg, 0.960 mmol) of diisopropylethylamine and 4 mL of     dichloromethane. Then a solution of 175 mg (0.754 mmol) of 4-bromo-2-methylbenzoyl chloride in 2 mL of dichloromethane was added over three minutes. The reaction was stirred at room temp for 18 hours. Then the solvent was removed under vacuum, 20 mL of isopropyl acetate added and washed with 20 mL of water, 20 mL of 10% citric acid and 20 mL of water and concentrated under vacuum to yield 333 mg of tert-butyl 6-(4-bromo-2-methylbenzamido)-3,4-dihydroisoquinoline-2(1H)- carboxylate in a quantitative yield.
Figure imgf000447_0001
[0219] Step 2: Synthesis of tert-butyl 6-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin- 4-yl)-2-methylbenzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate. A flask was charged with 333 mg (0.68 mmol) of tert-butyl 6-(4-bromo-2-methylbenzamido)-3,4-dihydroisoquinoline-2(1H)- carboxylate, 7 mg (0.030 mmol) of palladium acetate, 31 mg (0.075 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 301 mg (0.93 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.5 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 30 mL of isopropyl acetate, washed with 20 mL of water, dried and concentrated under vacuum to yield the tert-butyl 6-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate in quantitative yield.
Figure imgf000447_0002
[0220] Step 3: Synthesis of 2-methyl-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(1,2,3,6- tetrahydropyridin4-yl)benzamide. The tert-butyl 6-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-methylbenzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (370 mg, 0.68mmol) was dissolved with 4 mL dichloromethane. Then 6 mL (78 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. The next day the solvent was removed under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.    
Figure imgf000448_0001
[0221] Step 4: Synthesis of tert-butyl ((E)-(4-(4-((2-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)-3-methylphenyl)-3,6-dihydropyridin- 1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 334 mg (0.58 mmol) of 2-methyl-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl) benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 630 mg (6.24 mmol) of triethylamine was added over two minutes. Then 750 mg (2.32 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The next day the reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with 20 mL of water, 20 mL of 10% citric acid and 20 mL of water, dried and concentrated under vacuum to give the tert-butyl ((E)-(4-(4-((2-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)-3-methylphenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000448_0002
[0222] Step 5: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamide. A flask was charged with 480 mg (0.58 mmol) of tert-butyl ((E)-(4-(4-((2-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)-3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum, triturated with 20 mL of 1/1 isopropyl acetate/ether. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of N-(2-carbamimidoyl-1,2,3,4- tetrahydroisoquinolin-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamide was 26 mg (7%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (br s, 1 H) 7.72 (br s, 1 H) 7.56 (br d, J=8.79 Hz, 1 H) 7.38 - 7.49 (m, 3 H) 7.15 (br d, J=8.35 Hz, 1 H) 6.27 (br s, 1 H) 4.55 (s, 2 H) 3.65 (dt,     J=15.28, 5.77 Hz, 4 H) 3.17 (dt, J=3.08, 1.54 Hz, 2 H) 2.94 (br t, J=5.72 Hz, 2 H) 2.62 - 2.67 (m, 2 H) 2.43 (s, 3 H). LC/MS Rt = 2.7 mins., (M+H)+ =432, purity > 95%. [0223] Example 65: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2,6-difluorobenzamide.
Figure imgf000449_0001
[0224] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-2,6-difluorobenzamido)-2-methyl phenyl)piperazine-1-carboxylate. A flask was charged with 5 mL of dichloromethane, tert-butyl 4-(4- amino-2-methylphenyl)piperazine-1-carboxylate (257 mg, 0.883 mmol) and (145 mg, 1.12 mmol) of diisopropylethylamine. Then a solution of 205 mg (0.83 mmol) of 4-bromo-2,6-difluorobenzoyl chloride in 3 mL of dichloromethane was added over two minutes. The reaction stirred at room temp for two hours and solvent was removed under vacuum. Then 25 mL isopropyl acetate and 15 mL of water added. The organic phase was dried and concentrated under vacuum to yield 340 mg of tert-butyl 4-(4-(4-bromo-2,6-difluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000449_0002
[0225] Step 2: Synthesis of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,6- difluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 340 mg (0.82 mmol) of tert-butyl 4-(4-(4-bromo-2,6-difluorobenzamido)-2-methylphenyl)piperazine-1-carboxylate, 9 mg (0.040) of palladium acetate, 45mg ( 0.11 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 360 mg (1.92 mmol) of tert-butyl piperazine-1-carboxylate, 4 mL of 1,4-dioxane and 920mg (2.82 mmol) of cesium carbonate. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 25 mL of isopropyl acetate and washed with two 20 mL portions of water, dried and concentrated under vacuum to yield tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,6-difluorobenzamido)-2- methylphenyl)piperazine-1-carboxylate in quantitative yield.    
Figure imgf000450_0001
[0226] Step 3: Synthesis of 2,6-difluoro-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin- 1-yl)benzamide. The tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl) piperazin-1-yl)-2,6-difluorobenzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino) methylene)carbamate (505 mg, 0.82 mmol) was dissolved with 5 mL dichloromethane. Then dropwise addition of 7 mL (91 mmol) of trifluoroacetic acid was added over five minutes with stirring. Three hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000450_0002
[0227] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)piperazin-1-yl)-2,6-difluorobenzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxy carbonyl)amino)methylene)carbamate. A flask was charged with 450 mg (0.70 mmol) of 2,6-difluoro- N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1-yl)benzamide bis trifluoroacetic acid salt and 5 mL dichloromethane. Then 720 mg (7.13 mmol) of triethylamine was added over two minutes. Then 744 mg (2.40 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added and the reaction was stirred at room temp for 18 hours. The next day the reaction was concentrated under vacuum and 15 mL of isopropyl acetate added. The organic washed with 15 mL of 10% citric acid and 15 mL of water, dried and concentrated under vacuum to yield the tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'- bis(tert-butoxycarbonyl)carbamimidoyl)piperazin-1-yl)-2,6-difluoro benzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in quantitative yield.
Figure imgf000450_0003
[0228] Step 5: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3-methylphenyl)-2,6-difluorobenzamide. A flask was charged with 630 mg (0.70     mmol) tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)piperazin-1-yl)- 2,6-difluorobenzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum, dissolved with N,N-dimethylformamide, purified by prep HPLC. Yield of 4-(4- carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2,6-difluoro benzamide was 55 mg (10%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.49 - 7.53 (m, 2 H) 7.06 (s, 1 H) 6.75 (s, 1 H) 6.71 (s, 1 H) 3.60 (br d, J=3.52 Hz, 4 H) 3.45 (br d, J=5.28 Hz, 4 H) 3.17 (dt, J=2.86, 1.65 Hz, 4 H) 2.91 (br d, J=3.96 Hz, 4 H) 2.30 (s, 3 H). LC/MS method A: Rt = 2.8 mins., (M+H)+ =500, purity > 95%. [0229] Example 66:  Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-methylbenzamide. 
Figure imgf000451_0001
[0230] Step 1: Synthesis of tert-butyl 4-(4-(4-bromo-2-methylbenzamido)-2-methylphenyl) piperazine-1-carboxylate. A flask was charged with 3 mL of dichloromethane, tert-butyl 4-(4-amino- 2-methylphenyl)piperazine-1-carboxylate (330 mg, 1.13 mmol) and (186 mg, 1.44 mmol) of diisopropylethylamine. Then a solution of 240 mg (1.03 mmol) of 4-bromo-2-methylbenzoyl chloride in 1 mL of dichloromethane was added over two minutes. The reaction stirred at room temp for 18 hours. The next day the solvent was removed under vacuum. Then 10 mL isopropyl acetate and 15 mL of water added. The organic phase was dried and concentrated under vacuum to yield 390 mg of tert- butyl 4-(4-(4-bromo-2-methylbenzamido)-2-methylphenyl)piperazine-1-carboxylate in 87% yield.
Figure imgf000451_0002
[0231] Step 2: Synthesis of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- methylbenzamido)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 390 mg (0.90 mmol) of tert-butyl 4-(4-(4-bromo-2-methylbenzamido)-2-methylphenyl)piperazine-1-carboxylate, 8     mg (0.036 mmol) of palladium acetate, 37mg ( 0.09 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 337 mg (1.80 mmol) of tert-butyl piperazine-1-carboxylate, 4 mL of 1,4-dioxane and 733 mg (2.25 mmol) of cesium carbonate. The flask was swept with nitrogen for five minutes and heated at 95oC for for 18 hours.The reaction was allowed to cool and charged with 10 mg (0.045 mmol) of palladium acetate, 45 mg (0.11 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and swept with nitrogen for five minutes and heated at 95oC for 18 hours. Then reaction cooled and diluted with 20 mL of isopropyl acetate and washed with two 20 mL portions of water and concentrated under vacuum to yield the tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylbenzamido)-2- methylphenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000452_0001
[0232] Step 3: Synthesis of 2-methyl-N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1- yl)benzamide. The tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylbenzamido)-2- methylphenyl)piperazine-1-carboxylate (530 mg , 0.90 mmol) was dissolved with 5 mL dichloromethane. Then 5 mL (65 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000452_0002
[0233] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)piperazin-1-yl)-2-methylbenzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxy carbonyl)amino)methylene)carbamate. A flask was charged with 450 mg (0.70 mmol) of 2-methyl-N- (3-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1-yl)benzamide bis trifluoroacetic acid salt and 5 mL dichloromethane. Then 700 mg (6.93 mmol) of triethylamine was added over two minutes. Then 760 mg (2.41 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The next day 540 mg (1.74 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. After six hours of stirring the reaction was concentrated     under vacuum and 15 mL of isopropyl acetate added. The organic phase was washed with 15 mL of water, solids removed by filtration; organic phase was washed with 15 mL of 10% citric acid, washed with 15 mL of water, dried and concentrated under vacuum to yield the tert-butyl ((E)-(4-(4-(4-(4-((E)- N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)piperazin-1-yl)-2-methyl benzamido)-2- methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in quantitative yield.
Figure imgf000453_0001
[0234] Step 5: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3-methylphenyl)-2-methylbenzamide. A flask was charged with 630 mg (0.70 mmol)of tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)piperazin -1-yl)-2- methylbenzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene) carbamate, 4 mL of dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum, dissolved with N,N-dimethylformamide, purified by prep HPLC. Yield of 4-(4-carbamimidoylpiperazin-1-yl)- N-(4-(4-carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2-methylbenzamide was 212 mg (43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (s, 1 H) 7.47 (dd, J=8.57, 1.98 Hz, 1 H) 7.41 (br d, J=5.28 Hz, 1 H) 7.34 (d, J=8.35 Hz, 1 H) 6.98 (s, 1 H) 6.84 (s, 1 H) 3.51 - 3.58 (m, 4 H) 3.27 - 3.32 (m, 4 H) 3.10 (dt, J=3.41, 1.59 Hz, 4 H) 2.80 - 2.85 (m, 4 H) 2.35 (s, 3 H) 2.24 (s, 3 H). LC/MS Rt = 2.7 mins., (M+H)+ =478, purity > 95%. [0235] Example 67: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-2,6-difluorobenzamide
Figure imgf000453_0002
[0236] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methylphenyl)-2,6-difluorobenzamide. A flask was charged with 10 mL of dichloromethane, 1310 mg (7.04 mmol) of 4-bromo-3-methylaniline and (1150 mg, 9.00 mmol) of diisopropylethylamine. Then a solution of 1630 mg (6.40 mmol) of 4- bromo-2,6-difluorobenzoyl chloride in 5 mL of dichloromethane was added dropwise over ten minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 10 mL of     isopropyl acetate and 10 mL of water were added. Solids formed, slurry sonicated briefly and stirred for 30 minutes. The solid was collected and air dried for 18 hours. The yield was 1830 mg of 4-bromo- N-(4-bromo-3-methylphenyl)-2,6-difluorobenzamide in 71% yield.
Figure imgf000454_0001
[0237] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2,6-difluorobenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 315 mg (0778 mmol) of 4-bromo-N-(4-bromo-3-methylphenyl)-2,6-difluoro benzamide, 14 mg (0.062 mmol) of palladium acetate, 64 mg (0.156 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 578 mg (1.87 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 3.0 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of isopropyl acetate added over five minutes. After one hour of stirring, the solids were collected, rinsed with ether and air dried to yield 340 mg (72%).
Figure imgf000454_0002
[0238] Step 3: Synthesis of 2,6-difluoro-N-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxy carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,6-difluorobenzamido)-2-methylphenyl)-3,6-dihydro pyridine-1(2H)-carboxylate (340 mg, 0.56) was dissolved with 4 mL dichloromethane. Then 5 mL (52 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later, the reaction was concentrated under vacuum, triturated with 15 mL of 1/1 ether/ isopropyl acetate to yield a solid in quantitative yield.    
Figure imgf000455_0001
[0239] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,6-difluorobenzamido)-2-methylphenyl)- 3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 350 mg (0.48 mmol) of 2,6-difluoro-N-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 4 mL of N,N-dimethylformamide. Then 720 mg (7.13 mmol) of triethylamine was added over two minutes. Then 714 mg (2.30 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. The reaction was stirred at 37oC for two hours and room temp over the weekend. Then the reaction was concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with three 20 mL portion of water, dried and concentrated under vacuum to give the tert-butyl ((E)-(4-(4-(4-(1- ((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,6-difluoro benzamido)-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene) carbamate in a quantitative yield.
Figure imgf000455_0002
[0240] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-2,6-difluorobenzamide. A flask was charged with 430 mg (0.48 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,6-difluorobenzamido)-2-methyl phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-2,6- difluorobenzamide was 141 mg (41%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.53 (s, 1 H) 7.50 (s, 1 H) 7.39 - 7.46 (m, 1 H) 7.35 (d, J=9.23 Hz, 1 H) 7.12 (d, J=7.92 Hz, 1 H) 6.45 (s, 1 H) 5.63 (s, 1 H)     4.06 (br d, J=2.64 Hz, 2 H) 3.66 (q, J=6.01 Hz, 4 H) 3.15 - 3.18 (m, 2 H) 2.59 - 2.65 (m, 2 H) 2.41 - 2.47 (m, 2 H) 2.28 (s, 3 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ =494, purity > 95%. [0241] Example 68: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-2-methylbenzamide.
Figure imgf000456_0001
[0242] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methylphenyl)-2-methylbenzamide. A flask was charged with 25 mL of dichloromethane, 1220 mg (6.56 mmol) of 4-bromo-3-methylaniline and (1080 mg, 8.34 mmol) of diisopropylethylamine. Then a solution of 1400 mg (5.96 mmol) of 4- bromo-2-methyl benzoyl chloride in 10 mL of dichloromethane was added dropwise over 50 minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 35 mL of isopropyl acetate, washed with 20 mL 10% citric acid and 20 mL of water were added. The organic phase was concentrated under vacuum to yield 2200 mg of 4-bromo-N-(4-bromo-3-methylphenyl)-2- methylbenzamide in 88 % yield.
Figure imgf000456_0002
[0243] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 333 mg (0.870 mmol) of 4-bromo-N-(4-bromo-3- methylphenyl)-2-methylbenzamide, 16 mg (0.070 mmol) of palladium acetate, 72 mg (0.174 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 645 mg (2.09 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 8 mL of 1,4-dioxane and 3.3 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 15 mL water and 20 mL of isopropyl acetate added over five minutes. The organic phase was washed with 15 mL of water and concentrated to yield 510 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-     tetrahydropyridin-4-yl)-2-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate in quantitative yield.
Figure imgf000457_0001
[0244] Step 3: Synthesis of 2-methyl-N-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)- 4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate (510 mg, 0.87 mmol) was dissolved with 5 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later, the reaction was concentrated under vacuum, triturated with two portion of 15 mL of 1/1 ether/ isopropyl acetate to yield a solid in quantitative yield.
Figure imgf000457_0002
[0245] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-methylphenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 500 mg (0.80 mmol) of 2-methyl-N-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl) benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 4 mL of N,N-dimethylformamide. Then 713 mg (7.06 mmol) of triethylamine was added over two minutes. Then 794 mg (2.56 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp over the weekend. Then the reaction was concentrated under vacuum and diluted with 30 mL of isopropyl acetate and washed with 20 mL of 10% citric acid and 20 mL of water and concentrated under vacuum to give 700 mg of the tert-butyl ((E)-(4-(4-(4-(1-((E)- N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2- methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.    
Figure imgf000458_0001
[0246] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-2-methylbenzamide. A flask was charged with 430 mg (0.80 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-methyl phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate., 5 mL of dichloromethane and 8 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-methylphenyl)-2- methylbenzamide was 192 mg (34%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.53 - 7.59 (m, 2 H) 7.44 - 7.48 (m, 1 H) 7.41 (s, 1 H) 7.34 - 7.39 (m, 1 H) 7.09 (d, J=8.35 Hz, 1 H) 6.26 (br s, 1 H) 5.63 (br s, 1 H) 4.12 (br d, J=3.08 Hz, 2 H) 4.06 (br d, J=3.08 Hz, 2 H) 3.62 - 3.70 (m, 2 H) 2.77 (dt, J=3.85, 1.81 Hz, 2 H) 2.63 - 2.68 (m, 2 H) 2.43 (s, 3 H) 2.32 (dt, J=3.63, 1.92 Hz, 2 H) 2.28 (s, 3 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ =472, purity > 95%.%). [0247] Example 69: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methylbenzamide.
Figure imgf000458_0002
[0248] Step 1: Synthesis of 4-bromo-N-(4-bromophenyl)-3-methylbenzamide. A flask was charged with 7 mL of dichloromethane, 622 mg (3.62 mmol) of 4-bromoaniline and (607 mg, (4.71 mmol) of diisopropylethylamine and cooled in ice water bath. Then a solution of 802 mg (3.44 mmol) of 4-bromo-3-methylbenzoyl chloride in 8 mL of dichloromethane was added dropwise over five minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 10 mL of ethyl acetate added and stirred for 30 minutes. The solid was collected, air dried to yield 730 mg of 4-bromo-N-(4-bromophenyl)-3-methylbenzamide in 58 % yield.    
Figure imgf000459_0001
[0249] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-3-methylbenzamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 310 mg (0.84 mmol) of 4-bromo-N-(4-bromophenyl)-3-methylbenzamide, 15 mg (0.067 mmol) of palladium acetate, 69 mg (0.168 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 597mg (1.93 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5,6-dihydropyridine-1(2H)-carboxylate, 8 mL of 1,4-dioxane and 3.2 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 30 mL of isopropyl acetate added over five minutes. The organic phase was washed with 20 mL of water and concentrated to yield 510 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3- methylbenzamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000459_0002
[0250] Step 3: Synthesis of 3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-3-methylbenzamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (480 mg, 0.84 mmol) was dissolved with 5 mL dichloromethane. Then dropwise addition of 6 mL (78 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later, the reaction was concentrated under vacuum, triturated with two portion of 20 mL (1/1 ether/ isopropyl acetate) to yield a solid in quantitative yield.
Figure imgf000459_0003
[0251] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzamido)phenyl)-3,6-dihydropyridin-1     (2H)-yl)((tert-butoxy carbonyl)amino)methylene)carbamate. A flask was charged with 390 mg (0.65 mmol) of 3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 526 mg (5.21 mmol) of triethylamine was added over two minutes. Then 720 mg (2.32 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. Then the reaction was concentrated under vacuum and diluted with 25 mL of isopropyl acetate and washed with 5 mL of 10% citric acid and 15 mL of water and concentrated under vacuum to give 560 mg of the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzamido)phenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a nearly quantitative yield.
Figure imgf000460_0001
[0252] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-methylbenzamide. A flask was charged with 560 mg (0.65 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzamido)phenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-3-methylbenzamide was 121 mg (28%). 1H NMR (300 MHz, DMSO- d6) δ ppm 1H NMR (300 MHz, DMSO-d6) δ ppm 10.18 (s, 1 H) 7.80 - 7.83 (m, 2 H) 7.75 - 7.79 (m, 2 H) 7.45 - 7.50 (m, 2 H) 7.28 (d, J=7.92 Hz, 1 H) 6.16 - 6.20 (m, 1 H) 5.69 - 5.73 (m, 1 H) 4.10 (br dd, J=4.40, 3.08 Hz, 4 H) 3.67 (td, J=5.61, 2.42 Hz, 4 H) 2.77 (dt, J=3.85, 4 H) 2.38 (s, 3 H).LC/MS Rt = 3.0 mins., (M+H)+ =458, purity > 95%. [0253] Example 70: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-2-methylbenzamide.     Br
Figure imgf000461_0001
[0254] Step 1: Synthesis of 4-bromo-N-(4-bromo-2-methylphenyl)-2-methylbenzamide. A flask was charged with 5 mL of dichloromethane, 986 mg (5.30 mmol) of 4-bromo-3-methylaniline and (877 mg, 6.80 mmol) of diisopropylethylamine. Then a solution of 1180 mg (5.04 mmol) of 4- bromo-2-methyl benzoyl chloride in 5 mL of dichloromethane was added dropwise over 30 minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 5 mL of isopropyl acetate and 10 mL of water were added. After 30 minutes of stirring the solid was collected and air dried to yield 1800 mg of 4-bromo-N-(4-bromo-2-methylphenyl)-2-methylbenzamide in 93 % yield.
Figure imgf000461_0002
[0255] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate. A flask was charged with 400 mg (1.04 mmol) of 4-bromo-N-(4-bromo-2-methylphenyl)- 2-methylbenzamide, 19 mg (0.083 mmol) of palladium acetate, 85 mg (0.208 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 775 mg (2.50 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 8 mL of 1,4-dioxane and 3.9 mL of 2.0 molar potassium carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 25 mL of isopropyl acetate added over five minutes. The organic phase was washed with 20 mL of water and concentrated under vacuum to yield 610 mg of tert-butyl 4-(4-(4-(1-(tert- butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6- dihydropyridine-1(2H)-carboxylate in quantitative yield.    
Figure imgf000462_0001
[0256] Step 3: Synthesis of 2-methyl-N-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)- 4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate (510 mg, 0.87 mmol) was dissolved with 5 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later, the reaction was concentrated under vacuum, triturated with two portion of 15 mL of 1/1 ether/ isopropyl acetate to yield a solid in quantitative yield.
Figure imgf000462_0002
[0257] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 530 mg (0.85 mmol) of 2-methyl-N-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 4 mL of N,N- dimethylformamide. Then 630 mg (6.23 mmol) of triethylamine was added over two minutes. Then 790 mg (2.55 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp over the weekend. The reaction was then charged with 110 mg (0.345 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate and reaction stirred for three hours. Then the reaction was concentrated under vacuum and diluted with 30 mL of isopropyl acetate and washed with 30 mL of 10% citric acid, 20 mL of water and concentrated under vacuum to give 740 mg of the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate in a nearly quantitative yield.    
Figure imgf000463_0001
[0258] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-2-methylbenzamide. A flask was charged with 740 mg (0.85 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2- methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 5 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for three hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-2- methylbenzamide was 172 mg (29%).1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1 H) 7.45 - 7.50 (m, 1 H) 7.37 - 7.41 (m, 1 H) 7.31 - 7.37 (m, 2 H) 7.25 - 7.30 (m, 1 H) 6.19 - 6.23 (m, 1 H) 6.13 (m, 1 H) 3.61 (td, J=5.61, 2.86 Hz, 3 H) 3.11 (dt, J=3.19, 1.70 Hz, 6 H) 2.58 (br d, J=3.52 Hz, 2 H) 2.42 (s, 3 H) 2.23 - 2.26 (s, 3 H). LC/MS method A: Rt = 2.9 mins., (M+H)+ =472, purity > 95%. [0259] Example 71: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-2-methylphenyl)-2-methylbenzamide.
Figure imgf000463_0002
[0260] Step 1: Synthesis of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- methylbenzamido)-3-methylphenyl)piperazine-1-carboxylate. A flask was charged with 320 mg (0.84 mmol) of 4-bromo-N-(4-bromo-2-methylphenyl)-2-methylbenzamide, 15 mg (0.067 mmol) of palladium acetate, 69 mg (0.167 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 622 mg (3.34 mmol) of tert-butyl piperazine-1-carboxylate, 4 mL of 1,4-dioxane and 1330 mg (4.18 mmol) of cesium carbonate. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL water and 5 mL of isopropyl acetate added over five minutes. Solids formed and reaction stirred for 30 minutes; then solids collected and air dried     to yield 320 mg of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylbenzamido)-3- methylphenyl)piperazine-1-carboxylate in 64 % yield.
Figure imgf000464_0001
[0261] Step 2: Synthesis of 2-methyl-N-(2-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1- yl)benzamide. The tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylbenzamido)-3- methylphenyl)piperazine-1-carboxylate (320 mg, 0.54 mmol) was dissolved with 3 mL dichloromethane. Then dropwise addition of 3 mL (42 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two portions of 20 mL of ether to yield a solid in quantitative yield.
Figure imgf000464_0002
[0262] Step 3: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 340 mg (0.54 mmol) of 2-methyl-N-(2-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 720 mg (7.13 mmol) of triethylamine was added over two minutes. Then 837 mg (2.70 mmol) of tert-butyl (1H- pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. Then the reaction was concentrated under vacuum and diluted with 25 mL of isopropyl acetate and washed with 25 mL of 10% citric acid, 15 mL of water and concentrated under vacuum to give 470 mg of the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl) ((tert- butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000464_0003
    [0263] Step 4: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-2-methylphenyl)-2-methylbenzamide. A flask was charged with 470 mg (0.54 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert- butoxycarbonyl)amino)methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2-methylphenyl)- 2-methylbenzamide was 161 mg (43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.48 (br d, J=8.35 Hz, 1 H) 7.22 (br d, J=8.79 Hz, 1 H) 6.82 - 6.91 (m, 4 H) 4.19 - 4.25 (m, 2 H) 4.11 - 4.16 (m, 2 H) 3.60 (br d, J=3.96 Hz, 4 H) 3.32 - 3.38 (m, 4 H) 3.20 - 3.26 (m, 4 H) 2.44 (s, 3 H) 2.24 (s, 3 H).LC/MS method A: Rt = 2.5 mins., (M+H)+ =478, purity > 95%. [0264] Example 72: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)phenyl)-3-methylbenzamide
Figure imgf000465_0001
[0265] Step 1: Synthesis of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3- methylbenzamido)phenyl)piperazine-1-carboxylate. A flask was charged with 326 mg (0.883 mmol) of 4-bromo-N-(4-bromophenyl)-3-methylbenzamide, 16 mg (0.071 mmol) of palladium acetate, 73 mg (0.177 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 657 mg (3.53 mmol) of tert-butyl piperazine-1-carboxylate, 3.5 mL of 1,4-dioxane and 1440 mg (4.42 mmol) of cesium carbonate. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 7 mL of isopropyl acetate added over five minutes. Solids formed and reaction stirred for one hour; then solids collected and air dried to yield 510 mg of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzamido) phenyl)piperazine-1- carboxylate in quantitative yield.
Figure imgf000465_0002
    [0266] Step 2: Synthesis of 3-methyl-4-(piperazin-1-yl)-N-(4-(piperazin-1- yl)phenyl)benzamide. The tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- methylbenzamido)-3-methylphenyl)piperazine-1-carboxylate (510 mg, 0.88 mmol) was dissolved with 4 mL dichloromethane. Then 6 mL (78 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two portions of 20 mL of ether to yield a solid in quantitative yield.
Figure imgf000466_0001
[0267] Step 3: Synthesis of tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)piperazin-1-yl)-3-methylbenzamido)phenyl)piperazin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 430 mg (0.700 mmol) of 3- methyl-4-(piperazin-1-yl)-N-(4-(piperazin-1-yl)phenyl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 637 mg (6.30 mmol) of triethylamine was added over two minutes. Then 716 mg (2.31 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. The reaction was heated at 40o.C for 18 hours. After four hours of heating an addition charge of 160 mg (0.516 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was made. After heating for 18 hours the reaction was cooled was concentrated under vacuum; diluted with 25 mL of isopropyl acetate and washed with 25 mL of 10% citric acid, 15 mL of water and concentrated under vacuum to give 605 mg of the tert-butyl ((E)-(4-(4- (4-(4-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)piperazin-1-yl)-3-methylbenzamido) phenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000466_0002
[0268] Step 4: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)phenyl)-3-methylbenzamide. A flask was charged with 605 mg (0.70 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-3-methylphenyl)-3,6-dihydropyridin-1(2H)-yl) ((tert- butoxycarbonyl)amino)methylene)carbamate, 5 mL of dichloromethane and 7 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for two hours. The reaction was     concentrated under vacuum. Liquid was diluted with N,N-dimethylformamide and purified by prep HPLC. Yield of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-3- methylbenzamide was 279 mg (58%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.92 (s, 1 H) 7.72 - 7.79 (m, 2 H) 7.60 (d, J=9.38 Hz, 2 H) 7.50 (br d, J=9.96 Hz, 6 H) 7.08 (d, J=8.79 Hz, 1 H) 6.95 (d, J=9.38 Hz, 2 H) 3.11 - 3.18 (m, 4 H) 2.94 (br s, 4 H) 2.47 (dt, J=3.96, 1.83 Hz, 4 H) 2.32 (s, 3 H). LC/MS method A: Rt = 2.6 mins., (M+H)+ =464, purity > 95%. [0269] Example 73: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-2-methylbenzamide
Figure imgf000467_0001
[0270] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluorophenyl)-2-methylbenzamide. A flask was charged with 2.5 mL of dichloromethane and 450 mg (1.92 mmol) of 4-bromo-2-methyl benzoyl chloride. Then a solution of 401 mg (2.11 mmol) of 4-bromo-3-fluoroaniline and (334 mg, 2.59 mmol) of diisopropylethylamine in 2.5 mL of dichloromethane was added dropwise over ten minutes. After stirring for 18 hours at room temp the solvent was removed under vacuum. Then 3 mL of ethyl acetate and 5 mL of water were added. The organic phase was dried and concentrated under vacuum, triturated with 5 mL ether, solid collected and air dried to yield 420 mg of 4-bromo-N-(4- bromo-3-fluorophenyl)-2-methylbenzamide in 57 % yield.
Figure imgf000467_0002
[0271] Step 2: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 310 mg (0.80 mmol) of 4-bromo-N-(4-bromo-2-methylphenyl)-2-methylbenzamide, 14 mg (0.062 mmol) of palladium acetate, 66 mg (0.16 mmol) of 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl, 593 mg (1.92 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5,6-dihydropyridine-1(2H)-carboxylate, 7 mL of 1,4-dioxane and 3.0 mL of 2.0 molar potassium     carbonate aqueous solution. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 20 mL water and 30 mL of ethyl acetate added over five minutes. The organic phase was washed with 20 mL of water and concentrated to yield 480 mg of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- methylbenzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate in quantitative yield.
Figure imgf000468_0001
[0272] Step 3: Synthesis of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (480 mg, 0.80 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 7 mL (91 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later, the reaction was concentrated under vacuum, triturated with two portion of 20 mL of 1/1 ether/ isopropyl acetate to yield a solid in quantitative yield.
Figure imgf000468_0002
[0273] Step 4: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluorophenyl)-3,6-dihydro pyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 460 mg (0.65 mmol) of N-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-methyl-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 4 mL dichloromethane and 3 mL of N,N- dimethylformamide. Then 600 mg (5.94 mmol) of triethylamine was added over two minutes. Then 594 mg (1.69 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at room temp for 18 hours. The reaction was concentrated under vacuum and diluted with 30 mL of isopropyl acetate and washed with 20 mL of 10% citric acid , 20 mL of water and concentrated under vacuum to give 570 mg of the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluoro     phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a nearly quantitative yield.
Figure imgf000469_0001
[0274] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-2-methylbenzamide. A flask was charged with 570 mg (0.65 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylbenzamido)-2-fluoro phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 4 mL of dichloromethane and 6 mL (78 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for three hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluorophenyl)-2-methyl benzamide was 171 mg (37%).1H NMR (300 MHz, DMSO-d6) δ ppm 10.49 (s, 1 H) 7.76 - 7.77 (m, 1 H) 7.73 (br dd, J=14.07, 1.76 Hz, 1 H) 7.46 - 7.52 (m, 1 H) 7.38 - 7.44 (m, 2 H) 7.33 - 7.38 (m, 1 H) 6.25 - 6.30 (m, 1 H) 6.02 - 6.06 (m, 1 H) 3.61 - 3.70 (m, 4 H) 3.18 (dt, J=3.19, 1.70 Hz, 4 H) 2.57 - 2.68 (m, 4 H) 2.43 (s, 3 H). LC/MS method A: Rt = 3.0 mins., (M+H)+ =476, purity > 95%. [0275] Example 74: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-2-methylphenyl)benzamide.
Figure imgf000469_0002
[0276] Step 1: Synthesis of tert-butyl 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylate. A flask was charged with 3150 mg (20.3 mmol) of 4-fluoro-2-methyl-1-nitrobenzene, 20 mL of N,N- dimethylformamide and 3960 mg (21.3 mmol) of tert-butyl piperazine-1-carboxylate. The reaction was warmed to 37oC, 3530 mg (27.4 mmol) of diisopropylethylamine was added over 30 minutes. After three hours the reaction temperature was increased to 60oC for 18 hours. The reaction was cooled and 40 mL of water added and reaction stirred for 30 minutes. The solid was collected on a filter and rinsed with 25 mL of ether to yield 5200 mg (80%) of a yellow solid after air drying for two hours.    
Figure imgf000470_0001
[0277] Step 2: Synthesis of tert-butyl 4-(4-amino-3-methylphenyl)piperazine-1-carboxylate. A flask was charged with 5200 mg (16.2 mmol) of tert-butyl 4-(2-methyl-4-nitrophenyl)piperazine-1- carboxylate, 35 mL of tetrahydrofuran, 35 mL of methanol, 600 mg (10.0 mmol) of acetic acid and 6500 mg (120 mmol) of ammonium chloride. Then 6500 mg (100 mmol) of zinc dust was added one portion and after one hour the reaction was warmed to 40oC for three hours and at room temp over the weekend. The reaction was filtered thru Celite, rinsed with ethyl acetate and methanol. The filtrate was concentrated under vacuum, triturated with 25 mL of ethyl acetate, filtered, concentrated under vacuum to yield 4.3 grams of a black oil in 91 % yield.
Figure imgf000470_0002
[0278] Step 3: Synthesis of tert-butyl 4-(4-(4-bromobenzamido)-3-methylphenyl)piperazine- 1-carboxylate. A flask was charged with 1 mL of dichloromethane, 1mL of NN-dimethylformamide and 337 mg (1.54 mmol) of 4-bromobenzoyl chloride. Then a solution of tert-butyl 4-(4-amino-3- methylphenyl)piperazine-1-carboxylate (435 mg, 1.50 mmol) and (251 mg, 1.95 mmol) of diisopropylethylamine in a mixture of 2 mL dichloromethane and 2 mL dimethylformamide was added over ten minutes. The reaction stirred at room temp for two hours and dichloromethane was removed under vacuum. Then 3 mL ethyl acetate and 10 mL of water added. Solids formed and after 30 minutes of stirring, the solid was collected and air dried to yield 320 mg (45%) of tert-butyl 4-(4-(4- bromobenzamido)-3-methylphenyl)piperazine-1-carboxylate. B
Figure imgf000470_0003
[0279] Step 4: Synthesis of tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- methylphenyl)carbamoyl)phenyl)piperazine-1-carboxylate. A flask was charged with 300 mg (0.652 mmol) of tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine-1-carboxylate, 6 mg (0.026)     of palladium acetate, 27 mg (0.065 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 243 mg (1.30 mmol) of tert-butyl piperazine-1-carboxylate, 3 mL of 1,4-dioxane and cesium carbonate 540 mg (1.63 mmol). The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 10 mL of ethyl acetate and 10 mL water. Solids formed and after 30 minutes of stirring, the solid was collected and air dried to yield 250 mg of tert- butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylphenyl) carbamoyl)phenyl)piperazine- 1-carboxylate in 66 % yield.
Figure imgf000471_0001
[0280] Step 5: Synthesis of N-(2-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1- yl)benzamide. The tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylphenyl) carbamoyl)phenyl)piperazine-1-carboxylate (250 mg , 0.431 mmol) was dissolved with 3 mL dichloromethane. Then 4 mL (52 mmol) of trifluoroacetic acid was added dropwise over five minutes with stirring. Three hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000471_0002
[0281] Step 6: Synthesis of tert-butyl ((E)-(4-(4-((4-(4-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)piperazin-1-yl)-2-methylphenyl)carbamoyl)phenyl)piperazin-1-yl)((tert-butoxy carbonyl)amino)methylene)carbamate. A flask was charged with 260 mg (0.43 mmol) of N-(2-methyl- 4-(piperazin-1-yl)phenyl)-4-(piperazin-1-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 500 mg (4.95 mmol) of triethylamine was added over two minutes. Then 480 mg (1.54 mmol) of tert-butyl (1H-pyrazol-1-yl)methane diylidenedicarbamate was added. The reaction was stirred for 18 hours at room temp. The next day the reaction was charged with 120 mg (0.39 mmol) of tert-butyl (1H-pyrazol-1-yl)methane diylidenedicarbamate and heated at 40oC for three hours and stirred at room temperature over the weekend. The reaction was concentrated under vacuum and 25 mL of isopropyl acetate added. The     organic phase was washed with three 20 mL portions of water and concentrated under vacuum in quantitative yield.
Figure imgf000472_0001
[0282] Step 7: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-2-methylphenyl)benzamide. A flask was charged with 370 mg (0.43 mmol)of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4- yl)benzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum, dissolved with dimethylformamide, purified by prep HPLC to yield 77 mg (26%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.90 (d, J=9.23 Hz, 2 H) 7.43 (br d, J=3.96 Hz, 1 H) 7.17 (d, J=8.79 Hz, 1 H) 7.04 (d, J=9.23 Hz, 1 H) 6.90 (d, J=2.64 Hz, 1 H) 6.84 (dd, J=8.79, 2.64 Hz, 1 H) 3.57 - 3.66 (m, 4 H) 3.43 (br dd, J=6.38, 3.74 Hz, 4 H) 3.20 - 3.27 (m, 4 H) 3.15 - 3.19 (m, 4 H) 2.20 (s, 3 H). LC/MS method A: Rt = 2.4 mins., (M+H)+ =464, purity > 95%. [0283] Example 75: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-3-methylphenyl)benzamide.
Figure imgf000472_0002
[0284] Step 1: Synthesis of tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3- methylphenyl)carbamoyl)phenyl)piperazine-1-carboxylate. A flask was charged with 200 mg (0.653 mmol) of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid, 1.5 mL of dry N,N- dimethylformamide and (126 mg, 0.98 mmol) of diisopropylethylamine. Then 310 mg (0.816 mmol) of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluoro phosphate was added. After 45 minutes of stirring a solution of tert-butyl 4-(4-amino-3- methylphenyl)piperazine-1-carboxylate (220 mg, 0.75 mmol) in 1.2mL of dry dimethylformamide was added over one minute. The reaction was stirred at 38oC for 18 hours. The next day the reaction was diluted with 20 mL of water and stirred for one hour. The solid was collected and air dried to yield 380     mg of tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylphenyl) carbamoyl)phenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000473_0001
[0285] Step 2: Synthesis of N-(3-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1-yl) benzamide. The tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylphenyl) carbamoyl)phenyl)piperazine-1-carboxylate (380 mg, 0.65 mmol) was dissolved with 3 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with 20 mL of ether to yield a solid in quantitative yield.
Figure imgf000473_0002
[0286] Step 3: Synthesis of tert-butyl ((E)-(4-(4-((4-(4-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)piperazin-1-yl)-3-methylphenyl)carbamoyl)phenyl)piperazin-1-yl)((tert-butoxy carbonyl)amino)methylene)carbamate. A flask was charged with 350 mg (0.58 mmol) of N-(2-methyl- 4-(piperazin-1-yl)phenyl)-4-(piperazin-1-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 536 mg (5.30 mmol) of triethylamine was added over two minutes. Then 503 mg (1.62 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate was added. The reaction was stirred for 18 hours at 40oC. The next day the reaction was concentrated under vacuum and 25 mL of ethyl acetate added. The organic phase was washed with three 20 mL portions of water and concentrated under vacuum in quantitative yield.
Figure imgf000473_0003
[0287] Step 4: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-3-methylphenyl)benzamide. A flask was charged with 500 mg (0.58 mmol)of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4- yl)benzamido)-2-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino) methylene)carbamate, 3     mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for three hours. The reaction was concentrated under vacuum, dissolved with dimethylformamide, purified by prep HPLC to yield 130 mg (32%).1H NMR (300 MHz, DMSO-d6) δ ppm 7.90 (d, J=9.23 Hz, 2 H) 7.43 (br d, J=3.96 Hz, 1 H) 7.17 (d, J=8.79 Hz, 1 H) 7.04 (d, J=9.23 Hz, 1 H) 6.90 (d, J=2.64 Hz, 1 H) 6.84 (dd, J=8.79, 2.64 Hz, 1 H) 3.57 - 3.66 (m, 4 H) 3.43 (dd, J=6.38, 3.74 Hz, 4 H) 3.19 - 3.32 (m, 4 H) 3.15 - 3.19 (m, 4 H) 2.20 (s, 3 H). LC/MS Rt = 2.6 mins., (M+H)+ =464, purity > 95%. [0288] Example 76: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-2-methylphenyl)benzamide.
Figure imgf000474_0001
[0289] Step 1: Synthesis of tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)benzamido)-3-methylphenyl)piperazine-1-carboxylate. A flask was charged with 320 mg (0.685 mmol) of tert-butyl 4-(4-(4-bromobenzamido)-2-methylphenyl)piperazine-1- carboxylate, 6 mg ( 0.026) of palladium acetate, 28 mg (0.068 mmol) of 2-dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl, 250 mg (0.810 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 3 mL of 1,4-dioxane and 1.5 mL of 2.0 molar potassium carbonate. The flask was swept with nitrogen for five minutes and heated at 95oC for four hours.The reaction was allowed to cool and diluted with 30 mL of ethyl acetate and washed with two 20 mL water. The organic phase was dried and concentrated under vacuum to yield 390 mg of tert- butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-3-methyl phenyl)piperazine-1-carboxylate in quantitative yield.
Figure imgf000474_0002
[0290] Step 2: Synthesis of N-(2-methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-(4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)benzamido)-3-methylphenyl)piperazine-1-carboxylate (390 mg, 0.68 mmol)     was dissolved with 5 mL dichloromethane. Then dropwise addition of 6 mL (78 mmol) of trifluoroacetic acid was added over five minutes with stirring. Three hours later the reaction was concentrated under vacuum, triturated with two 20 mL portions of ether to yield a solid in quantitative yield.
Figure imgf000475_0001
[0291] Step 3: Synthesis of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-3-methylphenyl)piperazin-1-yl)((tert- butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 280 mg (0.47 mmol) of N-(2- methyl-4-(piperazin-1-yl)phenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N-dimethylformamide. Then 566 mg (5.60 mmol) of triethylamine was added over two minutes. Then 436 mg (1.40 mmol) of tert-butyl (1H-pyrazol-1- yl)methanediylidenedicarbamate was added. The reaction was stirred for 18 hours at 45oC. The next day the reaction was charged with 150 mg (0.48 mmol) of tert-butyl (1H-pyrazol-1-yl) methanediylidenedicarbamate and 210 mg (2.08)mmol)of triethylamine. The reaction was heated at 45oC for five hours and stirred at room temperature over the weekend. The reaction was concentrated under vacuum and 40 mL of ethyl acetate added. The organic washed with three 20 mL portions of water and concentrated under vacuum to yield the tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)-3-methylphenyl) piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in nearly quantitative yield.
Figure imgf000475_0002
[0292] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-2-methylphenyl)benzamide. A flask was charged with 405 mg (0.47 mmol) of tert-butyl ((E)-(4-(4-(4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)benzamido)-3-methylphenyl)piperazin-1-yl)((tert-butoxycarbonyl) amino)methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under     vacuum, dissolved with dimethylformamide, purified by prep HPLC to yield 156 mg (23%).1H NMR (300 MHz, DMSO-d6) δ ppm 9.71 (s, 1 H) 7.94 (d, J=8.21 Hz, 2 H) 7.58 (d, J=8.21 Hz, 2 H) 7.51 (br s, 6 H) 7.10 - 7.15 (m, 1 H) 6.87 (d, J=2.34 Hz, 1 H) 6.80 (dd, J=8.79, 2.34 Hz, 1 H) 6.33 (br s, 1 H) 4.09 (br s, 2 H) 3.62 (br t, J=5.57 Hz, 4 H) 3.54 (br d, J=5.28 Hz, 4 H) 2.61 (br s, 2 H) 2.45 - 2.49 (m, 4 H) 2.15 (s, 3 H). LC/MS Rt = 2.7 mins., (M+H)+ =461, purity > 95%. [0293] Example 77: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)-2-methylphenyl)-3-methylbenzamide.
Figure imgf000476_0001
[0294] Step 1: Synthesis of 4-bromo-N-(4-bromo-2-methylphenyl)-3-methylbenzamide. A flask was charged with 3 mL of dichloromethane, 3 mL of N,N-dimethylformamide and 1120 mg (4.79 mmol) of 4-bromo-3-methylbenzoyl chloride. Then a solution of 935 mg (5.03 mmol) of 4-bromo-2- methylaniline and (803 mg, 6.23 mmol) of diisopropylethylamine in 3 mL of dichloromethane was added dropwise over five minutes. After stirring for one hour at room temp, 15 mL of water added and briefly sonicated, stirred for 30 minutes, solid collected and rinsed with 10 mL of ethyl acetate and air dried to yield 2400 mg of 4-bromo-N-(4-bromo-2-methylphenyl)-3-methylbenzamide in quantitative yield.
