Pentacyclic derivatives as Zika virus inhibitors

Abstract

Provided herein are compounds of formula (I), wherein the various substituents are defined herein. JPEG2024519910000064.jpg25128

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This patent application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 191,678, filed May 21, 2021. The above-referenced application is hereby incorporated by reference in its entirety. [Background technology]

[0002] Zika virus is a mosquito-borne, single-stranded, positive-sense RNA flavivirus that emerged from relative obscurity and has caused epidemics that are of major public health concern. Outbreaks of Zika virus disease have been documented in Africa, the Americas, Asia, and the Pacific. The introduction of Zika virus into the Western Hemisphere is believed to have occurred in Haiti and Brazil in 2014-2015 and has rapidly spread to over 33 countries. Historically, symptomatic Zika virus infection in humans has been described as a self-limited mild febrile illness associated with rash, arthralgia, and conjunctivitis. However, recent Zika virus infections have also been associated with neurological complications, including Guillain-Barré syndrome and meningoencephalitis. Of major concern, Zika virus infection is now strongly associated with microcephaly and intrauterine growth retardation in fetuses of women infected with the virus during pregnancy. Zika infection in pregnancy can also result in pregnancy complications such as miscarriage, stillbirth, and premature birth.

[0003] Currently, there is no vaccine to prevent Zika virus disease. Thus, there is a need for therapeutic or prophylactic interventions to treat or prevent Zika virus disease, especially in women of childbearing age. Summary of the Invention [Means for solving the problem]

[0004] Provided herein are compounds and methods for the treatment or prevention of Zika virus infection.

[0005] In one embodiment, the compound generally has the formula (I):

[0006] [ka] [In the formula, R 1a and R 1b are each independently halo, C 1~6 is alkyl or cycloalkyl; P 1a teeth,

[0007] [ka] is selected from the group consisting of P 1b teeth,

[0008] [ka] is selected from the group consisting of V 1a and V 1b are each independently

[0009] [ka] is selected from the group consisting of E 1a and E 1b are each independently -N(H)(C 1~6 Alkoxycarbonyl), N(H)(C 3~12 Cycloalkylcarbonyl), N(H)(C 1~6 alkylcarbonyl), or -N(H)(C 3~12 or a stereoisomer, pharma- ceutically acceptable salt or solvate thereof.

[0010] In another embodiment, a compound of formula (I):

[0011] [ka] [In the formula, R 1 Halo, C 1~10 Alkyl, C 3~12 cycloalkyl or cyano; P 1a and P 1b are each independently

[0012] [ka] is selected from V 1a and V 1b are each independently

[0013] [ka] is selected from E 1a and E 1b are each independently -N(H)(C 1~6 -N(H)(cycloalkoxycarbonyl), -N(H)(cycloalkylcarbonyl), -N(H)(alkylcarbonyl), or -N(H)(cycloalkoxycarbonyl); However, P 1a but

[0014] [ka] and V 1a and V 1b Both

[0015] [ka] If R 1 Halo, C 1~6 Alkyl, C 4~7 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, together with a pharma- ceutically acceptable excipient.

[0016] In another embodiment of the invention, there is provided a method of treating a Zika virus infection in a subject in need thereof, comprising administering to the subject an antibody of formula (I):

[0017] [ka] [In the formula, R 1 Halo, C 1~10 Alkyl, C 3~12 cycloalkyl or cyano; P 1a and P 1b are each independently

[0018] [ka] is selected from V 1a and V 1b are each independently

[0019] [ka] is selected from E 1a and E 1b are each independently -N(H)(C 1~6 -N(H)(cycloalkoxycarbonyl), -N(H)(cycloalkylcarbonyl), -N(H)(alkylcarbonyl), or -N(H)(cycloalkoxycarbonyl); However, P 1a but

[0020] [ka] and V 1a and V 1b Both

[0021] [ka] If R 1 Halo, C 1~6Alkyl, C 4~7 provided that the compound is cycloalkyl or cyano, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0022] In another embodiment, the subject is a human.

[0023] In another embodiment, the subject is a female subject of childbearing age.

[0024] In another embodiment, the subject is a pregnant female.

[0025] In another embodiment, the compound is admixed with a pharma- ceutically acceptable excipient in a pharmaceutical composition.

[0026] In another embodiment, a method of preventing Zika virus infection is provided comprising administering to a subject in need thereof an antibody of formula (I):

[0027] [ka] [In the formula, R 1 Halo, C 1~10 Alkyl, C 3~12 cycloalkyl or cyano; P 1a and P 1b are each independently

[0028] [ka] is selected from V 1a and V 1b are each independently

[0029] [ka] is selected from E 1a and E 1bare each independently -N(H)(C 1~6 -N(H)(cycloalkoxycarbonyl), -N(H)(cycloalkylcarbonyl), -N(H)(alkylcarbonyl), or -N(H)(cycloalkoxycarbonyl); However, P 1a but

[0030] [ka] and V 1a and V 1b Both

[0031] [ka] If R 1 Halo, C 1~6 Alkyl, C 4~7 provided that the compound is cycloalkyl or cyano, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0032] In another embodiment, the subject is a human.

[0033] In another embodiment, the subject is a female subject of childbearing age.

[0034] In another embodiment, the subject is a pregnant female.

[0035] In another embodiment, the compound is mixed with a pharma- ceutically acceptable excipient in a pharmaceutical composition.Other and further embodiments will occur to those skilled in the art, and minor variations are intended to be encompassed within the scope of the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the invention as defined by the embodiments.

[0037] The compounds described herein may be, for example, 3 It will be understood that whenever "alkyl" is substituted with more than one of the same groups, the groups can be the same or different, i.e., each group is independently selected.

[0038] "Absent" - Some groups are defined such that they may not be present. When a group is absent, it becomes a bond connector. Two groups that would otherwise be connected to the absent group are connected to each other via a bond. For example, when W is absent, M is bonded to M.

[0039] "Alkyl" means a C1-C alkyl group containing normal, secondary, tertiary, or cyclic carbon atoms. 18It is a hydrocarbon. Examples include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3 )CH2CH3), 2-Methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2-CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3 )CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and cyclopropylmethyl

[0040] [ka] Examples include:

[0041] "Alkenyl" refers to an alkyl group containing normal, secondary, tertiary, or cyclic carbon atoms and at least one site of unsaturation, i.e., carbon-carbon, sp 2 C2-C containing double bonds18 It is a hydrocarbon. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0042] "Alkynyl" refers to a C-C alkyl group containing normal, secondary, tertiary, or cyclic carbon atoms and at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. 18 It is a hydrocarbon. Examples include, but are not limited to, acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0043] "Alkylene" refers to a saturated branched or straight chain or cyclic hydrocarbon radical of 1 to 18 carbon atoms having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0044] "Alkenylene" refers to an unsaturated branched or straight chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0045] "Alkynylene" refers to an unsaturated branched or straight chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CH2C≡C-), and 4-pentynyl (-CH2CH2CH2C≡C-).

[0046] "Aryl" means a monovalent aromatic hydrocarbon radical of 6 to 20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0047] "Arylalkyl" refers to an alkyl group consisting of a carbon atom, typically a terminal or sp 3 refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom of is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. An arylalkyl group contains 6 to 20 carbon atoms, e.g., the alkyl portion, including the alkanyl, alkenyl, or alkynyl group of the arylalkyl group, is 1 to 6 carbon atoms and the aryl portion is 5 to 14 carbon atoms.

[0048] The term "polycarbocycle" refers to a saturated or unsaturated polycyclic ring system having from about 6 to about 25 carbon atoms and having two or more rings (e.g., 2, 3, 4, or 5 rings). These rings can be fused and / or bridged to form a polycyclic ring system. For example, this term includes bicyclo[4,5], [5,5], [5,6], or [6,6] ring systems, as well as the following bridged ring systems:

[0049] [ka] (i.e., [2.1.1], [2.2.1], [3.3.3], [4.3.1], [2.2.2], [4.2.2], [4.2.1], [4.3.2], [3.1.1], [3.2.1], [4.3.3], [3.3.2], [3.2.2] and [3.3.1] polycyclic rings, respectively), which can be linked to the remainder of the compound of formula (I) through any synthetically feasible position. As with other polycarbocyclic rings, these representative bicyclic and fused ring systems can optionally contain one or more double bonds in the ring system.

