US Patent 8,697,641 — 4-amino-4-oxobutanoyl peptide cyclic analogues, inhibitors of viral replication

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Abstract

The invention provides 4-amino-4-oxobutanoyl peptides and cyclic analogues thereof of Formula I [structure] and the pharmaceutically salts thereof. The variables are defined herein. Certain compounds of Formula I are useful as antiviral agents. 4-amino-4-oxobutanoyl peptide cyclic analogues as disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more 4-amino-4-oxobutanoyl peptide cyclic analogues and one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions may contain a 4-amino-4-oxobutanoyl peptide cyclic analogue as the only active agent or may contain a combination of a 4-amino-4-oxobutanoyl peptide cyclic analogue and one or more other pharmaceutically active agents. The invention also provides methods for treating viral infections, including Hepatitis C infections, in patients.

Claims

26 · 1 independent · depth 6

26 granted claims

›1.independentA compound of the formula:+25

›2.↳ 1The compound or salt of claim 1, wherein R1 and R2 are joined to form a pyrrolidine, morpholine, piperidine, or piperazine ring, each of which is subs…d2+12

›4.↳ 2A compound or salt of claims 2, wherein R3 is hydrogen or methyl and R4 is hydrogen or C1-C4alkyl.d3+3

›10.↳ 2The compound or salt of claim 2, whereinnR9 is â€”NR10SO2R11; andR11 is C1-C4alkyl, C3-C6cycloalkyl, phenyl, or benzyl, each of which is substituted w…d3+1

›12.↳ 2The compound or salt of claim 2 whereinnY is O, â€”O(Câ• O)â€”, or â€”(NR20)(Câ• O)â€”; andR20 is hydrogen or methyl.d3

›13.↳ 2The compound or salt of claim 2 wherein Z isd3

›14.↳ 2The compound or salt of claim 2, wherein Z is a group of the formulad3+3

›3.↳ 1The compound or salt of claims 1 in which R1 and R2 are taken together to form a group of the formulad2

›8.↳ 1The compound or salt of claim 1, having the formulad2+1

›18.↳ 1A compound or salt of claim 1 of the formulad2+2

›20.↳ 1A method of treating hepatitis C infection in a patient, comprising providing a therapeutically effective amount of one or more compounds of claim 1 t…d2

›22.↳ 1A compound or salt of claim 1, wherein the compound isn(2R,6R,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-…d2

A compound or salt of claim 1, wherein the compound isn(2R,6R,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl4-fluoroisoindoline-2-carboxylate;(2R,6R,13aR,14aR,16a5)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(3S,13R,17R,18aS)-N-(cyclopropylsulfonyl)-17-(7-methoxy-2-phenylquinolin-4-yloxy)-1,14-dioxo-13-(2-oxo-2-(piperidin-1-yl)ethyl)octadecahydropyrrolo[1,2-a][1,4]diazacyclohexadecine-3-carboxamide;(3S,4S,12R,16R,17aS)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-4-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)hexadecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;(3R,12R,16R,17aS)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)hexadecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(3R,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide ;(3 S,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide ;tert-butyl2-((2R,6R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetate;2-((2R,6R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylc arb amoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetic acid;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-6-(2-morpholino-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(12R,16R,17aS,Z)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxylic acid;(3R,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;(3S,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;tert-butyl4-(2-((2R,6R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetyl)piperazine-1-carboxylate;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(2,6-dimethylpiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(3-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-(pyridin-2-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-6-(2-(2-methylmorpholino)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(2,6-dimethylmorpholino)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-6-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-6-(2-(3-methylpiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-2-(2-phenylquinoline-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-ly)ethyl)-2-(2-phenylquinoline-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-ly)ethyl)-2-(2-phenylquinoline-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-2-(2-(pyridin-2-yl)-8,9-dihydro furo[2,3-h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-2-(2-(pyridin-2-yl)-8,9-dihydrofuro[2,3-h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl) ethyl)-2-(2-(pyridin-2-yl)-8,9-dihydro furo[2,3-h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4-(ethylsulfonyl)piperazin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(pyrazin-2-yl)piperazin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a ][1,4]diazacyclopentadecine-14a-carboxamide;tert-butyl2-((2R,6R,14aR,16aS,Z)-2-(8-chloro-7methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetate;2-((2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetic acid;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(2-(trifluoromethyppyrrolidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(6-methoxy-2-(pyridin-2-yl)quinoline-4-carboxamido)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-2-(6-methoxy-2-(pyridin-2-yl)quinoline-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropyrro lidin-1-yl)-2-oxoethyl)-2-(6-methoxy-2-(pyridin-2-yl)quinoline-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS, Z)-N-(cyclopropylsulfonyl)-6-(24(2R,6S)-2,6-dimethylpiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3-fluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-6-(2-((S)-3-aminopyrrolidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;tert-butyl ((3S)-1-(2-((2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetyl)pyrrolidin-3-yl) methylcarbamate;tert-butyl ((3S)-1-(2-((2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetyl)pyrrolidin-3-yl) methylcarbamate;(2R,6R,14aR,16aS,Z)-6-(2-((S)-3-(aminomethyl)pyrrolidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-6-(2-((R)-3-aminopyrrolidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-6-(2-((R)-3-(2-aminoprop an-2-yl)pyrro lidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(24(S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-6-(24(Z)-3-(aminomethyl)-4-(methoxyimino)-3-methylpyrrolidin-1-yl)-2-oxoethyl)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-6-(2-((S)-3-(2-aminopropan-2-yl)pyrro lidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-6-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyppiperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-8-methyl-2-(pyridin-2-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-8-methyl-2-(pyridin-2-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(6-methoxy-3-phenylnaphthalen-1-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(2-(isopropylamino)thiazol-4-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl) ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,16aS,Z)-2-(5-chloro-6-methoxyisoquinolin-1-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,16aS,Z)-2-(5-chloro-6-methoxyisoquinolin-1-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin- 1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,16aS,Z)-2-(5-chloro-6-methoxyisoquinolin-1-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-2-(2-(pyridin-2-yl)-8,9-dihydro-7H-cyclop enta [h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl) ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-2-(2-(pyridin-2-yl)-8,9-dihydro-7H-cyclopenta[h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-8-methyl-2-(pyridin-3-yl)quinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(5-chloro-6-methoxy-3-(pyridin-2-yl)isoquinolin-1-yloxy)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-8-methyl-2-(pyridin-3-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-2-(5-chloro-6-methoxy-3-(pyridin-2-yl)isoquinolin-1-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-2-(2-(2-isopropylthiazol-4-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluorocyclohexyl)-2-oxoethyl)-2-(2-(2-(isopropylamino)thiazol-4-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; or(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3-fluoropiperidin-1-yl)-2-oxoethyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide.

›23.↳ 1A compound or salt thereof of claim 1, wherein the compound isd2

›24.↳ 1A compound or salt thereof of claim 1, wherein the compound isd2

›25.↳ 1A compound or salt thereof of claim 1, wherein the compound isd2

›26.↳ 1A compound or salt thereof of claim 1, wherein the compound isd2

Classifications

4 codes

IPC · International Patent Classification

Section A — Human necessities

A01N37/18

USPC · US Patent Classification

514/4.3530/331514/1.1

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Cecilia J Tsang

art unit 1654 · TC 1600

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17 Jul 2009

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Type	Document	Date
provisional	US 61226323	17 Jul 2009
related publication	US 20100152103 A1	17 Jun 2010

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