Figure imgf000476_0002
[0295] Step 2: Synthesis of tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- methylphenyl)carbamoyl)-2-methylphenyl)piperazine-1-carboxylate. A flask was charged with 310 mg (0.81 mmol) of 4-bromo-N-(4-bromo-2-methylphenyl)-3-methylbenzamide, 15 mg (0.065 mmol) of palladium acetate, 67 mg (0.162 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 602 mg (2.34 mmol) of tert-butyl piperazine-1-carboxylate, 1300 mg (4.0 mmol) of cesium carbonate The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 30 mL water added over five minutes. After one hour of stirring, the solid was     collected to yield the tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2- methylphenyl)carbamoyl)-2-methylphenyl)piperazine-1-carboxylate in a quantitative yield.
Figure imgf000477_0001
[0296] Step 3: Synthesis of 3-methyl-N-(2-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1- yl)benzamide. The tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methylphenyl) carbamoyl)-2-methylphenyl)piperazine-1-carboxylate (480 mg, 0.81 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 6 mL (78 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with two portions of 20 mL of ether to yield a solid in quantitative yield.
Figure imgf000477_0002
[0297] Step 4: Synthesis of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxy carbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-methyl phenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 370 mg (0.60 mmol) of 3-methyl-N-(2-methyl-4-(piperazin-1-yl)phenyl)-4-(piperazin-1- yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 2 mL of N,N-dimethylformamide. Then 490 mg (4.85 mmol) of triethylamine was added over two minutes. Then 510 mg (1.63 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at 37oC. The next day the reaction was cooled and concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with 20 mL of 10% citric acid, 20 mL of water and concentrated under vacuum to give 530 mg of the tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)- 1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridin- 1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate in a quantitative yield.
Figure imgf000477_0003
    [0298] Step 5: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)-2-methylphenyl)-3-methylbenzamide. A flask was charged with 520 mg (0.60 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridin-1-(2H)- yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 3 mL of dichloromethane and 4 mL (52 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for three hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2- methylphenyl)-3-methylbenzamide was 45 mg (11%).1H NMR (300 MHz, DMSO-d6) δ ppm 9.54 (s, 1 H) 7.74 - 7.80 (m, 1 H) 7.44 (br d, J=7.92 Hz, 7 H) 7.06 - 7.12 (m, 2 H) 6.86 (d, J=2.64 Hz, 1 H) 6.81 (d, J=3.08 Hz, 1 H) 3.56 (br d, J=3.96 Hz, 8 H) 3.17 - 3.21 (m, 4 H) 2.92 - 2.97 (m, 4 H) 2.32 (s, 3 H) 2.14 (s, 3 H). LC/MS Rt = 2.6 mins., (M+H)+ =478, purity > 95%. [0299] Example 78: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridine-1(2H)- carboxylate.
Figure imgf000478_0001
[0300] Step 1: Synthesis of tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro pyridin-4-yl)-2-methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate. A flask was charged with 230 mg (0.391 mmol) of 4-bromo-N-(4-bromo-2-methylphenyl)-3- methylbenzamide, 7 mg (0.03 mmol) of palladium acetate, 32 mg (0.08 mmol) of 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 242 mg (0.78 mmol) of tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 6 mL of 1,4-dioxane and 3.0 mL of 2.0 molar potassium carbonate. The flask was swept with nitrogen for five minutes and heated at 95oC for 18 hours. The reaction was allowed to cool and diluted with 40 mL of ethyl acetate and washed with two 20 mL portions of water, dried and concentrated under vacuum to yield the tert- butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)- 2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate in a quantitative yield.    
Figure imgf000479_0001
[0301] Step 2: Synthesis of 3-methyl-N-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)- 4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide. The tert-butyl 4-(4-((4-(4-(tert-butoxycarbonyl) piperazin-1-yl)-2-methylphenyl)carbamoyl)-2-methylphenyl)piperazine-1-carboxylate (230 mg, 0.39 mmol) was dissolved with 4 mL dichloromethane. Then dropwise addition of 5 mL (65 mmol) of trifluoroacetic acid was added over five minutes with stirring. Two hours later the reaction was concentrated under vacuum, triturated with 20 mL of ether to yield a solid in quantitative yield.
Figure imgf000479_0002
[0302] Step 3: Synthesis of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2-methylphenyl)-3,6- dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate. A flask was charged with 190 mg (0.30 mmol) of 3-methyl-N-(2-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-(1,2,3,6- tetrahydropyridin-4-yl)benzamide bis trifluoroacetic acid salt, 3 mL dichloromethane and 3 mL of N,N- dimethylformamide. Then 590 mg (5.84 mmol) of triethylamine was added over two minutes. Then 235 mg (0.75 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred at 30oC over the weekend. Then the reaction was cooled and concentrated under vacuum and diluted with 30 mL of ethyl acetate and washed with 20 mL of water, 20 mL of 10% citric acid, 20 mL of water and concentrated under vacuum. The concentrate was dissolved in dichloromethane and chromatographed on silica stepwise eluting with 0 to 100% of (15% isopropanol/dichloromethane)/dichloromethane to give 180 mg (69%) of tert-butyl ((E)-(4-(4-((4-(1- ((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl) amino)methylene)carbamate.
Figure imgf000479_0003
    [0303] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-3-methylbenzamide. A flask was charged with 180 mg (0.27 mmol) of tert-butyl ((E)-(4-(4-((4-(1-((E)-N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)carbamoyl)-2- methylphenyl)-3,6-dihydropyridin-1(2H)-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for three hours. The reaction was concentrated under vacuum. Liquid was diluted with dimethylformamide and purified by prep HPLC. Yield of 4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methylphenyl)-3- methylbenzamide was 68 mg (36%).1H NMR (300 MHz, METHANOL-d4) δ ppm 7.83 (d, J=1.32 Hz, 1 H) 7.78 (dd, J=7.92, 1.76 Hz, 1 H) 7.39 (s, 1 H) 7.33 - 7.36 (m, 2 H) 7.28 (d, J=7.92 Hz, 1 H) 6.13 - 6.17 (m, 1 H) 5.72 (dt, J=3.19, 1.70 Hz, 1 H) 4.13 (br d, J=2.20 Hz, 4 H) 3.71 (q, J=5.57 Hz, 4 H) 2.70 (br d, J=1.76 Hz, 2 H) 2.52 - 2.59 (m, 2 H) 2.40 (s, 3 H) 2.32 (s, 3 H). LC/MS method A: Rt = 2.9 mins., (M+H)+ =472, purity > 95%. [0304] Example 79: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4- carbamimidoylpiperazin-1-yl)phenyl)benzamide
Figure imgf000480_0001
[0305] Step 1: Synthesis of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate. A flask was charged with 4310 mg (30.6 mmol) of 4-fluoro-1-nitrobenzene, 30 mL of N,N-dimethylformamide and 5800 mg (31.2 mmol) of tert-butyl piperazine-1-carboxylate. Then 5323mg (41.3 mmol) of diisopropylethylamine was added over five minutes. The reaction was warmed to 43oC for 18 hours and four hours at 50oC. After cooling the reaction was diluted with 100 mL of ethyl acetate and washed with two 50 mL portions of water, dried and concentrated under vacuum to yield 9100 mg of a yellow solid in 97 % yield.
Figure imgf000480_0002
Figure imgf000480_0004
Figure imgf000480_0003
[0306] Step 2: Synthesis of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate. A flask was charged with 9240 mg (30 mmol) of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate, 40 mL of tetrahydrofuran, 60 mL of methanol and 16200 mg (300 mmol) of ammonium chloride. Then 9750 mg     (150 mmol) of zinc dust was added in portion over 30 minutes. The reaction was warmed to 45oC for 18 hours. The reaction was cooled, filtered thru Celite, rinsed with ethyl acetate and methanol. The filtrate was concentrated under vacuum, partitioned between 100 mL of ethyl acetate and 60 mL of water, organic phase dried and concentrated under vacuum to yield 7.7 grams of a dark brown solid in 93 % yield.
Figure imgf000481_0001
[0307] Step 3: Synthesis of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1- yl)benzamido)phenyl)piperazine-1-carboxylate. A flask was charged with 170 mg (0.473 mmol) of 4- (4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid, 4 mL of dry N,N-dimethylformamide and (98 mg, 0.757 mmol) of diisopropylethylamine. Then 274 mg (0.614 mmol) of 1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate was added. After 45 minutes of stirring a solution of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (147 mg, 0.53 mmol) was added. Then 2 mL dichloromethane used to rinse sides of flask. The reaction was stirred for 18 hours. The next day the reaction was concentrated under vacuum, diluted with 30 mL of ethyl acetate and washed with 30 mL of water. The insoluble solid was collected and air dried to yield 300 mg of tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzamido)phenyl)piperazine-1- carboxylate in quantitative yield.
Figure imgf000481_0002
[0308] Step 4: Synthesis of 4-(piperazin-1-yl)-N-(4-(piperazin-1-yl)phenyl)benzamide from tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzamido)phenyl)piperazine-1-carboxylate. The tert-butyl 4-(4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzamido)phenyl) piperazine-1- carboxylate (300 mg, 0.47 mmol) was dissolved with 2 mL dichloromethane. Then dropwise addition of 4 mL (52 mmol) of trifluoroacetic acid was conducted over five minutes with stirring. The next day the reaction was concentrated under vacuum, triturated with 20 mL of ether to yield a solid in nearly quantitative yield.    
Figure imgf000482_0001
[0309] Step 5: Synthesis of tert-butyl ((E)-(4-(4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl) carbamimidoyl)piperazin-1-yl)benzamido)phenyl)piperazin-1-yl)((tert-butoxycarbonyl)amino) methylene)carbamate. A flask was charged with240 mg (0.40 mmol) of 4-(piperazin-1-yl)-N-(4- (piperazin-1-yl)phenyl)benzamide bis trifluoroacetic acid salt, 2 mL dichloromethane and 2 mL N,N- dimethylformamide. Then 490 mg (4.85 mmol) of triethylamine was added over two minutes. Then 440 mg (1.42 mmol) of tert-butyl (1H-pyrazol-1-yl)methanediylidenedicarbamate was added. The reaction was stirred for 18 hours at room temp and 37oC for three hours and over the weekend at room temp. The next day the reaction was concentrated under vacuum and 25 mL of ethyl acetate added. The organic phase was washed with 15 mL of water and concentrated under vacuum. The concentrate was dissolved with dichloromethane and chromatographed on silica with (15% isopropanol/dichloromethane)/dichloromethane step gradient to yield 240 mg in 70% yield.
Figure imgf000482_0002
[0310] Step 6: Synthesis of 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoyl piperazin-1-yl)phenyl)benzamide. A flask was charged with 240 mg (0.28 mmol)of tert-butyl ((E)-(4- (4-(4-(4-((E)-N,N'-bis(tert-butoxycarbonyl)carbamimidoyl)piperazin-1-yl)benzamido)phenyl) piperazin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate, 3 mL of dichloromethane and 5 mL (65 mmol) of trifluoroacetic acid added over five minutes with stirring and stirred for 18 hours. The reaction was concentrated under vacuum, dissolved with dimethylformamide and half of material purified by prep HPLC to yield 24 mg (25%). 1H NMR (300 MHz, METHANOL-d4) δ ppm 7.83 (d, J=1.32 Hz, 2 H) 7.78 (dd, J=7.92, 1.76 Hz, 2 H) 7.33 - 7.36 (m, 3 H) 7.28 (d, J=7.92 Hz, 1 H) 6.13 - 6.17 (m, 1 H) 5.72 (dt, J=3.19, 1.70 Hz, 1 H) 4.13 (br d, J=2.20 Hz, 4 H) 3.71 (q, J=5.57 Hz, 4 H) 2.70 (br d, J=1.76 Hz, 4 H) 2.52 - 2.59 (m, 4 H) 2.40 (s, 3 H) 2.32 (s, 3 H). LC/MS method A: Rt = 2.7 mins., (M+H)+ =446, 518 purity > 95%. [0311] Example 80: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-2-trifluoromethyl-benzamide    
Figure imgf000483_0001
[0312] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methyl-phenyl)-2-trifluoromethyl- benzamide: To a mixture of 4-bromo-3-methyl-phenylamine (300 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol) in CHCl3 (5 mL) was added dropwise a solution of 4-bromo-2-trifluoromethyl-benzoyl chloride (515 mg, 1.79 mmol) in CHCl3 (5 mL). The reaction was stirred for 3 days. The reaction was concentrated, then the residue was treated with water (10 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with 1 N HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (1 mL), dried (Na2SO4), and concentrated to give 4-bromo- N-(4-bromo-3-methyl-phenyl)-2-trifluoromethyl-benzamide (682 mg, 97%) as a beige solid.
Figure imgf000483_0002
[0313] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate: A mixture of 4-bromo-N-(4-bromo-3-methyl-phenyl)-2- trifluoromethyl-benzamide (0.32 g, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.54 g, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol) in 1,4-dioxane (7 mL) and 2M K2CO3 (3 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 oC for 16 hours. The mixture was allowed to cool to 20 oC, then was treated with ethyl acetate (40 mL) and water (20 mL). The organic layer was washed with brine (3 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate/ hexanes), to give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (395 mg, 84%) as a white solid.    
Figure imgf000484_0001
[0314] Step 2: Synthesis of N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl-benzamide: To a solution of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3- (trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (394 mg, 0.61 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was added a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated to give N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl-benzamide (280 mg, 89%) as the bis- HCl salt as an off-white solid.
Figure imgf000484_0002
[0315] Step 3: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1- [(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridin-1-yl)methylidene]carbamate: A mixture of N-[3-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl-benzamide . 2 HCl (100 mg, 0.19 mmol) in CH2Cl2 (1 mL) and N,N-dimethylformamide (1 mL) was treated slowly with triethylamine (135 mg, 186 ^L, 1.33 mmol). The reaction was stirred for 15 minutes, then N,N’-bis- Boc-1-guanylpyrazole (190 mg, 0.61 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was allowed to cool to 20oC, then was concentrated. The residue was treated with ethyl acetate (30 mL), then was washed with water (40 mL), 5% citric acid aqueous solution (30 mL), water (40 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-     (trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridin-1-yl)methylidene]carbamate (138 mg, 79%) as a white solid.
Figure imgf000485_0001
[0316] Step 4: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-2-trifluoromethyl-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (137 mg, 0.15 mmol) in CH2Cl2 (2 mL) was treated with -trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was purified by preparative HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-2-trifluoromethyl-benzamide as the bis-trifluoroacetic acid salt (91 mg, 81%) as a white solid. MS: 526 M+H+: 1H NMR (300 MHz, dmso) δ 10.46-10.56 (m, 1H), 7.79-7.92 (m, 2H), 7.66 (d, J=8.20 Hz, 1H), 7.40-7.58 (m, 9H), 7.08 (d, J=8.20 Hz, 1H), 6.43 (br. s., 1H), 5.60 (s, 1H), 4.11 (d, J=1.17 Hz, 2H), 4.02 (d, J=1.76 Hz, 2H), 3.63 (dd, J=5.57, 11.42 Hz, 5H), 2.65 (br. s., 2H), 2.39 (br. s., 2H), 2.20-2.28 (m, 3H). [0317] Example 81: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethyl-phenyl]-3-fluoro-benzamide:
Figure imgf000485_0002
[0318] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-trifluoromethyl-phenyl)-3-fluoro- benzamide: A mixture of 4-bromo-3-trifluoromethyl-phenylamine (386 mg, 1.61 mmol) and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol) in CHCl3 (5 mL) was added dropwise a solution of 4-bromo-3-fluoro-benzoyl chloride (425 mg, 1.79 mmol) in CHCl3 (5 mL). The reaction was stirred for 3 days. The reaction was concentrated, then the residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined     organic extracts were washed with 1 N HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (3 mL), dried (Na2SO4), and concentrated, to give 4-bromo-N-(4-bromo- 3-trifluoromethyl-phenyl)-3-fluoro-benzamide (741 mg, >100%) as an off-white solid, which was used without further purification.
Figure imgf000486_0001
[0319] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-(trifluoromethyl)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl) carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N- (4-bromo-3-trifluoromethyl-phenyl)-3-fluoro-benzamide (0.32 g, 0.73 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.54 g, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4- yl}-3-(trifluoromethyl)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (362 mg, 77%) as a white solid.
Figure imgf000486_0002
[0320] Step 3: Synthesis of 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-3-trifluoromethyl-phenyl]-benzamide: To a solution of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-(trifluoromethyl)phenyl)carbamoyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (360 mg, 0.56 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was added a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated to give 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-3-trifluoromethyl-phenyl]-benzamide as the bis-HCl salt (267 mg, 92%) as a white solid.    
Figure imgf000487_0001
[0321] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-(trifluoromethyl)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1-yl) methylidene]carbamate: A mixture of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-(trifluoromethyl)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate .2 HCl (99 mg, 0.19 mmol) in CH2Cl2 (1 mL) and N,N-dimethylformamide (1 mL) was treated slowly with NEt3 (135 mg, 186 ^L, 1.33 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was allowed to cool to 20oC, then was concentrated. The residue was treated with ethyl acetate (30 mL), then was washed with water (40 mL), 5% citric acid aqueous solution (30 mL), water (40 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- (trifluoromethyl)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1-yl) methylidene]carbamate (133 mg, 75%) as a white solid.
Figure imgf000487_0002
[0322] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethyl-phenyl]-3-fluoro-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- (trifluoromethyl)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (133 mg, 0.14 mmol) in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified     by preparative HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethyl-phenyl]-3-fluoro-benzamide as the bis-TFA salt (70 mg, 66%) as a white solid. MS: 529.53 M+H+: 1H NMR (300 MHz, dmso) δ 10.64- 10.76 (m, 1H), 8.17 (d, J=1.76 Hz, 1H), 7.89-8.02 (m, 1H), 7.69 (t, J=7.91 Hz, 1H), 7.34-7.58 (m, 11H), 6.39-6.50 (m, 1H), 5.64 (d, J=1.17 Hz, 1H), 4.11 (d, J=1.76 Hz, 2H), 3.97-4.07 (m, 2H), 3.55- 3.70 (m, 4H), 2.61 (br. s., 2H), 2.36-2.45 (m, 2H). [0323] Example 82: Synthesis of 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-7- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide:
Figure imgf000488_0001
[0324] Step 1: Synthesis of 7-(4-bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester: A mixture of 3,4-Dihydro-1H-isoquinoline-2,7- dicarboxylic acid 2-tert-butyl ester (447 mg, 1.61 mmol) and 4-bromo-3-methyl-phenylamine (300 mg, 1.61 mmol) in N,N-dimethylformamide (8 mL) was added 1-hydroxybenzotriazole (261 mg, 1.93 mmol), diisopropylethylamine (521 mg, 701 ^L, 4.03 mmol), and N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide hydrochloride. HCl (370 mg, 1.93 mmol). The reaction was stirred for 3 days, then was treated with water (100 mL). The mixture was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (2 x 15 mL), and brine (3 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate/ hexanes), to give 7-(4-bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert- butyl ester (249 mg, 35%) as an off-white solid.
Figure imgf000488_0002
[0325] Step 2: Synthesis of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: A mixture of 7-(4-bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl     ester (249 mg, 0.56 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester (203 mg, 0.66 mmol), Pd(OAc)2 (5 mg, 0.0022 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (23 mg, 0.056 mmol) in 1,4-dioxane (4 mL) and 2M K2CO3 (1.2 mL) was degassed for 10 minutes by bubbling nitrogen through the mixture. The reaction was heated at 95oC for 16 hours. The mixture was allowed to cool to 20 oC , then was treated with ethyl acetate (40 mL) and water (20 mL). The organic layer was washed with brine (3 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate/ hexanes), to give 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenylcarbamoyl]-3,4- dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (241 mg, 79%) as a white solid.
Figure imgf000489_0001
[0326] Step 3: Synthesis of 1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid [3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide: A solution of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (241 mg, 0.44 mmol) in CH2Cl2 (1.5 mL) and methanol (0.75 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.1 mL). The reaction was stirred or 16 hours. The reaction was concentrated to give 1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid [3-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis-HCl salt (215 mg, >100%) as a pale green solid, that was used without further purification.
Figure imgf000489_0002
[0327] Step 4: Synthesis of {[4-(4-{[2-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,4-tetrahydro-isoquinoline-7-carbonyl]-amino}-2-methyl-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: A mixture of 1,2,3,4- tetrahydro-isoquinoline-7-carboxylic acid [3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- amide .2 HCl (80 mg, 0.19 mmol) in CH2Cl2 (1 mL0 and N,N-dimethylformamide (1 mL) was treated     slowly with triethylamine (135 mg, 186 ^L, 1.33 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was concentrated, then was partitioned between ethyl acetate (30 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-70% ethyl acetate/ hexanes), to give {[4-(4-{[2-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinoline-7-carbonyl]-amino}-2-methyl-phenyl)- 3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (84 mg, 53%) as a clear film.
Figure imgf000490_0001
[0328] Step 5: Synthesis of 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide: A mixture of {[4-(4-{[2-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro- isoquinoline-7-carbonyl]-amino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (84 mg, 0.10 mmol) in CH2Cl2 (1.5 mL0 was treated with trifluoroacetic acid (1.5 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative HPLC, to give 2-carbamimidoyl- 1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-3-methyl-phenyl]-amide as the bis-TFA salt (39 mg, 59%) as a white solid. MS: 432 M+H+: 1H NMR (300 MHz, dmso) δ 10.11-10.24 (m, 1H), 7.78-7.90 (m, 1H), 7.73 (d, J=1.17 Hz, 1H), 7.36- 7.65 (m, 11H), 7.09 (d, J=8.20 Hz, 1H), 5.61 (br. s., 1H), 4.64 (s, 2H), 4.02 (d, J=2.34 Hz, 2H), 3.56- 3.68 (m, 4H), 2.90-3.05 (m, 2H), 2.40 (d, J=1.17 Hz, 2H), 2.25 (s, 3H). [0329] Example 83: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl-phenyl]-2-methyl-benzamide    
Figure imgf000491_0001
[0330] Step 1: Synthesis of 4-bromo-2-methyl-benzoyl chloride: A mixture of 4-bromo-2- methyl-benzoic acid (385 mg, 1.79 mmol) in CHCl3 (10 mL) and N,N-dimethylformamide (3 drops) was added dropwise oxalyl chloride (364 mg, 246 ^L, 2.86 mmol). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with CHCl3 (20 mL), then was concentrated. 4-Bromo-2-methyl-benzoyl chloride was used without further purification.
Figure imgf000491_0002
[0331] Step 2: Synthesis of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl- benzamide: A mixture of 4-bromo-2-trifluoromethyl-phenylamine (386 mg, 1.61 mmol) and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol) in CHCl3 (5 mL) was added dropwise a solution of 4-bromo-2-methyl-benzoyl chloride in CHCl3. The reaction was stirred for 4 days. The reaction was concentrated, then the residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic extract were washed with 1N HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-10% ethyl acetate/ hexanes), to give 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2- methyl-benzamide (71 mg, 10%) as an off-white solid.
Figure imgf000491_0003
[0332] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methylbenzamido)-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine-1-     carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide (71 mg, 0.16 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan -2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (120 mg, 0.39 mmol), Pd(OAc)2 (3 mg, 0.014 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (14 mg, 0.033 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methyl benzamido)-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (93 mg, 91%) as a clear gum.
Figure imgf000492_0001
[0333] Step 4: Synthesis of 2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-2-trifluoromethyl-phenyl]-benzamide: A mixture of tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-3-(trifluoromethyl) phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (93 mg, 0.15 mmol) in CH2Cl2 (0.5 mL) and methanol (0.3 mL) was treated with a 4N solution of HCl in 1,4-dioxane (0.4 mL). The reaction was stirred or 16 hours, then was concentrated to give 2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl-phenyl]-benzamide as the bi-HCl salt (69 mg, 89%) as a pale yellow solid.
Figure imgf000492_0002
[0334] Step 5: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methylbenzamido)-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridin-1-yl}) methylidene]carbamate: A mixture of 2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-2-trifluoromethyl-phenyl]-benzamide . 2 HCl (69 mg, 0.13 mmol) in CH2Cl2 (0.75 mL) and N,N-dimethylformamide (0.75 mL) was treated slowly with triethylamine (97 mg, 134     ^L, 0.96 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (137 mg, 0.44 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was concentrated, then was partitioned between ethyl acetate (30 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with water (2 x 20 mL), 10% aqueous citric acid (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate/ hexanes), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-2- methylbenzamido)-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene] carbamate (38 mg, 32%) as a clear film.
Figure imgf000493_0001
[0335] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl-phenyl]-2-methyl-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-2- methylbenzamido)-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate (38 mg, 0.041 mmol) in CH2Cl2 (1 mL) was treated with TFA (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-2-trifluoromethyl-phenyl]-2-methyl-benzamide as the bis-TFA salt (8 mg, 26%) as a white solid. MS: 526 M+H+: 1H NMR (300 MHz, cd3od) δ 7.77-7.87 (m, 2H), 7.66 (d, J=8.20 Hz, 1H), 7.55 (d, J=8.79 Hz, 1H), 7.34-7.46 (m, 2H), 6.26-6.33 (m, 1H), 6.24 (t, J=3.22 Hz, 1H), 4.16 (dd, J=2.93, 5.27 Hz, 4H), 3.65-3.79 (m, 4H), 2.73 (td, J=1.76, 3.51 Hz, 4H), 2.51 (s, 3H). [0336] Example 84: Synthesis of 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-6- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide    
Figure imgf000494_0001
[0337] Step 1: Synthesis of 6-(4-bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester: A mixture of 3,4-dihydro-1H-isoquinoline-2,6- dicarboxylic acid 2-tert-butyl ester (447 mg, 1.61 mmol), 4-bromo-3-methyl-phenylamine (330 mg, 1.77 mmol), and triethylamine (572 mg, 788 ^L, 5.64 mmol) in N,N-dimethylformamide (5 mL) was added N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (2139 mg, 5.64 mmol). The reaction was stirred for 3 days. The mixture was treated with water (75 mL), then was extracted with ethyl acetate (4 x 20 mL). The combined organic extracts were washed with (2 x 15 mL), and brine (3 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-25% ethyl acetate/ hexanes), to give 6-(4-bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid tert-butyl ester (515 mg, 72%) as a white solid. B
Figure imgf000494_0002
[0338] Step 2: Synthesis of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 6-(4-bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester (300 mg, 0.67 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (244 mg, 0.79 mmol), Pd(OAc)2 (6 mg, 0.026 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (28 mg, 0.067 mmol), to give 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- phenylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (284 mg, 77%) as a white solid.    
Figure imgf000495_0001
[0339] Step 3: Synthesis of 1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide: A solution of 6-[4-(1-tert-Butoxycarbonyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (284 mg, 0.52 mmol) in CH2Cl2 (2 mL0 and methanol (1 mL) was treated with 4N HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 1,2,3,4- tetrahydro-isoquinoline-6-carboxylic acid [3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- amide as the bis-HCl salt (227 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000495_0002
[0340] Step 4: Synthesis of [(6-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methyl-phenylcarbamoyl}-3,4-dihydro-1H-isoquinolin-2- yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: A mixture of 1,2,3,4-tetrahydro- isoquinoline-6-carboxylic acid [3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide . 2 HCl (80 mg, 0.19 mmol) in CH2Cl2 (1 mL) and N,N-dimethylformamide (1 mL) was treated slowly with triethylamine (135 mg, 186 ^L, 1.33 mmol). The reaction was stirred for 15 minutes, then N,N’-bis- Boc-guanylpyrazole (190 mg, 0.61 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was concentrated, then was partitioned between ethyl acetate (25 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water (2 x 20 mL), 10% aqueous citric acid (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate/ hexanes), to give [(6-{4-[1-(tert-butoxycarbonylamino-tert-butoxy carbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methyl-phenylcarbamoyl}-3,4-dihydro-1H -isoquinolin-2-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (57 mg, 36%) as a tacky solid.    
Figure imgf000496_0001
[0341] Step 5: Synthesis of 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide: A mixture of [(6- {4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]- 3-methyl-phenylcarbamoyl}-3,4-dihydro-1H-isoquinolin-2-yl)-tert-butoxycarbonylimino-methyl]- carbamic acid tert-butyl ester (56 mg, 0.067 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative HPLC, to give 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide as the bix-TFA salt (23 mg, 52%) as a white solid. MS: 432 M+H+: 1H NMR (300 MHz, dmso) δ 9.78-9.90 (m, 1H), 7.78-7.91 (m, 2H), 7.43-7.57 (m, 7H), 7.23-7.41 (m, 4H), 6.19 (br. s., 1H), 4.65 (s, 2H), 4.08 (d, J=1.76 Hz, 2H), 3.58-3.69 (m, 4H), 2.99 (t, J=5.86 Hz, 2H), 2.53-2.66 (m, 2H), 2.23 (s, 3H). [0342] Example 85: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide
Figure imgf000496_0002
[0343] Step 1: Synthesis of 7-(4-bromo-3-fluoro-benzoylamino)-3,4-dihydro-1H-isoquinoline- 2-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 6-(4- bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester using 4-bromo-3-fluoro-benzoic acid (353 mg, 1.61 mmol), 7-amino-3,4-dihydro-1H-isoquinoline-2- carboxylic acid tert-butyl ester (440 mg, 1.77 mmol), triethylamine (572 mg, 788 ^L, 5.64 mmol), and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (2.14 g, 5.64 mmol), to give 7-(4-bromo-3-fluoro-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (666 mg, 92%) as a white solid.    
Figure imgf000497_0003
[0344] Step 2: Synthesis of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 7-(4-bromo-3-fluoro-benzoylamino)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester (252 mg, 0.56 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (203 mg, 0.66 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (23 mg, 0.056 mmol), to give 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (261 mg, 85%) as a pale yellow solid.
Figure imgf000497_0001
[0345] Step 3: Synthesis of 3-fluoro-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (261 mg, 0.47 mmol) in CH2Cl2 (2 mL0 and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro- N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (221 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000497_0002
    [0346] Step 3: Synthesis of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: A mixture of 3-fluoro-N-(1,2,3,4- tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide.2 HCl (81 mg, 0.19 mmol) in CH2Cl2 (1 mL) and N,N-dimethylformamide (1 mL) was treated slowly with triethylamine (135 mg, 186 ^L, 1.33 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was concentrated, then was treated with water (20 mL). The mixture was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water (2 x 15 mL), 10% aqueous citric acid (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7- ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxy carbonylimino-methyl]- carbamic acid tert-butyl ester (72 mg, 34%) as a white solid.
Figure imgf000498_0001
[0347] Step 4: Synthesis of give N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: A mixture of [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7- ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]- carbamic acid tert-butyl ester (72 mg, 0.086 mmol) in CH2Cl2 (1 mL) was treated with triflouroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative HPLC, to give N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide as the bis-TFA salt (43 mg, 75%) as a white solid. MS: 436 M+H+: 1H NMR (300 MHz, dmso) δ 10.31 (s, 1H), 7.74-7.86 (m, 2H), 7.63-7.74 (m, 1H), 7.38-7.62 (m, 10H), 7.16-7.29 (m, 1H), 6.10-6.22 (m, 1H), 4.56 (s, 2H), 4.10 (d, J=2.34 Hz, 2H), 3.56-3.67 (m, 4H), 2.82-2.94 (m, 2H), 2.54-2.67 (m, 2H).     [0348] Example 86: Synthesis of N-(2-Carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide
Figure imgf000499_0001
[0349] Step 1: Synthesis of 5-(4-bromo-3-fluoro-benzoylamino)-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 6-(4- bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester using 4-bromo-3-fluoro-benzoic acid (353 mg, 1.61 mmol), 5-Amino-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (415 mg, 1.77 mmol), triethylamine (572 mg, 788 ^L, 5.64 mmol), and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (2.14 g, 5.64 mmol), to give 5-(4-bromo-3-fluoro-benzoylamino)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (535 mg, 76%) as an off-white solid.
Figure imgf000499_0002
[0350] Step 2: Synthesis of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 5-(4-bromo-3-fluoro-benzoylamino)-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (244 mg, 0.56 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (203 mg, 0.66 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (23 mg, 0.056 mmol), to give 5- [4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-1,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (259 mg, 86%) as an off-white solid.    
Figure imgf000500_0001
[0351] Step 3: Synthesis of N-(2,3-Dihydro-1H-isoindol-5-yl)-3-fluoro-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- 3-fluoro-benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (259 mg, 0.48 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was added a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(2,3-Dihydro-1H-isoindol-5-yl)-3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (222 mg, >100%) as a beige solid, that was used without further purification.
Figure imgf000500_0002
[0352] Step 4: Synthesis of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)- tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl using N-(2,3-Dihydro-1H-isoindol-5-yl)-3-fluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide .2 HCl (78 mg, 0.19 mmol), triethylamine (135 mg, 186 ^L, 1.33 mmol), and N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol), to give [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-2- fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert- butyl ester (35 mg, 22%) as an off-white solid.    
Figure imgf000501_0001
[0353] Step 5: Synthesis of N-(2-Carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: A mixture of [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-2- fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert- butyl ester (35 mg, 0.043 mmol) in CH2Cl2 (1 ml) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-(2-Carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide as the bis-TFA salt (14 mg, 50%) as a white solid. MS: 422 M+H+: 1H NMR (300 MHz, dmso) δ 10.33-10.42 (m, 1H), 7.91-7.98 (m, 1H), 7.76-7.90 (m, 4H), 7.64-7.74 (m, 2H), 7.50-7.63 (m, 2H), 7.31-7.50 (m, 9H), 6.12-6.23 (m, 1H), 4.73 (dd, J=1.17, 12.89 Hz, 5H), 4.10 (d, J=1.76 Hz, 2H), 3.56-3.70 (m, 2H), 2.55-2.66 (m, 2H). [0354] Example 87: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenyl]-4-guanidinomethyl-benzamide
Figure imgf000501_0002
[0355] Step 1: Synthesis of [4-(4-bromo-3-methyl-phenylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of 6-(4-bromo-3-methyl- phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester using 4-(tert- butoxycarbonylamino-methyl)-benzoic acid (405 mg, 1.61 mmol), 4-bromo-3-methyl-phenylamine (329 mg, 1.77 mmol), triethylamine (572 mg, 788 ^L, 5.64 mmol), and N,N,N′,N′-tetramethyl-O-(1H- benzotriazol-1-yl)uronium hexafluorophosphate (1.22 g, 3.22 mmol), to give [4-(4-bromo-3-methyl- phenylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (485 mg, 72%) as an off-white solid.    
Figure imgf000502_0001
[0356] Step 2: Synthesis of 4-{4-[4-(tert-butoxycarbonylamino-methyl)-benzoylamino]-2- methyl-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of [4-(4-bromo- 3-methyl-phenylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (235 mg, 0.56 mmol), 4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (203 g, 0.66 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (23 mg, 0.056 mmol) in 1,4-dioxane (4 mL) and 2M K2CO3 (1.2 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 oC for 16 hours. The mixture was allowed to cool to 20 oC , then was treated with ethyl acetate (40 mL) and water (10 mL). The organic layer was washed with brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give 4-{4-[4-(tert- butoxycarbonylamino-methyl)-benzoylamino]-2-methyl-phenyl}-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (255 mg, 87 %) as a white solid.
Figure imgf000502_0002
[0357] Step 3: Synthesis of 4-aminomethyl-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-benzamide: A mixture of 4-{4-[4-(tert-butoxycarbonylamino-methyl)-benzoylamino]-2- methyl-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (255 mg, 0.49 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 4-aminomethyl-N-[3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide as the bis-HCl salt (200 mg, >100%) as a pale yellow solid, that was used without further purification.    
Figure imgf000503_0002
[0358] Step 4: Synthesis of give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[4- ({[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}methyl) benzamido]-2-methylphenyl}-1,2,3,6-tetrahydropyridin-1-yl)methylidene]carbamate: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 4-aminomethyl-N-[3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide . 2 HCl (75 mg, 0.19 mmol), triethylamine (135 mg, 186 ^L, 1.33 mmol), and N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol), to give tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[4-({[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}methyl)benzamido]-2-methylphenyl}-1,2,3,6- tetrahydropyridin-1-yl)methylidene]carbamate (90 mg, 59%) as a white solid.
Figure imgf000503_0001
[0359] Step 5: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- phenyl]-4-guanidinomethyl-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}(4-{4-[4-({[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}methyl)benzamido]-2-methylphenyl}-1,2,3,6-tetrahydropyridin-1-yl)methylidene] carbamate (90 mg, 0.11 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl] -4-guanidinomethyl-benzamide as the bis-TFA salt (25 mg, 36%) as a white solid. MS: 406 M+H+:     1H NMR (300 MHz, dmso) δ 10.10-10.24 (m, 1H), 8.03-8.16 (m, 1H), 7.95 (d, J=8.20 Hz, 2H), 7.54- 7.66 (m, 2H), 7.17-7.54 (m, 10H), 7.09 (d, J=8.20 Hz, 1H), 5.61 (s, 1H), 4.46 (d, J=6.44 Hz, 2H), 4.03 (d, J=2.93 Hz, 2H), 3.61 (t, J=5.57 Hz, 2H), 2.40 (dd, J=3.22, 4.39 Hz, 2H), 2.25 (s, 3H). [0360] Example 88: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenyl]-4-(2-guanidino-ethyl)-benzamide:
Figure imgf000504_0001
[0361] Step 1: Synthesis of {2-[4-(4-bromo-3-methyl-phenylcarbamoyl)-phenyl]-ethyl}- carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of 6-(4- bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester using 4-(2-tert-butoxycarbonylamino-ethyl)-benzoic acid (250 mg, 0.94 mmol), 4-bromo-3-methyl- phenylamine (193 mg, 1.04 mmol), triethylamine (335 mg, 461 ^L, 3.30 mmol), and N,N,N′,N′- tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (534 mg, 1.41 mmol), to give {2- [4-(4-bromo-3-methyl-phenylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (358 mg, 88%) as a beige solid.
Figure imgf000504_0002
[0362] Step 2: Synthesis of 4-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-benzoylamino]-2- methyl-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using {2-[4-(4-bromo-3-methyl-phenylcarbamoyl)-phenyl]-ethyl}- carbamic acid tert-butyl ester (243 mg, 0.56 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (203 mg, 0.66 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (23 mg, 0.056 mmol), to give 4-     {4-[4-(2-tert-butoxycarbonylamino-ethyl)-benzoylamino]-2-methyl-phenyl}-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (182 mg, 61%) as a white solid.
Figure imgf000505_0001
[0363] Step 3: Synthesis of 4-(2-amino-ethyl)-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-benzamide: A solution of 4-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-benzoylamino]-2- methyl-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (182 mg, 0.34 mmol) in CH2Cl2 (1.5 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 4-(2-amino-ethyl)-N-[3-methyl- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide (163 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000505_0002
[0364] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[4-(2- {[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) benzamido]-2-methylphenyl}-1,2,3,6-tetrahydropyridin-1-yl)methylidene]carbamate: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 4-(2-amino-ethyl)-N-[3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide . 2 HCl (78 mg, 0.19 mmol), triethylamine (135 mg, 186 ^L, 1.33 mmol), and N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol), to give tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[4-(2-{[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)benzamido]-2-methylphenyl}-1,2,3,6- tetrahydropyridin-1-yl)methylidene]carbamate (66 mg, 42%) as a white solid.    
Figure imgf000506_0001
[0365] Step 5: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- phenyl]-4-(2-guanidino-ethyl)-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}(4-{4-[4-(2-{[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)benzamido]-2-methylphenyl}-1,2,3,6-tetrahydropyridin-1-yl)methylidene] carbamate (66 mg, 0.081 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was purified by preparative HPLC, to give N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-(2- guanidino-ethyl)-benzamide as the bis-TFA salt (37 mg, 71%) as a white solid. MS: 420 M+H+: 1H NMR (300 MHz, dmso) δ 10.13 (s, 1H), 7.85-7.95 (m, 2H), 7.55-7.73 (m, 4H), 7.34-7.55 (m, 7H), 7.08 (d, J=8.20 Hz, 2H), 5.56-5.66 (m, 1H), 4.03 (d, J=2.34 Hz, 2H), 3.61 (t, J=5.57 Hz, 2H), 3.40 (q, J=6.44 Hz, 2H), 2.86 (t, J=7.32 Hz, 2H), 2.38-2.45 (m, 2H), 2.25 (s, 3H). [0366] Example 89: Synthesis of 2-carbamimidoyl-2,3-dihydro-1H-isoindole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide: B
Figure imgf000506_0002
[0367] Step 1: Synthesis of 5-(4-bromo-3-methyl-phenylcarbamoyl)-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 6-(4- bromo-3-methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester using 1,3-Dihydro-isoindole-2,5-dicarboxylic acid 2-tert-butyl ester (250 mg, 0.95 mmol), 4-bromo-3- methyl-phenylamine (198 mg, 1.06 mmol), triethylamine (196 mg, 268 ^L, 1.92 mmol), and N,N,N′,N′- tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (509 mg, 1.34 mmol), to give 5- (4-bromo-3-methyl-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (315 mg, 77%) as an off-white solid.    
Figure imgf000507_0001
[0368] Step 2: Synthesis of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenylcarbamoyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 5-(4-bromo-3-methyl-phenylcarbamoyl)-1,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (315 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (266 mg, 0.86 mmol), Pd(OAc)2 (7 mg, 0.028 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (30 mg, 0.073 mmol), to give 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- phenylcarbamoyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (287 mg, 74%) as a white solid.
Figure imgf000507_0002
[0369] Step 3: Synthesis of 2,3-dihydro-1H-isoindole-5-carboxylic acid [3-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide: A solution of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenylcarbamoyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (287 mg, 0.54 mmol) in CH2Cl2 (2.5 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2,3- dihydro-1H-isoindole-5-carboxylic acid [3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the bis-HCl salt (207 mg, 94%) as a grey solid.    
Figure imgf000508_0001
[0370] Step 4: Synthesis of give {[4-(4-{[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-2,3-dihydro-1H-isoindole-5-carbonyl]-amino}-2-methyl-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H- pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 2,3-dihydro-1H-isoindole-5-carboxylic acid [3- methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide . 2 HCl (77 mg, 0.19 mmol), triethylamine (135 mg, 186 ^L, 1.33 mmol), and N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol), to give {[4-(4- {[2-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindole-5- carbonyl]-amino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl} -carbamic acid tert-butyl ester (59 mg, 38%) as a white film.
Figure imgf000508_0002
[0371] Step 5: Synthesis of 2-carbamimidoyl-2,3-dihydro-1H-isoindole-5-carboxylic acid [4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide: A mixture of {[4-(4-{[2- (tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindole-5-carbonyl]- amino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonyl imino-methyl}-carbamic acid tert-butyl ester (59 mg, 0.072 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 2-carbamimidoyl-2,3-dihydro-1H-isoindole-5-carboxylic acid [4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide as the bis-TFA salt (18 mg, 39%) as a white solid. MS: 418 M+H+: 1H NMR (300 MHz, dmso) δ 10.20-10.31 (m, 1H), 7.90-8.01     (m, 2H), 7.58-7.69 (m, 2H), 7.36-7.58 (m, 8H), 7.06-7.16 (m, 1H), 5.56-5.67 (m, 1H), 4.81 (s, 3H), 3.98-4.09 (m, 2H), 3.55-3.66 (m, 2H), 2.38-2.44 (m, 2H), 2.25 (s, 3H). [0372] Example 90: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methyl-phenyl]-4-guanidino-benzamide
Figure imgf000509_0001
[0373] Step 1: Synthesis of give [4-(4-bromo-3-methyl-phenylcarbamoyl)-phenyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of 6-(4-bromo-3- methyl-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester using 4-tert- butoxycarbonylamino-benzoic acid (225 mg, 0.95 mmol), 4-bromo-3-methyl-phenylamine (198 mg, 1.06 mmol), triethylamine (196 mg, 268 ^L, 1.92 mmol), and N,N,N′,N′-tetramethyl-O-(1H- benzotriazol-1-yl)uronium hexafluorophosphate (509 mg, 1.34 mmol), to give [4-(4-bromo-3-methyl- phenylcarbamoyl)-phenyl]-carbamic acid tert-butyl ester (120 mg, 31%) as a beige solid.
Figure imgf000509_0002
[0374] Step 2: Synthesis of 4-[4-(4-tert-butoxycarbonylamino-benzoylamino)-2-methyl- phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: A mixture of [4-(4-bromo-3- methyl-phenylcarbamoyl)-phenyl]-carbamic acid tert-butyl ester (120 mg, 0.30 mmol), 4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (107 mg, 0.35 mmol), Pd(OAc)2 (3 mg, 0.012 mmol), and 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (12 mg, 0.030 mmol) in 1,4-dioxane (2 mL) and 2M K2CO3 (0.6 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 oC for 16 hours. The mixture was allowed to cool to 20 oC , then was treated with ethyl acetate (40 mL) and water (10 mL). The organic layer was washed with brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate/ hexanes), to give 4-[4-(4-     tert-butoxycarbonylamino-benzoylamino)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (85 mg, 56%) as a clear film.