[0050] The term "polyheterocycle" refers to a ring in which one or more carbon atoms are heteroatoms (e.g., O, S, S(O), S(O), N + (O - )R x , or NR x )[where each R x are independently H, (C1-10) alkyl, (C2-10) alkenyl, (C2-10) alkynyl, (C1-10) alkanoyl, S(O)NR n R p , S(O)2R x or (C1-10)alkoxy, each of (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C1-10)alkanoyl, and (C1-10)alkoxy optionally substituted with one or more halo.

[0051] "Substituted alkyl", "substituted aryl" and "substituted arylalkyl" refer to alkyl, aryl and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Exemplary substituents include, but are not limited to, halo (e.g., F, Cl, Br, I), -R, -OR, -SR, -NR2, -CF3, -CCl3, -OCF3, -CN, -NO2, -N(R)C(=O)R, -C(=O)R, -OC(=O)R, -C(O)OR, -C(=O)NRR, -S(=O)R, -S(=O)2OR, -S(=O)2R, -OS(=O)2OR, -S(=O)2NRR, where each R is independently -H, alkyl, aryl, arylalkyl or heterocycle. Alkylene, alkenylene and alkynylene groups can also be similarly substituted.

[0052] The term "optionally substituted" with respect to a particular moiety of a compound of Formula I (eg, an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more substituents.

[0053] Symbols in ring structures

[0054] [ka] means that the bond is a single bond or a double bond.

[0055] [ka] teeth,

[0056] [ka] It could be.

[0057] As used herein, "haloalkyl" includes alkyl groups substituted with one or more halogens, such as F, Cl, Br, or I. Representative examples of haloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.

[0058] As used herein, "heterocyclic ring" includes, by way of example and not limitation, those heterocyclic rings described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), especially volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one particular embodiment of the invention, "heterocyclic ring" includes "carbocyclic ring" as defined herein, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., O, N, or S).

[0059] Examples of heterocyclic rings include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidyl, and the like. nyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl , 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, furanyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and the following bis-tetrahydrofuranyl:

[0060] [ka]

[0061] By way of example and not of limitation, the carbon-bonded heterocycle is bonded at the 2-, 3-, 4-, 5-, or 6-position of a pyridine, the 3-, 4-, 5-, or 6-position of a pyridazine, the 2-, 4-, 5-, or 6-position of a pyrimidine, the 2-, 3-, 5-, or 6-position of a pyrazine, the 2-, 3-, 4-, or 5-position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of an oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of an isoxazole, pyrazole, or isothiazole, the 2- or 3-position of an aziridine, the 2-, 3-, or 4-position of an azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of a quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of an isoquinoline. Even more typically, the carbon-linked heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

[0062] By way of example and not limitation, nitrogen-linked heterocycles are bonded at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, nitrogen-linked heterocycles include 1-aziridyl, 1-azetyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0063] "Carbocycle" refers to a saturated, unsaturated or aromatic ring having up to about 25 carbon atoms. Typically, a carbocycle has about 3-7 carbon atoms as a monocycle, about 7-12 carbon atoms as a bicycle, and up to about 25 carbon atoms as a polycycle. A monocyclic carbocycle typically has 3-6 ring atoms, and even more typically has 5 or 6 ring atoms. A bicyclic carbocycle typically has 7-12 ring atoms arranged, for example, as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. The term carbocycle includes "cycloalkyl", which is a saturated or unsaturated carbocycle. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl, and naphthyl.

[0064] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0065] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0066] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.

[0067] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0068] With respect to a disease or condition, the term "treatment" or "treating" includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and / or alleviating one or more symptoms of the disease or condition.

[0069] Stereochemical definitions and rules used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes (D and L) or (R and S) are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and I, or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. The present invention includes all stereoisomers of the compounds described herein.

[0070] As used herein, the term "alkenyl" refers to a straight or branched chain group of 2 to 6 carbon atoms containing at least one carbon-carbon double bond.

[0071] The term "alkenyloxy," as used herein, refers to an alkenyl group attached to the parent molecular moiety through an oxygen atom.

[0072] The term "alkenyloxycarbonyl," as used herein, refers to an alkenyloxy group attached to the parent molecular moiety through a carbonyl group.

[0073] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.

[0074] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with one, two or three alkoxy groups.

[0075] The term "alkoxyalkylcarbonyl," as used herein, refers to an alkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.

[0076] The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0077] As used herein, the term "alkoxycarbonylalkyl" refers to an alkyl group substituted with one, two or three alkoxycarbonyl groups.

[0078] As used herein, the term "alkyl" refers to a group derived from a straight or branched chain saturated hydrocarbon containing from 1 to 6 carbon atoms.

[0079] The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.

[0080] As used herein, the term "alkylcarbonylalkyl" refers to an alkyl group substituted with one, two or three alkylcarbonyl groups.

[0081] The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group attached to the parent molecular moiety through an oxygen atom.

[0082] The term "alkylsulfanyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.

[0083] The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.

[0084] As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both of the rings are phenyl groups. A bicyclic fused ring system consists of a phenyl group fused to a 4- to 6-membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present disclosure include alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR X R Y , -(NR X R Y) alkyl, oxo, and -P(O)OR2, where each R is independently selected from hydrogen and alkyl, the alkyl portions of the arylalkyl and heterocyclylalkyl are unsubstituted, and the second aryl group, the aryl portion of the arylalkyl, the aryl portion of the arylcarbonyl, the heterocyclyl, and the heterocyclyl portions of the heterocyclylalkyl and heterocyclylcarbonyl are further optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

[0085] As used herein, the term "arylalkenyl" refers to an alkenyl group substituted with one, two or three aryl groups.

[0086] The term "arylalkoxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0087] As used herein, the term "arylalkoxyalkyl" refers to an alkyl group substituted with one, two or three arylalkoxy groups.

[0088] The term "arylalkoxyalkylcarbonyl," as used herein, refers to an arylalkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.

[0089] The term "arylalkoxycarbonyl," as used herein, refers to an arylalkoxy group attached to the parent molecular moiety through a carbonyl group.

[0090] As used herein, the term "arylalkyl" refers to an alkyl group substituted with one, two, or three aryl groups. The alkyl portion of an arylalkyl can be any of alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and -NR cR d and wherein heterocyclyl is selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR X R Y is optionally further substituted with 1 or 2 substituents independently selected from:

[0091] The term "arylalkylcarbonyl," as used herein, refers to an arylalkyl group attached to the parent molecular moiety through a carbonyl group.

[0092] The term "arylcarbonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group.

[0093] The term "aryloxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

[0094] As used herein, the term "aryloxyalkyl" refers to an alkyl group substituted with one, two or three aryloxy groups.

[0095] The term "aryloxycarbonyl," as used herein, refers to an aryloxy group attached to the parent molecular moiety through a carbonyl group.

[0096] The term "arylsulfanyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfur atom.

[0097] The term "arylsulfonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.

[0098] As used herein, the terms "Cap" and "cap" refer to a group placed on the nitrogen atom of a terminal nitrogen-containing ring. It should be understood that "Cap" or "cap" can refer to a reagent used to add a group to the terminal nitrogen-containing ring or a fragment in the final product.

[0099] As used herein, the term "carbonyl" refers to -C(=O)-.

[0100] As used herein, the term "carboxy" refers to -CO2H.

[0101] As used herein, the term "cyano" refers to --CN.

[0102] As used herein, the term "cyanoalkyl" refers to an alkyl group having at least one -CN substituent.