Figure imgf000510_0001
[0375] Step 3: Synthesis of 4-amino-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -benzamide: A mixture of 4-[4-(4-tert-butoxycarbonylamino-benzoylamino)-2-methyl-phenyl]-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (85 mg, 0.17 mmol) in CH2Cl2 (1 mL) and methanol (0.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (0.55 mL). The reaction was stirred for 16 hours, then was concentrated, to give 4-amino-N-[3-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-benzamide as the bis-HCl salt (94 mg, >100%) as a yellow gum, that was used without further purification.
Figure imgf000510_0002
[0376] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4- {[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}benzamido)-2- methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H- pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 4-amino-N-[3-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-benzamide . 2 HCl (94 mg, 0.25 mmol), triethylamine (178 mg, 245 ^L, 1.75 mmol), and N,N’-bis-Boc-guanylpyrazole (250 mg, 0.80 mmol), to give tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]amino}benzamido)-2-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene] carbamate (85 mg, 43%) as a white solid.    
Figure imgf000511_0001
[0377] Step 5: Synthesis of N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl -phenyl]-4-guanidino-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4- [4-(4-{[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]amino}benzamido)-2-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene] carbamate in CH2Cl2 (1 mL) was treated with TFA (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-guanidino-benzamide (23 mg, 34%) as a white solid. MS: 392 M+H+: 1H NMR (300 MHz, dmso) δ 10.07-10.27 (m, 2H), 8.02 (d, J=8.79 Hz, 2H), 7.66-7.79 (m, 4H), 7.52-7.66 (m, 3H), 7.44 (s, 4H), 7.35 (d, J=8.20 Hz, 2H), 7.09 (d, J=8.20 Hz, 1H), 5.61 (br. s., 1H), 3.99-4.10 (m, 2H), 3.61 (t, J=5.57 Hz, 6H), 2.38-2.44 (m, 2H), 2.25 (s, 3H). [0378] Example 91: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-chloro-benzamide
Figure imgf000511_0002
[0379] Step 1: Synthesis of 4-bromo-3-chloro-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-3-chloro- benzoic acid (422 mg, 1.79 mmol), and oxalyl chloride (364 mg, 246 ^L, 2.86 mmol), to give 4-bromo- 3-chloro-benzoyl chloride, that was used without further purification.
Figure imgf000511_0003
    [0380] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methyl-phenyl)-3-chloro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-3-chloro-benzoyl chloride, 4-bromo-3-methyl-phenyl amine (300 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol), to give 4- bromo-N-(4-bromo-3-methyl-phenyl)-3-chloro-benzamide (602 mg, 93%) as a beige solid.
Figure imgf000512_0001
[0381] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methylphenyl)carbamoyl]-2-chlorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methyl-phenyl)-3-chloro- benzamide (295 g, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (0.54 g, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-2-chloro phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (174 mg, 39%) as a clear gum.
Figure imgf000512_0002
[0382] Step 4: Synthesis of 3-chloro-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-2-chlorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (174 mg, 0.29 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.1 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-chloro-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-     (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide (156 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000513_0002
[0383] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-chloro-benzoylamino}-2-methyl-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using N-(2,3-Dihydro-1H-isoindol-5-yl)- 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (78 mg, 0.19 mmol), triethylamine (135 mg, 186 ^L, 1.33 mmol), and N,N’-bis-Boc-guanylpyrazole (190 mg, 0.61 mmol), to give {[4- (4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4- yl]-3-chloro-benzoylamino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonyl imino-methyl}-carbamic acid tert-butyl ester (125 mg, 50%) as a white solid. B
Figure imgf000513_0001
[0384] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-chloro-benzamide: A mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-chloro-benzoylamino}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-     butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (125 mg, 0.14 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- phenyl]-3-chloro-benzamide as the bis-TFA salt (60 mg, 60%) as a white solid. MS: 493 M+H+: 1H NMR (300 MHz, dmso) δ 10.29 (s, 1H), 8.04 (d, J=1.76 Hz, 1H), 7.91 (dd, J=1.76, 8.20 Hz, 1H), 7.41- 7.64 (m, 11H), 7.10 (d, J=8.79 Hz, 1H), 5.87 (s, 1H), 5.61 (s, 1H), 4.05 (dd, J=1.76, 14.65 Hz, 4H), 3.61 (q, J=5.27 Hz, 4H), 2.52 (br. s., 2H), 2.37-2.44 (m, 2H), 2.25 (s, 3H). [0385] Example 92: Synthesis of 4-{4-[6-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- 1,2,3,4-tetrahydroquinoline-1-carbonyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboximidamide:
Figure imgf000514_0001
[0386] Step 1: Synthesis of 4-bromo-3-fluoro-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-3-fluoro- benzoic acid (251 mg, 1.14 mmol), and oxalyl chloride (232 mg, 157 ^L, 1.82 mmol), to give 4-bromo- 3-fluoro-benzoyl chloride, that was used without further purification.
Figure imgf000514_0002
[0387] Step 2: Synthesis of give (6-bromo-3,4-dihydro-2H-quinolin-1-yl)-(4-bromo-3-fluoro- phenyl)-methanone: The title compound was prepared according to the procedure of 4-bromo-N-(4- bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 6- bromo-1,2,3,4-tetrahydro-quinoline (221 mg, 1.04 mmol), and diisopropylethylamine (209 mg, 281 ^L, 1.62 mmol), to give (6-bromo-3,4-dihydro-2H-quinolin-1-yl)-(4-bromo-3-fluoro-phenyl)- methanone (367 mg, 85%) as a tacky solid.    
Figure imgf000515_0001
[0388] Step 3: Synthesis of tert-butyl 4-[4-(6-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-1,2,3,4-tetrahydroquinoline-1-carbonyl)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using (6-bromo-3,4-dihydro-2H-quinolin-1- yl)-(4-bromo-3-fluoro-phenyl)-methanone (367 mg, 0.89 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (657 mg, 2.14 mmol), Pd(OAc)2 (17 mg, 0.077 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (74 mg, 0.18 mmol), to give tert-butyl 4-[4-(6-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,2,3,4- tetrahydroquinoline-1-carbonyl)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (532 mg, 97%) as a tacky solid.
Figure imgf000515_0002
[0389] Step 4: Synthesis of [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-[6-(1,2,3,6- tetrahydro-pyridin-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-methanone: A solution of tert-butyl 4-[4-(6- {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,2,3,4-tetrahydroquinoline-1-carbonyl)-2- fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (532 mg, 0.86 mmol) in CH2Cl2 (3 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3 mL). The reaction was stirred for 16 hours, then was concentrated, to give [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-[6- (1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-methanone as the bis-HCl salt (608 mg, >100%) as an orange solid, that was used without further purification.    
Figure imgf000516_0002
[0390] Step 5: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(6-{1- [(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-1,2,3,4-tetrahydroquinoline-1-carbonyl)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate: The title compound was prepared according to the procedure of [(4-{4-[2- (tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7- ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using [3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-3,4-dihydro -2H-quinolin-1-yl]-methanone . 2 HCl (137 mg, 0.28 mmol), triethylamine (200 mg, 274 ^L, 1.96 mmol), and N,N’-bis-Boc-guanylpyrazole (280 mg, 0.90 mmol), to give tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}({4-[4-(6-{1-[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,2,3,4-tetrahydroquinoline-1-carbonyl)-2-fluoro phenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (110 mg, 44%) as a yellow gum.
Figure imgf000516_0001
[0391]] Step 6: Synthesis of 4-{4-[6-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- 1,2,3,4-tetrahydroquinoline-1-carbonyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboximidamide: A mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(6-{1-[(1E)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}-1,2,3,4-tetrahydroquinoline-1-carbonyl)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-     yl})methylidene]carbamate (110 mg, 0.12 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-{4-[6-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)- 1,2,3,4-tetrahydroquinoline-1-carbonyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboximidamide as the bis-TFA salt (55 mg, 63%) as a white solid. MS: 502 M+H+: 1H NMR (300 MHz, dmso) δ 7.42-7.61 (m, 9H), 7.28-7.42 (m, 2H), 7.05-7.28 (m, 3H), 6.85-7.01 (m, 1H), 6.12 (d, J=14.06 Hz, 2H), 3.96-4.12 (m, 4H), 3.69-3.76 (m, 4H), 3.58 (t, J=5.27 Hz, 4H), 2.82 (t, J=6.74 Hz, 2H), 2.53-2.59 (m, 2H), 1.84-2.02 (m, 2H). [0392] Example 93: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-methoxy-benzamide
Figure imgf000517_0001
[0393] Step 1: Synthesis of 4-bromo-3-methoxy-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-3-methoxy- benzoic acid (414 mg, 1.79 mmol), and oxalyl chloride (364 mg, 246 ^L, 2.86 mmol), to give 4-bromo- 3-methoxy-benzoyl chloride, that was used without further purification.
Figure imgf000517_0002
[0394] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methyl-phenyl)-3-methoxy-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-methoxy-benzoyl chloride, 4-bromo-3-methyl- phenylamine (300 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol), to give 4-bromo-N-(4-bromo-3-methyl-phenyl)-3-methoxy-benzamide (625 mg, 97%) as an off-white solid.    
Figure imgf000518_0001
[0395] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methylphenyl)carbamoyl]-2-methoxyphenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methyl- phenyl)-3-methoxy-benzamide (291 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.54 g, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl) carbamoyl]-2-methoxyphenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (389 mg, 88%) as a white solid.
Figure imgf000518_0002
[0396] Step 4: Synthesis of 3-methoxy-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-2-methoxyphenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (389 mg, 0.64 mmol) in CH2Cl2 (2.5 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-methoxy-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (316 mg, >100%) as a pale yellow solid.     H
Figure imgf000519_0002
[0397] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methyl-phenylcarbamoyl}-2-methoxy-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 3-methoxy-N-[3-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (137 mg, 0.28 mmol), triethylamine (200 mg, 274 ^L, 1.96 mmol), and N,N’-bis-Boc-guanylpyrazole (280 mg, 0.90 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methyl-phenylcarbamoyl}-2-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (110 mg, 44%) as a yellow gum.
Figure imgf000519_0001
[0398] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-methoxy-benzamide: A mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-methyl-phenylcarbamoyl}-2-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (110 mg, 0.12 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 3 days, then was concentrated.     The crud material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-methoxy- benzamide as the bis-TFA salt (55 mg, 63%) as a white solid. MS: 488 M+H+: 1H NMR (300 MHz, dmso) δ 10.09-10.21 (m, 1H), 7.50-7.66 (m, 4H), 7.38-7.50 (m, 8H), 7.30 (d, J=7.62 Hz, 1H), 7.05- 7.15 (m, 1H), 5.87-5.97 (m, 1H), 5.61 (s, 1H), 4.04 (d, J=2.34 Hz, 4H), 3.86 (s, 3H), 3.56-3.65 (m, 4H), 2.54 (br. s., 2H), 2.41 (d, J=1.76 Hz, 2H), 2.25 (s, 3H). [0399] Example 94: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide
Figure imgf000520_0001
[0400] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3-methoxy- phenylamine (325 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3-fluoro-benzamide (352 mg, 54%) as a beige solid.
Figure imgf000520_0002
[0401] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-3-fluoro-benzamide (352 mg, 0.87 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (642 mg, 2.09 mmol), Pd(OAc)2 (17 mg, 0.077 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (72 mg, 0.18 mmol), to give tert-     butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl) carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (568 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000521_0001
[0402] Step 3: Synthesis of 3-fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2-fluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (568 mg, 0.94 mmol) in CH2Cl2 (4 mL) and methanol (2.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (466 mg, >10%) as a pale orange solid.
Figure imgf000521_0002
[0403] Step 4: Synthesis of {[4-(4-{4-[1-(tert-Butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 3-fluoro-N-[3-methoxy-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (113 mg, 0.24     mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (55 mg, 26%) as a tacky solid.
Figure imgf000522_0001
[0404] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide: A mixture of {[4-(4-{4-[1-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (55 mg, 0.062 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro- benzamide (20 mg, 45%) as a white solid. MS: 492 M+H+: 1H NMR (300 MHz, dmso) δ 10.26-10.37 (m, 1H), 7.76-7.90 (m, 2H), 7.33-7.64 (m, 12H), 7.15 (d, J=8.20 Hz, 1H), 6.11-6.25 (m, 1H), 5.84 (br. s., 1H), 4.10 (d, J=1.76 Hz, 2H), 3.98-4.07 (m, 2H), 3.62 (t, J=5.57 Hz, 2H), 3.55 (t, J=5.27 Hz, 2H), 2.54-2.66 (m, 3H), 2.53 (br. s., 2H). [0405] Example 95: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-phenyl]-3-fluoro-benzamide
Figure imgf000522_0002
[0406] Step 1: Synthesis of 4-bromo-N-(4-bromo-2-methoxy-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro     methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-2-methoxy- phenylamine (325 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol), to give 4-bromo-N-(4-bromo-2-methoxy-phenyl)-3-fluoro-benzamide (633 mg, 98%) as a light brown solid.
Figure imgf000523_0001
[0407] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methoxyphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-2-methoxy- phenyl)-3-fluoro-benzamide (352 mg, 0.87 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (642 mg, 2.09 mmol), Pd(OAc)2 (17 mg, 0.077 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (72 mg, 0.18 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methoxyphenyl) carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (457 mg, 86%) as a pale yellow solid.
Figure imgf000523_0002
[0408] Step 3: Synthesis of 3-fluoro-N-[2-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A mixture of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methoxyphenyl)carbamoyl]-2-fluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (457 mg, 0.75 mmol) in CH2Cl2 (3.2 mL) and methanol (2 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.4 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-[2-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-     phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (355 mg, 99%) as an orange solid.
Figure imgf000524_0001
[0409] Step 4: Synthesis of give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 3-fluoro-N-[2-methoxy-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (113 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-2-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (70 mg, 33%) as a clear film.
Figure imgf000524_0002
[0410] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-phenyl]-3-fluoro-benzamide: A mixture of give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-2-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro -2H-pyridin-1-yl]-tert-     butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (70 mg,0.078 mmol) in CH2Cl2 (1 mL) as treated with trifluoroacetic acid(1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-phenyl]-3-fluoro- benzamide as the bis-TFA salt (12 mg, 21%) as a white solid. MS: 492 M+H+: 1H NMR (300 MHz, dmso) δ 9.52-9.65 (m, 1H), 7.75-7.87 (m, 3H), 7.65-7.74 (m, 1H), 7.39-7.61 (m, 9H), 7.16 (d, J=1.17 Hz, 1H), 7.00-7.12 (m, 1H), 6.21-6.31 (m, 1H), 6.16 (br. s., 1H), 4.00-4.18 (m, 4H), 3.86 (s, 3H), 3.55- 3.70 (m, 5H), 2.54-2.67 (m, 4H). [0411] Example 96: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-(4- guanidinomethyl-phenyl)-benzamide
Figure imgf000525_0001
[0412] Step 1: Synthesis of [4-(4-bromo-benzoylamino)-benzyl]-carbamic acid tert-butyl ester: To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (358 mg, 1.61 mmol) and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol) in CHCl3 (5 mL) was added dropwise a solution of 4-bromo-benzoyl chloride (393 mg, 1.79 mmol) in CHCl3 (5 mL). The reaction was stirred for 3 days, then was concentrated. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was washed with 10% aqueous citric acid (20 mL), saturated aqueous NaHCO3 (15 mL), and brine (5 mL), dried (Na2SO4), and concentrated, to give [4-(4-bromo-benzoylamino)- benzyl]-carbamic acid tert-butyl ester (419 mg, 64%) as a white solid.
Figure imgf000525_0002
[0413] Step 2: Synthesis of 4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]- phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin- 4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-     carboxylate using [4-(4-bromo-benzoylamino)-benzyl]-carbamic acid tert-butyl ester (405 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (362 mg, 1.18 mmol), Pd(OAc)2 (9 mg, 0.039 mmol), and 2-dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl (41 mg, 0.10 mmol), to give 4-{4-[4-(tert-butoxy carbonylamino-methyl)- phenylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (289 mg, 57%) as a white solid.
Figure imgf000526_0001
[0414] Step 3: Synthesis of N-(4-aminomethyl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide: A solution of 4-{4-[4-(tert-butoxycarbonylamino-methyl)-phenylcarbamoyl]-phenyl}-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (289 mg, 0.57 mmol) in CH2Cl2 (2.5 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(4-aminomethyl-phenyl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide as the bis-HCl salt (274 mg, >100%) as a yellow solid.
Figure imgf000526_0002
[0415] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4- ({[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}methyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using N-(4-aminomethyl-phenyl)-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (91 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give tert-butyl N-[(1Z)- {[(tert-butoxy)carbonyl]amino}[4-(4-{[4-({[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)     carbonyl]imino})methyl]amino}methyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl] methylidene]carbamate (104 mg, 55%) as a white solid.
Figure imgf000527_0001
[0416] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-(4- guanidinomethyl-phenyl)-benzamide: A mixture of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-({[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]amino}methyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl] methylidene]carbamate (104 mg, 0.13 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-(4- guanidinomethyl-phenyl)-benzamide as the bis-TFA salt (57 mg, 71%) as a white solid. MS: 392 M+H+: 1H NMR (300 MHz, dmso) δ 10.21-10.36 (m, 1H), 7.88-8.02 (m, 3H), 7.77 (d, J=8.79 Hz, 2H), 7.62 (d, J=8.20 Hz, 2H), 7.42-7.56 (m, 4H), 7.17-7.36 (m, 4H), 6.30-6.45 (m, 1H), 4.27-4.39 (m, 2H), 4.04-4.18 (m, 2H), 3.61-3.69 (m, 2H), 2.59-2.70 (m, 2H). [0417] Example 97: Synthesis of N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide
Figure imgf000527_0002
[0418] Step 1: Synthesis of 5-(4-bromo-benzoylamino)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester: To a mixture of 5-amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (303 mg, 1.29 mmol), and diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol) in CHCl3 (4 mL) was added dropwise a solution of 4-bromo-benzoyl chloride (316 mg, 1.44 mmol) in CHCl3 (4 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was washed with 1N HCl (10 mL), saturated     aqueous NaHCO3 (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give 5-(4-bromo-benzoylamino)- 1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (440 mg, 82%) as a pale orange solid.
Figure imgf000528_0001
[0419] Step 2: Synthesis of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate using 5-(4-bromo-benzoylamino)-1,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester (440 mg, 1.05 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (385 mg, 1.24 mmol), Pd(OAc)2 (11 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (45 mg, 0.11 mmol), to give 5-[4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (258 mg, 47%) as a pale orange solid.
Figure imgf000528_0002
[0420] Step 3: Synthesis of give N-(2,3-dihydro-1H-isoindol-5-yl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (258 mg, 0.50 mmol) in CH2Cl2 (2.5 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(2,3-dihydro-1H-isoindol-5-yl)-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (223 mg, >100%) as a brown solid, that was used without further purification.    
Figure imgf000529_0001
[0421] Step 4: Synthesis of give [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl using N-(2,3-dihydro-1H-isoindol-5-yl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide .2 HCl (94 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give [(4-{4-[2-(tert-butoxycarbonyl amino-tert- butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-phenyl}-3,6-dihydro-2H- pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (89 mg, 46%) as a tacky gum.
Figure imgf000529_0002
[0422] Step 5: Synthesis of N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a mixture of [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]- phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (89 mg, 0.11 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide as the bis-TFA salt (35 mg, 50%) as a white solid. MS: 404 M+H+: 1H NMR (300 MHz, dmso) δ 10.34 (s, 1H), 7.93-8.04 (m, 2H), 7.82-7.90 (m, 1H), 7.58-7.76 (m, 3H), 7.39-7.58     (m, 8H), 7.35 (d, J=8.20 Hz, 1H), 6.37 (br. s., 1H), 4.64-4.82 (m, 4H), 4.04-4.19 (m, 2H), 3.62-3.69 (m, 2H), 2.63 (br. s., 2H). [0423] Example 98: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide
Figure imgf000530_0001
[0424] Step 1: Synthesis of 7-(4-bromo-benzoylamino)-3,4-dihydro-1H-isoquinoline-2- carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of The title compounds was prepared using 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (320 mg, 1.29 mmol), diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol), and 4-bromo-benzoyl chloride (316 mg, 1.44 mmol), to give 7-(4-bromo-benzoylamino)-3,4-dihydro-1H-isoquinoline-2- carboxylic acid tert-butyl ester (528 mg, 95%) as an off-white solid.
Figure imgf000530_0002
[0425] Step 2: Synthesis of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate using 7-(4-bromo-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (431 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (367 mg, 1.18 mmol), Pd(OAc)2 (11 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (43 mg, 0.11 mmol), to give 7-[4-(1- tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzoylamino]-3,4-dihydro-1H-isoquinoline-2- carboxylic acid tert-butyl ester (431 mg, 81%) as a white solid.    
Figure imgf000531_0002
[0426] Step 3: Synthesis of N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (431 mg, 0.81 mmol) in CH2Cl2 (3.5 mL) and methanol (1.8 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(1,2,3,4-tetrahydro- isoquinolin-7-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (307 mg, 93%) as a yellow solid.
Figure imgf000531_0001
[0427] Step 4: Synthesis of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl using N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide .2 HCl (98 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give [(4-{4-[2-(tert-butoxy carbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]- phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (80 mg, 41%) as a white solid.    
Figure imgf000532_0001
[0428] Step 5: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a mixture of [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7- ylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (80 mg, 0.098 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-TFA salt (46 mg, 73%) as a white solid. MS: 418 M+H+: 1H NMR (300 MHz, dmso) δ 10.20-10.31 (m, 1H), 7.90-8.02 (m, 2H), 7.69-7.78 (m, 1H), 7.51-7.69 (m, 4H), 7.39-7.51 (m, 8H), 7.21 (d, J=8.20 Hz, 1H), 6.30-6.44 (m, 1H), 4.56 (s, 2H), 4.04-4.17 (m, 2H), 3.56-3.69 (m, 4H), 2.87 (t, J=5.86 Hz, 2H), 2.56-2.70 (m, 2H). [0429] Example 99: Synthesis of N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-benzamide
Figure imgf000532_0002
[0430] Step 1: Synthesis of 4-bromo-2-methyl-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-2-methyl- benzoic acid (310 mg, 1.44 mmol), and oxalyl chloride (293 mg, 198 ^L, 2.30 mmol), to give 4-bromo- 2-methyl-benzoyl chloride, that was used without further purification.
Figure imgf000532_0003
[0431] Step 2: Synthesis of 5-(4-bromo-2-methyl-benzoylamino)-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-     bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-2-methyl-benzoyl chloride, 5-amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (300 mg, 1.28 mmol), and diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol), to give 5-(4-bromo-2-methyl-benzoylamino)- 1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (542 mg, 98%) as an off-white solid.
Figure imgf000533_0001
[0432] Step 3: Synthesis of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2- methyl-benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate using 5-(4-bromo-2-methyl-benzoylamino)-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (431 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (367 mg, 1.18 mmol), Pd(OAc)2 (11 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (43 mg, 0.11 mmol), to give 5- [4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-benzoylamino]-1,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (413 mg, 77%) as an off-white solid.
Figure imgf000533_0002
[0433] Step 4: Synthesis of N-(2,3-dihydro-1H-isoindol-5-yl)-2-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- 2-methyl-benzoylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (413 mg, 0.77 mmol) in CH2Cl2 (3.5 mL) and methanol (1.8 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(2,3-dihydro-1H-isoindol- 5-yl)-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (327 mg, >100%) as a brown solid.    
Figure imgf000534_0001
[0434] Step 5: Synthesis of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-3-methyl-phenyl}-3,6-dihydro-2H-pyridin-1-yl)- tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl using N-(2,3-dihydro-1H-isoindol-5-yl)-2-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide .2 HCl (98 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-3- methyl-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert- butyl ester (80 mg, 41%) as a white solid.
Figure imgf000534_0002
[0435] Step 6: Synthesis of N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-benzamide: To a mixture of [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2,3-dihydro-1H-isoindol-5-ylcarbamoyl]-3- methyl-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert- butyl ester (80 mg, 0.098 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-methyl-benzamide as the bis-TFA salt (42 mg, 66%) as a white solid. MS: 418 M+H+: 1H NMR (300 MHz, dmso) δ 10.29-10.45 (m, 1H), 7.85 (s, 1H), 7.53-7.68 (m, 1H), 7.26-7.53 (m, 12H),     6.26 (s, 1H), 4.63-4.79 (m, 4H), 4.00-4.15 (m, 2H), 3.58-3.69 (m, 2H), 2.59 (d, J=3.51 Hz, 2H), 2.39 (s, 3H). [0436] Example 100: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-benzamide
Figure imgf000535_0001
[0437] Step 1: Synthesis of 7-(4-bromo-2-methyl-benzoylamino)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-2- methyl-benzoyl chloride, 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (318 mg, 1.28 mmol), and diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol), to give 7-(4-bromo-2- methyl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (565 mg, 99%) as a pale brown solid.
Figure imgf000535_0002
[0438] Step 2: Synthesis of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2- methyl-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 7-(4-bromo-2-methyl-benzoylamino)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester (445 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (367 mg, 1.18 mmol), Pd(OAc)2 (11 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (43 mg, 0.11 mmol), to give 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl- benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (374 mg, 68%) as a white solid.    
Figure imgf000536_0001
[0439] Step 3: Synthesis of 2-methyl-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 7-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-methyl-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (374 mg, 0.68 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 30 minutes, then further CH2Cl2 (2 mL) was added. The reaction was broken up with a spatula, then was stirred for 16 hours. The reaction was concentrated, to give 2-methyl-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1,2,3,6-tetrahydro-pyridin- 4-yl)-benzamide as the bis-HCl salt (290 mg, >100%) as a pale yellow solid.
Figure imgf000536_0002
[0440] Step 4: Synthesis of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-3-methyl-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl using 2-methyl-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide.2 HCl (101 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7- ylcarbamoyl]-3-methyl-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]- carbamic acid tert-butyl ester (125 mg, 63%) as a clear film.    
Figure imgf000537_0001
[0441] Step 5: Synthesis of N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-benzamide: To a mixture of [(4-{4-[2-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7- ylcarbamoyl]-3-methyl-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]- carbamic acid tert-butyl ester (125 mg, 0.15 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-benzamide as the bis-TFA salt (65 mg, 66%) as a white solid. MS: 432 M+H+: 1H NMR (300 MHz, dmso) δ 10.20-10.35 (m, 1H), 7.64-7.75 (m, 1H), 7.31-7.62 (m, 12H), 7.19 (d, J=8.20 Hz, 1H), 6.26 (br. s., 1H), 4.56 (s, 2H), 4.09 (d, J=1.17 Hz, 2H), 3.52-3.66 (m, 4H), 2.79-2.92 (m, 2H), 2.60 (br. s., 2H), 2.38 (s, 3H). [0442] Example 101: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-fluoro-benzamide:
Figure imgf000537_0002
[0443] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methyl-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3-methyl-phenyl amine (300 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 435 ^L, 2.50 mmol), to give 4- bromo-N-(4-bromo-3-methyl-phenyl)-3-fluoro-benzamide (522 mg, 84%) as a white solid.     B
Figure imgf000538_0001
[0444] Step 2: Synthesis of give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methyl- phenyl)-3-fluoro-benzamide (283 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (540 mg, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl) carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (410 mg, 95%) as an off-white solid.
Figure imgf000538_0002
[0445] Step 3: Synthesis of 3-fluoro-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-2-fluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (410 mg, 0.69 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-[3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (342 mg, >100%) as a pale yellow solid.    
Figure imgf000539_0002
[0446] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methyl-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of [(4-{4-[2-(tert-butoxycarbonylamino-tert- butoxycarbonyl imino-methyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl using 3-fluoro-N-[3-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (112 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methyl-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (146 mg, 69%) as a white film.
Figure imgf000539_0001
[0447] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3-fluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-methyl-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (146 mg, 0.17 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated.     The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl -1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-3- fluoro-benzamide as the bis-TFA salt (31 mg, 26%) as a white solid. MS: 476 M+H+: 1H NMR (300 MHz, dmso) δ 10.15-10.34 (m, 1H), 7.75-7.91 (m, 2H), 7.37-7.68 (m, 11H), 7.00-7.18 (m, 1H), 6.11-6.25 (m, 1H), 5.56-5.71 (m, 1H), 4.07-4.18 (m, 2H), 3.98-4.07 (m, 2H), 3.54-3.68 (m, 4H), 2.56- 2.66 (m, 2H), 2.37-2.45 (m, 2H), 2.26 (s, 3H). [0448] Example 102: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (2-guanidino-ethyl)-phenyl]-benzamide
Figure imgf000540_0001
[0449] Step 1: Synthesis of give {2-[4-(4-bromo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester: To a mixture of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (305 mg, 1.29 mmol), and diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol) in CHCl3 (4 mL) was added dropwise a solution of 4-bromo-benzoyl chloride (316 mg, 1.44 mmol) in CHCl3 (4 mL). The reaction was treated with further CHCl3 (4 mL), then was stirred for 16 hours. The reaction was concentrated, then the residue was treated with ethyl acetate (20 mL). The ethyl acetate was decanted, then the solid was treated with water (20 mL), and was filtered. The solid was washed with isopropanol (15 mL), and hexanes (15 mL), to give {2-[4-(4-bromo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (490 mg, 91%) as a white solid.
Figure imgf000540_0002
[0450] Step 2: Synthesis of 4-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]- phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin- 4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1- carboxylate using {2-[4-(4-bromo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (419 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-     carboxylic acid tert-butyl ester (367 mg, 1.18 mmol), Pd(OAc)2 (11 mg, 0.042 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (43 mg, 0.11 mmol), to give 4-{4-[4-(2-tert- butoxycarbonylamino-ethyl)-phenylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (253 mg, 49%) as a white solid.
Figure imgf000541_0001
[0451] Step 3: Synthesis of N-[4-(2-amino-ethyl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide: A solution of 4-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]-phenyl}-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (253 mg, 0.49 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[4-(2-amino-ethyl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (243 mg, >100%) as a yellow solid.
Figure imgf000541_0002
[0452] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate: A mixture of N-[4-(2- amino-ethyl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (95 mg, 0.24 mmol) in CH2Cl2 (1.1 mL) and N,N-dimethylformamide (1.1 mL) was treated slowly with triethylamine (168 mg, 230 ^L, 1.65 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was concentrated, then was treated with water (20 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (10 mL), 10% aqueous citric acid (10 mL), and brine (5 mL). The combined aqueous washes were filtered through Celite, then the organic layer was combined with the previous organic extractes, dried     (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/hexanes), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert -butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl} phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate (56 mg, 29%) as a clear film. H2N
Figure imgf000542_0001
[0453] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2- guanidino-ethyl)-phenyl]-benzamide: To a mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate (56 mg, 0.070 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide as the bis-TFA salt (37 mg, 83%) as a pale yellow solid. MS: 406 M+H+: 1H NMR (300 MHz, dmso) δ 10.16-10.28 (m, 1H), 7.91-8.06 (m, 3H), 7.71 (d, J=8.20 Hz, 3H), 7.45-7.66 (m, 7H), 7.23 (d, J=8.79 Hz, 3H), 6.30-6.44 (m, 1H), 4.11 (br. s., 2H), 3.64 (t, J=4.10 Hz, 2H), 3.26-3.44 (m, 2H), 2.75 (t, J=6.44 Hz, 2H), 2.58-2.70 (m, 2H). [0454] Example 103: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-5-fluoro-2-methyl- benzamide
Figure imgf000542_0002
[0455] Step 1: Synthesis of 4-bromo-5-fluoro-2-methyl-benzoyl chloride: To a mixture of 4- bromo-5-fluoro-2-methyl-benzoic acid (280 mg, 1.20 mmol) in CHCl3 (7 mL) and N,N- dimethylformamide (3 drops) was added dropwise oxalyl chloride (244 mg, 165 ^L, 1.92 mmol). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with CHCl3 (15 mL),     then was concentrated, to give 4-bromo-5-fluoro-2-methyl-benzoyl chloride, which was used without further purification.
Figure imgf000543_0001
[0456] Step 2: Synthesis of 4-bromo-N-(4-bromo-5-fluoro-2-methyl-phenyl)-5-fluoro-2- methyl-benzamide: To a mixture of 4-bromo-5-fluoro-2-methyl-phenylamine (220 mg, 1.08 mmol) and diisopropylethylamine (217 mg, 292 ^L, 1.68 mmol) in CHCl3 (3.5 mL) was added dropwise a solution of 4-bromo-5-fluoro-2-methyl-benzoyl chloride in CHCl3 (3 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with ethyl acetate (40 mL), then was filtered. The solid was washed with water (15 mL). The organic filtrate was washed with 1N HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-20% ethyl acetate/ hexanes). The filtered solid and the pure fractions from the column were combined, to give 4-bromo-N-(4-bromo-5-fluoro-2-methyl- phenyl)-5-fluoro-2-methyl-benzamide (294 mg, 65%) as a white solid.
Figure imgf000543_0002
[0457] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-5-fluoro-2-methylbenzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydro pyridine-1-carboxylate: The title compound was prepared according to the procedure of tert-butyl 4- {4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3- (trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-5- fluoro-2-methyl-phenyl)-5-fluoro-2-methyl-benzamide (294 mg, 0.70 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (520 mg, 1.69 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (59 mg, 0.14 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-     5-fluoro-2-methylbenzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (380 mg, 87%) as a white solid.
Figure imgf000544_0001
[0458] Step 4: Synthesis of 5-fluoro-N-[5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-5-fluoro-2-methylbenzamido)-2-fluoro-5- methylphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (380 mg, 0.61 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 5-fluoro-N-[5-fluoro-2-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis- HCl salt (323 mg, >100%) as a yellow solid.
Figure imgf000544_0002
[0459] Step 5: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-5-fluoro-2-methylbenzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using 5-fluoro-N-[5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (119 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol),     to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy) carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-5- fluoro-2-methylbenzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate (135 mg, 62%) as a yellow film.
Figure imgf000545_0001
[0460] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-5-fluoro-2-methyl- benzamide: To a mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}-5-fluoro-2-methylbenzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate (135 mg, 0.15 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-5-fluoro-2-methyl- benzamide as the bis-TFA salt (56 mg, 51%) as a white solid. MS: 508 M+H+: 1H NMR (300 MHz, dmso) δ 9.79-9.97 (m, 1H), 7.50 (d, J=8.20 Hz, 7H), 7.37-7.45 (m, 2H), 7.32 (d, J=7.62 Hz, 1H), 7.26 (d, J=8.20 Hz, 1H), 6.08 (br. s., 1H), 6.03 (br. s., 1H), 3.98-4.15 (m, 4H), 3.57-3.68 (m, 4H), 2.56 (br. s., 4H), 2.38 (s, 3H), 2.24 (s, 3H). [0461] Example 104: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-benzamide
Figure imgf000545_0002
    [0462] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (393 mg, 1.79 mmol), 4-bromo-3- methoxy-phenylamine (325 mg, 1.61 mmol), and diisopropylethylamine (323 mg, 431 ^L, 2.50 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-benzamide (605 mg, 98%) as a white solid.
Figure imgf000546_0001
[0463] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}benzamido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy-phenyl)- benzamide (281 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (540 mg, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}benzamido)-2-methoxyphenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (394 mg, 92%) as a white solid.
Figure imgf000546_0002
[0464] Step 3: Synthesis of N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}benzamido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridine- 1-carboxylate (394 mg, 0.67 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated,     to give N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide as the bis-HCl salt (340 mg, >100%) as a yellow solid.
Figure imgf000547_0002
[0465] Step 4: Synthesis of give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-phenyl) -3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-methoxy-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (111 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (77 mg, 37%) as a white film.
Figure imgf000547_0001
[0466] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-benzamide: To a mixture of {[4- (4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4- yl]-3-methoxy-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-     methyl}-carbamic acid tert-butyl ester (77 mg, 0.088 mmol) in CH2Cl2 (1 mL) added trifluoroacetic acid (1 mL). The reaction was stirred for 6 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-benzamide as the bis-TFA salt (36 mg, 58%) as a white solid. MS: 474 M+H+: 1H NMR (300 MHz, dmso) δ 10.19-10.35 (m, 1H), 7.97 (d, J=8.79 Hz, 2H), 7.63 (d, J=8.20 Hz, 2H), 7.55 (s, 1H), 7.34-7.52 (m, 9H), 7.14 (d, J=8.20 Hz, 1H), 6.38 (br. s., 1H), 5.84 (br. s., 1H), 4.07-4.18 (m, 2H), 3.96-4.07 (m, 2H), 3.77 (s, 2H), 3.65 (t, J=5.27 Hz, 2H), 3.54-3.61 (m, 3H), 2.59-2.68 (m, 2H), 2.51-2.58 (m, 2H). [0467] Example 105: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2-methyl-benzamide
Figure imgf000548_0001
[0468] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2-methyl-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-2-methyl-benzoyl chloride, 4-bromo-3-methoxy- phenylamine (259 mg, 1.28 mmol), and diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2-methyl-benzamide (465 mg, 91%) as an off-white solid.
Figure imgf000548_0002
[0469] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-2-methylbenzamido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2-methyl-benzamide (291 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (540 mg, 1.76 mmol), Pd(OAc)2 (14 mg,     0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert- butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2- methoxyphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (400 mg, 91%) as a white solid.
Figure imgf000549_0001
[0470] Step 3: Synthesis of N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2- methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2-methoxyphenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (400 mg, 0.66 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was added a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (319 mg, >100%) as an orange solid.
Figure imgf000549_0002
[0471] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-3-methyl-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-methoxy-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (114 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-     tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (70 mg, 33%) as a clear film.
Figure imgf000550_0001
[0472] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2-methyl-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (70 mg, 0.079 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- phenyl]-2-methyl-benzamide as the bis –TFA salt (38 mg, 67 %) as a white solid. MS: 488 M+H+: 1H NMR (300 MHz, dmso) δ 10.24-10.37 (m, 1H), 7.34-7.59 (m, 12H), 7.25-7.34 (m, 1H), 7.07-7.17 (m, 1H), 6.20-6.34 (m, 1H), 5.74-5.86 (m, 1H), 4.09 (d, J=1.76 Hz, 2H), 3.99-4.05 (m, 2H), 3.74 (s, 3H), 3.60-3.67 (m, 2H), 3.55 (t, J=5.57 Hz, 2H), 2.56-2.65 (m, 2H), 2.52-2.56 (m, 2H), 2.39 (s, 3H). [0473] Example 106: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-methyl-benzamide:
Figure imgf000550_0002
[0474] Step 1: Synthesis of 4-bromo-3-methyl-benzoyl chloride: To a mixture of 4-bromo-3- methyl-benzoic acid (310 mg, 1.44 mmol) in CHCl3 (8 mL) and N,N-dimethylformamide (3 drops) was added dropwise oxalyl chloride (293 mg, 198 ^L, 2.30 mmol). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with CHCl3 (15 mL), then was concentrated, to give 4-bromo-3-methyl-benzoyl chloride, which was used without further purification.    
Figure imgf000551_0001
[0475] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3-methyl-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-methyl-benzoyl chloride, 4-bromo-3-methoxy- phenylamine (259 mg, 1.28 mmol), and diisopropylethylamine (260 mg, 349 ^L, 2.01 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3-methyl-benzamide (494 mg, 97%) as an off-white solid.
Figure imgf000551_0002
[0476] Step 3: Synthesis of give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylbenzamido)-2-methoxyphenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-3-methyl-benzamide (291 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (540 mg, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert- butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylbenzamido)-2- methoxyphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (412 mg, 94%) as a white solid.
Figure imgf000551_0003
    [0477] Step 4: Synthesis of N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3- methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylbenzamido)-2-methoxyphenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (412 mg, 0.68 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (360 mg, >100%) as a brown solid. H
Figure imgf000552_0001
[0478] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-methyl-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-methoxy-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (114 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (51 mg, 24%) as a clear film.    
Figure imgf000553_0002
[0479] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-methyl-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (51 mg, 0.057 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- phenyl]-3-methyl-benzamide as the bis-TFA salt (32 mg, 79%) as a white solid. MS: 488 M+H+: 1H NMR (300 MHz, dmso) δ 10.14-10.29 (m, 1H), 7.69-7.87 (m, 2H), 7.36-7.58 (m, 10H), 7.26 (d, J=7.62 Hz, 1H), 7.13 (d, J=8.20 Hz, 1H), 5.77-5.89 (m, 1H), 5.61-5.76 (m, 1H), 3.93-4.13 (m, 4H), 3.74-3.78 (m, 3H), 3.63 (t, J=5.57 Hz, 2H), 3.55 (t, J=5.27 Hz, 2H), 2.51 (br. s., 1H), 2.44 (d, J=5.86 Hz, 2H), 2.34 (s, 3H). [0480] Example 107: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2-fluoro-benzamide:
Figure imgf000553_0001
[0481] Step 1: Synthesis of 4-bromo-2-fluoro-benzoyl chloride: To a mixture of 4-bromo-2- fluoro-benzoic acid (241 mg, 1.10 mmol) in CHCl3 (6 mL) and dimethylformamide (3 drops) was added dropwise oxalyl chloride (224 mg, 151 ^L, 1.76 mmol). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with CHCl3 (15 mL), then was concentrated, to give 4-bromo- 2-fluoro-benzoyl chloride, which was used without further purification.    
Figure imgf000554_0001
[0482] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2-fluoro-benzamide: To a mixture of 4-bromo-2-fluoro-benzoyl chloride (198 mg, 0.98 mmol) and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol) in CHCl3 (3 mL) was added dropwise a solution of 4-bromo-2-fluoro-benzoyl chloride in CHCl3 (3 mL). The reaction was stirred for 16 hours. The reaction was concentrated, then the residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The organic layer was washed with 1N HCl (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated, to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2-fluoro- benzamide (350 mg, 89%) as an off-white solid.
Figure imgf000554_0002
[0483] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-3-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2-fluoro-benzamide (294 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (540 mg, 1.76 mmol), Pd(OAc)2 (14 mg, 0.063 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl) carbamoyl]-3-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (400 mg, 90%) as a white solid.    
Figure imgf000555_0001
[0484] Step 4: Synthesis of 2-fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-3-fluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (400 mg, 0.66 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2-fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (365 mg, >100%) as a yellow solid.
Figure imgf000555_0002
[0485] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-3-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using 2-fluoro-N-[3-methoxy-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide .2 HCl (113 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (75 mg, 35%) as a white solid.    
Figure imgf000556_0001
[0486] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2-fluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (75 mg,0.084 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- phenyl]-2-fluoro-benzamide as the bis-TFA salt (20 mg, 33%) as a white solid. MS: 492 M+H+: 1H NMR (300 MHz, dmso) δ 10.33-10.49 (m, 1H), 7.59-7.74 (m, 1H), 7.34-7.56 (m, 11H), 7.25-7.34 (m, 1H), 7.05-7.22 (m, 1H), 6.36-6.51 (m, 1H), 5.74-5.91 (m, 1H), 4.06-4.20 (m, 2H), 3.92-4.06 (m, 2H), 3.70-3.82 (m, 3H), 3.62-3.68 (m, 2H), 3.54-3.59 (m, 2H), 2.62 (d, J=1.17 Hz, 2H). [0487] Example 108: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-methoxy-2-methyl-phenyl]-3-fluoro-benzamide:
Figure imgf000556_0002
[0488] Step 1: Synthesis of 4-bromo-N-(4-bromo-5-methoxy-2-methyl-phenyl)-3-fluoro- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-5- methoxy-2-methyl-phenylamine (212 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-5-methoxy-2-methyl-phenyl)-3-fluoro-benzamide (196 mg, 48%) as an off-white solid.    
Figure imgf000557_0001
[0489] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-5-methoxy-2-methylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate (304: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4- {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3- (trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-5- methoxy-2-methyl-phenyl)-3-fluoro-benzamide (196 mg, 0.47 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (348 mg, 1.13 mmol), Pd(OAc)2 (9 mg, 0.041 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (39 mg, 0.097 mmol), to give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-5- methoxy-2-methylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (304 mg, >100%) as a white solid.
Figure imgf000557_0002
[0490] Step 3: Synthesis of 3-fluoro-N-[5-methoxy-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-5-methoxy-2-methylphenyl)carbamoyl]-2-fluoro phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (304 mg, 0.49 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hour, then was concentrated, to give 3-fluoro-N-[5-methoxy-2-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (298 mg, >100%) as a brown solid.    
Figure imgf000558_0002
[0491] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1- [(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-5-methoxy-2-methylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using 3-fluoro-N-[5-methoxy-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide .2 HCl (119 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give tert- butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-5- methoxy-2-methylphenyl)carbamoyl]-2-fluoro phenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (62 mg, 29%) as a tacky solid.
Figure imgf000558_0001
[0492] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-methoxy-2-methyl-phenyl]-3-fluoro-benzamide: To a mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-5-     methoxy-2-methylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (62 mg, 0.068 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-methoxy-2-methyl-phenyl]-3-fluoro-benzamide as the bis-TFA salt (36 mg, 72%) as a white solid. MS: 506 M+H+: 1H NMR (300 MHz, dmso) δ 9.89- 10.03 (m, 1H), 7.74-7.89 (m, 2H), 7.50-7.63 (m, 1H), 7.34-7.50 (m, 8H), 7.03 (d, J=11.72 Hz, 2H), 6.10-6.23 (m, 1H), 5.75-5.89 (m, 1H), 4.05-4.17 (m, 2H), 4.03 (d, J=1.76 Hz, 2H), 3.69-3.78 (m, 4H), 3.60-3.66 (m, 2H), 3.56 (t, J=5.57 Hz, 2H), 2.57-2.64 (m, 2H), 2.52 (d, J=1.76 Hz, 2H), 2.13 (s, 3H). [0493] Example 109: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-ethyl-phenyl]-3-fluoro-benzamide:
Figure imgf000559_0001
[0494] Step 1: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-ethylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3- ethyl-phenylamine (196 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-3-ethyl-phenyl)-3-fluoro-benzamide (197 mg, 50%) as a white solid.
Figure imgf000559_0002
[0495] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-ethylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro     methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-ethyl-phenyl) -3-fluoro-benzamide (197 mg, 0.49 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (364 mg, 1.18 mmol), Pd(OAc)2 (9 mg, 0.041 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (41 mg, 0.10 mmol), to give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-ethylphenyl)carbamoyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (235 mg, 79%) as a tacky yellow gum.
Figure imgf000560_0001
[0496] Step 3: Synthesis of N-[3-ethyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-ethylphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (235 mg, 0.39 mmol) in CH2Cl2 (1.6 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.2 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-ethyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (186 mg, 100%) as a dark gum.
Figure imgf000560_0002
[0497] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-ethyl-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-ethyl-4-(1,2,3,6-tetrahydro-     pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (110 mg, 0.23 mmol), triethylamine (161 mg, 220 ^L, 1.58 mmol), and N,N’-bis-Boc-guanylpyrazole (225 mg, 0.73 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-ethyl-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (76 mg, 37%) as a clear film.
Figure imgf000561_0001
[0498] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-ethyl-phenyl]-3-fluoro-benzamide: To a mixture of give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-ethyl-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (76 mg, 0.085 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was treated with dimethylformamide (1 mL), followed by dropwise addition of 0.1% trifluoroacetic acid in water (1 mL). The mixture was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL). The original filtrate was purified by preparative-HPLC, and combined with the solid, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-ethyl-phenyl]-3-fluoro-benzamide as the bis-TFA salt (52 mg, 85%) as a white solid. MS: 490 M+H+: 1H NMR (300 MHz, dmso) δ 10.14-10.36 (m, 1H), 7.90-8.03 (m, 1H), 7.74-7.90 (m, 2H), 7.35-7.72 (m, 11H), 7.00-7.17 (m, 1H), 6.09-6.26 (m, 1H), 5.51-5.70 (m, 1H), 4.08-4.20 (m, 2H), 3.95-4.07 (m, 2H), 3.54-3.69 (m, 2H), 2.56-2.65 (m, 2H), 2.36-2.43 (m, 2H), 1.09- 1.25 (m, 3H). [0499] Example 110: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethoxy-phenyl]-3-fluoro-benzamide:    
Figure imgf000562_0001
[0500] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-trifluoromethoxy-phenyl)-3-fluoro- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3- trifluoromethoxy-phenylamine (250 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-3-trifluoromethoxy-phenyl)-3-fluoro-benzamide (357 mg, 80%) as a white solid.
Figure imgf000562_0002
[0501] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-(trifluoromethoxy)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-trifluoro methoxy-phenyl)-3-fluoro-benzamide (357 mg, 0.78 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (578 mg, 1.89 mmol), Pd(OAc)2 (15 mg, 0.069 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (65 mg, 0.16 mmol), to give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- (trifluoromethoxy)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (437 mg, 85%) as a white solid. NBoc NH O O F HCl, !.4-dioxane N O F H F N O MeOH, CH2Cl H F F F 2 F F BocN HN     [0502] Step 3: Synthesis of 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-3-trifluoromethoxy-phenyl]-benzamide: A solution of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-(trifluoromethoxy)phenyl)carbamoyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (437 mg, 0.66 mmol) in CH2Cl2 (2.7 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethoxy-phenyl]-benzamide as the bis-HCl salt (347 mg, 98%) as a pale yellow solid.
Figure imgf000563_0001
[0503] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1- [(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-(trifluoromethoxy)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-3-trifluoromethoxy-phenyl]-benzamide . 2 HCl (128 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl ]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- (trifluoromethoxy)phenyl)carbamoyl]-2-fluoro phenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (178 mg, 78%) as a clear gum.    
Figure imgf000564_0001
[0504] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethoxy-phenyl]-3-fluoro-benzamide: To a mixture of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- (trifluoromethoxy)phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (178 mg, 0.19 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-trifluoromethoxy-phenyl]-3-fluoro-benzamide as the bis-TFA salt (92 mg, 63%) as a white solid. MS: 546 M+H+: 1H NMR (300 MHz, dmso) δ 10.41- 10.52 (m, 1H), 7.91 (d, J=2.93 Hz, 1H), 7.71-7.86 (m, 3H), 7.57 (t, J=8.20 Hz, 1H), 7.31-7.51 (m, 10H), 6.17 (t, J=3.51 Hz, 1H), 5.84-5.97 (m, 1H), 4.01-4.17 (m, 4H), 3.54-3.68 (m, 4H), 2.56-2.63 (m, 2H). [0505] Example 111: Synthesis of 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-3-fluoro-benzamide:
Figure imgf000564_0002
[0506] Step 1: Synthesis of N-(4-bromo-3-fluoro-phenyl)-3,4-difluoro-benzamide: To a 0 oC mixture of 4-bromo-3-fluoro-phenylamine (408 mg, 2.15 mmol) and diisopropylethylamine (361 mg, 485 ^L, 2. 80 mmol) in CHCl3 (5 mL) was slowly added a solution of 3,4-difluoro-benzoyl chloride (349 mg, 2.02 mmol) in CHCl3 (2.5 mL). The reaction was stirred at 0 oC for 30 minutes, then was allowed to warm to 20 oC, and was stirred for 16 hours. The reaction was concentrated, then the residue     was treated with water (10 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with 1 N HCl (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-20% ethyl acetate/ hexanes), to give N-(4-bromo-3- fluoro-phenyl)-3,4-difluoro-benzamide (583 mg, 87%) as a white solid.
Figure imgf000565_0001
[0507] Step 2: Synthesis of 4-[4-(4-bromo-3-fluoro-phenylcarbamoyl)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: A mixture of N-(4-bromo-3-fluoro-phenyl)-3,4-difluoro- benzamide (583 mg, 1.77 mmol) , piperazine-1-carboxylic acid tert-butyl ester (983 mg, 5.28 mmol), and diisopropylethylamine (340 mg, 457 ^L, 2.66 mmol) in N-methyl pyrrolidinone (2.3 mL) was heated in a sealed vessel at 130 oC for 22 hours. The mixture was treated with further piperazine-1- carboxylic acid tert-butyl ester (328 mg, 1.76 mmol), and diisopropylethylamine (113 mg, 152 ^L, 0.89 mmol). The reaction was heated in a sealed vessel at 130 oC for 22 hours. The mixture was treated with ethyl acetate (40 mL), then was washed with watr (20 mL), 10% aqueous citric acid (2 x 20 mL), water (20 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give 4-[4-(4-bromo-3-fluoro-phenylcarbamoyl)- 2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (720 mg, 82%) as a white solid.
Figure imgf000565_0002
[0508] Step 3: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-phenylcarbamoyl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-3-fluoro-phenylcarbamoyl)-2-fluoro-phenyl]-     piperazine-1-carboxylic acid tert-butyl ester (521 mg, 1.05 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (385 mg, 1.24 mmol), Pd(OAc)2 (11 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (45 mg, 0.11 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl carbamoyl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (538 mg, 86%) as a white solid.
Figure imgf000566_0001
[0509] Step 4: Synthesis of 3-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 4-piperazin-1-yl-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-phenylcarbamoyl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (538 mg, 0.90 mmol) in CH2Cl2 (3.5 mL0 and methanol (2.2 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro- N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-piperazin-1-yl-benzamide as the tris-HCl salt (455 mg, 100%) as a pale yellow solid.
Figure imgf000566_0002
[0510] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)- piperazin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: A mixture of 3- fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-piperazin-1-yl-benzamide. 3 HCl (122 mg, 0.24 mmol) in CH2Cl2 (1.1 mL) and dimethylformamide (1.1 mL) was treated slowly with triethylamine (168 mg, 230 ^L, 1.65 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-     Boc-guanylpyrazole (235 mg, 0.76 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The reaction was concentrated, then was treated with dilute aqueous NaHCO3 (40 mL). The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were filtered through Celite, then was washed with dilute aqueous NaHCO3 (20 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0- 50% ethyl acetate/ hexanes), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)- piperazin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (91 mg, 43%) as a tacky white solid.
Figure imgf000567_0001
[0511] Step 6: Synthesis of 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-3-fluoro-benzamide: To a mixture of {[4-(4-{4-[1- (tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3- fluoro-phenylcarbamoyl}-2-fluoro-phenyl)-piperazin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (91 mg, 0.10 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction as stirred for 16 hours, then was concentrated. The residue was treated with dimethylformamide 1 mL), followed by dropwise addition of 0.1% TFA in water (1 mL). The mixture was filtered. The solid was dissolved in 1:1 CH2Cl2: TFA (2 mL), then was concentrated. The residue was treated with ethyl acetate (10 mL), then was sonicated for 5 minutes. The mixture was filtered, to give 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-phenyl]-3-fluoro-benzamide as the tris-TFA slat (21 mg, 26%) as a white solid. MS: 483 M+H+: 1H NMR (300 MHz, dmso) δ 10.22-10.41 (m, 1H), 7.66-7.92 (m, 3H), 7.33-7.64 (m, 10H), 7.09-7.26 (m, 1H), 5.96-6.14 (m, 1H), 3.93-4.17 (m, 4H), 3.60 (br. s., 4H), 3.12-3.29 (m, 4H), 2.52-2.66 (m, 2H), 1.90-2.06 (m, 2H).     [0512] Example 112: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3,5-difluoro-benzamide:
Figure imgf000568_0001
[0513] Step 1: Synthesis of 4-bromo-3,5-difluoro-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-3,5- difluoro-benzoic acid (261 mg, 1.10 mmol), and oxalyl chloride (224 mg, 151 ^L, 1.76 mmol), to give 4-bromo-3,5-difluoro-benzoyl chloride, that was used without further purification. F Br
Figure imgf000568_0002
[0514] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3,5-difluoro-benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2-fluoro-benzamide using 4-bromo-3,5-difluoro-benzoyl chloride, 4-bromo-3-methoxy- phenylamine (198 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3,5-difluoro-benzamide (351 mg, 85%) as an off-white solid.
Figure imgf000568_0003
[0515] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2,6-difluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy-     phenyl)-3,5-difluoro-benzamide (351 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 (618 mg, 2.02 mmol), Pd(OAc)2 (16 mg, 0.074 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (70 mg, 0.17 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl) carbamoyl]-2,6-difluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (477 mg, 92%) as a tacky yellow solid.
Figure imgf000569_0001
[0516] Step 4: Synthesis of 3,5-difluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2,6-difluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (477 mg, 0.76 mmol) in CH2Cl2 (3 mL) and methanol (2 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3,5-difluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (406 mg, >100%) as a pale yellow solid.
Figure imgf000569_0002
[0517] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,6-difluoro-phenyl)- 3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]     imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using 3,5-difluoro-N-[3- methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (120 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc- guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxy carbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,6-difluoro- phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (100 mg, 46%) as a yellow gum.
Figure imgf000570_0001
[0518] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3,5-difluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,6-difluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.11 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction was stirred for 3 days, then was concentrated. The residue was treated with dimethylformamide (1 mL), followed by 0.1% trifluoroacetic acid in water (1 mL) dropwise. The mixture was filtered, then the solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3,5-difluoro-benzamide as the bis-TFA salt (36 mg, 44%) as an off-white solid. MS: 510 M+H+: 1H NMR (300 MHz, dmso) δ 10.28-10.46 (m, 1H), 7.84-7.99 (m, 1H), 7.68-7.83 (m, 2H), 7.34-7.64 (m, 11H), 7.09-7.23 (m, 1H), 5.96-6.11 (m, 1H), 5.74-5.92 (m, 1H), 4.07-4.18 (m, 2H), 4.02 (br. s., 2H), 3.77 (s, 3H), 3.60-3.69 (m, 2H), 3.51-3.60 (m, 2H). [0519] Example 113: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2,5-difluoro-benzamide:    
Figure imgf000571_0001
[0520] Step 1: Synthesis of 4-bromo-2,5-difluoro-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-2,5- difluoro-benzoic acid (261 mg, 1.10 mmol), and oxalyl chloride (224 mg, 151 ^L, 1.76 mmol), to give 4-bromo-2,5-difluoro-benzoyl chloride, which was used without further purification.
Figure imgf000571_0002
[0521] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2,5-difluoro-benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2-fluoro-benzamide using 4-bromo-2,5-difluoro-benzoyl chloride, 4-bromo-3-methoxy- phenylamine (198 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2,5-difluoro-benzamide (330 mg, 80%) as a beige solid.
Figure imgf000571_0003
[0522] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2,5-difluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2,5-difluoro-benzamide (330 mg, 0.78 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (584 mg, 1.91 mmol), Pd(OAc)2 (15 mg, 0.070 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (66 mg, 0.16 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)     carbamoyl]-2,5-difluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (404 mg, 83%) as a white solid.
Figure imgf000572_0001
[0523] Step 4: Synthesis of 2,5-difluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide : A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2,5-difluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (404 mg, 0.65 mmol) in CH2Cl2 (2.5 mL) and methanol (1.7 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.9 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2,5-difluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (330 mg, >100%) as a plae orange solid.
Figure imgf000572_0002
[0524] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,5-difluoro-phenyl)- 3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using 2,5-difluoro-N-[3- methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (120 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc- guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-     butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,5- difluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert- butyl ester (118 mg, 54%) as a pale yellow gum.
Figure imgf000573_0001
[0525] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2,5-difluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,5-difluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (118 mg, 0.13 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 4 days, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- phenyl]-2,5-difluoro-benzamide as the bis-TFA salt (27 mg, 28%) as an off-white solid. MS: 510 M+H+: 1H NMR (300 MHz, dmso) δ 10.47 (s, 1H), 7.55 (dd, J=6.15, 10.84 Hz, 1H), 7.35-7.51 (m, 10H), 7.22-7.34 (m, 1H), 7.14 (d, J=8.20 Hz, 1H), 6.13-6.27 (m, 1H), 5.83 (s, 1H), 4.05-4.16 (m, 2H), 4.02 (d, J=1.76 Hz, 2H), 3.75 (s, 3H), 3.58-3.65 (m, 2H), 3.55 (t, J=5.27 Hz, 2H), 2.55-2.62 (m, 2H), 2.51-2.55 (m, 2H). [0526] Example 114: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2,3-difluoro-benzamide:
Figure imgf000573_0002
[0527] Step 1: Synthesis of 4-bromo-2,3-difluoro-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-2,3-     difluoro-benzoic acid (261 mg, 1.10 mmol), and oxalyl chloride (224 mg, 151 ^L, 1.76 mmol), to give 4-bromo-2,3-difluoro-benzoyl chloride, which was used without further purification.
Figure imgf000574_0001
[0528] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2,3-difluoro-benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2-fluoro-benzamide using 4-bromo-2,3-difluoro-benzoyl chloride, 4-bromo-3-methoxy- phenylamine (198 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2,3-difluoro-benzamide (399 mg, 97%) as a white solid.
Figure imgf000574_0002
[0529] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2,3-difluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2,3-difluoro-benzamide (399 mg, 0.95 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (706 mg, 2.31 mmol), Pd(OAc)2 (18 mg, 0.084 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (80 mg, 0.19 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl) carbamoyl]-2,3-difluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (557 mg, 94%) as a tacky off-white solid.    
Figure imgf000575_0001
[0530] Step 4: Synthesis of 2,3-difluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2,3-difluorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (557 mg, 0.89 mmol) in CH2Cl2 (3.5 mL) and methanol (2.3 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2,3-difluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (518 mg, >100%) as a pale orange solid.
Figure imgf000575_0002
[0531] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,3-difluoro-phenyl)- 3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using 2,3-difluoro-N-[3-methoxy- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (120 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,3-difluoro-phenyl)-3,6-     dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (70 mg, 32%) as a pale yellow solid.
Figure imgf000576_0001
[0532] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-2,3-difluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2,3-difluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (70 mg, 0.077 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- phenyl]-2,3-difluoro-benzamide as the bis-TFA salt (34 mg, 60%) as a pale yellow solid. MS: 510 M+H+: 1H NMR (300 MHz, dmso) δ 10.47-10.61 (m, 1H), 7.20-7.57 (m, 14H), 7.08-7.20 (m, 2H), 6.12-6.28 (m, 1H), 5.73-5.89 (m, 1H), 4.11 (d, J=1.76 Hz, 2H), 3.95-4.06 (m, 2H), 3.71-3.80 (m, 3H), 3.62 (t, J=5.57 Hz, 2H), 3.53-3.59 (m, 2H), 2.55-2.63 (m, 2H). [0533] Example 115: Synthesis of 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide:
Figure imgf000576_0002
[0534] Step 1: Synthesis of N-(4-bromo-3-methoxy-phenyl)-3,4-difluoro-benzamide: The title compound was prepared accordinhg to the procude for N-(4-bromo-3-fluoro-phenyl)-3,4-difluoro- benzamide using 3,4-difluoro-benzoyl chloride (349 mg, 2.02 mmol), 4-bromo-3-methoxy-     phenylamine (404 mg, 2.00 mmol), and diisopropylethylamine (361 mg, 485 ^L, 2.80 mmol), to give N-(4-bromo-3-methoxy-phenyl)-3,4-difluoro-benzamide (668 mg, 98%) as a white solid.
Figure imgf000577_0001
[0535] Step 2: Synthesis of 4-[4-(4-bromo-3-methoxy-phenylcarbamoyl)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: A mixture of N-(4-bromo-3-methoxy-phenyl)-3,4- difluoro-benzamide (668 mg, 1.95 mmol) , piperazine-1-carboxylic acid tert-butyl ester (1084 mg, 5.82 mmol), and diisopropylethylamine (375 mg, 504 ^L, 2.93 mmol) in N-methyl pyrrolidinone (2.5 mL) was heated in a sealed vessel at 130 oC for 22 hours. The mixture was treated with further piperazine- 1-carboxylic acid tert-butyl ester (542 mg, 2.91 mmol), and diisopropylethylamine (188 mg, 252 ^L, 1.47 mmol). The reaction was heated in a sealed vessel at 130 oC for 22 hours. The mixture was treated with ethyl acetate (40 mL), then was washed with watr (20 mL), 10% aqueous citric acid (2 x 20 mL), water (20 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-50% ethyl acetate/ hexanes), to give 4-[4-(4-bromo-3-methoxy- phenylcarbamoyl)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (719 mg, 73%) as a white solid.
Figure imgf000577_0002
[0536] Step 3: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methoxy-phenylcarbamoyl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-3-methoxy-phenylcarbamoyl)-2-fluoro- phenyl]-piperazine-1-carboxylic acid tert-butyl ester (719 mg, 1.41 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (518 mg, 1.67     mmol), Pd(OAc)2 (15 mg, 0.057 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy- phenylcarbamoyl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (769 mg, 89%) as a pale yellow solid.
Figure imgf000578_0001
[0537] Step 4: Synthesis of 3-fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-piperazin-1-yl-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenylcarbamoyl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (769 mg, 1.26 mmol) in CH2Cl2 (5 mL) and methanol (3 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3- fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-piperazin-1-yl-benzamide as the tris-HCl salt (651 mg, 99%) as a pale brown solid.
Figure imgf000578_0002
[0538] Step 5: Synthesis of give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-fluoro-phenyl)- piperazin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4- {[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydr using 3-fluoro-N-[3-methoxy-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-4-piperazin-1-yl-benzamide.3 HCl (125 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-     (tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3- methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-piperazin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (113 mg, 53%) as a pale yellow gum.
Figure imgf000579_0001
[0539] Step 6: Synthesis of 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide: To a mixture of {[4-(4-{4- [1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3- methoxy-phenylcarbamoyl}-2-fluoro-phenyl)-piperazin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (113 mg, 0.13 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide as the tris-TFA salt (28 mg, 26%) as a white solid. MS: 495 M+H+: 1H NMR (300 MHz, dmso) δ 10.04-10.20 (m, 1H), 7.73-7.87 (m, 2H), 7.46-7.55 (m, 5H), 7.34-7.46 (m, 5H), 7.07-7.23 (m, 2H), 5.83 (s, 1H), 3.96-4.08 (m, 2H), 3.72-3.82 (m, 3H), 3.58 (dd, J=2.93, 4.69 Hz, 4H), 3.45-3.55 (m, 9H), 3.17-3.28 (m, 4H). [0540] Example 116: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-ethoxy-phenyl]-3-fluoro-benzamide:
Figure imgf000579_0002
[0541] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-ethoxy-phenyl)-3-fluoro-benzamide: To a mixture of 4-bromo-3-fluoro-benzoic acid (219 mg, 1.00 mmol), 4-bromo-3-ethoxy-phenylamine HCl (279 mg, 1.11 mmol), and triethylamine (406 mg, 559 ^L, 4.00 mmol) in N,N-dimethylformamide (3.2 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid     hexafluorophosphate (568 mg, 1.50 mmol). The reaction was stirred for 16 hours. The reaction was treated with water (50 mL), then was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-20% ethyl acetat/ hexanes), to give 4-bromo-N-(4- bromo-3-ethoxy-phenyl)-3-fluoro-benzamide (380 mg, 91%) as a pale yellow solid.
Figure imgf000580_0001
[0542] Step 2: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-ethoxyphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-ethoxy- phenyl)-3-fluoro-benzamide (380 mg, 0.91 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (678 mg, 2.22 mmol), Pd(OAc)2 (18 mg, 0.081 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (77 mg, 0.19 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-ethoxyphenyl) carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (595 mg, >100%) as a pale yellow solid.
Figure imgf000580_0002
[0543] Step 3: Synthesis of N-[3-ethoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-ethoxyphenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (595 mg, 0.96 mmol) in CH2Cl2 (3.8 mL) and methanol (2.5 mL) was     treated with a 4N solution of HCl in 1,4-dioxane (2.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-ethoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (554 mg, >100%) as a brown solid.
Figure imgf000581_0002
[0544] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-ethoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-ethoxy-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (119 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-ethoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (56 mg, 26%) as a clear film.
Figure imgf000581_0001
[0545] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-ethoxy-phenyl]-3-fluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-ethoxy-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-     butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (56 mg, 0.062 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with dimethylformamide (1 mL), followed by dropwise addition of 0.1% TFA in water (1 mL). The mixture was filtered, then the solid was washed with isopropanol (2 mL), and hexanes (2 mL). The original filtrate was purified by preparative-HPLC. The combined products gave 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-ethoxy-phenyl]-3-fluoro-benzamide as the bis-TFA salt (29 mg, 64%) as a pale yellow solid. MS: 506 M+H+: 1H NMR (300 MHz, dmso) δ 10.26-10.36 (m, 1H), 7.94 (s, 1H), 7.77-7.92 (m, 3H), 7.33-7.75 (m, 13H), 7.13-7.24 (m, 1H), 6.16-6.25 (m, 1H), 5.78-5.95 (m, 1H), 3.93-4.18 (m, 7H), 3.59-3.66 (m, 2H), 3.52-3.58 (m, 2H), 1.30-1.43 (m, 3H). [0546] Example 117: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-chloro-benzamide:
Figure imgf000582_0001
[0547] Step 1: Synthesis of 4-bromo-3-chloro-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-3-chloro- benzoic acid (259 mg, 1.10 mmol), and oxalyl chloride (224 mg, 151 ^L, 1.76 mmol), to give 4-bromo- 3-chloro-benzoyl chloride, which was used without further purification.
Figure imgf000582_0002
[0548] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-3-chloro-benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3-methoxy- phenyl)-2-fluoro-benzamide using 4-bromo-3-chloro-benzoyl chloride, 4-bromo-3-methoxy-phenyl amine (198 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4- bromo-N-(4-bromo-3-methoxy-phenyl)-3-chloro-benzamide (335 mg, 82%) as a white solid.    
Figure imgf000583_0001
[0549] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2-chlorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-methoxy- phenyl)-3-chloro-benzamide (329 mg, 0.78 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (583 mg, 1.91 mmol), Pd(OAc)2 (15 mg, 0.069 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (66 mg, 0.16 mmol), to give tert- butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl) carbamoyl]-2-chlorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (168 mg, 35%) as a white solid.
Figure imgf000583_0002
[0550] Step 4: Synthesis of 3-chloro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methoxyphenyl)carbamoyl]-2-chlorophenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate (168 mg, 0.27 mmol) in CH2Cl2 (1 mL) and methanol (0.7 mL) was treated with a 4N solution of HCl in 1,4-dioxane (0.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-chloro-N-[3-methoxy-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (159 mg, >100%) as a dark solid.    
Figure imgf000584_0002
[0551] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-chloro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydr using 3-chloro-N-[3-methoxy-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (119 mg, 0.24 mmol), triethylamine (168 mg, 230 ^L, 1.65 mmol), and N,N’-bis-Boc-guanylpyrazole (235 mg, 0.76 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- 1,2,3,6-tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-chloro-phenyl)-3,6-dihydro -2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (36 mg, 17%) as a pale yellow film.
Figure imgf000584_0001
[0552] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-chloro-benzamide: To a solution of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-methoxy-phenylcarbamoyl}-2-chloro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (36 mg, 0.040 mmol) in CH2Cl2 (1 mL) was treated with TFA (1 mL). The reaction was stirred for 16 hours, then was concentrated.     The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methoxy-phenyl]-3-chloro- benzamide as the bis-TFA salt (15 mg, 51%) as a pale yellow solid. MS: 509 M+H+: 1H NMR (300 MHz, dmso) δ 10.29-10.40 (m, 1H), 8.02-8.12 (m, 1H), 7.92 (dd, J=1.76, 8.20 Hz, 1H), 7.35-7.56 (m, 12H), 7.15 (d, J=8.20 Hz, 1H), 5.86 (d, J=11.13 Hz, 2H), 3.97-4.14 (m, 4H), 3.74-3.81 (m, 3H), 3.62 (t, J=5.27 Hz, 2H), 3.53-3.60 (m, 2H), 2.52 (d, J=1.17 Hz, 2H). [0553] Example 118: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide
Figure imgf000585_0001
[0554] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-fluoro-benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3-ethoxy-phenyl)- 3-fluoro-benzamide using 4-bromo-2-fluoro-benzoic acid (219 mg, 1.00 mmol), 4-bromo-3-fluoro- phenylamine (211 mg, 1.11 mmol), triethylamine (305 mg, 419 ^L, 3.00 mmol), and 1-[bis(dimethyl amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (568 mg, 1.50 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-fluoro-benzamide (140 mg, 36%) as a white solid.
Figure imgf000585_0002
[0555] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-2-fluorobenzamido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro- phenyl)-2-fluoro-benzamide (140 mg, 0.36 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (268 mg, 0.88 mmol), Pd(OAc)2 (7 mg,     0.032 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (30 mg, 0.073 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-fluorobenzamido)-2- fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (169 mg, 79%) as an off-white solid.
Figure imgf000586_0001
[0556] Step 3: Synthesis of 2-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (169 mg, 0.28 mmol) in CH2Cl2 (1 mL) and methanol (0.75 mL) was treated with a 4N solution of HCl in 1,4-dioxane (0.85 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamideas the bis-HCl salt (138 mg, >100%) as a pale yellow solid.
Figure imgf000586_0002
[0557] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxy carbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-fluoro-phenyl) -3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene] carbamate using 2-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide .2 HCl (138 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06     mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2-fluoro- phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (84 mg, 32%) as a clear film. B
Figure imgf000587_0001
[0558] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-2-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (84 mg, 0.096 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with dimethylformamide (1 mL), followed by 0.1% trifluoroacetic acid in water (1 mL) dropwise. The mixture was filtered, then the solid was washed with isopropanol (3 mL, and hexanes (3 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-3-fluoro-benzamide as the bis-TFA salt (42 mg, 62%) as a beige solid. MS: 480 M+H+: 1H NMR (300 MHz, dmso) δ 10.60 (s, 1H), 7.87-7.99 (m, 1H), 7.59-7.77 (m, 3H), 7.30-7.59 (m, 13H), 6.43 (br. s., 1H), 5.96-6.12 (m, 1H), 4.02-4.18 (m, 4H), 3.63 (dd, J=5.27, 10.54 Hz, 4H), 2.62 (d, J=2.93 Hz, 2H), 2.53-2.59 (m, 2H). [0559] Example 119: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-3-methyl-benzamide:
Figure imgf000587_0002
    [0560] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-phenyl)-3-methyl-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-3-methyl-benzoyl chloride, 4-Bromo-3-fluoro- phenylamine (186 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-phenyl)-3-methyl-benzamide (287 mg, 76%) as a white solid.
Figure imgf000588_0001
[0561] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-methylbenzamido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-phenyl)-3- methyl-benzamide (287 mg, 0.74 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (552 mg, 1.81 mmol), Pd(OAc)2 (14 mg, 0.066 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (62 mg, 0.15 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylbenzamido)-2-fluoro phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (434 mg, 99%) as a white solid.
Figure imgf000588_0002
[0562] Step 3: Synthesis of N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-methyl- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylbenzamido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (434 mg, 0.73 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.4 mL). The reaction was stirred for 16 hours, then     was concentrated, to give N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (380 mg, >100%) as a yellow solid, that was used without further purification. H
Figure imgf000589_0002
[0563] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-2-methyl-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-fluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-3-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide 2 HCl (139 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- 1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-2-methyl-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (89 mg, 34%) as a clear film.
Figure imgf000589_0001
[0564] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-3-methyl-benzamide: The title     compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-2-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (89 mg, 0.10 mmol), and trifluoroacetic acid (1 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-3-methyl-benzamide as the bis-TFA salt (28 mg, 40%) as a beige solid. MS: 476 M+H+: 1H NMR (300 MHz, dmso) δ 10.29-10.47 (m, 1H), 7.84-8.00 (m, 1H), 7.68-7.85 (m, 3H), 7.20-7.64 (m, 12H), 5.95-6.10 (m, 1H), 5.63-5.78 (m, 1H), 3.97-4.14 (m, 4H), 3.55-3.69 (m, 5H), 2.53-2.59 (m, 2H), 2.44 (dd, J=1.76, 3.51 Hz, 2H), 2.31 (br. s., 3H), 2.34 (s, 3H). [0565] Example 120: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-methyl-benzamide:
Figure imgf000590_0001
[0566] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-methyl-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-2-methyl-benzoyl chloride, 4-bromo-3-fluoro-phenyl amine (186 mg, 0.98 mmol), and diisopropylethylamine (199 mg, 267 ^L, 1.54 mmol), to give 4- bromo-N-(4-bromo-3-fluoro-phenyl)-2-methyl-benzamide (318 mg, 84%) as a white solid.
Figure imgf000590_0002
[0567] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methylbenzamido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)     carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-phenyl)-3-methyl- benzamide (318 mg, 0.82 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (613 mg, 2.01 mmol), Pd(OAc)2 (16 mg, 0.073 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (69 mg, 0.17 mmol), to give tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (467 mg, 96%) as a white solid.
Figure imgf000591_0001
[0568] Step 3: Synthesis of N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-methyl- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (467 mg, 0.79 mmol) in CH2Cl2 (3.2 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (412 mg, >100%) as an orange solid, that was used without further purification.
Figure imgf000591_0002
[0569] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]     amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3-fluoro-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (139 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (78 mg, 30%) as a clear film.
Figure imgf000592_0001
[0570] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-methyl-benzamide: To a mixture of give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (78 mg, 0.089 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-methyl- benzamide as the bis-TFA salt (23 mg, 37%) as a white solid. MS: 476 M+H+: 1H NMR (300 MHz, dmso) δ 10.52 (s, 1H), 7.71 (dd, J=1.17, 13.47 Hz, 1H), 7.27-7.54 (m, 13H), 6.22-6.35 (m, 1H), 5.92- 6.07 (m, 1H), 4.01-4.17 (m, 4H), 3.53-3.71 (m, 4H), 2.58-2.64 (m, 2H), 2.53-2.58 (m, 2H), 2.39 (s, 3H). [0571] Example 121: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3,5-difluoro-phenyl]-3-fluoro-benzamide:    
Figure imgf000593_0003
[0572] Step 1: Synthesis of 4-bromo-N-(4-bromo-3,5-difluoro-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3,5-difluoro -phenylamine (229 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3,5-difluoro-phenyl)-3-fluoro-benzamide (298 mg, 66%) as a white solid.
Figure imgf000593_0001
[0573] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,6-difluorophenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3,5-difluoro- phenyl)-3-fluoro-benzamide (298 mg, 0.73 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (545 mg, 1.79 mmol), Pd(OAc)2 (14 mg, 0.065 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (61 mg, 0.15 mmol), to give tert- butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,6- difluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (406 mg, 91%) as a white solid.
Figure imgf000593_0002
    [0574] Step 3: Synthesis of N-[3,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,6-difluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (406 mg, 0.66 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.4 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (334 mg, >100%) as a pale yellow solid, that was used without further purification. H
Figure imgf000594_0001
[0575] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3,5-difluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (146 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- 1,2,3,6-tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (158 mg, 59%) as a clear film.    
Figure imgf000595_0002
[0576] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3,5-difluoro-phenyl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (158 mg, 0.18 mmol) and trifluoroacetc acid (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3,5-difluoro-phenyl]-3-fluoro-benzamide as the bis- TFA salt (93 mg, 71%) as an off-white solid. MS: 498 M+H+: 1H NMR (300 MHz, dmso) δ 10.57- 10.73 (m, 1H), 7.90-8.02 (m, 1H), 7.73-7.87 (m, 2H), 7.42-7.65 (m, 11H), 6.18 (br. s., 1H), 5.92 (br. s., 1H), 4.01-4.18 (m, 4H), 3.61 (d, J=4.69 Hz, 4H), 2.59 (d, J=1.76 Hz, 2H), 2.45 (d, J=1.76 Hz, 2H). [0577] Example 122: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,5-difluoro-phenyl]-3-fluoro-benzamide:
Figure imgf000595_0001
[0578] Step 1: Synthesis of 4-bromo-N-(4-bromo-2,5-difluoro-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride 4-bromo-2,5-difluoro- phenylamine (229 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-2,5-difluoro-phenyl)-3-fluoro-benzamide (233 mg, 52%) as a white solid.    
Figure imgf000596_0001
[0579] Step 2: Synthesis of give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,5-difluorophenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3,5-difluoro- phenyl)-3-fluoro-benzamide (233 mg, 0.57 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (426 mg, 1.40 mmol), Pd(OAc)2 (11 mg, 0.051 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (48 mg, 0.12 mmol), to give tert- butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,5- difluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (332 mg, 95%) as a white solid.
Figure imgf000596_0002
[0580] Step 3: Synthesis of N-[2,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,5-difluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (332 mg, 0.54 mmol) in CH2Cl2 (2.2 mL) and methanol (1.1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[2,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (266 mg, >100%) as a yellow solid, that was used without further purification.    
Figure imgf000597_0002
[0581] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2,5-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[2,5-difluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (146 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- 1,2,3,6-tetrahydro-pyridin-4-yl]-2,5-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (170 mg, 63%) as a white solid.
Figure imgf000597_0001
[0582] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,5-difluoro-phenyl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-     tetrahydro-pyridin-4-yl]-2,5-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (170 mg, 0.18 mmol), and TFA (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-2,5-difluoro-phenyl]-3-fluoro-benzamide as the bis-TFA salt (99 mg, 76%) as a beige solid. MS: 498 M+H+: 1H NMR (300 MHz, dmso) δ 10.25-10.39 (m, 1H), 7.87-8.00 (m, 1H), 7.72-7.87 (m, 2H), 7.31-7.67 (m, 12H), 6.16 (d, J=11.72 Hz, 2H), 4.02-4.16 (m, 4H), 3.58-3.66 (m, 4H), 2.58 (dd, J=1.76, 3.51 Hz, 4H). [0583] Example 123: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-difluoro-phenyl]-3-fluoro-benzamide:
Figure imgf000598_0001
[0584] Step 1: Synthesis of 4-bromo-N-(4-bromo-2,3-difluoro-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride and 4-Bromo-2,3- difluoro-phenylamine (229 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-2,3-difluoro-phenyl)-3-fluoro-benzamide (275 mg, 61%) as a white solid.
Figure imgf000598_0002
[0585] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorobenzamido)-2,3-difluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-2,3-difluoro-phenyl)-3-fluoro- benzamide (275 mg, 0.67 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (503 mg, 1.65 mmol), Pd(OAc)2 (13 mg, 0.060 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (57 mg, 0.14 mmol), to give tert-butyl 4-[4-(4-{1-     [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,3-difluorophenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (353 mg, 86%) as a white solid.
Figure imgf000599_0001
[0586] Step 3: Synthesis of N-[2,3-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3- fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2,3-difluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (353 mg, 0.58 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.4 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[2,3-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (296 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000599_0002
[0587] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2,3-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[2,3-difluoro-4-(1,2,3,6-tetrahydro -pyridin-4-yl)-phenyl]-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 2 HCl (146 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-     tetrahydro-pyridin-4-yl]-2,3-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (198 mg, 74%) as a clear film. B
Figure imgf000600_0001
[0588] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-difluoro-phenyl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-2,3-difluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (198 mg, 0.22 mmol), and TFA (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-2,3-difluoro-phenyl]-3-fluoro-benzamide as the bis-HCl salt (106 mg, 66%) as a white solid. MS: 498 M+H+: 1H NMR (300 MHz, dmso) δ 10.38-10.51 (m, 1H), 7.74-7.90 (m, 2H), 7.35-7.67 (m, 11H), 7.15-7.33 (m, 1H), 6.06-6.26 (m, 2H), 4.10 (d, J=1.17 Hz, 4H), 3.55-3.70 (m, 4H). [0589] Example 124: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-3-fluoro-benzamide
Figure imgf000600_0002
[0590] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-2-methyl-phenyl)-3-fluoro- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3-     fluoro-2-methyl-phenylamine (225 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-2-methyl-phenyl)-3-fluoro-benzamide (309 mg, 69%) as a white solid.
Figure imgf000601_0001
[0591] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorobenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-2- methyl-phenyl)-3-fluoro-benzamide (309 mg, 0.76 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan -2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (572 mg, 1.88 mmol), Pd(OAc)2 (15 mg, 0.068 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (65 mg, 0.16 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido) -2- fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (484 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000601_0002
[0592] Step 3: Synthesis of 3-fluoro-N-[3-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-fluoro-3-methylphenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (484 mg, 0.79 mmol) in CH2Cl2 (3.2 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.7 mL). The reaction was stirred at 110oC for 16 hours, then was concentrated, to give 3-fluoro-N-[3-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-     pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (596 mg, >100%) as a dark orange solid, that was used without further purification.
Figure imgf000602_0001
[0593] Step 4: Synthesis of tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorobenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl}) methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using 3-fluoro-N-[3-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin -4-yl)-benzamide. 2 HCl (145 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert- butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorobenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (39 mg, 15%) as a clear film.
Figure imgf000602_0002
[0594] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-3-fluoro-benzamide: To a mixture of tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert-     butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorobenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (39 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-3-fluoro-benzamide as the bis-TFA salt (13 mg, 41%) as a white solid. MS: 494 M+H+: 1H NMR (300 MHz, dmso) δ 10.08-10.23 (m, 1H), 7.70-7.90 (m, 2H), 7.35-7.67 (m, 9H), 7.11-7.32 (m, 2H), 6.11-6.24 (m, 1H), 5.98-6.09 (m, 1H), 4.00-4.18 (m, 4H), 3.57- 3.71 (m, 4H), 2.55-2.67 (m, 4H), 2.08-2.15 (m, 3H). [0595] Example 125: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-5-methyl-phenyl]-3-fluoro-benzamide:
Figure imgf000603_0001
[0596] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-5-methyl-phenyl)-3-fluoro- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3- fluoro-5-methyl-phenylamine (250 mg, 1.23 mmol), and diisopropylethylamine (248 mg, 334 ^L, 1.93 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-5-methyl-phenyl)-3-fluoro-benzamide (413 mg, 83%) as an off-white solid.
Figure imgf000603_0002
[0597] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-fluoro-6-methylphenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro     methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-5- methyl-phenyl)-3-fluoro-benzamide (413 mg, 1.02 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan -2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (767 mg, 2.52 mmol), Pd(OAc)2 (20 mg, 0.091 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (87 mg, 0.22 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido) -2- fluoro-6-methylphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (640 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000604_0001
[0598] Step 3: Synthesis of 3-fluoro-N-[3-fluoro-5-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-fluoro-6-methylphenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (640 mg, 1.05 mmol) in CH2Cl2 (4.3 mL) and methanol (2.1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-[3-fluoro-5-methyl-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (478 mg, 94%) as a pale yellow solid.
Figure imgf000604_0002
[0599] Step 4: Synthesis of tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorobenzamido)-2-fluoro-6-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl}) methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-     [(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-fluoro-6-methylphenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate .2 HCl (145 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert-butyl N-[(1E)-{[(tert- butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-fluoro-6- methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (219 mg, 82%) as a white solid. B
Figure imgf000605_0001
[0600] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-5-methyl-phenyl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorobenzamido)-2-fluoro-6-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (219 mg, 0.25 mmol), and TFA (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-5-methyl-phenyl]-3-fluoro- benzamide as the bis-TFA salt (101 mg, 56%) as a white solid. MS: 494 M+H+: 1H NMR (300 MHz, dmso) δ 10.34-10.45 (m, 1H), 7.94 (s, 1H), 7.74-7.88 (m, 2H), 7.39-7.68 (m, 12H), 6.17 (br. s., 1H), 5.68 (br. s., 1H), 4.10 (d, J=1.17 Hz, 2H), 4.04 (d, J=1.17 Hz, 2H), 3.62 (t, J=5.27 Hz, 4H), 2.59 (d, J=1.17 Hz, 2H), 2.29-2.37 (m, 2H), 2.24 (s, 3H).     [0601] Example 126: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000606_0001
[0602] Step 1: Synthesis of 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo- benzoyl chloride (279 mg, 1.27 mmol), 4-(4-amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert- butyl ester (325 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4- [4-(4-bromo-3-fluoro-benzoylamino)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (464 mg, 88%) as an off-white solid.
Figure imgf000606_0002
[0603] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (464 mg, 0.97 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (356 mg, 1.14 mmol), Pd(OAc)2 (11 mg, 0.049 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (42 mg, 0.11 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (434 mg, 77%) as a pale yellow solid.    
Figure imgf000607_0001
[0604] Step 3: Synthesis of -fluoro-N-(3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (434 mg, 0.75 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro- N-(3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (386 mg, >100%) as a beige solid, that was used without further purification.
Figure imgf000607_0002
[0605] Step 4: Synthesis of {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N- (3-fluoro-5-methyl-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (147 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-piperazin-1-yl]-3-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (201 mg, 78%) as a clear film.     B
Figure imgf000608_0001
[0606] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4- (4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-fluoro- phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (201 mg, 0.23 mmol), and trifluoroacetic acid (2 mL), to give N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide as the bis-TFA salt (111 mg, 60%) as a white solid. MS: 483 M+H+: 1H NMR (300 MHz, dmso) δ 10.23-10.37 (m, 1H), 7.86-8.01 (m, 3H), 7.69-7.82 (m, 1H), 7.59-7.69 (m, 3H), 7.38-7.59 (m, 10H), 6.99-7.14 (m, 1H), 6.31-6.45 (m, 1H), 4.03-4.19 (m, 2H), 3.61-3.69 (m, 2H), 3.53-3.60 (m, 4H), 2.97-3.09 (m, 4H), 2.56-2.68 (m, 2H). [0607] Example 127: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000608_0002
[0608] Step 1: Synthesis of 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-chloro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo- benzoyl chloride (279 mg, 1.27 mmol), 4-(4-amino-2-chloro-phenyl)-piperazine-1-carboxylic acid tert- butyl ester (343 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-     [4-(4-bromo-3-fluoro-benzoylamino)-2-chloro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (509 mg, 94%) as a pale yellow solid.
Figure imgf000609_0001
[0609] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-2-chloro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-chloro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (509 mg, 1.03 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (378 mg, 1.21 mmol), Pd(OAc)2 (12 mg, 0.052 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (45 mg, 0.12 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- benzoylamino]-2-chloro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (597 mg, 97%) as a pale yellow solid.
Figure imgf000609_0002
[0610] Step 3: Synthesis of N-(3-chloro-4-piperazin-1-yl-phenyl)-3-fluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-2-chloro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (597 mg, 1.00 mmol) in CH2Cl2 (4 mL) and methanol (2 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(3- chloro-4-piperazin-1-yl-phenyl)-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as a tris-HCl salt (480 mg, 95%) as a pale yellow solid.    
Figure imgf000610_0002
[0611] Step 4: Synthesis of give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-chloro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-(3-chloro- 4-piperazin-1-yl-phenyl)-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (152 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- piperazin-1-yl]-3-chloro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (73 mg, 28%) as a white solid.