[0103] As used herein, the term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having 3 to 7 carbon atoms and no heteroatoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups of the present disclosure include alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and -NR x R y and aryl and heterocyclyl are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.

[0104] As used herein, the term "(cycloalkyl)alkenyl" refers to an alkenyl group substituted with one, two or three cycloalkyl groups.

[0105] As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group substituted with one, two, or three cycloalkyl groups. The alkyl portion of a (cycloalkyl)alkyl is substituted with hydroxy and -NR c R d and optionally further substituted with 1 or 2 groups independently selected from:

[0106] The term "cycloalkyloxy," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0107] As used herein, the term "cycloalkyloxyalkyl" refers to an alkyl group substituted with one, two or three cycloalkyloxy groups.

[0108] The term "cycloalkylsulfonyl," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through a sulfonyl group.

[0109] As used herein, the term "formyl" refers to --CHO.

[0110] As used herein, the terms “halo” and “halogen” refer to F, Cl, Br, or I.

[0111] The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0112] The term "haloalkoxycarbonyl," as used herein, refers to a haloalkoxy group attached to the parent molecular moiety through a carbonyl group.

[0113] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one, two, three or four halogen atoms.

[0114] The term "haloalkylsulfanyl," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through a sulfur atom.

[0115] As used herein, the term "heterocyclyl" refers to a 4-, 5-, 6-, or 7-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A 4-membered ring has no double bonds, a 5-membered ring has 0-2 double bonds, and a 6- and 7-membered ring has 0-3 double bonds. The term "heterocyclyl" also includes bicyclic groups in which the heterocyclyl ring is fused to another monocyclic heterocyclyl group or to a 4- or 6-membered aromatic or non-aromatic carbocyclic ring, as well as bridged bicyclic groups, such as 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-yl, and 2-azabicyclo[2.2.2]oc-3-yl. The heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through any carbon or nitrogen atom in the group. Examples of heterocyclyl groups include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, thiomorpholinyl, 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-yl, and 2-azabicyclo[2.2.2]oc-3-yl. Heterocyclyl groups of the present disclosure include alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR X R Y , -(NR X R Y) alkyl, and oxo; and the alkyl portions of the arylalkyl and heterocyclylalkyl are unsubstituted, and the aryl, the aryl portion of the arylalkyl, the aryl portion of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl portion of the heterocyclylalkyl and heterocyclylcarbonyl are further optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

[0116] As used herein, the term "heterocyclylalkenyl" refers to an alkenyl group substituted with one, two or three heterocyclyl groups.

[0117] The term "heterocyclylalkoxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group.

[0118] The term "heterocyclylalkoxycarbonyl," as used herein, refers to a heterocyclylalkoxy group attached to the parent molecular moiety through a carbonyl group.

[0119] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with one, two, or three heterocyclyl groups. The alkyl portion of a heterocyclylalkyl can be any of alkoxy, alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR c R d and wherein aryl is selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR X R Y is optionally further substituted with 1 or 2 substituents independently selected from:

[0120] The term "heterocyclylalkylcarbonyl," as used herein, refers to a heterocyclylalkyl group attached to the parent molecular moiety through a carbonyl group.

[0121] As used herein, the term "heterocyclylcarbonyl" means It refers to a heterocyclyl group attached to the parent molecular moiety through a carbonyl group.

[0122] The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an oxygen atom.

[0123] As used herein, the term "heterocyclyloxyalkyl" refers to an alkyl group substituted with one, two or three heterocyclyloxy groups.

[0124] The term "heterocyclyloxycarbonyl," as used herein, refers to a heterocyclyloxy group attached to the parent molecular moiety through a carbonyl group.

[0125] As used herein, the term "hydroxy" refers to --OH.

[0126] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one, two or three hydroxy groups.

[0127] The term "hydroxyalkylcarbonyl," as used herein, refers to a hydroxyalkyl group attached to the parent molecular moiety through a carbonyl group.

[0128] As used herein, the term "nitro" refers to --NO.

[0129] As used herein, "-NR a R b " refers to two groups, Ra and R b Refers to. R a and R b is independently selected from hydrogen, alkenyl, and alkyl.

[0130] As used herein, "(NR a R b The term "alkyl" refers to one, two or three -NR a R b It refers to an alkyl group substituted with a group.

[0131] As used herein, "(NR a R b The term "carbonyl" refers to an -NR a R b Refers to the base.

[0132] As used herein, "-NR c R d " The term "aryl" refers to two groups, R c and R d Refers to. R c and R d is hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f ) alkyl, (NR e R f ) alkylcarbonyl, (NR e R f ) carbonyl, (NR e R f)sulfonyl, -C(NCN)OR', and -C(NCN)NR X R Y R' is selected from alkyl and unsubstituted phenyl, and the alkyl portion of the arylalkyl, arylalkylcarbonyl, heterocyclylalkyl, and heterocyclylalkylcarbonyl is independently selected from -NR e R f The aryl moiety of aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, and arylsulfonyl, heterocyclyl, and the heterocyclyl moiety of heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, and heterocyclyloxycarbonyl are further optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

[0133] As used herein, "(NR c R d The term "alkenyl" refers to one, two or three -NR c R d It refers to an alkenyl group substituted with a group.

[0134] As used herein, "(NR c R d The term "alkyl" refers to one, two or three -NR c R d (NR c R d The alkyl portion of (NR )alkyl is alkoxy, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylsulfanyl, arylalkoxyalkylcarbonyl, carboxy, heterocyclyl, heterocyclylcarbonyl, hydroxy, and (NR e R f) carbonyl, where the heterocyclyl is further optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

[0135] As used herein, "(NR c R d The term "carbonyl" refers to an -NR c R d Refers to the base.

[0136] As used herein, "-NR e R f " refers to two groups, R e and R f Refers to. R e and R f is hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, -(NR X R Y ) alkyl, and -(NR X R Y ) carbonyl.

[0137] As used herein, "(NR e R f The term "alkyl" refers to one, two or three -NR e R f It refers to an alkyl group substituted with a group.

[0138] As used herein, "(NR e R f The term "alkylcarbonyl" refers to a (NR) alkyl group attached to the parent molecular moiety through a carbonyl group. e R f ) alkyl group.

[0139] As used herein, "(NR e R f The term "carbonyl" refers to an -NR e R f Refers to the base.

[0140] As used herein, "(NR e R f The term "sulfonyl" refers to an -NR e R f Refers to the base.

[0141] As used herein, "-NR X R Y " refers to two groups, R X and R Y Refers to. R X and R Y is hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X R Y ) carbonyl; R X and R Y is independently selected from hydrogen and alkyl.

[0142] As used herein, "(NR X R Y The term "alkyl" refers to one, two or three -NR X R Y It refers to an alkyl group substituted with a group.

[0143] As used herein, the term "oxo" refers to =O.

[0144] As used herein, the term "sulfonyl" refers to -SO2-.

[0145] As used herein, the term "trialkylsilyl" refers to -SiR3, where R is alkyl. The R groups can be the same or different.

[0146] As used herein, the term "trialkylsilylalkyl" refers to an alkyl group substituted with one, two or three trialkylsilyl groups.

[0147] The term "trialkylsilylalkoxy," as used herein, refers to a trialkylsilylalkyl group attached to the parent molecular moiety through an oxygen atom.

[0148] As used herein, the term "trialkylsilylalkoxyalkyl" refers to an alkyl group substituted with one, two, or three trialkylsilylalkoxy groups.

[0149] Prodrug As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a compound of the invention that inhibits Zika virus activity (an "active inhibitor compound"). The compound may be formed from the prodrug as a result of (i) spontaneous chemical reaction(s), (ii) enzyme-catalyzed chemical reaction(s), (iii) photolysis, and / or (iv) metabolic chemical reaction(s).