Figure imgf000610_0001
[0612] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4- (4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-chloro- phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-     methyl}-carbamic acid tert-butyl ester (73 mg, 0.083 mmol), and trifluoroacetic acid (1 mL), to give N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (45 mg, 64%) as a white solid. MS: 499 M+H+: 1H NMR (300 MHz, dmso) δ 10.24-10.38 (m, 1H), 7.87-8.03 (m, 4H), 7.59-7.81 (m, 3H), 7.35-7.59 (m, 9H), 7.13-7.26 (m, 1H), 6.37 (br. s., 1H), 4.04-4.20 (m, 2H), 3.61-3.69 (m, 2H), 3.54-3.61 (m, 4H), 3.00 (br. s., 4H), 2.57-2.69 (m, 2H). [0613] Example 128: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: B
Figure imgf000611_0001
[0614] Step 1: Synthesis of 4-[4-(4-Bromo-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4- bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (279 mg, 1.27 mmol), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (305 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-[4-(4-Bromo-benzoylamino)-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (322 mg, 64%) as a pale purple solid.
Figure imgf000611_0002
[0615] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin- 4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1- carboxylate using 4-[4-(4-bromo-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (322 mg, 0.70 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-     carboxylic acid tert-butyl ester (257 mg, 0.82 mmol), Pd(OAc)2 (8 mg, 0.036 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (30 mg, 0.079 mmol), to give 4-{4-[4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzoylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (77 mg, 20%) as a pale yellow solid. B
Figure imgf000612_0001
[0616] Step 3: Synthesis of N-(4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (338 mg, 0.60 mmol) in CH2Cl2 (2.4 mL) and methanol (1.2 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.1 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(4-piperazin-1-yl-phenyl)-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (302 mg, >100%) as a beige solid, that was used without further purification.
Figure imgf000612_0002
[0617] Step 4: Synthesis of {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert - butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-(4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin- 4-yl)-benzamide .3 HCl (142 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’- bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-     butoxycarbonylimino-methyl)-piperazin-1-yl]-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (165 mg, 65%) as a pale yellow solid.
Figure imgf000613_0001
[0618] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4-(4- {4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]- phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (165 mg, 0.20 mmol), and trifluoroacetic acid (2 mL), to give N-[4-(4- carbamimidoyl-piperazin-1-yl)-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)benzamide as the tris-TFA salt (95 mg, 60%) as a white solid. MS: 465 M+H+: 1H NMR (300 MHz, dmso) δ 10.00-10.16 (m, 1H), 7.88-8.04 (m, 3H), 7.58-7.75 (m, 5H), 7.39-7.58 (m, 8H), 6.88- 7.08 (m, 2H), 6.25-6.44 (m, 1H), 4.02-4.18 (m, 2H), 3.50-3.73 (m, 6H), 3.15-3.25 (m, 4H), 2.57-2.67 (m, 2H). [0619] Example 129: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3,5-difluoro-phenyl]-2-methyl-benzamide:
Figure imgf000613_0002
[0620] Step 1: Synthesis of 4-bromo-N-(4-bromo-3,5-difluoro-phenyl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro     methyl-phenyl)-2-methyl-benzamide using 4-bromo-2-methyl-benzoyl chloride, 4-bromo-3,5- difluoro-phenylamine (229 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3,5-difluoro-phenyl)-3-fluoro-benzamide (348 mg, 78%) as a white solid.
Figure imgf000614_0001
[0621] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methylbenzamido)-2,6-difluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3,5-difluoro-phenyl)-3- fluoro-benzamide (348 mg, 0.86 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro -2H-pyridine-1-carboxylic acid tert-butyl ester (643 mg, 2.12 mmol), Pd(OAc)2 (17 mg, 0.077 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (73 mg, 0.18 mmol), to give tert-butyl 4-[4-(4- {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2,6-difluoro phenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (455 mg, 87%) as a pale yellow solid.
Figure imgf000614_0002
[0622] Step 3: Synthesis of N-[3,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2- methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2,6-difluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (455 mg, 0.75 mmol) in CH2Cl2 (3.3 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.9 mL). The reaction was stirred for 3 days, then was concentrated, to give N-[3,5-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-methyl-     4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (369 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000615_0001
[0623] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6 -dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydr using N-[3,5-difluoro-4-(1,2,3,6-tetrahydro -pyridin-4-yl)-phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (145 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (246 mg, 92%) as a white solid. B
Figure imgf000615_0002
[0624] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3,5-difluoro-phenyl]-2-methyl-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-     benzamide usimhg {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- 1,2,3,6-tetrahydro-pyridin-4-yl]-3,5-difluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (246 mg, 0.28 mmol), and trifluoroacetic acid (3 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3,5-difluoro-phenyl]-2-methyl-benzamide as the bis- HCl salt (53 mg, 26%) as a white solid. MS: 494 M+H+: 1H NMR (300 MHz, dmso) δ 10.56-10.74 (m, 1H), 7.84-8.04 (m, 1H), 7.37-7.64 (m, 14H), 6.24-6.39 (m, 1H), 5.82-6.01 (m, 1H), 4.01-4.19 (m, 4H), 3.60-3.70 (m, 4H), 2.57-2.66 (m, 2H), 2.38-2.43 (m, 3H). [0625] Example 130: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2- fluoro-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide:
Figure imgf000616_0001
[0626] Step 1: Synthesis of {2-[4-(4-bromo-2-fluoro-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4- bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-2-fluoro-benzoyl chloride, [2- (4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (260 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give {2-[4-(4-bromo-2-fluoro-benzoyl amino)- phenyl]-ethyl}-carbamic acid tert-butyl ester (446 mg, 93%) as a white solid.
Figure imgf000616_0002
[0627] Step 2: Synthesis of 4-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]-3- fluoro-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate using {2-[4-(4-bromo-2-fluoro-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (446 mg, 1.02 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-     2H-pyridine-1-carboxylic acid tert-butyl ester (375 mg, 1.21 mmol), Pd(OAc)2 (11 mg, 0.051 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (44 mg, 0.11 mmol), to give 4-{4-[4-(2-tert- butoxycarbonylamino-ethyl)-phenylcarbamoyl]-3-fluoro-phenyl}-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (428 mg, 78%) as a white solid.
Figure imgf000617_0001
[0628] Step 3: Synthesis of N-[4-(2-amino-ethyl)-phenyl]-2-fluoro-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of give 4-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenyl carbamoyl]-3-fluoro-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (428 mg, 0.79 mmol) in CH2Cl2 (3.3 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.9 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[4-(2-amino-ethyl)- phenyl]-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (347 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000617_0002
[0629] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-[4-(2-amino-ethyl)-phenyl]-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide 2HCl (124 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]carbamoyl}-3-     fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate (243 mg, 98%) as a pale yellow film.
Figure imgf000618_0001
[0630] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-N- [4-(2-guanidino-ethyl)-phenyl]-benzamide: To a mixture of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]carbamoyl}-3-fluorophenyl)-1,2,3,6- tetrahydropyridin-1-yl]methylidene]carbamate (243 mg, 0.30 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-2-fluoro-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide as the bis-TFA salt (115 mg, 59%) as a white solid. MS: 424 M+H+: 1H NMR (300 MHz, dmso) δ 10.28-10.41 (m, 1H), 7.60-7.75 (m, 4H), 7.40- 7.60 (m, 7H), 7.20-7.38 (m, 3H), 6.36-6.49 (m, 1H), 4.08-4.19 (m, 2H), 3.60-3.69 (m, 2H), 3.33 (br. s., 2H), 2.69-2.83 (m, 2H), 2.56-2.69 (m, 2H). [0631] Example 131: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-ethyl-benzamide:
Figure imgf000618_0002
[0632] Step 1: Synthesis of 4-bromo-2-ethyl-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-3-ethyl- benzoic acid (277 mg, 1.21 mmol), and oxalyl chloride (246 mg, 166 ^L, 1.94 mmol), to give 4-bromo- 2-ethyl-benzoyl chloride, that was used without further purification.    
Figure imgf000619_0001
[0633] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-ethyl-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-2-ethyl-benzoyl chloride, 4-bromo-3-fluoro-phenyl amine (209 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4- bromo-N-(4-bromo-3-fluoro-phenyl)-2-ethyl-benzamide (376 mg, 85%) as a pale yellow solid.
Figure imgf000619_0002
[0634] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-ethylbenzamido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-ethyl-benzamide (376 mg, 0.94 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (701 mg, 2.31 mmol), Pd(OAc)2 (19 mg, 0.084 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (80 mg, 0.20 mmol), to give tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-ethylbenzamido)-2-fluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (536 mg, 94%) as a white solid.
Figure imgf000619_0003
[0635] Step 4: Synthesis of 2-ethyl-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert-butoxy)     carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-ethylbenzamido)-2-fluorophenyl]-1,2,3,6-tetrahydro pyridine-1-carboxylate (536 mg, 0.88 mmol) in CH2Cl2 (3.7 mL) and methanol (1.8 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.3 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2-ethyl-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (424 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000620_0001
[0636] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-ethyl-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 2-ethyl-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide .2 HCl (144 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis- Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-ethyl- phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (207 mg, 78%) as a white solid.     H2N
Figure imgf000621_0002
[0637] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-ethyl-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamideusing {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-fluoro-phenylcarbamoyl}-3-ethyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (207 mg, 0.23 mmol), and trifluoroacetic acid (2.5 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-ethyl-benzamide as the bis-TFA salt (124 mg, 75%) as a white solid. MS: 490 M+H+: 1H NMR (300 MHz, dmso) δ 10.52-10.66 (m, 1H), 7.88-8.02 (m, 1H), 7.66-7.81 (m, 1H), 7.29-7.63 (m, 13H), 6.21-6.38 (m, 1H), 5.95-6.09 (m, 1H), 4.02-4.19 (m, 4H), 3.55-3.71 (m, 4H), 2.73-2.81 (m, 2H), 2.61 (br. s., 2H), 2.53-2.59 (m, 2H), 1.14- 1.26 (m, 3H). [0638] Example 132: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-trifluoromethyl- phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide:
Figure imgf000621_0001
[0639] Step 1: Synthesis of 4-[4-(4-bromo-benzoylamino)-2-trifluoromethyl-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-     benzoyl chloride (279 mg, 1.27 mmol), 4-(4-amino-2-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (380 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-[4-(4-bromo-benzoylamino)-2-trifluoromethyl-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (570 mg, 98%) as a white solild.
Figure imgf000622_0001
[0640] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-2-trifluoromethyl-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-benzoylamino)-2-trifluoromethyl-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (570 mg, 1.08 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (397 mg, 1.28 mmol), Pd(OAc)2 (12 mg, 0.054 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (47 mg, 0.12 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzoylamino]-2- trifluoromethyl-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (580 mg, 85%) as a white solid.
Figure imgf000622_0002
[0641] Step 3: Synthesis of N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzoylamino]-2-trifluoromethyl-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (580 mg, 0.92 mmol) in CH2Cl2 (3.7 mL) and methanol (1.8 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.3 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(4-     piperazin-1-yl-3-trifluoromethyl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris- HCl salt (481 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000623_0002
[0642] Step 4: Synthesis of {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-trifluoromethyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-(4- piperazin-1-yl-3-trifluoromethyl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (162 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- piperazin-1-yl]-3-trifluoromethyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (208 mg, 76%) as an off-white solid. B
Figure imgf000623_0001
[0643] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4-(4- {4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-     trifluoromethyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (208 mg, 0.23 mmol), and TFA (2.5 mL), to give N-[4-(4- carbamimidoyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide as the tris-HCl salt (117 mg, 59%) as a white solid. MS: 515 M+H+: 1H NMR (300 MHz, dmso) δ 10.49 (s, 1H), 8.18 (d, J=2.34 Hz, 1H), 8.07 (dd, J=2.34, 8.79 Hz, 1H), 7.91- 8.03 (m, 3H), 7.58-7.74 (m, 4H), 7.42-7.58 (m, 8H), 6.32-6.48 (m, 1H), 4.01-4.19 (m, 2H), 3.64 (t, J=5.57 Hz, 2H), 3.52 (br. s., 4H), 2.88-2.93 (m, 4H), 2.60-2.68 (m, 2H). [0644] Example 133: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-2-methyl-phenyl]- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide:
Figure imgf000624_0001
[0645] Step 1: Synthesis of 4-(3-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert- butyl ester: A mixture of 4-fluoro-2-methyl-1-nitro-benzene (500 mg, 3.22 mmol), piperazine-1- carboxylic acid tert-butyl ester (630 mg, 3.38 mmol), and diisopropylethylamine (563 mg, 782 ^L, 4.39 mmol) in N,N-dimethylacetamide (4 mL) was heated at 125oC for 20 hours. The reaction was allowed to cool to 20oC, and was treated with water (40 mL). The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (10 mL), and hexane (10 mL), to give 4-(3- methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (935 mg, 90%) as a yellow solid.
Figure imgf000624_0002
[0646] Step 2: Synthesis of 4-(4-amino-3-methyl-phenyl)-piperazine-1-carboxylic acid tert- butyl ester: To a mixture of 4-(3-methyl-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (930 mg, 2.89 mmol) in tetrahydrofuran (5 mL) and methanol (6.5 mL) was added ammonium chloride (704 mg, 13.14 mmol) and acetic acid (114 mg, 109 ^L, 1.90 mmol), followed by slow portionwise addition of zinc (838 mg, 12.95 mmol). The reaction was stirred for 16 hours, then was filtered. The solid was washed with 5% methanol in CH2Cl2 (20 mL). The combined filtrates were concentrated. The residue was treated with ethyl acetate (30 mL), then was filtered. The filtrated was washed with     water (20 mL), and brine (5 mL), dried (Na2SO4), and concentrated, to give 4-(4-amino-3-methyl- phenyl)-piperazine-1-carboxylic acid tert-butyl ester (604 mg, 72%) as a grey solid.
Figure imgf000625_0001
[0647] Step 3: Synthesis of 4-[4-(4-bromo-benzoylamino)-3-methyl-phenyl]-piperazine-1- carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4- bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (829 mg, 3.77 mmol), 4-(4-amino-3-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (950 mg, 3.26 mmol), and diisopropylethylamine (662 mg, 889 ^L, 5.12 mmol), to give 4-[4-(4-bromo- benzoylamino)-3-methyl-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (309 mg, 20%) as an off-white solid.
Figure imgf000625_0002
[0648] Step 4: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-3-methyl-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate using 4-[4-(4-bromo-benzoylamino)-3-methyl-phenyl]-piperazine-1- carboxylic acid tert-butyl ester (395 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 (306 mg, 0.99 mmol), Pd(OAc)2 (9 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (36 mg, 0.093 mmol), to give 4- {4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzoylamino]-3-methyl-phenyl}- piperazine-1-carboxylic acid tert-butyl ester (372 mg, 78%) as an off-white solid.    
Figure imgf000626_0002
Figure imgf000626_0001
[0649] Step 5: Synthesis of N-(2-methyl-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4- yl)-benzoylamino]-3-methyl-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (372 mg, 0.65 mmol) in CH2Cl2 (2.6 mL) and methanol (1.3 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.3 mL). The reaction was stired for 16 hours, then was concentrated, to give N-(2-methyl-4-piperazin- 1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (336 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000626_0003
[0650] Step 6: Synthesis of give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-2-methyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-(2-methyl-4- piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide 3 HCl (146 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-2- methyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (119 mg, 46%) as a pale yellow solid.    
Figure imgf000627_0001
[0651] Step 7: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-2-methyl-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4-(4- {4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-2-methyl- phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (119 mg, 0.14 mmol), and TFA (2 mL), to give N-[4-(4-carbamimidoyl- piperazin-1-yl)-2-methyl-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-TFA salt (65 mg, 58%) as a beige solid.MS: 461 M+H+: 1H NMR (300 MHz, dmso) δ 9.70- 9.78 (m, 1H), 7.89-8.03 (m, 2H), 7.57-7.67 (m, 3H), 7.42-7.57 (m, 8H), 7.07-7.20 (m, 1H), 6.89 (d, J=1.17 Hz, 1H), 6.79-6.87 (m, 1H), 6.36 (d, J=2.93 Hz, 1H), 4.05-4.17 (m, 2H), 3.61-3.68 (m, 2H), 3.50-3.61 (m, 4H), 3.16-3.26 (m, 4H), 2.63 (d, J=1.76 Hz, 2H), 2.17 (s, 3H). [0652] Example 134: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-trifluoromethyl-benzamide:
Figure imgf000627_0002
[0653] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-trifluoromethyl- benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3- methoxy-phenyl)-2-fluoro-benzamide, using 4-bromo-2-trifluoromethyl-benzoyl chloride (365 mg, 1.27 mmol 4-bromo-3-fluoro-phenylamine (209 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-trifluoromethyl-benzamide (484 mg, 100%) as a white solid.    
Figure imgf000628_0001
[0654] Step 2: Synthesis of 4-[4-(4-bromo-2-trifluoromethyl-benzoylamino)-phenyl]-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-trifluoromethyl-benzamide (484 mg, 1.10 mmol), 4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (816 mg, 2.64 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), and 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (94 mg, 0.23 mmol), to give 4-[4-(4-bromo-2-trifluoromethyl-benzoylamino)- phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (750 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000628_0002
[0655] Step 3: Synthesis of N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6 -tetrahydro-pyridin-4-yl)-2-trifluoromethyl-benzamide: A solution of 4-[4-(4-bromo-2-trifluoro methyl-benzoylamino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (750 mg, 1.16 mmol) in CH2Cl2 (5 mL) and methanol (2.5 mL) was treated with a 4N solution of HCl in 1,4- dioxane (4.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-fluoro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethyl- benzamide as the bis-HCl salt (580 mg, 97%) as a yellow solid.    
Figure imgf000629_0002
[0656] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-(trifluoromethyl)benzamido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl}) methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1- yl]methylidene]carbamate using N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-2-trifluoromethyl-benzamide .2 HCl (156 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-(trifluoromethyl) benzamido)-2- fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (160 mg, 57%) as a white solid.
Figure imgf000629_0001
[0657] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-trifluoromethyl-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert-     butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-2- (trifluoromethyl)benzamido)-2-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (160 mg, 0.17 mmol), and trifluoroacetic acid (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- trifluoromethyl-benzamide as the bis-TFA salt (95 mg, 74%) as a white solid. MS: 530 M+H+: 1H NMR (300 MHz, dmso) δ 10.77-10.93 (m, 1H), 7.82-7.99 (m, 3H), 7.59-7.80 (m, 3H), 7.31-7.59 (m, 10H), 6.39-6.52 (m, 1H), 5.99-6.11 (m, 1H), 4.01-4.18 (m, 4H), 3.56-3.71 (m, 5H), 2.62-2.69 (m, 2H), 2.53-2.61 (m, 2H). [0658] Example 135: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-5-fluoro-phenyl]-benzamide:
Figure imgf000630_0001
[0659] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-chloro-5-fluoro-phenyl)-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (283 mg, 1.29 mmol), 4-bromo-3- chloro-5-fluoro-phenylamine (250 mg, 1.11 mmol), and diisopropylethylamine (226 mg, 304 ^L, 1.75 mmol), to give 4-bromo-N-(4-bromo-3-chloro-5-fluoro-phenyl)-benzamide (408 mg, 90%) as a pale yellow solid.
Figure imgf000630_0002
[0660] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}benzamido)-2-chloro-6-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-chloro-5-fluoro-phenyl)-benzamide     (408 mg, 1.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (743 mg, 2.40 mmol), Pd(OAc)2 (20 mg, 0.10 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (86 mg, 0.21 mmol), to give tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}benzamido)-2-chloro-6-fluoro phenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (345 mg, 56%) as an off-white solid.
Figure imgf000631_0001
[0661] Step 3: Synthesis of N-[3-chloro-5-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}benzamido)-2-chloro-6-fluorophenyl]-1,2,3,6-tetrahydro pyridine-1-carboxylate (345 mg, 0.56 mmol) in CH2Cl2 (2.4 mL) and methanol (1.2 mL0 was treated with a 4N solution of HCl in 1,4-dioxane (2.2 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-chloro-5-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (315 mg, >100%) as a yellow solid.
Figure imgf000631_0002
[0662] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-chloro-5-fluoro-phenylcarbamoyl}-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-[3-chloro-5-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide. 2 HCl (146 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-     Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-chloro-5-fluoro-phenylcarbamoyl}- phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (135 mg, 50%) as a white solid.
Figure imgf000632_0001
[0663] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-5-fluoro-phenyl]-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-3-chloro-5-fluoro-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (135 mg (160 mg, 0.15 mmol), and trifluoroacetic acid (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-5-fluoro-phenyl]-benzamide as the bis-TFA salt (77 mg, 71%) as a white solid. MS: 497 M+H+: 1H NMR (300 MHz, dmso) δ 10.54-10.64 (m, 1H), 7.92-8.06 (m, 3H), 7.61-7.91 (m, 5H), 7.41-7.60 (m, 9H), 6.32-6.47 (m, 1H), 5.76-5.88 (m, 1H), 4.00-4.20 (m, 4H), 3.57-3.70 (m, 4H), 2.60-2.67 (m, 2H), 2.38 (br. s., 2H). [0664] Example 136: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-2-methyl-benzamide:
Figure imgf000632_0002
[0665] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-2-methyl-phenyl)-2-methyl- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-     trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-2-methyl-benzoyl chloride, 4-bromo-3- fluoro-2-methyl-phenylamine (225 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-2-methyl-phenyl)-2-methyl-benzamide (384 mg, 87%) as a pale yellow solid.
Figure imgf000633_0001
[0666] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-2-methylbenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro-2- methyl-phenyl)-2-methyl-benzamide (384 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 (713 mg, 2.30 mmol), Pd(OAc)2 (19 mg, 0.087 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (83 mg, 0.20 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methyl benzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (542 mg, 93%) as a white solid.
Figure imgf000633_0002
[0667] Step 3: Synthesis of N-[3-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2-fluoro-3-methylphenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (542 mg, 0.90 mmol) in CH2Cl2 (3.9 mL0 and methanol (1.9 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.5 mL). The reaction was stirred for 16     hours, then was concentrated, to give N-[3-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (432 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000634_0001
[0668] Step 4: Synthesis of give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4- {1-[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methylbenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl}) methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using N-[3-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (144 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert- butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2- fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (169 mg, 63%) as a clear film.
Figure imgf000634_0002
[0669] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-2-methyl-benzamide: The     title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-2- methylbenzamido)-2-fluoro-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (169 mg, 0.159mmol), and trifluoroacetic acid (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-2- methyl-benzamide as the bis-TFA salt (83 mg, 61%) as a white solid. MS: 490 M+H+: 1H NMR (300 MHz, dmso) δ 9.90-10.03 (m, 1H), 7.94 (s, 1H), 7.35-7.66 (m, 12H), 7.16-7.33 (m, 2H), 6.27 (br. s., 1H), 5.92-6.07 (m, 1H), 4.01-4.17 (m, 4H), 3.56-3.69 (m, 4H), 2.53-2.65 (m, 4H), 2.43 (s, 3H), 2.16 (s, 3H). [0670] Example 137: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-difluoro-phenyl]-2-methyl-benzamide:
Figure imgf000635_0001
[0671] Step 1: Synthesis of 4-bromo-N-(4-bromo-2,3-difluoro-phenyl)-2-methyl-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoro methyl-phenyl)-2-methyl-benzamide using 4-bromo-2-methyl-benzoyl chloride, 4-bromo-2,3- difluoro-phenylamine (229 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-2,3-difluoro-phenyl)-2-methyl-benzamide (266 mg, 60%) as white solid.
Figure imgf000635_0002
[0672] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-methylbenzamido)-2,3-difluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-     butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-2,3-difluoro-phenyl)-2- methyl-benzamide (266 mg, 0.66 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (488 mg, 1.57 mmol), Pd(OAc)2 (13 mg, 0.060 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (57 mg, 0.14 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2,3-difluoro phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (418 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000636_0001
[0673] Step 3: Synthesis of N-[2,3-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2- methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-methylbenzamido)-2,3-difluorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (418 mg, 0.69 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[2,3-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-methyl-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (429 mg, >100%) as an orange solid.
Figure imgf000636_0002
[0674] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2,3-difluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6 -dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)     carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene] carbamate using N-[2,3-difluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-methyl-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide.2 HCl (145 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2,3- difluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonyl imino-methyl}-carbamic acid tert-butyl ester (87 mg, 32%) as a pale yellow film. B
Figure imgf000637_0001
[0675] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-difluoro-phenyl]-2-methyl-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-2,3-difluoro-phenylcarbamoyl}-3-methyl-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (87 mg, 0.097 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with dimethylformamide (1 ML), followed by dropwise addition of 0.1% TFA in water (1 mL). The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-difluoro- phenyl]-2-methyl-benzamide as the bis-TFA salt (16 mg, 23%) as a beige solid. The original dimethylformamide/water filtrate was purified by preparative-HPLC, to give 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3- difluoro-phenyl]-2-methyl-benzamide as the bis-TFA salt (14 mg, 20%) as a white solid. MS: 494 M+H+: 1H NMR (300 MHz, dmso) δ 10.24-10.38 (m, 1H), 7.36-7.62 (m, 15H), 7.18-7.29 (m, 1H),     6.24-6.35 (m, 1H), 6.06-6.17 (m, 1H), 4.02-4.16 (m, 4H), 3.55-3.71 (m, 4H), 2.56-2.65 (m, 4H), 2.42 (s, 3H). [0676] Example 138: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-phenyl]-2-fluoro-benzamide:
Figure imgf000638_0001
[0677] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-chloro-phenyl)-2-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-2-fluoro-benzoyl chloride, 4-bromo-3-chloro-phenyl amine (227 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4- bromo-N-(4-bromo-3-chloro-phenyl)-2-fluoro-benzamide (401 mg, 90%) as a white solid.
Figure imgf000638_0002
[0678] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-fluorobenzamido)-2-chlorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-chloro-phenyl)-2-fluoro-benzamide (401 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 (728 mg, 2.34 mmol), Pd(OAc)2 (19 mg, 0.090 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (85 mg, 0.21 mmol), to give tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-fluorobenzamido)-2-chlorophenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (400 mg, 67%) as a white solid.    
Figure imgf000639_0001
[0679] Step 3: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-2-fluorobenzamido)-2-chlorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: A solution of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-2-fluoro benzamido)-2-chlorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (400 mg, 0.65 mmol) in CH2Cl2 (3 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[3-chloro-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (383 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000639_0002
[0680] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-chloro-phenylcarbamoyl}-3-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-[3-chloro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide. 2 HCl (146 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis- Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-3-chloro-phenylcarbamoyl}-3-fluoro-     phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (119 mg, 44%) s a clear film.
Figure imgf000640_0001
[0681] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-phenyl]-2-fluoro-benzamide: To a mixture of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro- pyridin-4-yl]-3-chloro-phenylcarbamoyl}-3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (119 mg, 0.13 mmol) in CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-phenyl]-2-fluoro- benzamide as the bis-TFA salt (13 mg, 14%) as a white solid. MS: 496 M+H+: 1H NMR (300 MHz, dmso) δ 10.53-10.65 (m, 1H), 7.91 (d, J=1.76 Hz, 1H), 7.57-7.74 (m, 3H), 7.39-7.57 (m, 10H), 7.26- 7.38 (m, 1H), 7.32 (br. s., 1H), 7.29 (d, J=8.79 Hz, 1H), 6.43 (br. s., 1H), 5.73-5.85 (m, 1H), 3.97-4.17 (m, 4H), 3.54-3.70 (m, 5H), 2.55-2.68 (m, 2H). [0682] Example 139: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-6-methyl-benzamide:
Figure imgf000640_0002
[0683] Step 1: Synthesis of 4-bromo-2-fluoro-6-methyl-benzoyl chloride: The title compound was prepared according to the procedure of 4-bromo-2-methyl-benzoyl chloride using 4-bromo-2- fluoro-6-methyl-benzoic acid (296 mg, 1.27 mmol), and oxalyl chloride (259 mg, 174 ^L, 2.03 mmol), to give 4-bromo-2-fluoro-6-methyl-benzoyl chloride, which was used without further purification.    
Figure imgf000641_0001
[0684] Step 2: Synthesis of 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-fluoro-6-methyl- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-2-fluoro-6-methyl-benzoyl chloride, 4- bromo-3-fluoro-phenylamine (209 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3-fluoro-phenyl)-2-fluoro-6-methyl-benzamide (437 mg, 98%) as an off-white solid.
Figure imgf000641_0002
[0685] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorophenyl)carbamoyl]-3-fluoro-5-methylphenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-fluoro- phenyl)-2-fluoro-6-methyl-benzamide (437 mg, 1.08 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (802 mg, 2.58 mmol), Pd(OAc)2 (21 mg, 0.099 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (94 mg, 0.23 mmol), to give tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluoro phenyl)carbamoyl]-3-fluoro-5-methylphenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (565 mg, 86%) as a white solid.
Figure imgf000641_0003
    [0686] Step 4: Synthesis of 2-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 6-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorophenyl)carbamoyl]-3-fluoro-5-methyl phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (565 mg, 0.93 mmol) in CH2Cl2 (4.3 mL) and methanol (2.1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.7 mL). The reaction was stirred for 16 hours, then was concentrate, to give 2-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin- 4-yl)-phenyl]-6-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (441 mg, 98%) as a pale yellow solid.
Figure imgf000642_0001
[0687] Step 5: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1- [(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorophenyl)carbamoyl]-3-fluoro-5-methylphenyl}-1,2,3,6-tetrahydropyridin-1-yl) methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using 2-fluoro-N-[3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-6 -methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide 2 HCl (145 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert-butyl N- [(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1Z)-{[(tert-butoxy)carbonyl]amino} ({[(tert- butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorophenyl)carbamoyl]-3- fluoro-5-methylphenyl}-1,2,3,6-tetrahydropyridin-1-yl)methylidene]carbamate (158 mg, 59%) as a white solid.    
Figure imgf000643_0001
[0688] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-6-methyl-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}(4-{4-[(4-{1-[(1Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorophenyl)carbamoyl]-3-fluoro-5-methylphenyl}-1,2,3,6-tetrahydropyridin-1- yl)methylidene]carbamate (169 mg, 0.159mmol), and trifluoroacetic acid (2 mL), to give 4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4- yl)-3-fluoro-phenyl]-2-fluoro-6-methyl-benzamide as the bis-TFA salt (99 mg, 76%) as a white solid. MS: 494 M+H+: 1H NMR (300 MHz, dmso) δ 10.80-10.89 (m, 1H), 7.91-8.00 (m, 1H), 7.64-7.74 (m, 2H), 7.39-7.59 (m, 11H), 7.24-7.35 (m, 2H), 6.33 (br. s., 1H), 5.97-6.08 (m, 1H), 4.03-4.15 (m, 4H), 3.59-3.66 (m, 4H), 2.52-2.64 (m, 4H), 2.32 (s, 3H). [0689] Example 140: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (2-guanidino-ethoxy)-phenyl]-benzamide: Br
Figure imgf000643_0002
[0690] Step 1: Synthesis of give {2-[4-(4-bromo-benzoylamino)-phenoxy]-ethyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4- bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (252 mg, 1.15 mmol), [2-(4-amino-phenoxy)-ethyl]-carbamic acid tert-butyl ester (250 mg, 0.99 mmol), and     diisopropylethylamine (202 mg, 271 ^L, 1.56 mmol), to give {2-[4-(4-bromo-benzoylamino)- phenoxy]-ethyl}-carbamic acid tert-butyl ester (274 mg, 64%) as a beige solid.
Figure imgf000644_0001
K2CO3, H2O, 1,4-dioxane [0691] Step 2: Synthesis of 4-{4-[4-(2-tert-butoxycarbonylamino-ethoxy)-phenylcarbamoyl]- phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin- 4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1- carboxylate using {2-[4-(4-bromo-benzoylamino)-phenoxy]-ethyl}-carbamic acid tert-butyl ester (274 mg, 0.63 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (232 mg, 0.75 mmol), Pd(OAc)2 (7 mg, 0.0032 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (27 mg, 0.071 mmol), to give 4-{4-[4-(2-tert- butoxycarbonylamino-ethoxy)-phenylcarbamoyl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (142 mg, 42%) as a beige solid.
Figure imgf000644_0002
[0692] Step 3: Synthesis of N-[4-(2-amino-ethoxy)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-benzamide: A solution of 4-{4-[4-(2-tert-butoxycarbonylamino-ethoxy)-phenylcarbamoyl]- phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (142 mg, 0.26 mmol) in CH2Cl2 (1.2 mL) and methanol (0.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.1 mL). The reaction was stirred for 3 days, then was concentrated, to give N-[4-(2-amino-ethoxy)-phenyl]-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (196 mg, >100%) as a pale green solid, that was used without further purification.    
Figure imgf000645_0002
[0693] Step 4: Synthesis of give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4- (2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethoxy) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-[4-(2-amino-ethoxy)-phenyl]-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt . 2 HCl (190 mg, 0.46 mmol), triethylamine (322 mg, 442 ^L, 3.16 mmol), and N,N’-bis-Boc-guanyl pyrazole (451 mg, 1.46 mmol), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethoxy) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate (170 mg, 45%) as a clear film.
Figure imgf000645_0001
[0694] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2- guanidino-ethoxy)-phenyl]-benzamide: To a mixture of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethoxy)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate (170 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified     by preparative-HPLC, to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2- guanidino-ethoxy)-phenyl]-benzamide as the bis-TFA salt (60 mg, 44%) as a white solid. MS: 422 M+H+: 1H NMR (300 MHz, dmso) δ 10.15 (s, 1H), 7.91-8.01 (m, 2H), 7.67-7.84 (m, 4H), 7.52 (s, 4H), 6.94 (d, J=8.79 Hz, 2H), 6.36 (br. s., 1H), 4.11 (br. s., 2H), 4.04 (t, J=4.98 Hz, 3H), 3.64 (t, J=5.57 Hz, 3H), 3.51 (q, J=4.88 Hz, 3H), 2.57-2.69 (m, 2H). [0695] Example 141: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide F Br
Figure imgf000646_0001
[0696] Step 1: Synthesis of 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-chloro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3- fluoro-benzoyl chloride, 4-(4-amino-2-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (343 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-[4-(4-bromo- 3-fluoro-benzoylamino)-2-chloro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (540 mg, 96%) as a pale yellow solid.
Figure imgf000646_0002
[0697] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-2-chloro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-chloro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (540 mg, 1.05 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (387 mg, 1.24     mmol), Pd(OAc)2 (12 mg, 0.0052 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (46 mg, 0.12 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- benzoylamino]-2-chloro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (474 mg, 73%) as an off- white solid.
Figure imgf000647_0001
[0698] Step 3: Synthesis of N-(3-chloro-4-piperazin-1-yl-phenyl)-3-fluoro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-2-chloro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (474 mg, 0.77 mmol) in CH2Cl2 (3.1 mL) and methanol (1.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.7 mL). The reaction was stirred for 2 days, then was concentrated, to give N-(3- chloro-4-piperazin-1-yl-phenyl)-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris- HCl salt (418 mg, >100%) as an off-white solid, that was used without further purification.
Figure imgf000647_0002
[0699] Step 4: Synthesis of {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-chloro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-(3-chloro- 4-piperazin-1-yl-phenyl)-3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (157 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg,     0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- piperazin-1-yl]-3-chloro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (110 mg, 41%) as a clear film.
Figure imgf000648_0001
[0700] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3- chloro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (110 mg, 0.12mmol), and trifluoroacetic acid (1.5 mL), to give N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (29 mg, 29%) as a white solid. MS: 499 M+H+: 1H NMR (300 MHz, dmso) δ 10.34-10.45 (m, 1H), 7.95 (d, J=1.17 Hz, 2H), 7.76-7.88 (m, 2H), 7.69 (dd, J=1.76, 8.79 Hz, 1H), 7.43-7.65 (m, 10H), 7.16-7.28 (m, 1H), 6.17 (br. s., 1H), 4.04-4.17 (m, 2H), 2.93-3.09 (m, 4H), 2.60 (d, J=2.34 Hz, 2H), 2.49 (br. s., 7H). [0701] Example 142: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-benzamide
Figure imgf000648_0002
[0702] Step 1: Synthesis of 4-bromo-N-(4-bromo-phenyl)-3-fluoro-benzamide: The title compounds was prepared according to the procedure of 4-bromo-N-(4-bromo-3-methoxy-phenyl)-2- fluoro-benzamide, using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-phenylamine (189 mg, 1.10     mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo- phenyl)-3-fluoro-benzamide (400 mg, 98%) as a beige solid.
Figure imgf000649_0001
[0703] Step 3: Synthesis of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-phenyl)-3-fluoro-benzamide (400 mg, 1.07 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (798 mg, 2.57 mmol), Pd(OAc)2 (21 mg, 0.10 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (93 mg, 0.23 mmol), to give tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (486 mg, 79%) as an off-white solid.
Figure imgf000649_0002
[0704] Step 4: Synthesis of 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-benzamide: A solution of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate (486 mg, 0.84 mmol) in CH2Cl2 (3.9 mL) and methanol (1.9 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6-tetrahydro-pyridin-4- yl)-phenyl]-benzamide as the bis-HCl salt (408 mg, >100%) as a pale yellow solid, that was used without further purification.     H
Figure imgf000650_0002
[0705] Step 5: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4- {[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide . 2 HCl (135 mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanyl pyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H- pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (100 mg, 39%) as a clear film.
Figure imgf000650_0001
[0706] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4- (4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-     yl]-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (100 mg, 0.12mmol), and trifluoroacetic acid (1.5 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-3-fluoro-benzamide as the bis-TFA salt (50 mg, 60%) as a yellow solid. MS: 462 M+H+: 1H NMR (300 MHz, dmso) δ 10.31-10.43 (m, 1H), 7.94 (br. s., 1H), 7.75-7.89 (m, 4H), 7.41-7.64 (m, 12H), 6.12-6.26 (m, 2H), 4.03-4.17 (m, 4H), 3.62 (br. s., 5H), 2.59 (d, J=1.17 Hz, 4H). [0707] Example 143: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl- 6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000651_0001
[0708] Step 1: Synthesis of 4-bromo-N-(5-bromo-pyridin-2-yl)-3-fluoro-benzamide: To a mixture of 5-bromo-pyridin-2-ylamine (380 mg, 2.20 mmol) and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol) in CHCl3 (6 mL) was added dropwise a solution of 4-bromo-3-fluoro-benzoyl chloride in CHCl3 (6 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (50 mL) and dilute aqueous NaHCO3 (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (15 mL), and brine (10 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-15% ethyl acetate: hexanes), to give 4-bromo- N-(5-bromo-pyridin-2-yl)-3-fluoro-benzamide (~75% purity) (187 mg, 46%) as a white solid, that was used without further purification.
Figure imgf000651_0002
[0709] Step 2: Synthesis of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]- 1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-     tetrahydropyridine-1-carboxylate using 4-bromo-N-(5-bromo-pyridin-2-yl)-3-fluoro-benzamide (~75% purity) (686 mg, 1.83 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (1368 mg, 4.41 mmol), Pd(OAc)2 (36 mg, 0.17 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (159 mg, 0.39 mmol), to give 6-[4-(1-tert- butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-3',6'-dihydro-2'H-[3,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester (647 mg, 61%) as a pale yellow solid.
Figure imgf000652_0001
[0710] Step 3: Synthesis of 3-fluoro-N-(1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (647 mg, 1.12 mmol) in CH2Cl2 (5.2 mL) and methanol (2.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (4.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-(1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide as the tris-HCl salt (564 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000652_0002
[0711] Step 4: Synthesis of give [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro- 2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4- {[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]     amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N-(1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide .3 HCl (146 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis- Boc-guanylpyrazole (294 mg, 0.95 mmol), to give [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxy carbonylimino-methyl)-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (172 mg, 66%) as a yellow solid.
Figure imgf000653_0001
[0712] Step 5: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using [(4- {4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (172 mg, 0.20mmol), and trifluoroacetic acid (2 mL), to give N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (112 mg, 70%) as a white solid. MS: 463 M+H+: 1H NMR (300 MHz, dmso) δ 10.91-11.02 (m, 1H), 8.47-8.57 (m, 1H), 8.11-8.23 (m, 1H), 7.85-8.03 (m, 4H), 7.43-7.62 (m, 9H), 6.30 (br. s., 1H), 6.13-6.23 (m, 1H), 4.09 (br. s., 4H), 3.63 (br. s., 4H), 2.61 (d, J=2.93 Hz, 4H). [0713] Example 144: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-benzamide:    
Figure imgf000654_0001
[0714] Step 1: Synthesis of 4-[4-(4-bromo-2-fluoro-benzoylamino)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-2- fluoro-benzoyl chloride, 4-(4-Amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (325 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-[4-(4-bromo- 2-fluoro-benzoylamino)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (467 mg, 86%) as a pale yellow solid.
Figure imgf000654_0002
[0715] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2- fluoro-benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-2-fluoro-benzoylamino)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (467 mg, 0.94 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (345 mg, 1.11 mmol), Pd(OAc)2 (11 mg, 0.049 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (41 mg, 0.11 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro- benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (424 mg, 75%) as a pale yellow solid.    
Figure imgf000655_0001
[0716] Step 3: Synthesis of 2-fluoro-N-(3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-fluoro-benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (424 mg, 0.71 mmol) in CH2Cl2 (3.3 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2-fluoro- N-(3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (378 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000655_0002
[0717] Step 4: Synthesis of {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-fluoro-phenylcarbamoyl}-3-fluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 2-fluoro-N- (3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (152 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- piperazin-1-yl]-3-fluoro-phenylcarbamoyl}-3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (120 mg, 45%) as a clear film.    
Figure imgf000656_0001
[0718] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4- (4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-fluoro- phenylcarbamoyl}-3-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (120 mg, 0.14mmol), and trifluoroacetic acid (1.5 mL), to give N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-fluoro-benzamide as the tris-TFA salt (65 mg, 56%) as a pale yellow solid. MS: 483 M+H+: 1H NMR (300 MHz, dmso) δ 10.35-10.48 (m, 1H), 7.61-7.72 (m, 2H), 7.36-7.60 (m, 12H), 7.01-7.14 (m, 1H), 6.37-6.49 (m, 1H), 4.10 (br. s., 2H), 3.54-3.67 (m, 6H), 2.97-3.11 (m, 4H), 2.60 (br. s., 2H). [0719] Example 145: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: F Br
Figure imgf000656_0002
[0720] Step 1: Synthesis of 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3- fluoro-benzoyl chloride, 4-(4-amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (325 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-[4-(4-bromo-     3-fluoro-benzoylamino)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (463 mg, 85%) as a white solid.
Figure imgf000657_0001
[0721] Step 2: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[4-(4-bromo-3-fluoro-benzoylamino)-2-fluoro-phenyl]- piperazine-1-carboxylic acid tert-butyl ester (463 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 (344 mg, 1.10 mmol), Pd(OAc)2 (11 mg, 0.046 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (41 mg, 0.11 mmol), to give 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoyl amino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (439 mg, 79%) as a white solid.
Figure imgf000657_0002
[0722] Step 3: Synthesis of 3-fluoro-N-(3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (424 mg, 0.71 mmol) in CH2Cl2 (3.3 mL) and methanol (1.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro- N-(3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (378 mg, >100%) as a pale yellow solid.    
Figure imgf000658_0002
[0723] Step 4: Synthesis of give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin- 1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2- {[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N- (3-fluoro-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (152 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)- piperazin-1-yl]-3-fluoro-phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (142 mg, 54%) as a clear film. Bo
Figure imgf000658_0001
[0724] Step 5: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4- (4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-fluoro- phenylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (142 mg, 0.16 mmol), and trifluoroacetic acid (1.5 mL), to give     N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (89 mg, 68%) as a white solid. MS: 483 M+H+: 1H NMR (300 MHz, dmso) δ 10.27-10.41 (m, 1H), 7.63-7.86 (m, 3H), 7.38-7.62 (m, 10H), 7.02-7.16 (m, 1H), 6.16 (br. s., 1H), 4.10 (br. s., 2H), 3.50-3.67 (m, 6H), 3.21-3.48 (m, 6H), 2.99-3.11 (m, 4H), 2.59 (br. s., 2H). [0725] Example 146: Step 6: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro- [2,4']bipyridinyl-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000659_0001
[0726] Step 1: Synthesis of 4-bromo-3-fluoro-benzoyl chloride: To a mixture of 4-bromo-3- fluoro-benzoic acid (536 mg, 2.54 mmol) in CHCl3 (14 mL) and dimethylformamide (5 drops) was added dropwise oxalyl chloride (518 mg, 348 ^L, 4.06 mmol). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with CHCl3 (30 mL), then was concentrated, to give 4-bromo-3-fluoro-benzoyl chloride, which was used without further purification.
Figure imgf000659_0002
[0727] Step 2: Synthesis of 4-bromo-N-(6-bromo-pyridin-3-yl)-3-fluoro-benzamide: To a mixture of 6-bromo-pyridin-3-ylamine (380 mg, 2.20 mmol) and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol) in CHCl3 (6 mL) was added dropwise a solution of 4-bromo-3-fluoro-benzoyl chloride in CHCl3 (6 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was partitioned between ethyl acetate (50 mL) and dilute aqueous NaHCO3 (20 ML). The organic layer was washed with saturated aqueous NaHCO3 (15 mL), and brine (10 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate/ hexanes), to give 4-bromo-N-(6-bromo-pyridin-3-yl)-3-fluoro-benzamide (610 mg, 74%) as a pale yellow solid.     B
Figure imgf000660_0001
[0728] Step 3: Synthesis of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl] -1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-bromo-N-(6-bromo-pyridin-3-yl)-3-fluoro-benzamide (610 mg, 1.63 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylic acid tert-butyl ester (1219 mg, 3.93 mmol), Pd(OAc)2 (32 mg, 0.15 mmol), and 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (142 mg, 0.35 mmol), to give 5-[4-(1-tert-butoxy carbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-3',6'-dihydro-2'H-[2,4']bipyridinyl- 1'-carboxylic acid tert-butyl ester (644 mg, 68%) as a yellow solid.
Figure imgf000660_0002
[0729] Step 4: Synthesis of 3-fluoro-N-(1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide: A solution of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzoylamino]-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (644 mg, 1.11 mmol) in CH2Cl2 (5.2 mL) and methanol (2.5 mL) was treated with a 4N solution of HCl in 1,4-dioxane (4.8 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-(1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide as the tris-HCl salt (548 mg, >100%) as a pale yellow solid, that was used without further purification.    
Figure imgf000661_0002
[0730] Step 5: Synthesis of give [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro- 2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4- {[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N-(1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide .3 HCl (146 mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis- Boc-guanylpyrazole (294 mg, 0.95 mmol), to give [(4-{4-[1'-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-ylcarbamoyl]-2-fluoro-phenyl} -3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (69 mg, 27%) as a yellow solid.
Figure imgf000661_0001
[0731] Step 6: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using [(4- {4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1',2',3',6'-tetrahydro-     [2,4']bipyridinyl-5-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (69 mg, 0.080 mmol), and trifluoroacetic acid (1 mL), to give N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (36 mg, 56%) as a white solid. MS: 463 M+H+: 1H NMR (300 MHz, dmso) δ 10.44-10.62 (m, 1H), 8.83-8.98 (m, 1H), 8.12-8.27 (m, 1H), 7.76-8.00 (m, 3H), 7.34-7.73 (m, 11H), 6.58-6.75 (m, 1H), 6.09-6.25 (m, 1H), 3.99-4.24 (m, 4H), 3.62 (d, J=3.52 Hz, 4H), 2.82-2.91 (m, 1H), 2.64-2.76 (m, 4H), 2.56-2.63 (m, 2H). [0732] Example 147: Synthesis of N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-methoxy- phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide:
Figure imgf000662_0001
[0733] Step 1: Synthesis of 4-(2-methoxy-4-nitro-phenyl)-piperazine-1-carboxylic acid tert- butyl ester: A mixture of 1-fluoro-2-methoxy-4-nitro-benzene (551 mg, 3.22 mmol), piperazine-1- carboxylic acid tert-butyl ester (630 mg, 3.38 mmol), and diisopropylethylamine (563 mg, 782 ^L, 4.39 mmol) in N,N-dimethylacetamide (4 mL) was heated at 125 oC for 20 hours. The reaction was allowed to cool to 20 oC, then was treated with water (40 mL). The mixture was sonicated for 5 minutes, then was extracted with ethyl acetae (2 x 40 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate/ hexanes), to give 4-(2-methoxy-4-nitro-phenyl)-piperazine-1- carboxylic acid tert-butyl ester (891 mg, 82%) as a yellow solid.
Figure imgf000662_0002
[0734] Step 2: Synthesis of 4-(2-methoxy-4-nitro-phenyl)-piperazine-1-carboxylic acid tert- butyl ester: To a mixture of 4-(2-methoxy-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg, 2.64 mmol) in tetrahydrofuran (4.6 mL) and methanol (5.9 mL) was added ammonium chloride (643 mg, 12.01 mmol), and acetic acid (104 mg, 100 ^L, 1.74 mmoL), followed by slow portionwise addition of zinc (766 mg, 11.83 mmol). The reaction was stirred for 16 hours, then was     filtered through Celite. The Celite pad was washed with ethyl acetate (30 mL). The combined organic filtrates were concentrated, then the residue was partitioned between ethyl acetate (40 mL), and water (20 mL). The organic layer was washed with water (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-75% ethyl acetate/ hexanes), to give 4-(4-amino-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (520 mg, 64%) as a dark solid.
Figure imgf000663_0001
[0735] Step 3: Synthesis of 4-[4-(4-bromo-benzoylamino)-2-methoxy-phenyl]-piperazine-1- carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4- bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (396 mg, 1.80 mmol), 4-(4-amino-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (480 mg, 1.56 mmol), and diisopropylethylamine (317 mg, 426 ^L, 2.46 mmol), to give 4-[4-(4-bromo- benzoylamino)-2-methoxy-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (796 mg, >100%) as a white solid, that was used without further purification.
Figure imgf000663_0002
[0736] Step 3: Synthesis of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)- benzoylamino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6-tetrahydro pyridine-1-carboxylate using 4-[4-(4-bromo-benzoylamino)-2-methoxy-phenyl]-piperazine-1- carboxylic acid tert-butyl ester (796 mg, 1.63 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (597 mg, 1.90 mmol), Pd(OAc)2 (18 mg, 0.080 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (70 mg, 0.18 mmol), to give 4-     {4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzoylamino]-2-methoxy-phenyl}- piperazine-1-carboxylic acid tert-butyl ester (749 mg, 78%) as a beige solid.
Figure imgf000664_0001
[0737] Step 4: Synthesis of N-(3-methoxy-4-piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 4-{4-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4- yl)-benzoylamino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (749 mg, 1.26 mmol) in CH2Cl2 (5.1 mL) and methanol (2.6 mL) was treated with a 4N solution of HCl in 1,4-dioxane (4.3 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-(3-methoxy-4- piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (673 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000664_0002
[0738] Step 5: Synthesis of give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-3-methoxy-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using N-(3-methoxy-4- piperazin-1-yl-phenyl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 3 HCl (151mg, 0.30 mmol), triethylamine (241 mg, 330 ^L, 2.36 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{4-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-     methoxy-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino- methyl}-carbamic acid tert-butyl ester (133 mg, 51%) as a beige solid.
Figure imgf000665_0001
[0739] Step 6: Synthesis of give N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-methoxy-phenyl]- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a mixture of {[4-(4-{4-[4-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-3-methoxy- phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (133 mg, 0.15 mmol) in CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with dimethylformamide (1 mL), followed by dropwise addition of 0.1% TFA in water (1 mL). The mixture was sonicated for 5 minutes, then was purified by preparative-HPLC, to give N-[4-(4-carbamimidoyl- piperazin-1-yl)-3-methoxy-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-TFA salt (88 mg, 72%) as a white solid. MS: 477 M+H+: 1H NMR (300 MHz, dmso) δ 10.06-10.19 (m, 1H), 7.95 (d, J=8.20 Hz, 2H), 7.61 (d, J=8.79 Hz, 2H), 7.49 (d, J=1.76 Hz, 9H), 7.35 (dd, J=2.05, 8.49 Hz, 1H), 6.88 (d, J=8.79 Hz, 1H), 6.36 (br. s., 1H), 4.11 (d, J=1.76 Hz, 2H), 3.64 (t, J=5.57 Hz, 2H), 3.54 (br. s., 4H), 2.98 (br. s., 4H), 2.63 (br. s., 2H). [0740] Example 148: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-2-methyl-phenyl]-3-fluoro-benzamide: F Br
Figure imgf000665_0002
[0741] Step 1: Synthesis of 4‐bromo‐N‐(4‐bromo‐3‐chloro‐2‐methyl‐phenyl)‐3‐fluoro‐ benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-     trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride , 4-bromo-3- chloro-2-methyl-phenylamine (243 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4‐bromo‐N‐(4‐bromo‐3‐chloro‐2‐methyl‐phenyl)‐3‐fluoro‐benzamide (407 mg, 88%) as a beige solid.
Figure imgf000666_0001
[0742] Step 2: Synthesis of tert‐butyl  4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-chloro-3-methylphenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compound was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3- (trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3- chloro‐2‐methyl‐phenyl)‐3‐fluoro‐benzamide (407 mg, 0.97 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (722 mg, 2.33 mmol), Pd(OAc)2 (19 mg, 0.089 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (84 mg, 0.21 mmol), to give tert‐butyl 4‐[4‐(4‐{1‐[(tert‐butoxy)carbonyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}‐ 3‐fluorobenzamido)‐2‐chloro‐3‐methylphenyl]‐1,2,3,6‐tetrahydropyridine‐1‐carboxylate (560 mg, 92%) (80% purity by LCMS) as a pale yellow solid, that was used without further purification.
Figure imgf000666_0002
[0743] Step 3: Synthesis of N‐[3‐chloro‐2‐methyl‐4‐(1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐phenyl]‐ 3‐fluoro‐4‐(1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐benzamide: A solution of tert‐butyl  4‐[4‐(4‐{1‐[(tert‐ butoxy)carbonyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}‐3‐fluorobenzamido)‐2‐chloro‐3‐methylphenyl]‐     1,2,3,6‐tetrahydropyridine‐1‐carboxylate (560 mg, 0.89 mmol) in CH2Cl2 (3.6 mL) and methanol (1.8 mL) was treated with a 4N solution of HCl in 1,4-dioxane (2.0 mL). The reaction was stirred for 16 hours, then was concentrated, to give N‐[3‐chloro‐2‐methyl‐4‐(1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐ phenyl]‐3‐fluoro‐4‐(1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐benzamide as the bis-HCl salt (436 mg, 98%) (80% purity by LCMS) as a pale orange solid.
Figure imgf000667_0001
[0744] Step 4: Synthesis of tert‐butyl N‐[(1E)‐{[(tert‐butoxy)carbonyl]amino}({4‐[4‐(4‐{1‐[(1E)‐ {[(tert‐butoxy)carbonyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐ yl}‐3‐fluorobenzamido)‐2‐chloro‐3‐methylphenyl]‐1,2,3,6‐tetrahydropyridin‐1‐ yl})methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl] imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene] carbamate using N‐[3‐chloro‐2‐methyl‐4‐(1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐phenyl]‐ 3‐fluoro‐4‐(1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐benzamide. 2 HCl (150mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give tert‐ butyl  N‐[(1E)‐{[(tert‐butoxy)carbonyl]amino}({4‐[4‐(4‐{1‐[(1E)‐{[(tert‐butoxy)carbonyl]amino}({[(tert‐ butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}‐3‐fluorobenzamido)‐2‐chloro‐3‐ methylphenyl]‐1,2,3,6‐tetrahydropyridin‐1‐yl})methylidene]carbamate (133 mg, 49%) as a clear film. B
Figure imgf000667_0002
    [0745] Step 5: Synthesis of 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐N‐[4‐(1‐ carbamimidoyl‐1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐3‐chloro‐2‐methyl‐phenyl]‐3‐fluoro‐benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using tert‐butyl  N‐[(1E)‐{[(tert‐butoxy)carbonyl]amino}({4‐[4‐(4‐{1‐[(1E)‐{[(tert‐ butoxy)carbonyl]amino}({[(tert‐butoxy)carbonyl]imino})methyl]‐1,2,3,6‐tetrahydropyridin‐4‐yl}‐3‐ fluorobenzamido)‐2‐chloro‐3‐methylphenyl]‐1,2,3,6‐tetrahydropyridin‐1‐yl})methylidene]carbamate (133 mg, 0.15 mmol), and TFA (1.5 mL), to give 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydro‐pyridin‐4‐yl)‐3‐chloro‐2‐methyl‐phenyl]‐3‐fluoro‐ benzamide as the bis-TFA salt (29 mg, 26%) as an off-white solid. MS: 492 M+H+: 1H NMR (300 MHz, dmso) δ 10.15-10.28 (m, 1H), 7.93 (s, 1H), 7.73-7.87 (m, 2H), 7.52-7.64 (m, 2H), 7.37-7.52 (m, 9H), 7.25-7.37 (m, 2H), 7.08-7.22 (m, 1H), 6.12-6.22 (m, 1H), 5.67-5.80 (m, 1H), 3.97-4.16 (m, 4H), 3.56-3.68 (m, 4H), 2.55-2.63 (m, 2H), 2.24 (s, 3H). [0746] Example 149: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-2-fluoro-phenyl]-3-fluoro-benzamide:
Figure imgf000668_0001
[0747] Step 1: Synthesis of 4-bromo-N-(4-bromo-3-chloro-2-fluoro-phenyl)-3-fluoro- benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-bromo-3- chloro-2-fluoro-phenylamine (247 mg, 1.10 mmol), and diisopropylethylamine (223 mg, 300 ^L, 1.73 mmol), to give 4-bromo-N-(4-bromo-3-chloro-2-fluoro-phenyl)-3-fluoro-benzamide (316 mg, 68%) as a white solid.
Figure imgf000668_0002
    [0748] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorobenzamido)-2-chloro-3-fluorophenyl]-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-3-chloro-2- fluoro-phenyl)-3-fluoro-benzamide (316 mg, 0.74 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (551 mg, 1.80 mmol), Pd(OAc)2 (14 mg, 0.066 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (62 mg, 0.15 mmol), to give tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido) -2- chloro-3-fluorophenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (280 mg, 60%) (75% purity by LCMS) as a white solid, that was used without further purification.
Figure imgf000669_0001
[0749] Step 3: Synthesis of N-[3-chloro-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: A solution of tert-butyl 4-[4-(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2-chloro-3-fluorophenyl]- 1,2,3,6-tetrahydropyridine-1-carboxylate (280 mg, 0.44 mmol) in CH2Cl2 (1.8 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 3 days, then was concentrated, to give N-[3-chloro-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (277 mg, >100%) (75% purity by LCMS) as a yellow solid, that was used without further purification. H
Figure imgf000669_0002
    [0750] Step 4: Synthesis of tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1- [(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4-yl}-3-fluorobenzamido)-2-chloro-3-fluorophenyl]-1,2,3,6-tetrahydropyridin-1- yl})methylidene]carbamate: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert- butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin- 1-yl]methylidene]carbamate using N-[3-chloro-2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]- 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide. 2 HCl (277mg, 0.55 mmol), triethylamine (386 mg, 529 ^L, 3.78 mmol), and N,N’-bis-Boc-guanylpyrazole (540 mg, 1.75 mmol), to give tert- butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1E)-{[(tert-butoxy)carbonyl]amino} ({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzamido)-2- chloro-3-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (298 mg, 59%) (75% purity by LCMS) as a white solid, that was used without further purification.
Figure imgf000670_0001
[0751] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-2-fluoro-phenyl]-3-fluoro-benzamide: To a mixture of tert-butyl N-[(1E)-{[(tert-butoxy)carbonyl]amino}({4-[4-(4-{1-[(1E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-3- fluorobenzamido)-2-chloro-3-fluorophenyl]-1,2,3,6-tetrahydropyridin-1-yl})methylidene]carbamate (298 mg, 0.33 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred for 3 days, then was concentrated. The crude material was treated with DMS (2 mL), followed by dropwise addition of 0.1% TFA in water (2 mL). The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL). The solid was treated with methanol (10 mL), then the mixture was heated to boiling, then was filtered hot. The solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-     pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-2-fluoro-phenyl]-3- fluoro-benzamide as the bis-TFA salt (79 mg, 32%) as a white solid. MS: 514 M+H+: 1H NMR (300 MHz, dmso) δ 10.26-10.39 (m, 1H), 7.67-7.83 (m, 3H), 7.36-7.61 (m, 14H), 7.11 (d, J=8.20 Hz, 1H), 6.02-6.17 (m, 1H), 5.72-5.86 (m, 1H), 4.14-4.33 (m, 2H), 3.94-4.10 (m, 6H), 3.62-3.75 (m, 2H), 3.15- 3.32 (m, 4H), 2.51 (d, J=1.17 Hz, 3H). [0752] Example 150: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-3-fluoro-benzamide:
Figure imgf000671_0001
[0753] Step 1: Synthesis of 4-bromo-N-(6-bromo-pyridazin-3-yl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 6-bromo-pyridazin-3-ylamine (383 mg, 2.20 mmol), and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol), to give 4-bromo-N- (6-bromo-pyridazin-3-yl)-3-fluoro-benzamide (569 mg, 69%) as a beige solid.
Figure imgf000671_0002
[0754] Step 2: Synthesis of tert-butyl 4-{4-[(6-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}pyridazin-3-yl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(6-bromo-pyridazin-3-yl) -3-fluoro-benzamide (569 mg, 1.52 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1129 mg, 3.69 mmol), Pd(OAc)2 (28 mg, 0.14 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (126 mg, 0.32 mmol), to give tert-butyl 4-{4-[(6-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}pyridazin-3-yl)carbamoyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (150 mg, 17%) as a pale yellow solid.    
Figure imgf000672_0001
[0755] Step 3: Synthesis of 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1,2,3,6- tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-benzamide: A solution of tert-butyl 4-{4-[(6-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}pyridazin-3-yl)carbamoyl]-2-fluorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (274 mg, 0.47 mmol) in CH2Cl2 (1.8 mL) and methanol (1 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1,2,3,6-tetrahydro- pyridin-4-yl)-pyridazin-3-yl]-benzamide as the tris-HCl salt (330 mg, >100%) as a pale orange solid, that was used without further purification.
Figure imgf000672_0002
[0756] Step 4: Synthesis of give {[4-(4-{6-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-pyridazin-3-ylcarbamoyl}-2-fluoro-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]- benzamide . 3 HCl (323mg, 0.71 mmol), triethylamine (499 mg, 685 ^L, 4.90 mmol), and N,N’-bis- Boc-guanylpyrazole (699 mg, 2.26 mmol), to give {[4-(4-{6-[1-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-pyridazin-3-ylcarbamoyl}-2-fluoro-     phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (134 mg, 22%) as a white solid.
Figure imgf000673_0001
[0757] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{6-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-pyridazin-3-ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (134 mg, 0.16 mmol), and trifluoroacetic acid (1.6 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyridazin-3-yl]-3-fluoro-benzamide as the tris-TFA salt (93 mg, 84%) as a pale orange solid. MS: 464 M+H+: 1H NMR (300 MHz, dmso) δ 11.41-11.56 (m, 1H), 8.20-8.32 (m, 1H), 7.97 (d, J=9.96 Hz, 1H), 7.83 (d, J=9.37 Hz, 3H), 7.29-7.55 (m, 10H), 6.66 (br. s., 1H), 6.00-6.17 (m, 1H), 4.08 (br. s., 2H), 4.01 (br. s., 2H), 3.54 (td, J=5.49, 10.69 Hz, 5H), 2.71 (d, J=2.34 Hz, 2H), 2.51 (d, J=4.69 Hz, 2H). [0758] Example 151: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-3-fluoro-benzamide:
Figure imgf000673_0002
[0759] Step 1: Synthesis of 4-bromo-3-fluoro-benzoyl chloride: To a mixture of 4-bromo-3- fluoro-benzoic acid (556 mg, 2.54 mmol) in CHCl3 (14 mL) and dimethylformamide (5 drops), was added dropwise oxalyl chloride (518 mg, 348 ^L, 4.06 mmol). The reaction was stirred at 20 oC for 2     hours, then was concentrated. The residue was treated with CHCl3 (30 mL), then was concentrated, to give 4-bromo-3-fluoro-benzoyl chloride, which was used without further purification.
Figure imgf000674_0001
[0760] Step 2: Synthesis of 4-bromo-N-(5-bromo-pyrazin-2-yl)-3-fluoro-benzamide: To a mixture of 5-bromo-pyrazin-2-ylamine (383 mg, 2.20 mmol), in pyridine (2 mL) was added dropwise a mixture of 4-bromo-3-fluoro-benzoyl chloride in pyridine (2 mL). The reaction was stirred at 20oC for 3 days, then was concentrated. The residue was treated with ethyl acetate (80 mL) and 1N HCl (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate/ hexanes), to give 4-bromo-N-(5-bromo-pyrazin-2-yl)-3-fluoro-benzamide (467 mg, 57%) as a beige solid.
Figure imgf000674_0002
[0761] Step 3: Synthesis of give tert-butyl 4-{4-[(5-{1-[(tert-butoxy)carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}pyrazin-2-yl)carbamoyl]-2-fluorophenyl}-1,2,3,6-tetrahydropyridine-1- carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoro methyl)phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(5-bromo-pyrazin-2-yl)- 3-fluoro-benzamide (651 mg, 1.74 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1289 mg, 4.21 mmol), Pd(OAc)2 (32 mg, 0.16 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (144 mg, 0.37 mmol), to give tert-butyl 4-{4-[(5-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}pyrazin-2-yl)carbamoyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate (554 mg, 55%) as a pale yellow solid.    
Figure imgf000675_0001
[0762] Step 4: Synthesis of 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1,2,3,6- tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-benzamide: A solution of tert-butyl 4-{4-[(5-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}pyrazin-2-yl)carbamoyl]-2-fluorophenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate (554 mg, 0.96 mmol) in CH2Cl2 (3.7 mL) and methanol (2 mL) was treated with a 4N solution of HCl in 1,4-dioxane (3.1 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1,2,3,6-tetrahydro- pyridin-4-yl)-pyrazin-2-yl]-benzamide as the tris-HCl salt (469 mg, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000675_0002
[0763] Step 5: Synthesis of {[4-(4-{5-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-pyrazin-2-ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro -2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl] imino})methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene] carbamate using 3-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1,2,3,6-tetrahydro-pyridin-4-yl)- pyrazin-2-yl]-benzamide . 3 HCl (136mg, 0.30 mmol), triethylamine (210 mg, 288 ^L, 2.06 mmol), and N,N’-bis-Boc-guanylpyrazole (294 mg, 0.95 mmol), to give {[4-(4-{5-[1-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-pyrazin-2-     ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (157 mg, 61%) as a pale yellow solid.
Figure imgf000676_0001
[0764] Step 6: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{5-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-pyrazin-2-ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (157 mg, 0.16 mmol), and trifluoroacetic acid (1.8 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-3-fluoro-benzamide as the tris-TFA salt (91 mg, 63%) as a pale pink solid. MS: 464 M+H+: 1H NMR (300 MHz, dmso) δ 11.09-11.22 (m, 1H), 9.25 (s, 1H), 8.58-8.70 (m, 1H), 7.74-7.87 (m, 3H), 7.27-7.52 (m, 10H), 6.63-6.77 (m, 1H), 6.00-6.16 (m, 1H), 3.97- 4.13 (m, 4H), 3.49-3.58 (m, 4H), 2.47-2.54 (m, 2H). [0765] Example 152: Synthesis of N-(1'-carbamimidoyl-4-methoxy-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000676_0002
[0766] Step 1: Synthesis of 4-bromo-3-fluoro-benzoyl chloride: To a mixture of 4-bromo-3- fluoro-benzoic acid (556 mg, 2.54 mmol) in CHCl3 (14 mL) and dimethylformamide (5 drops), was added dropwise oxalyl chloride (518 mg, 348 ^L, 4.06 mmol). The reaction was stirred for 2 hours, then was concentrated. The residue was treated with CHCl3 (30 mL), then was concentrated, to give 4-bromo-3-fluoro-benzoyl chloride, which was used without further purification.    
Figure imgf000677_0001
[0767] Step 2: Synthesis of 4-bromo-N-(5-bromo-4-methoxy-pyridin-2-yl)-3-fluoro- benzamide: To a mixture of 5-bromo-4-methoxy-pyridin-2-ylamine (447 mg, 2.20 mmol), and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol) in CHCl3 (6 mL) was added a solution of 4- bromo-3-fluoro-benzoyl chloride in CHCl3 (6 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with ethyl acetate (80 mL), then was washed with saturated aqueous NaHCO3 (10 mL), and brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (5-15% ethyl acetate/ hexanes), to give 4-bromo-N-(5-bromo-4- methoxy-pyridin-2-yl)-3-fluoro-benzamide (257 mg, 9%) as a white solid.
Figure imgf000677_0002
[0768] Step 3: Synthesis of -[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-4-methoxy-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(5-bromo-4-methoxy-pyridin-2- yl)-3-fluoro-benzamide (257 mg, 0.64 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (474 mg, 1.55 mmol), Pd(OAc)2 (12 mg, 0.059 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (53 mg, 0.14 mmol), to give 6-[4-(1- tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-4-methoxy-3',6'- dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (73 mg, 19%) as a clear film.    
Figure imgf000678_0001
[0769] Step 4: Synthesis of 3-fluoro-N-(4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6- yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a solution of 6-[4-(1-tert-butoxycarbonyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-4-methoxy-3',6'-dihydro-2'H-[3,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester (210 mg, 0.35 mmol) in CH2Cl2 (1.3 mL) and methanol (0.7 mL) was added a 4N solution of HCl in 1,4-dioxane (1.1 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-(4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6- yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide (220 mg, >100%) as a beige solid, that was used without further purification.
Figure imgf000678_0002
[0770] Step 5: Synthesis of [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N-(4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-benzamide . 3 HCl (220mg, 0.43 mmol), triethylamine (341 mg, 467 ^L, 3.34 mmol), and N,N’- bis-Boc-guanylpyrazole (416 mg, 1.35 mmol), to give [(4-{4-[1'-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-     fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert- butyl ester (51 mg, 13%) as a white solid.
Figure imgf000679_0001
[0771] Step 6: Synthesis of N-(1'-carbamimidoyl-4-methoxy-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: To a mixture of [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-4-methoxy- 1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)- tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (51 mg,0.057 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with dimethylformamide (1 mL), followed by 0.1% TFA in water (1 mL) dropwise. The mixture was sonicated for 5 minutes, then was filtered. The solid was washed with isopropanol (2 mL), and hexanes (2 mL), to give N-(1'-carbamimidoyl-4-methoxy- 1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzamide as the tris-TFA salt (10 mg, 21%) as a pale pink solid. The original dimethylformamide/water filtrate was purified by preparative-HPLC, to give N-(1'-carbamimidoyl-4- methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-benzamide as the tris-TFA salt (26 mg, 55%) as a white solid. MS: 493 M+H+: 1H NMR (300 MHz, dmso) δ 10.71-10.89 (m, 1H), 7.90-8.00 (m, 1H), 7.69-7.86 (m, 4H), 7.19-7.50 (m, 10H), 6.00-6.10 (m, 1H), 5.74-5.86 (m, 1H), 3.88-4.01 (m, 4H), 3.74 (br. s., 3H), 3.41-3.53 (m, 4H), 2.43-2.49 (m, 2H). [0772] Example 153: Synthesis of N-[5-(4-carbamimidoyl-piperazin-1-yl)-pyridin-2-yl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:     F Br
Figure imgf000680_0001
[0773] Step 1: Synthesis of 4-[6-(4-bromo-3-fluoro-benzoylamino)-pyridin-3-yl]-piperazine- 1-carboxylic acid tert-butyl ester: The title compound was prepared according to the procedure of 4- bromo-N-(4-bromo-2-trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (612 mg, 2.20 mmol), and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol), to give 4-[6-(4-bromo-3-fluoro- benzoylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (406 mg, 39%) as a pale yellow solid.
Figure imgf000680_0002
[0774] Step 2: Synthesis of 4-{6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6- tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}-1,2,3,6- tetrahydropyridine-1-carboxylate using 4-[6-(4-bromo-3-fluoro-benzoylamino)-pyridin-3-yl]- piperazine-1-carboxylic acid tert-butyl ester (406 mg, 0.85 mmol), 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (312 mg, 0.99 mmol), Pd(OAc)2 (9 mg, 0.042 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (37 mg, 0.094 mmol), to give 4-{6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- benzoylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (143 mg, 29%) as a yellow solid.    
Figure imgf000681_0001
[0775] Step 3: Synthesis of 3-fluoro-N-(5-piperazin-1-yl-pyridin-2-yl)-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide: A solution of 4-{6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4- yl)-3-fluoro-benzoylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (195 mg, 0.34 mmol) in CH2Cl2 (1.3 mL) and methanol (0.7 mL) was treated with a 4N solution of HCl in 1,4-dioxane (1.1 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-(5-piperazin- 1-yl-pyridin-2-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tetra HCl salt (211 mg, >100%) as a yellow solid, that was used without further purification. H
Figure imgf000681_0002
[0776] Step 3: Synthesis of {[4-(4-{5-[4-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-piperazin-1-yl]-pyridin-2-ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1- yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[4-(4-{[4-(2-{[(1E)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N- (5-piperazin-1-yl-pyridin-2-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide . 4 HCl (211mg, 0.40 mmol), triethylamine (455 mg, 623 ^L, 4.45 mmol), and N,N’-bis-Boc-guanylpyrazole (387 mg, 1.26 mmol), to give {[4-(4-{5-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin- 1-yl]-pyridin-2-ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonyl imino-methyl}-carbamic acid tert-butyl ester (103 mg, 30%) as a pale yellow solid.    
Figure imgf000682_0001
[0777] Step 4: Synthesis of N-[5-(4-carbamimidoyl-piperazin-1-yl)-pyridin-2-yl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using {[4- (4-{5-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-pyridin-2- ylcarbamoyl}-2-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (103 mg, 0.12 mmol), and TFA (1.2 mL), to give N-[5-(4-carbamimidoyl- piperazin-1-yl)-pyridin-2-yl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- benzamide as the tetra-TFA salt (75 mg, 68%) as a pale yellow solid. [0778] Example 154: Synthesis of N-(1'-carbamimidoyl-2-methoxy-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000682_0002
[0779] Step 1: Synthesis of 4-bromo-N-(5-bromo-pyridin-2-yl)-3-fluoro-benzamide: To a mixture of 4-bromo-3-fluoro-benzoic acid (1487 mg, 6.79 mmol), 5-bromo-6-methoxy-pyridin-2-yl amine (919 mg, 4.53 mmol), and triethylamine (1449 mg, 1714 ^L, 12.24 mmol) in N,N- dimethylformamide (12 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxid hexafluorophosphate (2318 mg, 6.12 mmol). The reaction was stirred for 16 hours, then was treated with water (180 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 brine (10 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-15% ethyl acetate/ hexanes), to give 4-bromo-N-(5-bromo-pyridin-2-yl)-3-fluoro-benzamide (595 mg, 33%) as a pale yellow solid.    
Figure imgf000683_0001
[0780] Step 2: Synthesis of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-2-methoxy-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: A mixture of 4-bromo-N-(5-bromo-pyridin-2-yl)-3-fluoro-benzamide (730 mg, 1.81 mmol), 4- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1338 mg, 4.38 mmol), Pd(OAc)2 (34 mg, 0.17 mmol), and 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (150 mg, 0.40 mmol) in 1,4-dioxane (19 mL) and 2M K2CO3 (7.6 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 oC for 16 hours. The reaction was treated with ethyl acetate (80 mL), then was washed with water (15 mL). The organic layer was filtered through Celite, then was washed with brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate/ hexanes), to give 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-2- methoxy-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (417 mg, 38%) as a pale yellow solid.
Figure imgf000683_0002
[0781] Step 3: Synthesis of 3-fluoro-N-(2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6- yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a solution of give 6-[4-(1-tert-butoxycarbonyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-2-methoxy-3',6'-dihydro-2'H-[3,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester (417 mg, 0.69 mmol) in CH2Cl2 (2.6 mL) and methanol (1.4 mL) was added a solution of HCl in 1,4-dioxane (2.2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-(2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (332 mg, 93%) as an orange solid.    
Figure imgf000684_0001
[0782] Step 4: Synthesis of [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 3-fluoro-N-(2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6-tetrahydro-pyridin-4- yl)-benzamide .3 HCl (220 mg, 0.43 mmol), triethylamine (341 mg, 467 ^L, 3.34 mmol), and N,N’- bis-Boc-guanylpyrazole (416 mg, 1.35 mmol), to give [(4-{4-[1'-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2- fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert- butyl ester (266 mg, 69%) as a white solid.
Figure imgf000684_0002
[0783] Step 5: Synthesis of N-(1'-carbamimidoyl-2-methoxy-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-2-     methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H- pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (266 mg, 0.30 mmol), and TFA (3 mL), to give N-(1'-carbamimidoyl-2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (154 mg, 62%) as a cream solid. [0784] Example 155: Synthesis of N-(1'-carbamimidoyl-5-methyl-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide:
Figure imgf000685_0001
[0785] Step 1: Synthesis of 4-bromo-N-(5-bromo-3-methyl-pyridin-2-yl)-3-fluoro-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2- trifluoromethyl-phenyl)-2-methyl-benzamide using 4-bromo-3-fluoro-benzoyl chloride, 5-bromo-3- methyl-pyridin-2-ylamine (411 mg, 2.20 mmol), and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol), to give 4-bromo-N-(5-bromo-3-methyl-pyridin-2-yl)-3-fluoro-benzamide (681 mg, 80%) as a white solid.
Figure imgf000685_0002
[0786] Step 2: Synthesis of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-benzoylamino]-5-methyl-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: A mixture of 4-bromo-N-(5-bromo-3-methyl-pyridin-2-yl)-3-fluoro-benzamide (760 mg, 1.96 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1297 mg, 4.25 mmol), Pd(OAc)2 (33 mg, 0.17 mmol), and 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (145 mg, 0.39 mmol) in 1,4-dioxane (6 mL) and 2M K2CO3 (3 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated in a sealed vessel at 120 oC for 2 hours. The reaction was treated with ethyl acetate (70 mL), and water (10 mL), then was     filtered through Celite. The organic layer was washed with brine (5 mL), dried (Na2SO4), and concentrated. The residue was treated with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (649 mg, 2.13 mmol), Pd(OAc)2 (17 mg, 0.09 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (73 mg, 0.20 mmol) in 1,4-dioxane (5 mL) and 2M K2CO3 (2.5 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated in a sealed vessel at 120 oC for 3 hours. The reaction was treated with ethyl acetate (70 mL), and water (10 mL), then was filtered through Celite. The organic layer was washed with brine (5 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate/ hexanes), to give 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-benzoylamino]-5-methyl-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert- butyl ester (202 mg, 17%) as a yellow solid.
Figure imgf000686_0001
[0787] Step 3: Synthesis of 3-fluoro-N-(5-methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a solution of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-fluoro-benzoylamino]-5-methyl-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'- carboxylic acid tert-butyl ester (202 mg, 0.34 mmol) in CH2Cl2 (2 mL) and methanol (1 mL) was added a 4N solution of HCl in 1,4-dioxane (1.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 3-fluoro-N-(5-methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the tris-HCl salt (204 mg, >100%) as a pale orange solid, that was used without further purification. H
Figure imgf000686_0002
    [0788] Step 4: Synthesis of give [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-5-methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6- dihydro-2H-pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene] carbamate using 3-fluoro-N-(5-methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide .3 HCl (200 mg, 0.40 mmol), triethylamine (316 mg, 433 ^L, 3.10 mmol), and N,N’-bis-Boc-guanylpyrazole (386 mg, 1.25 mmol), to give [(4-{4-[1'-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-5-methyl-1',2',3',6'-tetrahydro-[3,4'] bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert-butoxycarbonyl imino-methyl]-carbamic acid tert-butyl ester (140 mg, 40%) as a white solid.
Figure imgf000687_0001
[0789] Step 5: Synthesis of N-(1'-carbamimidoyl-5-methyl-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2- fluoro-benzamide using [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-5- methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-2-fluoro-phenyl}-3,6-dihydro-2H- pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (140 mg, 0.16 mmol), and trifluoroacetic acid (1.6 mL), to give N-(1'-carbamimidoyl-5-methyl-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide as the tris-TFA salt (96 mg, 73%) as a white solid. [0790] Example 156: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4- (1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-benzamide:    
Figure imgf000688_0001
[0791] Step 1: Synthesis of 4-bromo-N-(4-bromo-5-fluoro-2-methyl-phenyl)-benzamide: The title compound was prepared according to the procedure of 4-bromo-N-(4-bromo-2-trifluoromethyl- phenyl)-2-methyl-benzamide using 4-bromo-benzoyl chloride (558 mg, 2.54 mmol), 4-bromo-5- fluoro-2-methyl-phenylamine (449 mg, 2.20 mmol), and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol), to give 4-bromo-N-(4-bromo-5-fluoro-2-methyl-phenyl)-benzamide (646 mg, 76%) as a beige solid.
Figure imgf000688_0002
[0792] Step 2: Synthesis of tert-butyl 4-[4-(4-{1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydro pyridin-4-yl}benzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(4-bromo-5-fluoro-2-methyl-phenyl)- benzamide (646 mg, 1.67 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (1231 mg, 4.03 mmol), Pd(OAc)2 (31 mg, 0.16 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (130 mg, 0.37 mmol), to give tert-butyl 4-[4-(4-{1- [(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}benzamido)-2-fluoro-5-methylphenyl]-1,2,3,6- tetrahydropyridine-1-carboxylate (962 mg, 97%) as a pale yellow solid. B
Figure imgf000688_0003
    [0793] Step 3: Synthesis of N-[5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl] -4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a solution of tert-butyl 4-[4-(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}benzamido)-2-fluoro-5-methylphenyl]-1,2,3,6-tetrahydro pyridine-1-carboxylate (962 mg, 1.63 mmol) in CH2Cl2 (9.6 mL) and methanol (4.8 mL) was added a 4N solution of HCl in 1,4-dioxane (7.2 mL). The reaction was stirred for 16 hours, then was concentrated, to give N-[5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide as the bis-HCl salt (741 mg, 98%) as a pale yellow solid.
Figure imgf000689_0001
[0794] Step 4: Synthesis of {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl-phenylcarbamoyl}-phenyl)-3,6- dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy) carbonyl]amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino}) methyl]amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene] carbamate using N-[5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide .2 HCl (153 mg, 0.33 mmol), triethylamine (233 mg, 320 ^L, 2.29 mmol), and N,N’-bis-Boc-guanylpyrazole (326 mg, 1.05 mmol), to give {[4-(4-{4-[1-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2- methyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-tert-butoxycarbonylimino-methyl}- carbamic acid tert-butyl ester (182 mg, 63%) as a clear film.    
Figure imgf000690_0002
[0795] Step 5: Synthesis of 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro- benzamide using {[4-(4-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1,2,3,6- tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl-phenylcarbamoyl}-phenyl)-3,6-dihydro-2H-pyridin-1-yl]- tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (182 mg, 0.21 mmol), and trifluoroacetic acid (2 mL), to give 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-benzamide as the bis-TFA salt (104 mg, 70%) as a beige solid. [0796] Example 157: Synthesis of 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]- amide:
Figure imgf000690_0001
[0797] Step 1: Synthesis of 6-bromo-N-(4-bromo-5-fluoro-2-methyl-phenyl)-nicotinamide: To a mixture of 6-bromo-nicotinic acid (49 mg, 2.22 mmol), 4-bromo-5-fluoro-2-methyl-phenylamine (453 mg, 2.22 mmol), and diisopropylethylamine (446 mg, 600 ^L, 3.46 mmol) in N,N- dimethylformamide (8 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1258 mg, 3.33 mmol). The reaction was stirred for 16 hours, then was treated with water (120 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 NaHCO3     (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-30% ethyl acetate/ hexanes), to give 6-bromo-N-(4-bromo-5-fluoro-2-methyl- phenyl)-nicotinamide (333 mg, 39%) as a pale yellow solid.
Figure imgf000691_0001
[0798] Step 2: Synthesis of 5-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5- fluoro-2-methyl-phenylcarbamoyl]-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl) phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 6-bromo-N-(4-bromo-5-fluoro-2-methyl- phenyl)-nicotinamide (329 mg, 0.85 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (625 mg, 2.05 mmol), Pd(OAc)2 (16 mg, 0.081 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (70 mg, 0.19 mmol), to give 5-[4-(1- tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenylcarbamoyl]-3',6'- dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (270 mg, 54%) as a white solid.
Figure imgf000691_0002
[0799] Step 3: Synthesis of 1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-carboxylic acid [5-fluoro- 2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide: To a solution of 5-[4-(1-tert-butoxy carbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenylcarbamoyl]-3',6'-dihydro-2'H- [2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (270 mg, 0.46 mmol) in CH2Cl2 (2.7 mL) and methanol (1.3 mL) was added a 4N solution of HCl in 1,4-dioxane (2 mL). The reaction was stirred for 16 hours, then was concentrated, to give 1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-carboxylic acid [5- fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the tris-HCl salt (292 mg, >100%) as a pale orange solid, that was used without further purification.    
Figure imgf000692_0001
[0800] Step 4: Synthesis of [(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl-phenylcarbamoyl}-3',6'-dihydro-2'H- [2,4']bipyridinyl-1'-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl] amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-carboxylic acid [5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-amide .3 HCl (292 mg, 0.58 mmol), triethylamine (467 mg, 640 ^L, 4.58 mmol), and N,N’-bis-Boc-guanylpyrazole (570 mg, 1.84 mmol), to give [(5-{4-[1-(tert-butoxy carbonylamino- tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl - phenylcarbamoyl}-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-yl)-tert-butoxycarbonylimino-methyl]- carbamic acid tert-butyl ester (118 mg, 23%) as a clear film.
Figure imgf000692_0002
[0801] Step 5: Synthesis of 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]- amide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- phenyl]-2-fluoro-benzamide using [(5-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-     methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl-phenylcarbamoyl}-3',6'-dihydro-2'H- [2,4']bipyridinyl-1'-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (118 mg, 0.14 mmol), and trifluoroacetic acid (1.4 mL), to give 1'-carbamimidoyl-1',2',3',6'-tetrahydro- [2,4']bipyridinyl-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2- methyl-phenyl]-amide as the tris-TFA salt (60 mg, 61%) as a beige solid. [0802] Example 158: Synthesis of 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]- amide:
Figure imgf000693_0001
[0803] Step 1: Synthesis of 5-bromo-pyridine-2-carboxylic acid (4-bromo-5-fluoro-2-methyl- phenyl)-amide: To a mixture of 5-bromo-pyridine-2-carboxylic acid (50 mg, 2.72 mmol), 4-bromo-5- fluoro-2-methyl-phenylamine (529 mg, 2.59 mmol), and diisopropylethylamine (546 mg, 734 ^L, 4.24 mmol) in N,N-dimethylformamide (10 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1540 mg, 4.08 mmol). The reaction was stirred for 16 hours, then was treated with water (150 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 25 mL), saturated aqueous NaHCO3 (15 mL), and brine (10 mL), dried (Na2SO4), and concentrated, to give 5-bromo-pyridine-2- carboxylic acid (4-bromo-5-fluoro-2-methyl-phenyl)-amide (1.04 g, >100%) as a pale yellow solid, that was used without further purification.
Figure imgf000693_0002
[0804] Step 2: Synthesis of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5- fluoro-2-methyl-phenylcarbamoyl]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert- butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)     phenyl}-1,2,3,6-tetrahydropyridine-1-carboxylate using 5-bromo-pyridine-2-carboxylic acid (4- bromo-5-fluoro-2-methyl-phenyl)-amide (967 mg, 2.50 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1837 mg, 6.03 mmol), Pd(OAc)2 (47 mg, 0.24 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (206 mg, 0.56 mmol), to give 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl- phenylcarbamoyl]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (347 mg, 36%) as a white solid.
Figure imgf000694_0001
[0805] Step 3: Synthesis of 1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-carboxylic acid [5-fluoro- 2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide: To a solution of 6-[4-(1-tert-butoxy carbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenylcarbamoyl]-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (337 mg, 0.57 mmol) in CH2Cl2 (3.3 mL) and methanol (1.6 mL) was added a 4N solution of HCl in 1,4-dioxane (2.5 mL). The reaction was stirred for 16 hours, then was concentrated, to give 1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-carboxylic acid [5- fluoro-2-methyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide as the tris-HCl salt (351 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000694_0002
[0806] Step 4: Synthesis of [(6-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl-phenylcarbamoyl}-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: The title compound was prepared according to the procedure of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]     amino}[4-(4-{[4-(2-{[(1E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] amino}ethyl)phenyl] carbamoyl}phenyl)-1,2,3,6-tetrahydropyridin-1-yl]methylidene]carbamate using 1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-carboxylic acid [5-fluoro-2-methyl-4-(1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-amide .3 HCl (345 mg, 0.69 mmol), triethylamine (553 mg, 759 ^L, 5.43 mmol), and N,N’-bis-Boc-guanylpyrazole (676 mg, 2.18 mmol), to give [(6-{4-[1-(tert-butoxy carbonylamino- tert-butoxycarbonylimino-methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl - phenylcarbamoyl}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-yl)-tert-butoxycarbonylimino-methyl]- carbamic acid tert-butyl ester (227 mg, 38%) as a clear film.
Figure imgf000695_0001
[0807] Step 5: Synthesis of 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6- carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]- amide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro- phenyl]-2-fluoro-benzamide using [(6-{4-[1-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-5-fluoro-2-methyl-phenylcarbamoyl}-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (227 mg, 0.26 mmol), and trifluoroacetic acid (2.6 mL), to give 1'-carbamimidoyl-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2- methyl-phenyl]-amide as the tris-TFA salt (99 mg, 47%) as an off-white solid. [0808] Example 159: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl- 6-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-benzamide
Figure imgf000695_0002
    [0809] Step 1: Synthesis of 4-bromo-N-(5-bromo-pyridin-2-yl)-2-methoxy-benzamide: To a mixture of 4-bromo-2-methoxy-benzoic acid (739 mg, 3.20 mmol), 5-bromo-pyridin-2-ylamine (504 mg, 2.91 mmol), and diisopropylethylamine (1.01 g, 1.36 mL, 7.85 mmol) in N,N-dimethyl formamide (6 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (2.20 g, 5.81 mmol). The reaction was heated at 60 oC for 16 hours. The reaction was treated with water (90 mL), then was extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with water (2 x 20 mL), and brine (10 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-40% ethyl acetate/ hexanes), to give 4-bromo-N-(5-bromo-pyridin-2-yl)-2-methoxy-benzamide (681 mg, 61%) as a white solid.