[0150] A "prodrug moiety" refers to a labile functional group that separates from an active inhibitory compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes capable of enzymatic activation mechanisms with the prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases. Prodrug moieties can serve to enhance solubility, absorption, and lipophilicity, optimizing drug delivery, bioavailability, and efficacy. Prodrug moieties may include active metabolites or the drug itself.

[0151] Exemplary prodrug moieties include hydrolytically sensitive or unstable acyloxymethyl esters, -CHOC(=O)R 99 , and acyloxymethyl carbonate -CH2OC(=O)OR 99 R 99 is C1-C6 alkyl, C1-C6 substituted alkyl, C6-C 20 Aryl or C6-C 20The aryl is substituted. Acyloxyalkyl esters were first used as a prodrug strategy for carboxylic acids, and then applied to phosphates and phosphonates by Farquhar et al. (1983) J.Pharm.Sci.,72:324; and U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756. Acyloxyalkyl esters were then used to deliver phosphonic acids across cell membranes and enhance oral bioavailability. Close variants of acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters (carbonates), can also enhance oral bioavailability as prodrug moieties in the compounds of the combination of the present invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy (POM)-CH2OC(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethyl carbonate (POC)-CH2OC(=O)OC(CH3)3.

[0152] Aryl esters of phosphorus groups, especially phenyl esters, have been reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37:498). Phenyl esters containing a carboxylate ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters have been reported to generate the parent phosphonic acid. In some cases, substituents at the ortho or para positions can promote hydrolysis. Benzyl analogs bearing acylated or alkylated phenols can generate phenolic compounds through the action of enzymes, e.g., esterases, oxidases, etc., which are then cleaved with a benzylic CO bond to generate a phosphate and a quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. II 2345; Glazier WO 91 / 19721. Still other benzyl prodrugs have been described that contain a carboxylic acid ester-containing group attached to the benzyl methylene (Glazier WO 91 / 19721). Thio-containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates a free thio intermediate, which is subsequently decomposed to a phosphate and an episulfide (Puech et al. (1993) Antiviral Res., 22:155-174; Benzaria et al. (1996) J. Med. Chem. 39:4958).

[0153] protecting group In the context of this invention, protecting groups include prodrug moieties and chemical protecting groups.

[0154] "Protecting group" refers to a moiety of a compound that masks or changes the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to aid in the effectiveness of desired chemical reactions, for example, to create and break chemical bonds in an orderly and planned manner. Protection of a functional group of a compound changes other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates can themselves be biologically active or inactive.

[0155] Protected compounds may also exhibit altered, and in some cases optimized, properties in vitro and in vivo, such as passage through cell membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of the protecting group is to convert the parent drug into a prodrug, whereby the parent drug is released upon in vivo conversion of the prodrug. Since the active prodrug may be absorbed more effectively than the parent drug, the prodrug may have greater efficacy in vivo than the parent drug. Protecting groups are removed in vitro in the case of chemical intermediates, or in vivo in the case of prodrugs. In the case of chemical intermediates, it is not particularly important that the product obtained after deprotection, such as an alcohol, is physiologically acceptable, but it is generally more desirable if the product is pharmacologically harmless.

[0156] Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during the synthetic procedures, i.e., routes or methods, for preparing the compounds of the present invention. In most cases, the decision as to which group to protect, when to protect, and the nature of the chemical protecting group "PG" will depend on the chemical nature of the reaction to be protected (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. If a compound is substituted with multiple PGs, the PGs do not need to be, and generally are not, the same. In general, PGs are used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups, thus preventing side reactions or otherwise facilitating the efficiency of the synthesis. The order of deprotection to obtain the free deprotected groups will depend on the intended direction of the synthesis and the reaction conditions encountered, and may occur in any order as determined by one of skill in the art.

[0157] Various functional groups of the compounds of the present invention can be protected. For example, the protecting group of -OH group (whether hydroxyl, carboxylic acid, phosphonic acid, or other functional group) includes "ether- or ester-forming group". Ether- or ester-forming group can function as chemical protecting group in the synthesis scheme described herein. However, some hydroxyl- and thio-protecting groups are not ether- or ester-forming groups, as will be understood by those skilled in the art, and are included with amides discussed below.

[0158] A large number of hydroxyl protecting groups and amide forming groups, as well as the corresponding chemical cleavage reactions, are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated herein by reference in its entirety. In particular, Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, and Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other protecting groups for acids, see Greene, infra.

[0159] By way of example and not limitation, R 1 , R 3 , R A1 , R A3 and X A are recursive substituents in certain embodiments. Typically, in a given embodiment, each of these may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 times. More typically, in a given embodiment, each of these may independently occur 12 or fewer times. When the compounds described herein contain multiple groups with the same designated group, e.g., "R 1 " or "R 3", it is understood that whenever more than one of ", " is substituted, the groups can be the same or different, i.e., each group is independently selected. The wavy lines indicate the site of covalent attachment to the adjacent group, moiety, or atom.

[0160] In one embodiment of the present invention, the compound is in isolated and purified form. In general, the term "isolated and purified" means that the compound is substantially free of biological material (e.g., blood, tissue, cells, etc.). In one particular embodiment of the present invention, the term means that the compound or complex of the present invention is at least about 50% free by weight of biological material, in another particular embodiment, the term means that the compound or complex of the present invention is at least about 75% free by weight of biological material, in another particular embodiment, the term means that the compound or complex of the present invention is at least about 90% free by weight of biological material, in another particular embodiment, the term means that the compound or complex of the present invention is at least about 98% free by weight of biological material, in another particular embodiment, the term means that the compound or complex of the present invention is at least about 99% free by weight of biological material. In another particular embodiment, the present invention provides a compound or complex of the present invention that is synthetically prepared (e.g., ex vivo).

[0161] stereoisomer The compounds of the present invention may have chiral centers, such as chiral carbon or phosphorus atoms. Thus, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, the chiral centers evident from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as individual isolated or synthesized optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. Racemic mixtures are separated into their individual substantially optically pure isomers through well-known techniques, for example, separation of diastereomeric salts formed with optically active auxiliaries, such as acids or bases, followed by conversion to optically active substances. In most cases, the desired optical isomer is synthesized by stereospecific reactions beginning with the appropriate stereoisomer of the desired starting material.

[0162] The compounds of the present invention may also exist as tautomeric isomers in certain cases.Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the present invention.For example, ene-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention.

[0163] Salts and hydrates Examples of "physiologically acceptable salts" of the compounds herein include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. + (X is C 1~Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid; salts of organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of compounds of hydroxy groups include salts of Na + and NX4 + (X is independently selected from H or a C1-C4 alkyl group).

[0164] For therapeutic use, the salts of the active ingredients of the compounds of the present invention are typically physiologically acceptable. That is, they are salts derived from physiologically acceptable acids or bases. However, salts of non-physiologically acceptable acids or bases can also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts are within the scope of the present invention, whether derived from physiologically acceptable acids or bases or not.

[0165] Metal salts are typically prepared by reacting the metal hydroxide with a compound herein. Examples of metal salts thus prepared are Li + , Na + , and K + A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0166] In addition, salts may be formed from the acid addition of certain organic and inorganic acids, such as HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it should be understood that the compositions herein include the compounds of the invention in their non-ionized, as well as zwitterionic forms, and combinations with a stoichiometric amount of water in hydrates.

[0167] Salts of the parent compound with one or more amino acids are also included within the scope of the invention. Any natural or unnatural amino acid is suitable, particularly the naturally occurring amino acids found as protein components, but the amino acids typically have side chains with basic or acidic groups, e.g., lysine, arginine, or glutamic acid, or neutral groups, e.g., glycine, serine, threonine, alanine, isoleucine, or leucine.

[0168] Methods for inhibiting Zika virus Another aspect of the invention relates to a method of inhibiting the activity of Zika virus comprising treating a sample suspected of containing Zika virus with a compound or composition of the invention.

[0169] The compounds of the present invention may act as inhibitors of Zika virus, either as intermediates for such inhibitors or with other utilities as described below. The inhibitors generally bind to locations on the surface or in the cavity of the liver. Compounds that bind within the liver may bind with varying degrees of reversibility. These compounds bind substantially irreversibly and are ideal candidates for use in this method of the present invention. Compounds that bind substantially irreversibly when labeled are useful as probes for detecting Zika virus. Thus, the present invention relates to a method for detecting NS3 in a sample suspected of containing Zika virus, comprising treating the sample suspected of containing Zika virus with a composition comprising a compound of the present invention bound to a label, and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostic arts and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups, and chromogens. The compounds herein are labeled in conventional ways using functional groups such as hydroxyl or amino. In one embodiment, the present invention provides a compound of formula (I) that comprises one or more detectable labels or is bound or linked to one or more detectable labels. Within the context of the present invention, samples suspected of containing Zika virus include natural or artificial materials such as living organisms, tissue or cell cultures, biological samples such as biomaterial samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.), laboratory samples, food, water, or air samples, biological product samples such as extracts of cells, especially recombinant cells that synthesize the desired glycoprotein, etc. Typically, the sample is suspected of containing Zika virus. The sample may be contained in any medium, including water and organic solvent / water mixtures. Samples include organisms such as humans, and artificial materials such as cell cultures.

[0170] The treating step of the present invention comprises adding a compound of the present invention to the sample, or it comprises adding a precursor of the composition to the sample. The adding step comprises any of the administration methods described above.

[0171] If necessary, the activity of Zika virus after application of the compound can be observed by any method, including direct and indirect methods of detecting Zika virus activity. Quantitative, qualitative, and semi-qualitative methods of determining Zika virus activity are all contemplated. Typically, one of the above screening methods is applied, but any other method, such as observing the physiological characteristics of an organism, can also be applied.

[0172] Many organisms contain the Zika virus. The compounds of the invention are useful for treating or preventing conditions associated with Zika virus activation in animals or humans.

[0173] However, in screening for compounds that can inhibit Zika virus activity, it should be kept in mind that the results of enzyme assays may not necessarily correlate with cell culture assays, therefore cell-based assays should typically be the primary screening tool.

[0174] Pharmaceutical preparations The compounds of the invention are formulated with conventional carriers and excipients selected in accordance with normal practice. Tablets contain excipients, lubricants, fillers, binders, and the like. Aqueous formulations are prepared in sterile form and are generally isotonic if intended for delivery other than by oral administration. All formulations optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulations ranges from about 3 to about 11, but is usually about 7 to 10.

[0175] Although it is possible for the active ingredient to be administered alone, it may be preferable to present them as pharmaceutical formulations.The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and optionally other additional therapeutic ingredients.The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically harmless to the recipient thereof.

[0176] Formulations include those suitable for the aforementioned routes of administration. Formulations may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0177] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0178] Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0179] For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount, for example, of 0.075 to 20% w / w (including in 0.1% w / w increments ranging from 0.1% to 20% active ingredient, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0180] Optionally, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.

[0181] The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The phase can simply comprise an emulsifier (otherwise known as emulsion), but desirably comprises at least one emulsifier mixed with fat or oil, or with both fat and oil. Preferably, a hydrophilic emulsifier is comprised together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to comprise both oil and fat. Together, the emulsifier with or without stabilizer constitutes the so-called emulsifying wax, which, together with oil and fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations.

[0182] Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0183] The selection of suitable oils or fats for the formulation is based on achieving the desired aesthetic properties. The cream should preferably be a non-greasy, non-staining, washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters may be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, the last three being the preferred esters. These may be used alone or in combination, depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

[0184] A pharmaceutical formulation according to the present invention comprises one or more compounds of the present invention together with one or more pharma- ceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0185] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0186] The aqueous suspensions of the present invention contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecathyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxy-benzoates, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0187] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin. Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0188] The dispersible powders and granules of the present invention suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0189] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners, such as glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring, or a coloring agent.

[0190] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any non-solvent fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0191] The amount of active ingredient that may be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain approximately 1-1000 mg of active ingredient, compounded with a convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3-500 μg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 mL / hour.

[0192] Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0193] Formulations suitable for topical administration in the mouth include lozenges which comprise the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles which comprise the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes which comprise the active ingredient in a suitable liquid carrier.

[0194] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0195] Formulations suitable for pulmonary or nasal administration have, for example, a particle size in the range of 0.1 to 500 micrometers (including particle sizes in the range of 0.1 to 500 micrometers in increments of micrometers such as 0.5, 1, 30 micrometers, 35 micrometers, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveoli. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents, such as compounds previously used in the treatment or prevention of conditions associated with Zika virus activity.

[0196] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0197] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0198] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0199] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the invention may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0200] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0201] Veterinary carriers can be solid, liquid, or gaseous substances that are useful for the purpose of administering the compositions and are otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0202] The compounds of the present invention can also be formulated to provide a controlled release of the active ingredient to allow for less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Thus, the present invention also provides compositions comprising one or more compounds of the present invention formulated for sustained or controlled release.

[0203] The effective dose of the active ingredient will depend, at least, on the nature of the condition being treated, the toxicity, whether the compound is used prophylactically (low doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.

[0204] Route of administration One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). It will be understood that the preferred route may vary, for example, depending on the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0205] [Table 5] EXAMPLES

[0206] EXAMPLES Procedure and Compound Examples Procedure 1, Example 24 Methyl ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0207] [ka]

[0208] 2-(2-(9-(((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carbonyl)oxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-(tert-butyl)(2S,5S)-5-methylpyrrolidine-1,2-dicarboxylate A suspension of 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (5 g, 11.11 mmol), (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (6.37 g, 27.77 mmol) and cesium carbonate (4.52 g, 13.89 mmol) in THF (100 mL) was heated at 40° C. for 24 h. The reaction was quenched with 75 mL of EtOAc and 60 mL of water. The brown solution was partitioned. 50 mL of 1N HCl was added. The aqueous phase was back-extracted with 2×40 mL of EtOAc. The combined organic phase was dried over sodium sulfate. ES / MS:746.7(M + ).

[0209] tert-Butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate A suspension of 2-(2-(9-(((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carbonyl)oxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-(tert-butyl)(2S,5s)-5-methylpyrrolidine-1,2-dicarboxylate (8.3 g, 11.11 mmol) and ammonium acetate (17.12 g, 222.16 mmol) in toluene (100 mL) and isopropanol (10 mL) was heated at 90° C. overnight. The reaction was partitioned with water. The aqueous phase was back-extracted with EtOAc. The combined organic phase was transferred to a 500 mL rb containing 30 mL of MeOH. 5 g of Celite, 25 mL of brine, and 13 mL of 6N NaOH (approximately 6 eq.) were slowly added. Stirred for 30 min, then filtered through a plug of Celite. Rinsed with toluene and IPA (50 mL). The organic extract was separated and washed with water. The organic extract was dried over sodium sulfate and purified by normal phase SiO2 chromatography (eluent: ethyl acetate / DCM) to give the desired product. ES / MS:707.3(M + ). 1H NMR (400MHz, chloroform-d) δ10.57(d,J=106.4Hz,2H),7.88-7.39(m,5H),6.75(s,1H),5.13(d,J=10.6Hz,3H),5.07-4.80(m, 3H),3.96(s,4H),3.02(s,3H),2.86(s,6H),2.03(s,12H),1.99-1.73(m,4H),1.50(d,J=5.3Hz,31H),1.30-1.04(m,15H).

[0210] tert-Butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate To a solution of tert-butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (4.51 g, 6.38 mmol) in DCM (60 mL) was added manganese dioxide (16.63 g, 191.32 mmol). The reaction was stirred open to air at room temperature for 4 days. 150 mL of DCM and 30 g of Celite were added. Filtered through a Celite plug. Concentrated to give the desired product. ES / MS:705.3(M + ). 1H NMR (400MHz, chloroform-d) δ8.24(s,1H),7.74(d,J=90.6Hz,8H),5.25(d,J=35.1Hz,5H),4.99(d,J=7.4H) z,2H),4.00(s,4H),2.42-2.09(m,7H),1.89(s,3H),1.52(d,J=10.1Hz,38H),1.14(d,J=68.3Hz,17H).