Figure imgf000696_0001
[0810] Step 2: Synthesis of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2- methoxy-benzoylamino]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester: The title compounds was prepared according to the procedure of tert-butyl 4-{4-[(4-{1-[(tert-butoxy) carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-3-methylphenyl)carbamoyl]-3-(trifluoromethyl)phenyl}- 1,2,3,6-tetrahydropyridine-1-carboxylate using 4-bromo-N-(5-bromo-pyridin-2-yl)-2-methoxy- benzamide (681 mg, 1.76 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester (1289 mg, 4.23 mmol), Pd(OAc)2 (33 mg, 0.17 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (145 mg, 0.40 mmol), to give 6-[4-(1-tert-butoxy carbonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-benzoylamino]-3',6'-dihydro-2'H-[3,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester (820 mg, 79%) as a white solid.
Figure imgf000696_0002
    [0811] Step 3: Synthesis of 2-methoxy-N-(1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4- (1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide: To a solution of 6-[4-(1-tert-butoxycarbonyl-1,2,3,6- tetrahydro-pyridin-4-yl)-2-methoxy-benzoylamino]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (820 mg, 1.39 mmol) in CH2Cl2 (8 mL) and methanol (4 mL) was added a 4N solution of HCl in 1,4-dioxane (6 mL). The reaction was stirred for 16 hours, then was concentrated, to give 2-methoxy-N-(1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide as the tris-HCL salt (773 mg, >100%) as a yellow solid, that was used without further purification.
Figure imgf000697_0001
[0812] Step 4: Synthesis of [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino- methyl)-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-3-methoxy-phenyl}-3,6-dihydro-2H- pyridin-1-yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester: A mixture of 2- methoxy-N-(1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)- benzamide .3 HCl (200 mg, 0.40 mmol) in CH2Cl2 (1.9 mL) and N, N-dimethylformamide (1.9 mL) was treated slowly with triethylamine (321 mg, 440 ^L, 3.15 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35 oC for 16 hours. The reaction was concentrated, then the residue was treated with water (25 mL), and ethyl acetate (40 mL). The mixture was filtered through Celite, then the solid was washed with ethyl acetate (20 mL). The combined organic filtrates were washed with water (2 x 10 mL), 10% aqueous citric acid (10 mL), and brine (10 mL). The combined aqueous washed were filtered through Celite, and the layers were separated. The combined organic layers were dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-100% ethyl acetate/ hexanes), to give [(4-{4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonyl imino-methyl)- 1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-ylcarbamoyl]-3-methoxy-phenyl}-3,6-dihydro -2H-pyridin-1- yl)-tert-butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (159 mg, 45%) as a white solid.    
Figure imgf000698_0001
[0813] Step 5: Synthesis of N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-benzamide: The title compound was prepared following the procedure to prepare 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N- [4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide using [(4- {4-[1'-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-1',2',3',6'-tetrahydro- [3,4']bipyridinyl-6-ylcarbamoyl]-3-methoxy-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-tert- butoxycarbonylimino-methyl]-carbamic acid tert-butyl ester (159 mg, 0.18 mmol), and trifluoroacetic acid (1.8 mL), to give N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1- carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methoxy-benzamide as the tris-TFA salt (66 mg, 45%) as a pale pink solid. [0814] Example 160: Synthesis of 4-(2-guanidino-ethyl)-N-[4-(3-guanidino-propyl)-phenyl]- benzamide
Figure imgf000698_0002
[0815] Step 1: Synthesis of 4-(2-tert-butoxycarbonylamino-ethyl)-benzoic acid: To 4-(2- amino-ethyl)-benzoic acid (2.27 g, 11.2 mmol) in dichloromethane (30 mL) in a 100 mL round-bottom flask at 20 oC was added triethylamine (1.42 g, 2.00 mL, 14.0 mmol) dropwise over five minutes. To the resulting heterogeneous mixture was added a solution of di-tert-butyl dicarbonate (2.50 g, 11.2 mmol) in dichloromethane (3 mL) dropwise over ten minutes. The reaction was stirred at 20 oC for 64 hours. The mixture was concentrated. The resulting solid was slurried in a mixture of ethyl acetate (20 mL) and water (5 mL) before carefully adding 1.0 N HCl solution (3 mL). Over approximately one minute, the two separate phases each became homogeneous and were then separated. The organic layer     was dried (Na2SO4), filtered, and concentrated under vacuum to yield 4-(2-tert-butoxycarbonylamino- ethyl)-benzoic acid (3.0 g, quantitative) as a fluffy, white solid.
Figure imgf000699_0001
[0816] Step 2: Synthesis of tert-butyl 3-(4-nitrophenyl)prop-2-ynylcarbamate: A mixture of 1- bromo-4-nitro-benzene (1.94 g, 9.61 mmol), prop-2-ynyl-carbamic acid tert-butyl ester (2.01 g, 13.0 mmol), copper(I) iodide (0.110 g, 0.580 mmol), and triethylamine (5.84 g, 8.04 mL, 57.7 mmol) in tetrahydrofuran (10 mL) in a 100 mL round-bottomed flask was degassed by bubbling nitrogen through the mixture for several minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.539 g, 0.769 mmol) was added, and the reaction was purged with nitrogen for several more minutes, then heated at 60 °C for 18 hours. The mixture was concentrated under vacuum, diluted with ethyl acetate (40 mL) and water (20 mL), then filtered through Celite and rinsed with additional ethyl acetate. The layers were separated, and the organic layer was dried (Na2SO4), filtered, and concentrated under vacuum to yield a black solid (3.4 grams, quantitative), which was used without further purification in the next reaction.
Figure imgf000699_0002
[0817] Step 3: Synthesis of [3-(4-amino-phenyl)-propyl]-carbamic acid tert-butyl ester: A mixture of tert-butyl 3-(4-nitrophenyl)prop-2-ynylcarbamate (0.900 g, 3.26 mmol) and ethyl acetate (35 mL) in a 500 mL Parr flask was purged with nitrogen. Palladium hydroxide (20%, wet) on carbon (0.160 g) and 10% palladium on carbon (0.133 g) were added, and the reaction was shaken under hydrogen (45 psi) for 18 hours. The mixture was purged with nitrogen, filtered through Celite, then concentrated and dried under vacuum to yield a wax-like solid (0.740 g, 2.96 mmol, 91%).
Figure imgf000699_0003
    [0818] Step 4: Synthesis of 4-(2-amino-ethyl)-N-[4-(3-amino-propyl)-phenyl]-benzamide trifluoroacetate: A mixture of 4-(2-amino-ethyl)-benzoic acid (0.137 g, 0.517 mmol), N,N- diisopropylethylamine (0.0935 g, 0.126 mL, 0.724 mmol), and (1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.236 g, 0.620 mmol) in dimethylformamide (3.0 mL) in a 100 mL round-bottomed flask at 20 oC was stirred for 45 minutes, before adding [3-(4-amino-phenyl)-propyl]-carbamic acid tert-butyl ester (0.569 g, 0.142 mmol) and stirring at 20 oC for 18 hours. The reaction was heated at 33 °C for three hours, then stirred at 20 oC for 18 hours. The mixture was diluted with ethyl acetate (15 mL) and water (15 mL), and a precipitate began to form. The solid was collected by filtration and air-dried for 30 minutes to yield 95 mg. The mother liquor was diluted with additional ethyl acetate (15 mL) and water (15 mL) and separated. The organic layer was washed with water (2 x 20 mL), then dried (Na2SO4), filtered, and concentrated. The resulting material and the isolated solid were both separately treated with trifluoroacetic acid for 2 hours. The reaction mixtures were combined and concentrated. Trituration with ether (2 x 15 mL) yielded a gum that was used without further purification in the next reaction.
Figure imgf000700_0001
[0819] Step 5: Synthesis of 4-(2-guanidino-ethyl)-N-[4-(3-guanidino-propyl)-phenyl]- benzamide trifluoroacetate: To a gummy suspension of 4-(2-amino-ethyl)-N-[4-(3-amino-propyl)- phenyl]-benzamide trifluoroacetate (0.500 mmol) and triethylamine (0.500 g, 0.689 mL, 4.94 mmol) in dichloromethane (2.0 mL) in a 100 mL round-bottomed flask at 20 oC was added N,N- dimethylformamide (2.0 mL). The mixture became homogeneous. After adding tert-butyl N-[(Z)- {[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.434 g, 1.40 mmol), the reaction was heated at 30 °C for 18 hours. Additional tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H- pyrazol-1-yl)methyl]carbamate (0.100 g, 0.323 mmol) and triethylamine (0.156 g, 0.215 mL, 1.54 mmol) were added, and the mixture was again heated at 30 °C for 18 hours. The reaction was concentrated under vacuum. The residue was dissolved in ethyl acetate (30 mL) and washed with water (3 x 25 mL), then dried (Na2SO4), filtered, and concentrated. The resulting oil was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 20 oC for 3 hours, then concentrated. The residue was dissolved in 25% MeCN – water, then purified by     reverse-phase HPLC (18 to 75% MeCN – water (both with 0.1% trifluoroacetic acid)) to yield 4-(2- guanidino-ethyl)-N-[4-(3-guanidino-propyl)-phenyl]-benzamide trifluoroacetate (0.046 g, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1 H), 1.66 - 1.83 (m, 2 H), 7.89 (d, J=8.20 Hz, 3 H), 7.62 - 7.77 (m, 5 H), 7.40 (d, J=8.20 Hz, 4 H), 7.16 (d, J=8.20 Hz, 5 H), 3.09 (d, J=5.27 Hz, 2 H), 2.85 (t, J=7.32 Hz, 2 H), 2.56 (t, J=7.62 Hz, 2 H); LC/MS (M + H)+ = 382. [0820] Example 161: Synthesis of N-[2-Amino-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-benzamide
Figure imgf000701_0001
[0821] Step 1: Synthesis of N-(2-amino-4-bromo-phenyl)-4-bromo-3-chloro-benzamide: A mixture of 4-bromo-3-chloro-benzoic acid (0.450 g, 1.91 mmol), N,N-diisopropylethylamine (0.368 g, 0.530 mL, 2.85 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (0.971 g, 2.48 mmol) in N,N-dimethylformamide (4.0 mL) in a 100 mL round-bottomed flask at 20 oC was stirred for 50 minutes, before adding a solution of 4-bromo-benzene- 1,2-diamine (0.340 g, 1.81 mmol) in dichloromethane (3 mL) and stirring at 20 oC for 18 hours. The reaction was diluted with water (25 mL) and left standing for 60 minutes. The resulting solid was collected by filtration and air dried. A significant amount of the solid remained stuck to the walls of the reaction flask; it was azeotroped with acetonitrile, then ethyl acetate to remove water, then dried under vacuum and used without further purification.
Figure imgf000701_0002
[0822] Step 2: Synthesis of N-[2-amino-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-chloro- 4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzamide trifluoroacetate: An impure mixture of N-(2-amino-4- bromo-phenyl)-4-bromo-3-chloro-benzamide (0.350 g, 0.911 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (0.650 g, 2.10 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.0640 g, 0.091 mmol), and 2 M K2CO3 solution (3.7 mL, 7.4 mmol) in 1,4-dioxane (7.7 mL) in a 50 mL round-bottomed flask was degassed by bubbling     nitrogen through the mixture for several minutes. The reaction was heated at 60 °C for three hours, then at 75 °C for 18 hours. The mixture was diluted with ethyl acetate (35 mL) and washed with water (2 x 20 mL), then dried (Na2SO4), filtered, and concentrated under vacuum. The resulting oil was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (8 mL) was then added, and the mixture was stirred at 20 oC for four hours. Concentration followed by trituration with ether (2 x 20 mL) yielded an oil, which was used without further purification in the next reaction.
Figure imgf000702_0001
[0823] Step 3: Synthesis of N-[2-Amino-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-benzamide trifluoroacetate: To a suspension of N-[2-amino-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-3-chloro-4-(1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide trifluoroacetate (0.700 mmol) and triethylamine (0.425 g, 0.585 mL, 4.20 mmol) in dichloromethane (4.0 mL) in a 100 mL round-bottomed flask at 20 oC was added dimethylformamide (2.0 mL). The mixture became homogeneous. After adding tert-butyl N-[(Z)- {[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.434 g, 1.40 mmol), the reaction was heated at 30 °C for 18 hours. The reaction was concentrated and dried under vacuum. The residue was dissolved in ethyl acetate (30 mL) and washed with water (20 mL), 10% aqueous citric acid solution (20 mL), and water (20 L), then dried (Na2SO4), filtered, and concentrated. The resulting solid was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (6 mL) was added. The reaction was stirred at 20 oC for 18 hours, then concentrated. The residue was dissolved in dimethylformamide, then purified by reverse-phase choromatography. The good fractions were lyophilized to yield N-[2-amino- 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-benzamide trifluoroacetate (0.020 g, 4%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.38 (s, 1 H), 9.04 (s, 1 H), 8.39 (d, J=1.17 Hz, 1 H), 7.93 (dd, J=7.91, 1.47 Hz, 1 H), 7.45 - 7.53 (m, 13 H), 6.26 - 6.35 (m, 1 H), 5.84 – 5.92 (m, 1 H), 4.06 - 4.13 (m, 4 H), 3.62 - 3.65 (m, 4 H), 2.58 - 2.66 (m, 2 H), 2.53 - 2.67 (m, 2 H). LC/MS (M + H)+ = 493.     [0824] Example 162: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- pyrimidine-2-carboxylic acid (4-guanidinomethyl-phenyl)-amide
Figure imgf000703_0001
[0825] Step 1 Synthesis of 5-bromo-pyrimidine-2-carbonyl chloride: To a suspension of 5- bromo-pyrimidine-2-carboxylic acid (0.370 g, 1.82 mmol) in chloroform (10 mL) in a dry 100 mL round-bottomed flask at 20 oC under N2 was added N,N-dimethylformamide (0.010 mL), followed by dropwise addition of oxalyl chloride (0.370 g, 0.250 mL, 2.92 mmol). After one hour, a second equal portion of oxalyl chloride was added, and the reaction was stirred at 20 oC for 18 hours. The mixture was concentrated under vacuum. The residue was triturated with chloroform, and the soluble portions were transferred to another flask and concentrated to yield a tan solid (0.380 g, 94%), which was used without further purification.
Figure imgf000703_0002
[0826] Step 2: Synthesis of (4-amino-benzyl)-carbamic acid tert-butyl ester: To a solution of 4-(aminomethyl)benzenamine (5.24 g, 43.0 mmol) in ethyl acetate (60 mL) in a 200 mL round- bottomed flask at 20 oC was added a solution of di-tert-butyl dicarbonate (4.08 g, 18.7 mmol) in ethyl acetate (10 mL) dropwise as over 25 minutes in order to keep the reaction temperature below 35 °C. The mixture was stirred at 20 oC for 18 hours. The reaction was washed with 10% citric acid solution (20 mL) and water (20 mL), then dried (Na2SO4), filtered, and concentrated under vacuum to yield a solid (8.2 g, 86%).
Figure imgf000703_0003
[0827] Step 3: Synthesis of {4-[(5-bromo-pyrimidine-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester: To a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (0.364 g, 1.64 mmol), diisopropylethylamine (0.481 g, 0.649 mL, 3.73 mmol) in dichloromethane (3.0 mL) in a 100 mL round-bottomed flask vial at 20 oC was added a solution of 5-bromo-pyrimidine-2-carbonyl     chloride (0.330 g, 1.49 mmol) in dichloromethane (3.0 mL) dropwise over five minutes. The reaction was stirred at 20 oC for 60 minutes, then concentrated under vacuum. Ethyl acetate (10 mL) and water (10 mL) were added to the residue, and the mixture was stirred for 18 hours. The layers were separated, and the organic layer was dried (Na2SO4), filtered, and concentrated to yield a solid (0.480 g, 79%).
Figure imgf000704_0001
[0828] Step 4: Synthesis of 5-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide trifluoroacetate: A 100 mL round-bottomed flask was charged with solids {4-[(5-bromo-pyrimidine-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester (0.220 g, 0.541 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)- carboxylate (0.200 g, 0.649 mmol), palladium(II) acetate (0.0050 g, 0.021 mmol), and [2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl] (0.018 g, 0.043 mmol).1,4-dioxane (4.0 mL) and 2 M K2CO3 solution (1.1 mL, 2.16 mmol) were added, and the mixture was degassed with nitrogen for several minutes. The reaction was heated at 95 °C for 18 hours. The mixture was cooled to 20 oC, then diluted with ethyl acetate (5 mL) and water (4 mL). The precipitated solid was collected by filtration and dissolved in dichloromethane (4 mL), to which trifluoroacetic acid (4 mL) was then added. This solution was stirred at 20 oC for 90 minutes, then concentrated under vacuum. Ether (15 mL) was added to the resulting oil, and the mixture was sonicated before allowing the precipitated solids to settle. The ether was decanted, and the trituration was repeated before drying the solid under vacuum to yield a solid, which was used without further purification.
Figure imgf000704_0002
[0829] Step 4: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine- 2-carboxylic acid (4-guanidinomethyl-phenyl)-amide: To a solution of 5-(1,2,3,6-tetrahydro-pyridin- 4-yl)-pyrimidine-2-carboxylic acid (4-aminomethyl-phenyl)-amide trifluoroacetate (0.450 mmol) and triethylamine (0.354 g, 0.488 mL, 3.50 mmol) in a mixture of dichloromethane (3.0 mL) and N,N-     dimethylformamide (3.0 mL) in a 100 mL round-bottomed flask at 20 oC was added tert-butyl N-[(Z)- {[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.350 g, 1.13 mmol). The reaction was stirred at 20 oC for 64 hours, then concentrated under vacuum. The residue was dissolved in ethyl acetate (40 mL) and washed with water (3 x 30 mL), then dried (Na2SO4), filtered, and concentrated to yield an oil. Silica gel chromatography (0 to 100% ethyl acetate – 100 to 0% dichloromethane) was followed by concentration and drying of two separate sets of fractions, both containing the desired product. The resulting residues were separately (in two different reactions) dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (2 mL). After 60 minutes, the two separate reactions were combined and concentrated. The residue was dissolved in ~2 : 1 water – acetonitrile, frozen, then lyophilized. The residue was dissolved in N,N-dimethylformamide, then purified by reverse-phase HPLC to yield a solid (0.118 g, 42%).1H NMR (300 MHz, METHANOL-d4) δ ppm 9.08 (s, 2 H), 7.85 - 7.91 (m, 2 H), 7.36 - 7.41 (m, 3 H), 6.50 - 6.57 (m, 1 H), 4.41 (t, J=2.93 Hz, 2 H), 4.23 (q, J=2.54 Hz, 2 H), 3.76 (t, J=5.86 Hz, 2 H), 2.76 - 2.83 (m, 2 H). LC/MS (M + H)+ = 394. [0830] Example 163: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- thiophene-2-carboxylic acid [4-(3-guanidino-propyl)-phenyl]-amide Br
Figure imgf000705_0001
Synthesis of 4-(5-carboxy-thiophen-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert- butyl [0831] Step 1: ester: A 100 mL round-bottomed flask was charged with 5-bromo-thiophene-2- carboxylic acid methyl ester (2.12 g, 9.0 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine-1(2H)-carboxylate (3.50 g, 11.3 mmol), palladium(II) acetate (0.081 g, 0.360 mmol), and [2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl] (0.370 g, 0.900 mmol). Dioxane (25 mL) and 2 M K2CO3 solution (1.4 mL, 2.70 mmol) were added, and the mixture was degassed with nitrogen for 25 minutes. The reaction was heated at 85 °C for 18 hours. The mixture was cooled to 20 oC, then diluted with ethyl acetate (20 mL) and water (10 mL) and the layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum, then azeotroped with toluene (40 mL) and dried again. The residue was dissolved in 1 : 1 tetrahydrofuran – methanol (50 mL), and water (10 mL) was added, followed by LiOH ^ H2O (0.450 g, 10.7 mmol). After     stirring at 20 oC for 60 minutes, additional water (10 mL) was added, and the reaction was stirred at 20 oC for 18 hours. The mixture was concentrated, and the residue was extracted with ether (2 x 30 mL). The resulting aqueous slurry was cooled to 0 °C and 2.0 N HCl solution (20 mL) was added dropwise over five minutes. The mixture was stirred for 15 minutes, then ethyl acetate (40 mL) was added, and the layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated, then air- dried to yield a gray solid (0.800 g, 29%).
Figure imgf000706_0001
[0832] Step 2: Synthesis of 5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4- (3-amino-propyl)-phenyl]-amide trifluoroacetate: A mixture of 4-(5-carboxy-thiophen-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.300 g, 0.970 mmol), N,N- diisopropylethylamine (0.375 g, 0.540 mL, 2.91 mmol), and (1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.480 g, 1.26 mmol) in N,N- dimethylformamide (2.0 mL) in a 100 mL round-bottomed flask at 20 oC was stirred for 30 minutes, before adding a solution of [3-(4-amino-phenyl)-propyl]-carbamic acid tert-butyl ester (0.262 g, 1.05 mmol) in dichloromethane (2 mL) and stirring at 20 oC for 18 hours. The reaction was diluted with ethyl acetate (30 mL) and washed with water (2 X 20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. The resulting solid (0.300 g) was dissolved in dichloromethane (4.0 mL) and treated with trifluoroacetic acid (4.0 mL), then stirred for 18 hours at 20 oC. This mixture was concentrated, and the residue was triturated with ether (2 x 25 mL), dissolved in 20% MeCN – water, frozen, and lyophilized. The product was used without further purification in the next reaction.
Figure imgf000706_0002
[0833] Step 3: Synthesis of 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2- carboxylic acid [4-(3-guanidino-propyl)-phenyl]-amide trifluoroacetate: To a solution of 5-(1,2,3,6- tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(3-amino-propyl)-phenyl]-amide     trifluoroacetate (0.510 mmol) and triethylamine (0.315 g, 0.442 mL, 3.06 mmol) in a mixture of dichloromethane (3.0 mL) and N,N-dimethylformamide (2.0 mL) in a 100 mL round-bottomed flask at 20 oC was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.354 g, 1.14 mmol). The reaction was stirred at 20 oC for 64 hours, then concentrated under vacuum. Silica gel chromatography (0 to 60% ethyl acetate – 100 to 40% dichloromethane), followed by concentration and drying under vacuum. This material was dissolved in dichloromethane (4.0 mL) and treated with trifluoroacetic acid (4.0 mL), then stirred at 20 oC for 18 hours. After concentration and lyophilization, about one-third of the 261 mg of material was purified by reverse-phase preparative HPLC (0.072 g, 22%).1H NMR (300 MHz, METHANOL-d4) δ ppm 7.79 (d, J=4.10 Hz, 1 H), 7.53 - 7.62 (m, 2 H), 7.17 - 7.26 (m, 3 H), 6.26 - 6.35 (m, 1 H), 4.10 - 4.18 (m, 2 H), 3.71 (t, J=5.57 Hz, 2 H), 3.19 (t, J=7.03 Hz, 2 H), 2.63 - 2.77 (m, 4 H), 1.90 (quin, J=7.33 Hz, 2 H). LC/MS (M + H)+ = 426. [0834] Example 164: Synthesis of 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- pyrimidine-5-carboxylic acid (4-guanidinomethyl-phenyl)-amide
Figure imgf000707_0001
[0835] Step 1: Synthesis of {4-[(2-chloro-pyrimidine-5-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester: To a suspension of 2-chloro-pyrimidine-5-carboxylic acid (0.373 g, 2.36 mmol) in chloroform (15 mL) in a dry 100 mL round-bottomed flask at 20 oC under N2 was added N,N- dimethylformamide (0.010 mL), followed by dropwise addition of oxalyl chloride (0.600 g, 0.400 mL, 4.72 mmol) over 10 minutes. The reaction was stirred at 20 oC for 48 hours. The homogeneous mixture was then concentrated, dried under vacuum, then slurried in dichloromethane (3.0 mL). To this acid chloride mixture was added a solution of (4-amino-benzyl)-carbamic acid tert-butyl ester (0.565 g, 2.55 mmol) and triethylamine (0.606 g, 0.875 mL, 6.00 mmol) in dichloromethane (10 mL) dropwise over 20 minutes at 20 oC. The mixture was stirred at 20 oC for 64 hours. After concentrating under vacuum, the residue was diluted with ethyl acetate (5 mL) and water (5 mL), sonicated for five minutes, then stirred for 30 minutes. The precipitated solid was collected by filtration, rinsed with additional ethyl acetate, then dried under vacuum to yield a solid which was used without further purification.    
Figure imgf000708_0001
[0836] Step 2: Synthesis of 2-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-5-carboxylic acid (4-aminomethyl-phenyl)-amide trifluoroacetate: A 100 mL round-bottomed flask was charged with solids {4-[(2-chloro-pyrimidine-5-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester (2.00 mmol), tert-butyl 5,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-1(2H)- carboxylate (0.765 g, 2.50 mmol), palladium(II) acetate (0.0.0230 g, 0.100 mmol), and [2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl] (0.103 g, 0.250 mmol).1,4-dioxane (7.0 mL) and 2 M K2CO3 solution (3.50 mL, 7.00 mmol) were added, and the mixture was degassed with nitrogen for several minutes. The reaction was heated at 95 °C for four hours, then stirred at 20 oC for 18 hours. The mixture was diluted with ethyl acetate (3.0 mL) and water (3.0 mL) and stirred at 20 oC for 30 minutes. Additional ethyl acetate (30 mL) and water (20 mL) were added, and the layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum. Silica gel chromatography (0 to 100% ethyl acetate – 100 to 0% dichloromethane), followed by concentration and drying under vacuum, yielded the desired intermediate. The resulting solid (0.180 g) was dissolved in dichloromethane (3.0 mL) and treated with trifluoroacetic acid (3.0 mL), then stirred for 18 hours at 20 oC. This mixture was concentrated, and the residue was triturated with ether (2 x 20 mL) and air dried to yield a solid that was used without further purification.
Figure imgf000708_0002
[0837] Step 3: Synthesis of 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine- 5-carboxylic acid (4-guanidinomethyl-phenyl)-amide trifluoroacetate: To a cloudy solution of 2- (1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-5-carboxylic acid (4-aminomethyl-phenyl)-amide trifluoroacetate (0.300 mmol) and triethylamine (0.182 g, 0.260 mL, 1.80 mmol) in a mixture of dichloromethane (2.0 mL) and N,N-dimethylformamide (1.0 mL) at 20 oC was added tert-butyl N-[(Z)-     {[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (0.210 g, 0.675 mmol). The reaction was stirred at 20 oC for 18 hours.1-methylpiperazine (0.120 mL) was added, and the reaction was stirred at 20 oCfor two hours. The mixture was diluted with ethyl acetate (25 mL) and washed with water (10 mL), 10% NaHSO4 solution (20 mL), and water (20 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 100% ethyl acetate – 100 to 0% dichloromethane), followed by concentration and drying under vacuum, yielded the desired intermediate. The compound was dissolved in dichloromethane and treated with trifluoroacetic acid, then stirred at 20 oC for 18 hours. This mixture was concentrated, and the residue was triturated with ether (15 mL), dissolved in 20% MeCN – water, frozen, then lyophilized to yield a solid (0.0520 g, 28%). 1H NMR (300 MHz, METHANOL-d4) δ ppm 9.23 (s, 2 H), 7.74 - 7.78 (m, 2 H), 7.35 - 7.38 (m, 2 H), 4.40 (s, 2 H), 4.27 (q, J=2.93 Hz, 2 H), 3.72 (t, J=5.57 Hz, 2 H), 2.87 - 2.97 (m, 2 H). LC/MS (M + H)+ = 394. [0838] Example 165: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide
Figure imgf000709_0001
[0839] Step 1: Synthesis of tert-butyl N-{[4-(5-bromothiophene-2- amido)phenyl]methyl}carbamate To a stirred, ice-cold solution of 5-bromothiophene-2-carboxylic acid (500 mg, 2.4 mmol) in CH2Cl2 (5 mL) was added N,N-dimethylforamide (2 drops), followed by a solution of oxalyl chloride (0.31 mL, 3.6 mmol) in CH2Cl2 (1 mL) dropwise over 10 min. The mixture was allowed to warm to 25 oC and stirred for 3 hours. The solution was concentrated, redissolved in CH2Cl2 and concentrated. To a stirred, ice cold solution of this material in CH2Cl2 (10 mL) were added N,N-diisopropylethylamine (0.8 mL, 4.5 mmol) and tert-butyl N-[(4-aminophenyl)methyl]carbamate (510 mg, 2.25 mmol). The mixture was allowed to warm to 25 oC, stirred for 18 hours, diluted with ethyl adetate (80 mL) and 5% aq HCl (20 mL), and filtered. The solid collected was dried in vacuo to give tert-butyl N-{[4-(5-bromothiophene-2-amido)phenyl]methyl}carbamate (280 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.17 - 10.36 (m, 1 H), 7.85 (d, J=3.96 Hz, 1 H), 7.60 (br d, J=7.91 Hz, 2 H), 7.34 (br d, J=3.96 Hz, 1 H), 7.19 (br d, J=7.91 Hz, 2 H), 4.07 (br d, J=5.71 Hz, 2 H), 1.37 (s, 9 H).    
Figure imgf000710_0001
[0840] Step 2: Synthesis of tert-butyl 4-(5-{[4-({[(tert-butoxy)carbonyl]amino}methyl) phenyl] carbamoyl}thiophen-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate A flask was charged with tert-butyl N-{[4-(5-bromothiophene-2-amido)phenyl]methyl}carbamate (240 mg,0.58 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (217 mg, 0.7 mmol), S-Phos (24 mg, 0.03 mmol), Pd(OAc)2 (6 mg, 0.03 mmol) and K2CO3 (300 mg, 2.2 mmol), and sealed with a septum. The flask was flushed with N2 for 10 minutes and N2-sparged 3:1 1,4-dioxane/water (10 mL) was introduced by syringe. The mixture was heated at 100 ⁰C for 4 h. The mixture was diluted with EtOAc (90 mL), washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left a brown oil (470 mg) which was chromatographed on silica with a 0-100% EtOAc in hexanes gradient, to afford tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl] carbamoyl}thiophen-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (200 mg, 81%) as a white solid. LC-MS tR 5.82 min, m/z 514.
Figure imgf000710_0002
[0841] Step 3: Synthesis of N-[4-(aminomethyl)phenyl]-5-(1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxamide: To a solution of tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}thiophen-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (200 mg,0.39 mmol) in CH2Cl2 (5 mL) was added CF3CO2H (5 mL). The mixture was stirred for 18 hours at 25 oC and concentrated. The residue was taken up in acetonitrile (10 mL) and 10% aq HCl (1 mL) and concentrated to leave N-[4-(aminomethyl)phenyl]-5-(1,2,3,6- tetrahydropyridin-4-yl)thiophene-2-carboxamide 2HCl salt as a yellow solid which was used directly. LC-MS tR 2.20 min, m/z 314.    
Figure imgf000711_0001
[0842] Step 4: Synthesis of tert-butyl N-[(Z)-({[4-(5-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}thiophene-2-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a stirred suspension of N-[4-(aminomethyl)phenyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)thiophene-2- carboxamide 2HCl salt in triethylamine (0.36 mL, 2.5 mmol) and N,N-dimethylforamide (6 mL) was added tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (300 mg, 0.97 mmol). The mixture was stirred at 25 oC for 1 day. 4-amino-1-methylpiperidine (0.5 mL) was added, stirring at 25 oC was continued for 3 hours and the mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (90 mL), washed with water (10 mL), 10% aq NaHSO4 (10 mL) and 9:1 brine/satd aq NaHCO3 (10 mL), and dried over Na2SO4. Removal of the solvent left a yellow solid (320 mg) which was chromatographed on silica gel to give tert-butyl N-[(Z)-({[4-(5-{1- [(Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6- tetrahydropyridin-4-yl}thiophene-2-amido)phenyl]methyl}amino)({[(tert- butoxy)carbonyl]imino})methyl]carbamate (230 mg, 74% over two steps) as a pale yellow solid. LC- MS tR 4.87 min, m/z 798.
Figure imgf000711_0002
[0843] Step 5: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-5-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide: tert-Butyl N-[(Z)-({[4-(5-{1-[(Z)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydro pyridin-4- yl}thiophene-2-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl] carbamate     (230 mg, 0.29 mmol) was stirred with 1:1 CF3CO2H/CH2Cl2 at rt for 3 hours and concentrated. The residue was purified by prep HPLC to give the N-[4-(carbamimidamidomethyl)phenyl]-5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide 2TFA salt (101 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.28 (s, 1 H), 7.86 - 8.06 (m, 2 H), 7.60 - 7.77 (m, 2 H), 7.50 (br s, 5 H), 7.27 (br d, J=7.03 Hz, 6 H), 6.26 - 6.36 (m, 1 H), 4.32 (br d, J=5.27 Hz, 2 H), 4.14-4.02 (m, 2 H), 3.56-3.62 (m, 2 H), 2.54 - 2.65 (m, 2 H). LC-MS tR 2.58 min, m/z 398. [0844] Example 166: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide
Figure imgf000712_0001
[0845] Step 1: Synthesis of tert-butyl N-{[4-(5-bromofuran-2- amido)phenyl]methyl}carbamate: To a stirred, ice-cold solution of 5-bromofuran-2-carboxylic acid (500 mg, 2.6 mmol) in CH2Cl2 (10 mL) was added N,N-dimethylforamide (2 drops), followed by a solution of oxalyl chloride (0.34 mL, 3.9 mmol) in CH2Cl2 (1 mL) dropwise over 10 minutes. The mixture was allowed to warm to 25 oC and stirred for 3 hours. The solution was concentrated, redissolved in CH2Cl2 and concentrated. To a stirred, ice cold solution of the this material in CH2Cl2 (10 mL) were added N,N-diisopropylethylamine (0.94 mL, 5.2 mmol) and tert-butyl N-[(4- aminophenyl)methyl]carbamate (580 mg, 2.6 mmol). The mixture was allowed to warm to rt, stirred overnight, diluted with EtOAc (80 mL) and 5% aq HCl (20 mL), and filtered. The dark solid collected was dried in vacuo to give tert-butyl N-{[4-(5-bromofuran-2-amido)phenyl]methyl}carbamate (880 mg, 86%). LC-MS tR 5.11 min, m/z 417, 395.
Figure imgf000712_0002
[0846] Step 2: Synthesis of tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate: A flask was charged with tert-butyl N-{[4-(5-bromofuran-2- amido)phenyl]methyl}carbamate (880 mg, 2.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-     dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (826 mg, 2.7 mmol), [2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl] (91 mg, 0.22 mmol), Pd(OAc)2 (20 mg, 0.22 mmol) and K2CO3 (1.14g, 8.2 mmol), and sealed with a septum. The flask was flushed with N2 for 10 minutes and N2-sparged 3:11,4-dioxane/water (20 mL) was introduced by syringe. The mixture was heated at 100 ⁰C for 4 hours. The mixture was diluted with EtOAc (90 mL), washed with water tert-butyl 4-(5- {[4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left a brown oil (470 mg) which was chromatographed on a 40 g silica cartridge, eluted with a 0-100% EtOAc in hexanes gradient, to afford tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (1.52 g) as a solid. LC-MS tR 5.78 min, m/z 520, 498.
Figure imgf000713_0001
[0847] Step 3: Synthesis of N-[4-(aminomethyl)phenyl]-5-(1,2,3,6-tetrahydropyridin-4- yl)furan-2-carboxamide: To a stirred solution of tert-butyl 4-(5-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}furan-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (1.52 g, 3.5 mmol) in CH2Cl2 (8 mL) was added CF3CO2H (2 mL). The mixture was stirred 18 hours at 25 oC and concentrated to leave crude N-[4-(aminomethyl)phenyl]-5-(1,2,3,6- tetrahydropyridin-4-yl)furan-2-carboxamide 2TFA salt (2.61 g) as an oil. LC-MS tR 2.28 min, m/z 298.
Figure imgf000713_0002
[0848] Step 4: Synthesis of tert-butyl N-[(Z)-({[4-(5-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}furan-2-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a stirred mixture of crude N-[4-(aminomethyl)phenyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)furan-2-     carboxamide 2TFA salt (2.61 g, 3.7 mmol), triethylamine (5 mL, 37 mmol) and 3:1 N,N- dimethylformamide/CH2Cl2 (10 mL) was added tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}(1H- pyrazol-1-yl)methyl]carbamate (2.90 g, 9.3 mmol). The mixture was stirred overnight at rt and 4- amino-1-methylpiperidine (1.0 mL) was added. Stirring at 25 oC was continued 18 hours and the mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (90 mL), washed with water (2 x 10 mL), 10% aq NaHSO4 (10 mL) and 9:1 brine/satd aq NaHCO3 (10 mL), and dried over Na2SO4. Removal of the solvent left a yellow solid (3.36g) which was chromatographed on silica with a 0-100% EtOAc in hexanes gradient, to give tert-butyl N-[(Z)-({[4-(5-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}furan-2-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (1.46 g, 87% over 3 steps) as a foam. LC-MS tR 4.85 min, m/z 782.
Figure imgf000714_0001
[0849] Step 4: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-5-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide: tert-Butyl N-[(Z)-({[4-(5-{1-[(Z)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4- yl}furan-2-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (330 mg, 0.42 mmol) was stirred with 1:1 CH2Cl2/CF3CO2H (5 mL) at 25 oC for 3 hours and concentrated. The residue was purified by prep HPLC to afford N-[4-(carbamimidamidomethyl)phenyl]-5-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2-carboxamide 2TFA salt (110 mg, 68%) as a white solid. 1H NMR (300 MHz, METHANOL-d4) δ ppm 7.64 - 7.81 (m, 2 H), 7.17 - 7.42 (m, 4 H), 6.54 - 6.69 (m, 1 H), 4.39 (s, 2 H), 4.20 (d, J=3.08 Hz, 2 H), 3.70 (s, 2 H), 2.65 (br d, J=1.76 Hz, 2 H). LC-MS tR 2.60 min, m/z 382. [0850] Example 167: Synthesis of  N-[4-(carbamimidamidomethyl)phenyl]-4-(1- carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-2-carboxamide    
Figure imgf000715_0001
[0851] Step 1: Synthesis of tert-butyl N-{[4-(4-bromo-1,3-thiazole-2- amido)phenyl]methyl}carbamate: To a stirred, ice-cold solution of 4-bromothiazole-2-carboxylic acid (250 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added N,N-dimetylformamide (2 drops), followed by oxalyl chloride (0.16 mL, 1.8 mmol). The mixture was allowed to warm to 25 oC and stirred for 2 hours. The solution was concentrated to leave a pale yellow solid. To a stirred, ice cold solution of this material and tert-butyl N-[(4-aminophenyl)methyl]carbamate (265 mg, 1.2 mmol) in CH2Cl2 (10 mL) was added i-Pr2NEt (0.43 mL, 2.4 mmol). The mixture was allowed to warm to 25 oC, stirred for 72 hours, diluted with EtOAc (90 mL), washed with 5% aq HCl (15 mL)and 4:1 brine/ satd aq NaHCO3 (15 mL), and dried over Na2SO4. Removal of the solvent left an oil (420 mg) which was purified by chromatography on silica with a 0-50% EtOAc in hexanes gradient, to give tert-butyl N-{[4-(4-bromo-1,3-thiazole-2- amido)phenyl]methyl}carbamate (350 mg, 67%) as a yellow solid. LC-MS tR 5.25 min, m/z 434.
Figure imgf000715_0002
[0852] Step 2: Synthesis of tert-butyl 4-(2-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}-1,3-thiazol-4-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate: A flask was charged with tert-butyl N-{[4-(4-bromo-1,3-thiazole-2- amido)phenyl]methyl}carbamate (350 mg, 0.85 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (315 mg, 1.0 mmol), [2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl] (35 mg, 0.08 mmol), Pd(OAc)2 (8 mg, 0.03 mmol) and K2CO3 (435 mg, 3.1 mmol), and sealed with a septum. The flask was flushed with N2 for 10 minutes and N2-sparged 3:11,4-dioxane/water (20 mL) was introduced by syringe. The mixture was heated at 100 ⁰C for 4 hours. The mixture was diluted with EtOAc (90 mL), washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left a brown oil (650 mg) which was chromatographed on silica with a 0-100% EtOAc in hexanes gradient, to afford tert-butyl     4-(2-{[4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}-1,3-thiazol-4-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (380 mg, 87%) as a solid. LC-MS tR 6.19 min, m/z 537.
Figure imgf000716_0001
[0853] Step 3: Synthesis of N-[4-(aminomethyl)phenyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)- 1,3-thiazole-2-carboxamide: A solution of tert-butyl 4-(2-{[4-({[(tert- butoxy)carbonyl]amino}methyl)phenyl]carbamoyl}-1,3-thiazol-4-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (380 mg, 0.73 mmol) in 1: CH2Cl2/CF3CO2H was stirred at 25 oC for 16 hours and concentrated, The residue was taken up in MeCN (5 mL) and 10% aq HCl (2 mL) and concentrated to leave N-[4-(aminomethyl)phenyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-2-carboxamide 2HCl salt (270 mg, 69%). LC-MS tR 2.40 min, m/z 315.
Figure imgf000716_0002
[0854] Step 4: Synthesis of tert-butyl N-[(E)-({[4-(4-{1-[(E)-{[(tert- butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}- 1,3-thiazole-2-amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate: To a stirred mixture of N-[4-(aminomethyl)phenyl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-2- carboxamide 2HCl salt (270 mg, 0.70 mmol), CH2Cl2 (10 mL) and N,N-dimethylformamide (10 mL) were added triethylamine (0.75 mL, 7.7 mmol) and tert-butyl N-[(E)-{[(tert- butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (650 mg, 2.1 mmol). The mixture was stirred at 25 oC for 18 hours and 4-amino-1-methylpiperidine (0.1 mL) was added. The mixture was stirred for 18 hours and concentrated. The residue was taken up in EtOAc (90 mL), washed with water (2 x 10 mL), 10% aq NaHSO4 (10 mL) and 9:1 brine/satd aq NaHCO3 (10 mL), and dried over Na2SO4. Removal of the solvent left a solid (710 mg), which was purified by chromatography on silica gel to give tert-butyl N-[(E)-({[4-(4-{1-[(E)-{[(tert-butoxy)carbonyl]amino}({[(tert-     butoxy)carbonyl]imino})methyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-thiazole-2- amido)phenyl]methyl}amino)({[(tert-butoxy)carbonyl]imino})methyl]carbamate (670 mg) as a solid. LC-MS tR 5.08 min, m/z 821, 799.
Figure imgf000717_0001
[0855] Step 4: Synthesis of N-[4-(carbamimidamidomethyl)phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydropyridin-4-yl)-1,3-thiazole-2-carboxamide: To a stirred solution of tert-butyl N-[(E)- ({[4-(4-{1-[(E)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl] -1,2,3,6- tetrahydropyridin-4-yl}-1,3-thiazole-2-amido)phenyl]methyl}amino)({[(tert- butoxy)carbonyl]imino})methyl]carbamate (670 mg, 0.83 mmol) in CH2Cl2 (5 mL) was added CF3CO2H (5 mL). The mixture was stirred at 25 oC for 18 hours and concentrated to leave a residue (690 mg). Prep HPLC afforded N-[4-(carbamimidamidomethyl)phenyl]-4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-1,3-thiazole-2-carboxamide 2TFA salt (310 mg, 70% over 2 steps) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.54 (s, 1 H), 8.18 (t, J=6.15 Hz, 1 H), 7.99 (s, 1 H), 7.75 - 7.86 (m, 2 H), 7.65 (s, 4 H), 7.55-7.35 (m, 4 H), 7.31 (d, J=8.79 Hz, 2 H), 6.77 - 6.96 (m, 1 H), 4.35 (d, J=6.15 Hz, 2 H), 4.16 (br d, J=2.20 Hz, 2 H), 3.65 (br t, J=5.71 Hz, 2 H), 2.65 (br s, 2 H). LC- MS tR 2.75 min, m/z 399. [0856] Example 168: Synthesis of  5-(4-carbamimidoylpiperazin-1-yl)-N-[4-(4- carbamimidoylpiperazin-1-yl)phenyl]thiophene-2-carboxamide
Figure imgf000717_0002
[0857] Step 1: Synthesis of 4-(5-methoxycarbonyl-thiophen-2-yl)-piperazine-1-carboxylic acid tert-butyl ester: A mixture of piperazine-1-carboxylic acid tert-butyl ester (0.300 g, 1.36 mmol) in toluene (8.0 mL) in a small pressure tube was degassed by bubbling nitrogen through the mixture for several minutes. Cesium carbonate (1.33 g, 4.07 mmol), 5-bromo-thiophene-2-carboxylic acid methyl     ester (0.758 mL, 4.07 mmol), RuPhos (0.0633 g, 0.136 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.124 g, 0.136 mmol) were added and degassing was continued for about two more minutes. The reaction was heated at 95 °C for seven hours, then stirred at 23 oC for 18 hours. The mixture was partitioned between dichloromethane (80 mL) and saturated NaHCO3 solution (15 mL) and separated. The aqueous layer was re-extracted with dichloromethane (2 x 20 mL). The organic layers were combined and washed with brine (15 mL), then dried (Na2SO4), filtered, and concentrated. The brownish solid was adsorbed onto Florisil. Silica gel chromatography (0 to 40% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the title compound as a yellow solid. Li
Figure imgf000718_0001
[0858] Step 2: Synthesis of 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-thiophene-2-carboxylate, lithium salt: To a solution of 4-(5-methoxycarbonyl-thiophen-2-yl)-piperazine-1-carboxylic acid tert- butyl ester (0.194 g, 0.594 mmol) in a mixture of methanol (1.5 mL) and tetrahydrofuran (1.5 mL) in a 20 mL vial at 23 oC under N2 was added 1 N LiOH solution (0.654 mL, 0.654 mmol). The mixture was stirred at 23 oC for three hours, then heated at 40 °C for 18 hours. The reaction was heated at 60 °C for two hours, then at 70 °C for 90 minutes. After adding additional LiOH solution (0.120 mL, 0.120 mmol), the mixture was heated at 70 °C for four hours, then stirred at 23 oC for 18 hours. The reaction was concentrated. The residue was suspended in acetonitrile and concentrated again (2x), before drying under vacuum to yield the title compound as a tan solid, which was used without further purification.
Figure imgf000718_0002
[0859] Step 3: Synthesis of tert-butyl 4-{5-[(4-{4-[(tert-butoxy)carbonyl]piperazin-1-yl} phenyl)carbamoyl]thiophen-2-yl}piperazine-1-carboxylate: A mixture of 5-(4-tert-butoxycarbonyl- piperazin-1-yl)-thiophene-2-carboxylate, lithium salt (0.594 mmol), N, N-diisopropylethylamine (0.307 g, 0.414 mL, 2.38 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.294 g, 0.772 mmol) in N,N-dimethylformamide (3.0 mL) in a 20 mL vial at 23 oC under N2 was stirred for 20 minutes, before adding t-butyl 4-(4-     aminophenyl)piperazine-1-carboxylate (0.148 g, 0.535 mmol) and stirring at 23 oC for 64 hours. After adding additional t-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (0.0500 g, 0.180 mmol), the reaction was heated at 50 °C for six hours, then stirred at 23 oC for 18 hours. The mixture was partitioned between ethyl acetate (130 mL) and saturated NaHCO3 solution (20 mL) and separated. The organic layer was washed with water (2 x 15 mL), then brine (15 mL), then dried (Na2SO4), filtered, concentrated, and adsorbed onto Florisil. Silica gel chromatography (0 to 80% ethyl acetate – 100 to 20% DCM), followed by concentration and drying under vacuum, yielded the title compound as a brown solid. H
Figure imgf000719_0001
[0860] Step 4: Synthesis of 5-piperazin-1-yl-thiophene-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide hydrochloride: To a solution of tert-butyl 4-{5-[(4-{4-[(tert-butoxy)carbonyl]piperazin- 1-yl}phenyl)carbamoyl]thiophen-2-yl}piperazine-1-carboxylate (0.165 g, 0.289 mmol) and anisole (0.156 g, 0.157 mL, 1.44 mmol) in dichloromethane (2.5 mL) at 23 oC under N2 was added 4 N HCl – dioxane solution (2.0 mL, 8.00 mmol) dropwise. The reaction was stirred at 23 oC for four hours, then concentrated. The residue was suspended in acetonitrile and concentrated again (2x), then dried under vacuum to yield the tilte compound as an off-white solid.
Figure imgf000719_0002
[0861] Step 4: Synthesis of {[4-(5-{4-[4-(tert-butoxycarbonylamino-tert- butoxycarbonylimino-methyl)-piperazin-1-yl]-phenylcarbamoyl}-thiophen-2-yl)-piperazin-1-yl]-tert- butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester: To a suspension of 5-piperazin-1-yl- thiophene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (0.121 g, 0.234 mmol) and N,N-diisopropylethylamine (0.302 g, 0.407 mL, 2.34 mmol) in N,N-dimethylformamide (3.0 mL) in a 20 mL vial at 23 oC under N2 was added tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol- 1-yl)methyl]carbamate (0.218 g, 0.702 mmol). The suspension was stirred at 23 oC for 18 hours. The     mixture was partitioned between ethyl acetate (130 mL) and saturated NaHCO3 solution (20 mL) and separated. The organic layer was washed with water (15 mL), then brine (15 mL), then dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (0 to 75% ethyl acetate - hexanes), followed by concentration and drying under vacuum, yielded the title compound as an off-white solid. H
Figure imgf000720_0001
[0862] Step 5: Synthesis of 5-(4-carbamimidoylpiperazin-1-yl)-N-[4-(4-carbamimidoyl piperazin-1-yl)phenyl]thiophene-2-carboxamide hydrochloride: To a solution of {[4-(5-{4-[4-(tert- butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-piperazin-1-yl]-phenylcarbamoyl}- thiophen-2-yl)-piperazin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester (0.167 g, 0.195 mmol) and anisole (0.211 g, 0.212 mL, 1.95 mmol) in dichloromethane (2.5 mL) at RT under N2 was added 4 N HCl – dioxane solution (2.0 mL, 8.00 mmol) dropwise. The reaction was stirred at 23 oC overnight. The mixture was concentrated. The residue was suspended in acetonitrile (3 mL) and concentrated again (2x), then dried under vacuum to yield the title compound as an off-white solid.1H NMR (300 MHz, DMSO-d6) δ ppm 9.84 (s, 1 H) 7.78 (d, J=4.10 Hz, 1 H) 7.52 - 7.68 (m, 11 H) 6.99 (br d, J=8.79 Hz, 2 H) 6.27 (d, J=4.10 Hz, 1 H) 3.56 - 3.59 (m, 8 H) 3.24 - 3.29 (m, 4 H) 3.14 - 3.19 (m, 4 H). LC/MS (M + H)+ = 456. [0863] Example 169: Synthesis of 4-(1-carbamimidoyl-2,5-dihydro-1H-pyrrol-3-yl)-N-[4-(2- guanidino-ethyl)-phenyl]-benzamide B
Figure imgf000720_0002
[0864] Step 1: Synthesis of {2-[4-(4-Bromo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert- butyl ester. To a mixture of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (709 mg, 3.00 mmol) and diisoproylethylamine (605 mg, 812 ^L, 4.67 mmol) in chloroform (9 mL) was added dropwise a solution of 4-bromo-benzoyl chloride (735 mg, 3.35 mmol) in chloroform (9 mL). The reaction was treated with further chloroform (9 mL), then was stirred for 3 days. The reaction was concentrated, then the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The     mixture was shaken, then was filtered. The solid was washed with isopropanol (30 mL), and hexanes (30 mL), to give {2-[4-(4-bromo-benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester as a white solid. O
Figure imgf000721_0001
[0865] Step 2: Synthesis of 3-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]- phenyl}-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester. A mixture of {2-[4-(4-bromo- benzoylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (765 mg, 1.82 mmol), 4-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (636 mg, 2.15 mmol), Pd(OAc)2 (20 mg, 0.077 mmol), and 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (79 mg, 0.20 mmol) in 1,4-dioxane (13.7 mL) and 2M K2CO3 (4.4 mL) was degassed by bubbling nitrogen through the mixture for 10 minutes. The reaction was heated at 95 oC for 16 hours. The mixture was allowed to cool to 20 oC, then was treated with ethyl acetate (60 mL) and water (20 mL). The mixture was shaken, then was filtered. The solid was washed with isopropanol (20 mL), and hexanes (20 mL) to give 3-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]- phenyl}-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester as a grey solid. H
Figure imgf000721_0002
[0866] Step 3: Synthesis of N-[4-(2-amino-ethyl)-phenyl]-4-(2,5-dihydro-1H-pyrrol-3-yl)- benzamide. To a mixture of 3-{4-[4-(2-tert-butoxycarbonylamino-ethyl)-phenylcarbamoyl]-phenyl}- 2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (765 mg, 1.51 mmol) in dichloromethane (7.6 mL) was added trifluoroacetic acid (3.8 mL). The reaction was stirred for 16 hours, then was concentrated. The residue was treated with ethyl acetate (40 mL), then was sonicated for 5 minutes. The mixture was filtered, and the solid was washed with diethyl ether (20 mL), followed by drying     under high vacuum, to give N-[4-(2-amino-ethyl)-phenyl]-4-(2,5-dihydro-1H-pyrrol-3-yl)-benzamide as the bis-TFA salt as a grey solid, that was used without further purification. H
Figure imgf000722_0001
[0867] Step 4: Synthesis of tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[3-(4-{[4-(2- {[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-2,5-dihydro-1H-pyrrol-1-yl]methylidene]carbamate. To a mixture of N-[4- (2-amino-ethyl)-phenyl]-4-(2,5-dihydro-1H-pyrrol-3-yl)-benzamide . 2 TFA (214 mg, 0.40 mmol) in N,N-dimethylformamide (3.8 mL) was added triethylamine (280 mg, 384 ^L, 2.74 mmol). The reaction was stirred for 15 minutes, then N,N’-bis-Boc-guanylpyrazole (392 mg, 1.26 mmol) was added. The reaction was stirred for 15 minutes, then was heated at 35oC for 16 hours. The residue was treated with water (60 mL), then was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), 5% citric acid aqueous solution (20 mL), and brine (10 mL), dried (Na2SO4), and concentrated. The crude material was purified by column on silica (0-60% ethyl acetate/ hexanes), to give tert-butyl N-[(1Z)-{[(tert-butoxy)carbonyl]amino}[3-(4-{[4-(2-{[(1Z)- {[(tert-butoxy)carbonyl]amino}({[(tert-butoxy)carbonyl]imino})methyl]amino}ethyl) phenyl]carbamoyl}phenyl)-2,5-dihydro-1H-pyrrol-1-yl]methylidene]carbamate as a white solid. H
Figure imgf000722_0002
[0868] Step 5: Synthesis of 4-(1-carbamimidoyl-2,5-dihydro-1H-pyrrol-3-yl)-N-[4-(2- guanidino-ethyl)-phenyl]-benzamide. To a mixture of tert-butyl N-[(1Z)-{[(tert- butoxy)carbonyl]amino}[3-(4-{[4-(2-{[(1Z)-{[(tert-butoxy)carbonyl]amino}({[(tert-     butoxy)carbonyl]imino})methyl]amino}ethyl)phenyl]carbamoyl}phenyl)-2,5-dihydro-1H-pyrrol-1- yl]methylidene]carbamate (223 mg, 0.28 mmol) in dichloromethane (2.8 ML) was added trifluoroacetic acid (2.8 mL). The reaction was stirred for 16 hours, then was concentrated. The crude material was purified by preparative-HPLC, to give 4-(1-carbamimidoyl-2,5-dihydro-1H-pyrrol-3-yl)- N-[4-(2-guanidino-ethyl)-phenyl]-benzamide.as the bis-TFA salt as a white solid. MS: 392 M+H+. 1H NMR (300MHz, dmso) δ = 11.16 - 11.00 (m, 1H), 8.85 (d, J=8.2 Hz, 2H), 8.55 (d, J=8.8 Hz, 2H), 8.43 (d, J=8.2 Hz, 2H), 8.24 (br. s., 3H), 8.08 (d, J=8.2 Hz, 2H), 7.53 (br. s., 1H), 5.46 (br. s., 2H), 5.23 (br. s., 2H), 3.60 (br. s., 2H), 3.42 - 3.36 (m, 2H). FORMULATIONS [0869] The present invention also relates to compositions or formulations which comprise the antifungal agents according to the present invention. In general, the compositions of the present invention comprise an effective amount of one or more compounds of the disclosure and salts thereof according to the present invention which are effective for providing treatment of a fungal infection; and one or more excipients. [0870] For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.” [0871] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability. [0872] The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington’s Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing     Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions. [0873] Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antifungal agents. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99 % of the compound. [0874] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like. [0875] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying     agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed. [0876] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo- regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants. [0877] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form. [0878] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, 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 package     form. Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient’s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. [0879] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient. [0880] In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze- actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.     [0881] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms. [0882] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. [0883] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). [0884] Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature. [0885] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository’s melting point, and glycerin.     Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used. [0886] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art. [0887] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein. [0888] Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings inclding its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder. [0889] Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more compounds of the disclosure according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more compounds of the disclosure according to the present invention; and one or more excipients. PROCEDURES [0890] The following procedures can be utilized in evaluating and selecting compounds as antifungal agents. [0891] Fungal MIC Protocol: RPMI/MOPS media (Roswell Park Memorial Institute/3- morpholinopropane-1-sulfonic acid media) is prepared by dissolving 8.4 grams RPMI 1640 (Sigma cat # R1383), 34.52 grams MOPS buffer (Sigma cat # M3183) and 2 grams glucose in 900 mL deionized water. The pH is adjusted to 7.0 with NaOH and filter sterilized. 0.1 mL of a stock spore suspension     (or loop from frozen stock) is inoculated to a 75 mL tissue culture flask (Falcon cat # 353136) containing 50 mL of Potato Dextrose Agar (PDA, 24 grams PD broth (Fisher cat # DF 0549179), 20 grams agar (Fisher cat # BP 1423500) per liter water). Aspergillus and Fusarium strains are grown at 35 oC and Mucor strains are grown at room temperature for 3-5 days. Spores are harvested by flooding the flask with 5 mL phosphate buffered saline (PBS) pH 7.4 + 0.1%Tween-20 and several glass beads (Fisher cat # S800243) are added to aid in agitation. The supernatant is removed and the OD530 of a 1:100 dilution is measured. Spores are diluted in RPMI/MOPS to a final OD530 of 0.002 for Aspergillus and an OD530 of 0.005 for Fusarium and Mucor. The final concentration of spores is approximately 2 x 104 cfu/mL. Test compound(s) are diluted to 200 ug/mL in RPMI/MOPS (28 ul of 10mg/mL DMSO stock in 1400 ul media). Ten (10) serial dilutions are prepared with RPMI/MOPS in a 96-well round bottom plate (Fisher cat # 353136). For Mucor strains a sterile flat-bottom 96-well plate is used.50 µl of compound dilutions in duplicate are added to a sterile 96-well round bottom plate. 50 ul of diluted spores are added to the compound-containing plates. Control wells include 1) compound but no cells and 2) spores but no compound. Mix the plates gently by hand, place in ziplock bags and incubate at 35 oC for 48 hours. Score the MIC visually (lowest concentration of compound showing > 50% growth inhibition) using an inverted mirror. For Mucorales strains the plates are read at OD530 and the concentration of compound that shows 50% growth inhibition is the MIC-50. [0892] Candida Minimal Inhibitory Concentration (MIC): RPMI/MOPS media is prepared by dissolving 8.4g RPMI 1640, 34.52g MOPS buffer and 2g glucose in 900mL water. The pH is adjusted to 7.0 with NaOH. The total volume is brought to 1L and the resulting solution is filter sterilized. The Candida stock is streaked on a Yeast extract Peptone Dextrose (YPD) agar plate and grown at 35 oC for isolation of single colonies. Compounds of the disclosure are diluted to 200 µg/mL in RPMI/MOPS (4.8ul of 10mg/mL DMSO stock in 240ul media). Ten (10) 1:2 serial dilutions are prepared in RPMI/MOPS in a 96-well round bottom plate. Fifty (50) µl of compound dilutions are transferred in duplicate to a sterile tissue culture-treated 96-well flat-bottom, black-sided polypropylene plate. A single colony of Candida from the YPD plate is re-suspended in 5mL phosphate buffered saline (BS) and optical density (OD) at 600nm is measured. The suspension is adjusted to OD = 1.0 and a 1:1000 dilution is prepared in RPMI/MOPS. Fifty (50) ul aliquots of the diluted yeast are added to the plates containing 50µL of compound to all wells except 12E-H. Control wells include: 12 A-D cells, no compound and 12 E-H no cells, no compound. The plates are mixed gently by hand and placed in Ziplok bags in a 35 oC incubator. The OD600 is measured at 24 and 48 hours. The lowest concentration     of a compound that shows a significant reduction in fungal growth is recorded as the MIC and MIC-50 is the concentration of compound that shows 50% growth inhibition. [0893] Table 7: Fungal strains employed in Fungal MIC Protocol
Figure imgf000730_0001
[0894] Table 8: Antifungal activity of exemplary compounds of the disclosure.
Figure imgf000730_0002
   
Figure imgf000731_0001
   
Figure imgf000732_0001
   
Figure imgf000733_0001
   
Figure imgf000734_0001
   
Figure imgf000735_0001
   
Figure imgf000736_0001
 

Claims

  WHAT IS CLAIMED IS: 1. A compound having formula (I):
Figure imgf000737_0001
Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein: ,
Figure imgf000737_0002
X1 is selected from the group consisting of N and CR2a; X2 is selected from the group consisting of N and CR2b; X3 is selected from the group consisting of O, and S; X4 is selected from the group consisting of O, S, and NR1a;    
Figure imgf000738_0001
X5 is selected from the group consisting of N and CR2c; X6 is selected from the group consisting of N and CR2d; A3 is selected from the group consisting of
Figure imgf000738_0002
H H H H H H N N 4 N N N N O R O n R4 S R4 S n R4 NH , NH ,  NH ,  NH ,  R5d NH R5c R4 N N H H H H N N NH NH N R4 N N n R4 N N R5b R5f NH , R5f NH ,  HN R4 , HN R4 , R5a , HN H R5d NH R5d NH R5d NH R5d N R4 R5c R4 R5c R4 R5c R4 R5c NH N N N N H H H R5b R5b R5b R5b R5a ,  R5a , R5a ,  R5a ,    
Figure imgf000739_0001
m is 0, 1, or 2; n is 1, 2, or 3; A4 is selected from the group consisting of
Figure imgf000739_0002
Figure imgf000739_0003
 
Figure imgf000740_0001
, ; q is 0, 1, 2, or 3; t is 1, 2, or 3; R1 is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl; R1 and R2c may be taken together to form a ring consisting of 5 or 6 members; R1a is selected from the group consisting of H, C1-4 alkyl; R2a is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b N ), 9
Figure imgf000740_0002
R ; Y1 is selected from the group consisting of O, NR7; R2b is selected from the group consisting of H, C1-4 alkyl, C3-C5 branched alkyl, C1-4 alkoxy, C3-5 N branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b),
Figure imgf000740_0003
, , S , a d SO2R9; R2c is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 6 N branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R a)(R6b), O2R9;
Figure imgf000740_0004
Y2 is selected from the group consisting of O, NR7; R2d is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 oxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a N branched alk )(R6b), 9
Figure imgf000740_0005
O2R ; Y3 is selected from the group consisting of O and NR7;     R3a is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 N branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a)(R6b), 9
Figure imgf000741_0001
O2R ; Y4 is selected from the group consisting of O and NR7; R3b is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 nched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6a N bra )(R6b), 9
Figure imgf000741_0002
SO2R ; R3c is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 ranched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R6 N b a)(R6b), 9
Figure imgf000741_0003
SO2R ; Y5 is selected from the group consisting of O and NR7; R3d is selected from the group consisting of H, C1-4 alkyl, C3-5 branched alkyl, C1-4 alkoxy, C3-5 6a 6 N branched alkoxy, F, Cl, CN, OCF3, CHF2, CF3, N(R )(R b), 9
Figure imgf000741_0004
O2R ; r is 0, 1, 2, or 3; Y6 is selected from the group consisting of O and NR7; R4 is at each occurrence independently selected from the group consisting of H, C1-4 alkyl, CN, - CH2(CH2)gC1-4 alkoxy, and -CH2(CH2)gC3-5 branched alkoxy; g is 1 or 2; R4a is selected from the group consisting of H and C1-4 alkyl; R4b is selected from the group consisting of H and C1-4 alkyl; R4c is selected from the group consisting of H and C1-4 alkyl; R4d is selected from the group consisting of H and C1-4 alkyl; R4e is selected from the group consisting of H and C1-4 alkyl; R5a is selected from the group consisting of H and C1-4 alkyl; R5b is selected from the group consisting of H and C1-4 alkyl; R5c is selected from the group consisting of H and C1-4 alkyl; R5d is selected from the group consisting of H and C1-4 alkyl; R5e is selected from the group consisting of H and C1-4 alkyl;     R5f is selected from the group consisting of C1-4 alkyl, C3-5 branched alkyl, and C3-5 cycloalkyl; R6a is selected from the group consisting of hydrogen and C1-4 alkyl; R6b is selected from the group consisting of hydrogen and C1-4 alkyl; R7 is a C1-4 alkyl; R8 is a C1-4 alkyl; R9 is a C1-4 alkyl; R3b and R4b are joined to form a heterocyclic ring consisting of five or six members; and R3d and R4c are joined to form a heterocyclic ring consisting of five or six members. 2. The compound of claim 1 having the formula (II)
Figure imgf000742_0001
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 3. The compound of claim 1 having the formula (III)
Figure imgf000742_0002
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 4. The compound of claim 1 having the formula (IV)
Figure imgf000742_0003
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 5. The compound of claim 1 having the formula (V)    
Figure imgf000743_0001
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 6. The compound of claim 1 having the formula (VI)
Figure imgf000743_0003
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 7. The compound of claim 1 having the formula (VII) R4 N H
Figure imgf000743_0002
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 8. The compound of claim 1 having the formula (VIII) including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 9. The compound of claim 1 having the formula (IX)    
Figure imgf000744_0001
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 10. The compound of claim 1 having the formula (X)
Figure imgf000744_0002
including enantiomers, diasteroemers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof. 11. The compound according to claim 1 that is N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3- fluorobenzamide; 4-(carbamimidamidomethyl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-3- fluorophenyl]benzamide; N-[4-(carbamimidamidomethyl)phenyl]-2-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3- thiazole-5-carboxamide; N‐[4‐(2‐carbamimidamidoethyl)phenyl]‐4‐(1‐carbamimidoyl ‐1,2,3,6‐tetrahydropyridin‐4‐ yl)thiophene‐2‐carboxamide; N‐[4‐(2‐carbamimidamidoethyl)phenyl]‐5‐(1-carbamimidoyl ‐1,2,3,6‐tetrahydropyridin‐4‐yl)furan‐2‐ carboxamide; N‐[4‐(2‐carbamimidamidoethyl)phenyl]‐2‐ (1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐1,3‐ thiazole‐5‐carboxamide; N‐[4‐(carbamimidamidomethyl)phenyl]‐5‐(3‐carbamimid amidopropyl)furan‐2‐carboxamide trifluoroacetate;     2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl) ‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]thiophene‐2‐carboxamide; N‐[4‐(carbamimidamidomethyl)phenyl]‐4‐(1‐ carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐ yl)thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐fluorophenyl]thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐methoxyphenyl]thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4yl)phenyl]‐3‐methylthiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐5‐methylthiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ [4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐3‐methoxythiophene‐2‐carboxamide; ‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐3‐fluorothiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydro pyridin‐4‐yl)‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]furan‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐fluorophenyl]furan‐2‐carboxamide; N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl) phenyl]‐4‐(4‐carbamimidoylpiperazin‐1‐ yl)thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐1‐methyl‐1H‐pyrrole‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (4‐carbamimidoylpiperazin‐1‐ yl)phenyl]furan‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐fluorophenyl]‐1‐methyl‐1H‐pyrrole‐2‐carboxamide;     N‐{1'‐carbamimidoyl‐1',2',3',6'‐tetrahydro‐[3,4'‐bipyridin]‐ 6‐yl}‐4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)furan‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[5‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)thiophen‐2‐yl]benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3,5‐difluorophenyl]furan‐2‐carboxamide; 2-(4-carbamimidoyl-piperazin-1-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ (4‐{2‐[(Z)‐N',N',N''‐ trimethylcarbamimidamido]ethyl}phenyl)benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4 ‐yl)‐N‐{4‐[2‐(N‐ methylcarbamimidamido)ethyl]phenyl}benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ [4‐(1‐ carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin ‐4‐yl)‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐N‐methylbenzamide: 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]‐N‐ methylbenzamide; 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]benzamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)furan-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-methoxyphenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2,5-difluorophenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((2-guanidinoethyl)thio)phenyl)thiophene- 2-carboxamide;     5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-guanidinoethoxy)phenyl)thiophene-2- carboxamide: 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorophenyl)thiophene-2-carboxamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-2-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorophenyl)-2-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-guanidinophenyl)-2-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-(4- (guanidinomethyl)henyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)-3-(trifluoromethyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-2-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-chlorophenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-2-chlorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-2-methoxybenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-3-chlorobenzamide; N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-4-(4- carbamimidoylpiperazin-1-yl)-3-fluorobenzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- fluorophenyl)-2-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)-3-chlorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoylazetidin-3-yl)phenyl)-2- methylbenzamide; N-(2-carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2,6- difluorobenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2- methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-methylphenyl)-2,6-difluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-methylphenyl)-2-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-3-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)-2-methylbenzamide;     4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2-methylphenyl)-2- methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-3- methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)-2-methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2- methylphenyl)benzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2- methylphenyl)benzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2-methylphenyl)-3- methylbenzamide; tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)phenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-2-trifluoromethyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-trifluoromethyl-phenyl]-3-fluoro-benzamide; 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-trifluoromethyl-phenyl]-2-methyl-benzamide; 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide; N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-(2-Carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-benzamide;     N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-guanidinomethyl- benzamide; N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-(2-guanidino-ethyl)- benzamide; 2-carbamimidoyl-2,3-dihydro-1H-isoindole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide; N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-guanidino-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-3-chloro-benzamide; 4-{4-[6-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroquinoline-1-carbonyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboximidamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-3-methoxy-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-methoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-(4-guanidinomethyl-phenyl)-benzamide; N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-benzamide; N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide; N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-2-methyl-benzamide; N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-5-fluoro-2-methyl-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-5-methoxy-2-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-ethyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-trifluoromethoxy-phenyl]-3-fluoro-benzamide; 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3,5-difluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2,5-difluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2,3-difluoro-benzamide; 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-ethoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3-chloro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-3-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3,5-difluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2,5-difluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2,3-difluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-5-methyl-phenyl]-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- 3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3,5-difluoro-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-N-[4-(2-guanidino-ethyl)-phenyl]- benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-ethyl-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-2-methyl-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-trifluoromethyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-5-fluoro-phenyl]-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2,3-difluoro-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-phenyl]-2-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-6-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2-guanidino-ethoxy)-phenyl]-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-3-fluoro-benzamide; N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-methoxy-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-2-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-2-fluoro-phenyl]-3-fluoro-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-pyridazin-3-yl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-pyrazin-2-yl]-3-fluoro-benzamide; N-(1'-carbamimidoyl-4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-[5-(4-carbamimidoyl-piperazin-1-yl)-pyridin-2-yl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-benzamide; N-(1'-carbamimidoyl-2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-(1'-carbamimidoyl-5-methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-benzamide; 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-carboxylic acid [4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-amide; 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-carboxylic acid [4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-amide; N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-2-methoxy-benzamide; 4-(2-guanidino-ethyl)-N-[4-(3-guanidino-propyl)-phenyl]-benzamide; N-[2-Amino-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-benzamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-2-carboxylic acid (4- guanidinomethyl-phenyl)-amide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(3-guanidino- propyl)-phenyl]-amide; 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-5-carboxylic acid (4- guanidinomethyl-phenyl)-amide; N-[4-(carbamimidamidomethyl)phenyl]-5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxamide;     N-[4-(carbamimidamidomethyl)phenyl]-5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2- carboxamide; N-[4-(carbamimidamidomethyl)phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3- thiazole-2-carboxamide; 5-(4-carbamimidoylpiperazin-1-yl)-N-[4-(4-carbamimidoylpiperazin-1-yl)phenyl]thiophene-2- carboxamide; 4-(1-carbamimidoyl-2,5-dihydro-1H-pyrrol-3-yl)-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide; or a pharmaceutically acceptable form thereof. 12. A composition comprising an effective amount of at least one compound according to claim 1. 13. A composition according to claim 12, further comprising at least one excipient. 14. A composition according to claim 13, wherein the at least one compound is at least one member selected from the group consisting of: N-[4-(2-carbamimidamidoethyl)phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3- fluorobenzamide; 4-(carbamimidamidomethyl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro pyridin-4-yl)-3- fluorophenyl]benzamide; N-[4-(carbamimidamidomethyl)phenyl]-2-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3- thiazole-5-carboxamide; N‐[4‐(2‐carbamimidamidoethyl)phenyl]‐4‐(1‐carbamimidoyl ‐1,2,3,6‐tetrahydropyridin‐4‐ yl)thiophene‐2‐carboxamide; N‐[4‐(2‐carbamimidamidoethyl)phenyl]‐5‐(1-carbamimidoyl ‐1,2,3,6‐tetrahydropyridin‐4‐yl)furan‐2‐ carboxamide; N‐[4‐(2‐carbamimidamidoethyl)phenyl]‐2‐ (1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐1,3‐ thiazole‐5‐carboxamide; N‐[4‐(carbamimidamidomethyl)phenyl]‐5‐(3‐carbamimid amidopropyl)furan‐2‐carboxamide trifluoroacetate; 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl) ‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]thiophene‐2‐carboxamide;     N‐[4‐(carbamimidamidomethyl)phenyl]‐4‐(1‐ carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐ yl)thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐fluorophenyl]thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐methoxyphenyl]thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4yl)phenyl]‐3‐methylthiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐5‐methylthiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ [4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐3‐methoxythiophene‐2‐carboxamide; ‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐ N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐3‐fluorothiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydro pyridin‐4‐yl)‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]furan‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐fluorophenyl]furan‐2‐carboxamide; N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl) phenyl]‐4‐(4‐carbamimidoylpiperazin‐1‐ yl)thiophene‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐1‐methyl‐1H‐pyrrole‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (4‐carbamimidoylpiperazin‐1‐ yl)phenyl]furan‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3‐fluorophenyl]‐1‐methyl‐1H‐pyrrole‐2‐carboxamide; N‐{1'‐carbamimidoyl‐1',2',3',6'‐tetrahydro‐[3,4'‐bipyridin]‐ 6‐yl}‐4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)furan‐2‐carboxamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[5‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)thiophen‐2‐yl]benzamide;     4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐[4‐ (1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)‐3,5‐difluorophenyl]furan‐2‐carboxamide; 2-(4-carbamimidoyl-piperazin-1-yl)-thiazole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-phenyl]-amide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ (4‐{2‐[(Z)‐N',N',N''‐ trimethylcarbamimidamido]ethyl}phenyl)benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4 ‐yl)‐N‐{4‐[2‐(N‐ methylcarbamimidamido)ethyl]phenyl}benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin‐4‐yl)‐N‐ [4‐(1‐ carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]benzamide; 4‐(1‐carbamimidoyl‐1,2,3,6‐tetrahydropyridin ‐4‐yl)‐N‐[4‐(1‐carbamimidoyl‐1,2,3,6‐ tetrahydropyridin‐4‐yl)phenyl]‐N‐methylbenzamide: 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]‐N‐ methylbenzamide; 4‐(4‐carbamimidoylpiperazin‐1‐yl)‐N‐[4‐(4‐carbamimidoyl piperazin‐1‐yl)phenyl]benzamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)furan-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-methoxyphenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2,5-difluorophenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl)thiophene-2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-((2-guanidinoethyl)thio)phenyl)thiophene- 2-carboxamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(2-guanidinoethoxy)phenyl)thiophene-2- carboxamide: 5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)thiophene-2-carboxamide;     5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorophenyl)thiophene-2-carboxamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-2-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-fluorophenyl)-2-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-guanidinophenyl)-2-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N-(4- (guanidinomethyl)henyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)-3-(trifluoromethyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-2-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-chlorophenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-2-chlorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-2-methoxybenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-3-chlorobenzamide; N-(4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-4-(4- carbamimidoylpiperazin-1-yl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- fluorophenyl)-2-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-2-methylphenyl)-3-fluorobenzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-chlorophenyl)-3-chlorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)-3-fluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoylazetidin-3-yl)phenyl)-2- methylbenzamide; N-(2-carbamimidoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2,6- difluorobenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3-methylphenyl)-2- methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-methylphenyl)-2,6-difluorobenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-methylphenyl)-2-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-3-methylbenzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-2-methylphenyl)-2-methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2-methylphenyl)-2- methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)phenyl)-3- methylbenzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(1-carbamimidoyl-1,2,3,6- tetrahydropyridin-4-yl)-3-fluorophenyl)-2-methylbenzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2- methylphenyl)benzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-3- methylphenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2- methylphenyl)benzamide; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)-2-methylphenyl)-3- methylbenzamide; tert-butyl 4-(4-((4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2- methylphenyl)carbamoyl)-2-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate; 4-(4-carbamimidoylpiperazin-1-yl)-N-(4-(4-carbamimidoylpiperazin-1-yl)phenyl)benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-2-trifluoromethyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-trifluoromethyl-phenyl]-3-fluoro-benzamide; 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-trifluoromethyl-phenyl]-2-methyl-benzamide; 2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide; N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-(2-Carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-benzamide; N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-guanidinomethyl- benzamide; N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-(2-guanidino-ethyl)- benzamide;     2-carbamimidoyl-2,3-dihydro-1H-isoindole-5-carboxylic acid [4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-amide; N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-phenyl]-4-guanidino-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-3-chloro-benzamide; 4-{4-[6-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroquinoline-1-carbonyl]-2- fluorophenyl}-1,2,3,6-tetrahydropyridine-1-carboximidamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-3-methoxy-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-methoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-(4-guanidinomethyl-phenyl)-benzamide; N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-benzamide; N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide; N-(2-carbamimidoyl-2,3-dihydro-1H-isoindol-5-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-2-methyl-benzamide; N-(2-carbamimidoyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-5-fluoro-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2-methyl-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-5-methoxy-2-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-ethyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-trifluoromethoxy-phenyl]-3-fluoro-benzamide; 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- fluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3,5-difluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2,5-difluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-2,3-difluoro-benzamide; 4-(4-carbamimidoyl-piperazin-1-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3- methoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-ethoxy-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-methoxy-phenyl]-3-chloro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-3-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-methyl-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3,5-difluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2,5-difluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2,3-difluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-5-methyl-phenyl]-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)- 3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3,5-difluoro-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-fluoro-N-[4-(2-guanidino-ethyl)-phenyl]- benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-ethyl-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-2-methyl-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-trifluoromethyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-5-fluoro-phenyl]-benzamide;     4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-2-methyl-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2,3-difluoro-phenyl]-2-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-phenyl]-2-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-phenyl]-2-fluoro-6-methyl-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(2-guanidino-ethoxy)-phenyl]-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-chloro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-3-fluoro-benzamide; N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-2-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-fluoro-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-fluoro-benzamide; N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-[4-(4-carbamimidoyl-piperazin-1-yl)-3-methoxy-phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-2-methyl-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-3-chloro-2-fluoro-phenyl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[6-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-pyridazin-3-yl]-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[5-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-pyrazin-2-yl]-3-fluoro-benzamide;     N-(1'-carbamimidoyl-4-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-[5-(4-carbamimidoyl-piperazin-1-yl)-pyridin-2-yl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin- 4-yl)-3-fluoro-benzamide; N-(1'-carbamimidoyl-2-methoxy-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; N-(1'-carbamimidoyl-5-methyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-benzamide; 4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-N-[4-(1-carbamimidoyl-1,2,3,6-tetrahydro- pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-benzamide; 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-5-carboxylic acid [4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-amide; 1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-carboxylic acid [4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-5-fluoro-2-methyl-phenyl]-amide; N-(1'-carbamimidoyl-1',2',3',6'-tetrahydro-[3,4']bipyridinyl-6-yl)-4-(1-carbamimidoyl-1,2,3,6- tetrahydro-pyridin-4-yl)-2-methoxy-benzamide; 4-(2-guanidino-ethyl)-N-[4-(3-guanidino-propyl)-phenyl]-benzamide; N-[2-Amino-4-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-4-(1-carbamimidoyl- 1,2,3,6-tetrahydro-pyridin-4-yl)-3-chloro-benzamide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-2-carboxylic acid (4- guanidinomethyl-phenyl)-amide; 5-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-thiophene-2-carboxylic acid [4-(3-guanidino- propyl)-phenyl]-amide; 2-(1-carbamimidoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidine-5-carboxylic acid (4- guanidinomethyl-phenyl)-amide; N-[4-(carbamimidamidomethyl)phenyl]-5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4- yl)thiophene-2-carboxamide; N-[4-(carbamimidamidomethyl)phenyl]-5-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)furan-2- carboxamide; N-[4-(carbamimidamidomethyl)phenyl]-4-(1-carbamimidoyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3- thiazole-2-carboxamide;     5-(4-carbamimidoylpiperazin-1-yl)-N-[4-(4-carbamimidoylpiperazin-1-yl)phenyl]thiophene-2- carboxamide; 4-(1-carbamimidoyl-2,5-dihydro-1H-pyrrol-3-yl)-N-[4-(2-guanidino-ethyl)-phenyl]-benzamide; or a pharmaceutically acceptable form thereof. 15. A method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein said method comprises: - selecting a subject in need of treating and preventing disease or conditions associated with fungal infection; and - administering to said subject an effective amount of at least one compound according to any one of claims 1 – 14, thereby treating or preventing disease or conditions associated with fungal infection in the subject. 16. The method of claim 15, wherein the at least one compound is administered in a composition further comprising at least one excipient. 17. The method of any one of claims 15 – 16 wherein the fungal infection is an organism from a genus selected from the group consisting of Candida, Cryptococcus, Trichosporon, Malassezia, Aspergillus, Fusarium, Mucor, Blastomyces, Coccidioides, Pneumocystis, Histoplasma, Trichophyton, Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Scedosporium, and Lomentospora. 18. The method of any one of claims 15 - 17, wherein the at least one compound is administered in a composition further comprising at least one excipient. 19. The method of any one of claims 15 – 18, wherein the fungal infection is an organism selected from the group consisting of Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida parapsilosis, Candida dubliniensis Candida auris, Cryptococcus neoformans, Cryptococcus gatti, Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon dermatis, Trichosporon dohaense, Trichosporon inkin, Trichosporon loubieri, Trichosporon mucoides, Trichosporon ovoides, Malassezia globose, Malassezia restricta, Aspergillus fumigatus. Aspergillus. flavis, Aspergillus terreus, Aspergillus niger, Fusarium solani, Fusarium falciforme, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum, Mucor circinelloides, Mucor ramosissimus, Mucor indicus, Mucor rasemosus, Mucor piriformis, Blastomyces     dermatitidis, Blastomyces brasiliensis, Coccidioides immitis, Coccidioides posadasii, Pneumocystis carinii, Pneumocystis jiroveci, Histoplasma capsulatum, Trichophyton schoenleinii, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton rubrum, Rhizopus oryzae, Rhizopus stolonifera, Apophysomyces variabilis, Rhizomucor pusillus, Rhizomucor regularior, Rhizomucor chlamydosporus, Lichtheimia ramosa, Lichtheimia corymbifera, Scedosporium apiospermum, and Lomentospora prolificans. 20. The method of any one of claims 15 - 19, wherein the at least one compound is administered in a composition further comprising at least one excipient. 21. A method of treating or preventing disease or conditions associated with fungal infection in a subject, wherein the fungal infection is selected from the group consisting of candidemia, oral candidiasis, vulvovaginal candidiasis, aspergillosis, allergic bronchopulmonary aspergillosis, allergic aspergillus sinusitis, invasive aspergillosis, disseminated aspergillosis, cryptococcosis, pulmonary cryptococcosis, meningeal cryptococcosis, skin keratitis, athlete’s foot, ringworm, ocular keratitis, onychomycosis, sinusitis, endophthalmitis, otitis, endocarditism pneumonia, osteomyelitis, meningitis, ventriculitis, COVID-19 Associated Pulmonary Aspergillosis (CAPA), Influenza Associated Pulmonary Aspergillosis (IAPA), and combinations thereof, wherein said method comprises: - selecting a subject in need of treating or preventing disease or conditions associated with fungal infection; and - administering to a subject an effective amount of at least one compound according to any one of claims 1 – 14, thereby treating or preventing disease or conditions associated with fungal infection in the subject. 22. The method of claim 21, wherein the at least one compound is administered in a composition further comprising at least one excipient. 23. A method of treating or preventing fungal infection in a plant or plants including wilt disease in tomato, wilt disease cotton, wilt disease banana, wilt of gram, downy mildew of cereals, damping of seedling, rot of ginger, late blight of potato, early blight of potato, blast disease of rice, powdery mildews, tikka disease of groundnut, leaf rust of coffee, red rot of sugarcane, brown rot in pear, brown rot in plum, brown rot in peach, leaf spot of oats, black wart disease of potato, yellow rust of wheat, white rust of crucifers, maize smut, loose smut of wheat, flag     smut of wheat, covered smut of barley, black rust of wheat, bakanese disease, foot rot of rice, and ergot disease of rye wherein said method comprises: - selecting a plant or plants in need of treating or preventing said fungal infection; and - administering to the plant or plants an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing said fungal infection in the plant or plants. 24. The method of claim 23, wherein the at least one compound is administered in a composition further comprising at least one excipient. 25. A method of treating or preventing fungal infections in an animal selected from the group consisting of domesticated animals, livestock, and companion animals, wherein said domesticated animals, livestock and companion animals are selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, buffalo, oxen, llamas, camels, dogs, cats, horses, rabbits, ferrets, and guinea pigs, further wherein said fungal infection includes candidiasis infections, wherein said method comprises: - selecting said domesticated animal, livestock, or companion animal in need of treating or preventing fungal infections; and - administering to said domesticated animal, livestock, or companion animal an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing said fungal infections and said domesticated animal, livestock, or companion animal. 26. The method of claim 25, wherein the at least one compound is administered in a composition further comprising at least one excipient. 27. A method of treating or preventing aspergillosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats, wherein said method comprises: - selecting said animal in need of treating or preventing aspergillosis infections; and - administering to said animal an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing aspergillosis infections in said animal.     28. The method of claim 27, wherein the at least one compound is administered in a composition further comprising at least one excipient. 29. A method of treating or preventing mucormycosis infections in an animal selected from the group consisting of horses, cattle, sheep, goats, dogs and cats wherein said method comprises: - selecting said animal in need of treating or preventing mucormycosis infections; and - administering to said animal an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing mucormycosis infections in said animal. 30. The method of claim 29, wherein the at least one compound is administered in a composition further comprising at least one excipient. 31. A method of treating or preventing coccidioidomycosis in an animal selected from the group consisting of dogs and cats, wherein said coccidioidomycosis infection is caused by infection with an organism selected from the group consisting of Coccidioides immitis and Coccidioides posadasii, wherein said method comprises: - selecting an animal in need of treating or preventing coccidioidomycosis; and - administering to said animal an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing coccidioidomycosis in said animal. 32. The method of claim 31, wherein the at least one compound is administered in a composition further comprising at least one excipient. 33. A method of treating or preventing blastomycosis in an animal selected from the group consisting of dogs and cats, wherein said blastomycosis is caused by infection with Blastomyces dermatitidis, wherein said method comprises: - selecting said animal in need of treating or preventing blastomycosis; and - administering to said animal an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing blastomycosis in said animal. 34. The method of claim 33, wherein the at least one compound is administered in a composition further comprising at least one excipient.     35. A method of treating or preventing Paracoccidioidomycosis in dogs caused by infection with Paracoccidioides brasiliensis, wherein said method comprises: - selecting a dog in need of treating or preventing Paracoccidioidomycosis; and - administering to said dog an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing Paracoccidioidomycosis in said dog. 36. The method of claim 35, wherein the at least one compound is administered in a composition further comprising at least one excipient. 37. A method of treating or preventing dermatophytosis (ringworm) in an animal selected from the group consisting of cats and dogs, wherein said dermatophytosis (ringworm) is caused by infection with an organism selected from the group consisting of Microsporum canis, Microsporum gypseum, and Trichophyton mentagrophytes, wherein said method comprises: - selecting a dog or cat in need of treating or preventing dermatophytosis (ringworm); and - administering to said dog or cat an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing dermatophytosis (ringworm) in the dog or cat. 38. The method of claim 37, wherein the at least one compound is administered in a composition further comprising at least one excipient. 39. A method of treating or preventing cryptococcosis in an animal selected from the group consisting of dogs and cats, wherein said cryptococcosis is caused by infection with an organism selected from the group consisting of Cryptococcus neoformans and Cryptococcus gattii, wherein said method comprises: - selecting a dog or cat in need of treating or preventing cryptococcosis; and - administering to the dog or cat an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing cryptococcosis in the dog or cat. 40. The method of claim 39, wherein the at least one compound is administered in a composition further comprising at least one excipient.     41. A method of treating or preventing histoplasmosis in dogs, wherein said histoplasmosis is caused by infection with Histoplasma capsulatum, wherein said method comprises: - selecting a dog in need of treating or preventing histoplasmosis caused by infection with Histoplasma capsulatum; and - administering to said dog an effective amount of a compound according to any one of claims 1 – 14, thereby treating or preventing histoplasmosis caused by infection with Histoplasma capsulatum in the dog. 42. The method of claim 41, wherein the at least one compound is administered in a composition further comprising at least one excipient.  
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