[0211] tert-Butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate To a suspension of tert-butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (999.3 mg, 1.418 mmol) in MeOH (40 mL) was added AcOH (0.05 mL, 0.873 mmol) and n-chlorosuccinimide (208.9 mg, 1.564 mmol). The orange solution was stirred overnight at room temperature. The reaction was diluted with DCM, washed with saturated NaHCO3 solution and dried over sodium sulfate. Purification by normal phase SiO2 chromatography (eluent: ethyl acetate / DCM) afforded the desired product. ES / MS:739.2(M + ). 1H NMR (400MHz, methanol-d4) δ8.43(s,1H),7.79(d,J=8.4Hz,1H),7.72(d,J=8.9Hz,1 H),7.60(s,1H),5.48(s,4H),5.23(s,2H),5.10(s,3H),4.09(q,J=7.1Hz,1H),4 .02(s,1H),2.68(s,1H),2.38(s,2H),2.24(s,4H),2.00(s,1H),1.77(s,2H),1. 48(d,J=5.5Hz,5H),1.41(d,J=6.4Hz,4H),1.32(s,16H),1.23(t,J=7.1Hz,1H).

[0212] Methyl ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate Methyl ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, tert- in DCM (4 mL) and MeOH (1 mL). To a solution of butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (50.1 mg, 0.068 mmol) was added 4M hydrochloric acid (4M in dioxane) (0.475 mL). The reaction was heated at 40 degrees for 4 hours. The reaction was concentrated to dryness.

[0213] To a solution of hydrochloride (41.47 mg, 0.068 mmol), moc-trifluoro-L-tert-leucine (34.6 mg, 0.142 mmol), and HATU (55.5 mg, 0.146 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (120 μL, 0.689 mmol). Stirred at room temperature overnight. The reaction mixture was cooled to 0 degrees and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as the bis-trifluoroacetate salt. ES / MS:989.4(M + ). 1H NMR (400MHz, methanol-d4) δ8.58(d,J=2.4Hz,1H),8.11(t,J=7.8Hz,1H),8.02-7.80(m,3H),7.69-7.57(m,3H),7. 48(dd,J=26.1,11.1Hz,1H),5.33-5.20(m,4H),5.01-4.92(m,1H),4.78-4.57(m,2H),3.68(d,J=8.1Hz,5H),3.5 7(s,1H),3.28(s,1H),2.61-2.24(m,5H),2.20-1.98(m,2H),1.92(dd,J=12.4,6.4Hz,1H),1.66(d,J=6.6Hz,3H) ,1.56(d,J=6.6Hz,3H),1.51-1.35(m,1H),1.40-1.27(m,5H),1.24(q,J=7.7,7.3Hz,7H),1.08(d,J=7.3Hz,5H).

[0214] Procedure 2, Example 10 Methyl ((S)-2-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate

[0215] [ka] Methyl ((S)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((2S,5S)-2-(5-(2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1,11-diaminopyrrolidin-2-yl in methanol (1 mL). A solution of hydroisochromeno[4',3':6,7[naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-2-oxoethyl)carbamate (80.0 mg, 0.0834 mmol), n-bromosuccinimide (18.0 mg, 0.101 mmol), and acetic acid (2.5 mg, 0.0417 mmol) was stirred at room temperature for 30 min. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as a trifluoroacetate salt. ES / MS: 1038.9(M + ). 1H NMR (400MHz, methanol-d4) δ8.59(dd,J=8.4,3.5Hz,1H),8.16-7.97(m,2H),7.94-7.76(m,2H),7 .70-7.57(m,2H),5.29(dt,J=11.1,5.3Hz,3H),5.00(dd,J=9.9,7.6Hz,1H),4.81-4.67(m,1H) ,4.42-4.02(m,4H),3.79(d,J=8.9Hz,0H),3.71-3.58(m,5H),3.52(q,J=14.0,10.4Hz,1H),2. 90-2.74(m,1H),2.68-1.84(m,7H),1.80-1.34(m,8H),1.33-1.02(m,13H),1.00-0.82(m,3H).

[0216] Procedure 3, Example 33 Methyl ((S)-1-((2S,5S)-2-(4-fluoro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[0217] [ka] Methyl ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate To a solution of tert-butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (100.1 mg, 0.142 mmol) in DCM (8 mL) and MeOH (2 mL) was added 4M hydrochloric acid (4M in dioxane) (1.0 mL). The reaction was heated at 40 degrees for 3 h. The reaction was concentrated to dryness.

[0218] To a solution of hydrochloride (82.02 mg, 0.142 mmol), Moc-L-valine (52.8 mg, 0.301 mmol), and HATU (113.4 mg, 0.298 mmol) in DMF (2.0 mL) was added N,N-diisopropylethylamine (250 μL, 1.435 mmol). Stirred at room temperature overnight. The reaction mixture was cooled to 0 degrees and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as the bis-trifluoroacetate salt.

[0219] The product was washed with sodium bicarbonate, diluted with ethyl acetate and the organic layer was dried over sodium sulfate and concentrated to dryness to give the desired product. ES / MS:819.5(M + ). 1H NMR (400MHz, methanol-d4) δ8.33(t,J=14.8Hz,2H),8.10(s,1H),8.00-7.86(m,2H),7.74-7.55(m,4H),7.51(s,2H),7.34(d,J =7.0Hz,1H),5.60(s,1H),5.37(s,2H),5.29-5.04(m,7H),4.74(dt,J=13.7,6.9Hz,1H),4.24(dq,J=20.0,7.1Hz,2H),4.16 -4.02(m,3H),3.88(s,2H),3.73-3.60(m,8H),2.33(dt,J=13.6,7.3Hz,1H),2.19-1.99(m,2H),2.00(s,2H),1.97(s,2H),1 .56(d,J=6.6Hz,3H),1.48(d,J=6.6Hz,4H),1.32-1.18(m,4H),1.10(s,19H),1.08-0.90(m,13H),0.86(s,1H),0.84(s,8H).

[0220] Methyl ((S)-1-((2S,5S)-2-(4-fluoro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate To a slurry of methyl ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (61.8 mg, 0.075 mmol) and NaHCO3 (9.9 mg, 0.228 mmol) in DCM / acetone (1 mL each) was added N-fluorobenzenesulfonimide (26.18 mg, 0.083 mmol). Stirred at 40° for 1.5 h. The reaction mixture was cooled to 0°C and 10 drops of TFA were added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as the bis-trifluoroacetate salt. ES / MS:837.4(M + ). 1H NMR (400MHz, methanol-d4) δ8.58(d,J=9.8Hz,1H),8.21(d,J=4.8Hz,0H),8.06(dd,J =19.4,8.2Hz,2H),7.90(d,J=12.6Hz,1H),7.70-7.58(m,2H),7.47(s,1H),5.87( s,0H),5.39(d,J=6.8Hz,0H),5.28(d,J=6.1Hz,3H),4.32(s,0H),4.22(d,J=8.0H z,1H),4.14(d,J=8.9Hz,1H),4.05(d,J=9.4Hz,1H),3.79(s,2H),3.66(d,J=6.4Hz ,4H),2.81(s,0H),2.69(d,J=9.4Hz,0H),2.65-2.55(m,1H),2.40(s,3H),2.39-2 .24(m,1H),2.17-2.07(m,0H),2.08-1.88(m,2H),1.63(d,J=6.8Hz,3H),1.50(d, J=6.6Hz,2H),1.27(d,J=6.4Hz,1H),1.19(d,J=6.3Hz,1H),1.05(dd,J=26.3,6.7 Hz,4H),0.95(t,J=7.2Hz,4H),0.85(dd,J=6.8,3.3Hz,4H),0.09(d,J=2.2Hz,0H).

[0221] Step 4, Example 31 Methyl ((S)-1-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-5-methyl-1-(propionyl-L-valyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[0222] [ka] tert-Butyl (2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate To a slurry of tert-butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (500.3 mg, 0.710 mmol) in DCM (20 mL) at 0° C. was added N-bromosuccinimide (138.9 mg, 0.780 mmol). The reaction was gradually warmed to room temperature and stirred for 30 min. The reaction was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic extract was dried over sodium sulfate and purified by normal phase SiO2 chromatography (eluent: ethyl acetate / hexanes) to give the desired product. ES / MS:785.2(M + ). 1H NMR (400MHz, methanol-d4) δ8.43(s,0H),8.06(d,J=8.3Hz,0H),7.96(s,1H),7.79(d,J=8.2H) z,0H),7.72(d,J=8.9Hz,0H),7.58(d,J=15.7Hz,1H),5.23(s,1H),5.09(s,1H),4.09(q,J =7.1Hz,3H),3.34(s,2H),2.67(s,1H),2.38(s,0H),2.24(s,1H),2.25-2.17(m,0H),2.00 (s,4H),1.76(s,1H),1.44(dd,J=29.0,6.4Hz,3H),1.36-1.19(m,16H),0.93-0.82(m,2H).

[0223] Methyl ((S)-1-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-5-methyl-1-(propionyl-L-valyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate To a solution of tert-butyl (2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (32.6 mg, 0.042 mmol) in DCM (4 mL) and MeOH (1 mL) was added 4M hydrochloric acid (4M in dioxane) (0.300 mL). The reaction was heated to 40 degrees for 5 hours. The reaction was concentrated to dryness. Proceed to the following step, assuming 100% yield.

[0224] To a solution of hydrochloride (27.30 mg, 0.045 mmol), Moc-L-valine (17.9 mg, 0.095 mmol), and HATU (36.4 mg, 0.096 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (80 μL, 0.459 mmol). Stirred overnight at room temperature. The reaction mixture was cooled to 0 degrees and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as the bis-trifluoroacetate salt. ES / MS:899.3(M + ). 1H NMR (400MHz, methanol-d4) δ8.62(d,J=6.0Hz,1H),8.15-7.96(m,3H),7.92-7.83(m,1H),7.67(s,1H),7.71-7.59(m,1H),5.31(d,J=4.3Hz,3H) ),5.05-4.96(m,1H),4.23(dd,J=12.8,5.7Hz,1H),4.21-4.11(m,1H),4.07(d,J=9.4Hz,1H),3.79(d,J=4.4Hz,1H),3.72-3.63(m,6H),2.7 9(s,1H),2.68-2.55(m,1H),2.45(s,3H),2.34(dtt,J=20.5,13.0,6.2Hz,2H),2.20-2.04(m,1H),2.04(s,3H),1.94(ddd,J=18.5,11.3,4. 9Hz,2H),1.63(d,J=6.7Hz,3H),1.51(d,J=6.7Hz,2H),1.28(d,J=6.2Hz,1H),1.20(d,J=6.2Hz,2H),1.12-0.91(m,10H),0.89-0.82(m,5H).

[0225] Step 5, Example 43 Methyl ((S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[0226] [ka] tert-Butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-(prop-1-en-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate tert-Butyl (2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate ( A solution of 323.1 mg, 0.412 mmol), isopropenylboronic acid pinacol ester 95% (310 μL, 1.649 mmol), palladium acetate (9.5 mg, 0.042 mmol), butyldi-1-adamantylphosphine min. 95% (29.8 mg, 0.083 mmol) and potassium carbonate (228.9 mg, 1.656 mmol) was degassed with argon for 10 min and then heated at 100°C overnight. The reaction was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and purified by normal phase SiO2 chromatography (eluent: ethyl acetate / DCM) to give the desired product. ES / MS:745.5(M + ). 1H NMR (400MHz, methanol-d4) δ 8.39 (s, 1H), 7.97 (d, J = 8.1Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.62-7.52 (m, 2H), 7.42 (s, 1H), 5.19 (s, 2H), 4.87 (s, 5H), 4.80 (s, 1H), 4.09 (q, J = 7 .1Hz,2H),4.01(s,1H),2.37(s,1H),2.25(s,4H),2.26-2.09(m,1H),2.01(d,J=7.2Hz,4H ),1.78-1.69(m,2H),1.44(dd,J=27.3,6.2Hz,6H),1.37-1.30(m,17H),1.29-1.16(m,2H).

[0227] tert-Butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate A solution of tert-butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-(prop-1-en-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (266.1 mg, 344 μmol) in EtOH (15 mL) was degassed with Ar / Vac 3x. Pd / C (10%, 19 mg, 17.85 μmol) was added and stirred overnight at room temperature with a balloon of hydrogen. The reaction was filtered through a plug of Celite and rinsed with DCM. It was concentrated and used in the next step without purification. ES / MS:747.3(M + ). 1H NMR (400MHz, methanol-d4) δ 8.40 (s, 1H), 8.01 (d, J = 8.2Hz, 1H), 7.92 (s, 1H), 7.70 (d, J = 8.9Hz, 1H), 7.60-7.51 (m, 2H), 7.36 (d, J = 1.5Hz, 1H), 5.21 (s, 2H), 5.07 (s, 1H), 4.09 (s, 1H), 4.02 (s, 1H ),3.60(q,J=7.0Hz,5H),3.27(t,J=6.8Hz,0H),2.37(d,J=7.8Hz,1H),2.29(s,2H),2.21(s,2H) ),2.26-2.05(m,1H),1.45(dd,J=23.7,6.3Hz,6H),1.36-1.22(m,7H),1.17(t,J=7.1Hz,10H).

[0228] Methyl ((S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate To a solution of tert-butyl (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (50.6 mg, 0.068 mmol) in DCM (4 mL) and MeOH (1 mL) was added 4M hydrochloric acid (4M in dioxane) (0.5 mL). The reaction was heated to 40 degrees for 6 hours. The reaction was concentrated to dryness.

[0229] To a solution of hydrochloride (41.98 mg, 0.068 mmol), Moc-L-valine (25.2 mg, 0.144 mmol), and HATU (54.4 mg, 0.143 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (120 μL, 0.684 mmol). Stirred overnight at room temperature. The reaction mixture was cooled to 0 degrees and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as the bis-trifluoroacetate salt. ES / MS:861.5(M + ). 1H NMR (400MHz, methanol-d4) δ8.62(d,J=11.4Hz,1H),8.26-8.18(m,1H),8.04-7.91(m,2H),7.67(d,J=8.8Hz,1H),7.66-7.54(m ,1H),7.42(d,J=5.5Hz,1H),5.36-5.24(m,3H),5.08(dd,J=10.9,6.8Hz,1H),4.28(dd,J=22.6,8.0Hz,1H),4.17-4.05(m,2 H),3.79(s,1H),3.73-3.63(m,5H),2.86(d,J=12.5Hz,0H),2.54(ddt,J=32.9,11.8,6.3Hz,2H),2.41-2.31(m,1H),2.32(s ,3H),2.09-1.89(m,3H),1.59(dd,J=23.3,6.6Hz,5H),1.48-1.32(m,6H),1.24(dd,J=8.5,6.3Hz,2H),1.13-0.81(m,13H).

[0230] Step 6, Example 9 Methyl ((S)-2-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate

[0231] [ka] Methyl((S)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((2S,5S)-2-(5-(2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7[naphtho[1,2 A solution of [-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-2-oxoethyl]carbamate (40.0 mg, 0.0417 mmol), n-chlorosuccinimide (6.1 mg, 0.0459 mmol) and acetic acid (1.25 mg, 0.0209 mmol) was stirred at room temperature for 2 hours. Purification was performed by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product as a trifluoroacetate salt. ES / MS:993.6(M + ). 1H NMR (400MHz, methanol-d4) δ8.65-8.47(m,1H),8.12-7.93(m,2H),7.88-7.71(m,2H),7.69-7.55(m,2H),5.42(d ,J=6.4Hz,0H),5.36-5.18(m,3H),5.06-4.91(m,1H),4.38-4.05(m,4H),3.86-3.73(m,1H),3.67(dd,J=15.4, 9.2Hz,6H),3.59-3.39(m,1H),2.71-1.99(m,5H),1.90(dd,J=12.4,6.3Hz,1H),1.83-1.49(m,7H),1.43(td, J=13.3,6.2Hz,1H),1.28(d,J=6.1Hz,2H),1.19(dd,J=6.6,4.1Hz,3H),1.14-1.04(m,6H),1.00-0.81(m,3H).

[0232] Step 7, Example 18 Methyl ((2S,3S)-1-((2S,4S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-allyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

[0233] [ka] Methyl ((2S,3S)-1-((2S,4S)-2-(4-bromo-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine in toluene / water (20 / 1 v / v, 2 mL). A solution of 3-methyl-1-oxopentan-2-yl)carbamate (40 mg, 0.0425 mmol), cyclopropylboronic acid (5.5 mg, 0.0637 mmol), palladium acetate (0.667 mg, 0.0030 mmol), tricyclohexylphosphine (2.38 mg, 0.0085 mmol) and potassium phosphate (27 mg, 0.127 mmol) was heated at 100° C. overnight. The reaction mixture was evaporated to dryness, dissolved in water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and then evaporated to dryness. The residue was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product as a trifluoroacetate salt. ES / MS:903.5(M + ). 1H NMR (400MHz, methanol-d4) δ8.64(d,J=5.9Hz,1H),8.30-8.18(m,1H),8.01(dd,J=12.4,9.0Hz,1H),7.92(s,1H),7.84-7.76( m,1H),7.75-7.57(m,2H),5.38-5.25(m,3H),5.15(dd,J=10.8,7.2Hz,1H),4.45-4.07(m,3H),3.80(s,1H),3.72-3.45(m, 8H),3.40(s,3H),3.30-3.24(m,10H),2.85-2.72(m,1H),2.61(dd,J=12.9,6.9Hz,2H),2.51-2.26(m,2H),2.24-1.87(m,2 H),1.77(s,1H),1.62(d,J=6.6Hz,2H),1.48(d,J=11.7Hz,1H),1.31-1.01(m,6H),1.01-0.79(m,10H),0.82-0.69(m,2H).

[0234] Step 8, Example 16 Methyl ((2S,3S)-1-((2S,4S)-2-(4-cyano-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

[0235] [ka] Methyl ((2S,3S)-1-((2S,4S)-2-(4-bromo-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4- A mixture of (methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate (15 mg, 0.0159 mmol), Pd(dppf)Cl2 (1.17 mg, 0.00159 mmol), Zn powder (0.521 mg, 0.00796 mmol), and Zn(CN)2 (5.61 mg, 0.0478 mmol) was degassed with argon for 2 min. The reaction was heated at 180 degrees in a microwave for 15 min. The reaction mixture was filtered and purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product as a trifluoroacetate salt. ES / MS:889.4(M + ). 1H NMR (400MHz, methanol-d4) δ8.58(s,1H),8.35-8.07(m,2H),8.07-7.79(m,3H),7.77-7.49(m,2H),5.28(d,J=11.9Hz,3H),5.07(t,J=8.7Hz) ,1H),4.46-4.03(m,4H),3.79(s,1H),3.72-3.35(m,12H),2.93-2.22(m,4H),2.16-1.89(m,3H),1.86-1.37(m,4H),1.32-0.63(m,16H).

[0236] Compound table The following compounds were prepared from the examples and procedures described herein and shown in Table 1, using the appropriate starting material(s) and appropriate protecting group chemistry where necessary.

[0237] [Table 1]

[0238] 1HNMR Proton NMR data is shown in Table 2.

[0239] [Table 2-1]

[0240] [Table 2-2]

[0241] [Table 2-3]

[0242] [Table 2-4]

[0243] [Table 2-5]

[0244] [Table 2-6]

[0245] [Table 3-7]

[0246] [Table 3-1]

[0247] [Table 3-2]

[0248] [Table 3-3]

[0249] [Table 3-4]

[0250] Biological assays A protocol for ZIKV reporter virus-based antiviral screening on Huh7 cells

[0251] 1.Cells Human hepatocellular carcinoma cell line (Huh7)

[0252] 2. Reagents ViviRen™ Live Cell Substrate (Promega, Catalog No. E6492) or Nano Glo Assay System (Promega: N1130) White opaque 96-well TC-treated microplate (Corning, Cat. No. 3916) 96-well clear V-bottom TC-treated microplates (Corning, Cat. No. 3894) Complete cell culture medium: DMEM (Gibco, catalog number 10569) supplemented with 10% FBS (HyClone, catalog number SH30071.03IH25-40) + 1% MEM non-essential amino acids solution 100x (Gibco, catalog number 11140050) + 1% penicillin-streptomycin (10,000 U / mL) (Gibco, catalog number 15140122). Assay medium: DMEM medium (Gibco, Cat#31053028) supplemented with 2% FBS, 2% GlutaMAX™ supplement (Gibco Cat#35050061), 1% sodium pyruvate solution (Gibco, Cat#11360070), 1% MEM non-essential amino acid solution 100X, and 1% penicillin-streptomycin (10,000 U / mL). Trypsin-EDTA solution (Gibco, catalog number 25200056).

[0253] 3. Viruses Recombinant ZIKV strains carrying the Renilla luciferase gene (FSS-Rlu strain) or nanoluciferase gene (PRV-Nano strain, Dakar-Nano)

[0254] 4. Equipment BioTek Cytation5 or other plate reader for chemiluminescence detection model. Eppendorf Plate Centrifuge Plate shaker Eppendorf Multichannel Pipettes

[0255] procedure Day 1. Preparation of cells Human hepatocellular carcinoma cell line (Huh7) cells were detached from a T-175 flask using trypsin-EDTA solution. The detached cells were suspended in complete culture medium in a 50 mL sterile conical tube. The 50 mL conical tube was centrifuged at 1200× rpm for 3 minutes at room temperature. The cells were resuspended in assay medium. The cell number was counted and the cells were diluted to 3×10 5 The cells were diluted to a density of 1000 cells / mL. Cells were seeded into white opaque 96-well plates (assay plates) at 50 μL cells per well. Plates were gently shaken to ensure cells attached evenly to the plate. The seeded cells were incubated in a humidified incubator (37° C., 5% CO 2 ).

[0256] Day 2 infection 1) Nine serially (2- or 3-fold) concentrated compounds were prepared in clear V-bottom 96-well plates (compound plates) using 90% DMSO solutions and a DMSO control. for example,

[0257] [Table 6] 2) Dilute the reporter virus stock to 3 x 10 in assay medium. 4 The virus was diluted to a concentration of 1000 FFU (FFU: focus forming units) / mL. 200 μL of diluted virus was dispensed per well into a clear V-bottom 96-well plate (mixing plate). 3) 1 μL of >400× concentrated compound dilutions was added from the compound plate to each well of the mixing plate. The plate was shaken for 5 minutes on a plate shaker. 4) 50 μL of the compound-virus mixture was added to each well of the assay plate (MOI is about 0.1). The plate was gently shaken to mix the virus evenly. Assay plate format examples

[0258] [Table 7] CC stands for cell control. 5) The plate was centrifuged at 1000 rpm for 15 seconds. 6) The plates were incubated in a humidified incubator at 37° C. with 5% CO2 for 48 hours.

[0259] Day 4: Reading the luciferase signal 7) ViviRen™ Live Cell Substrate was diluted 3000-fold in assay medium. 25 μL of diluted substrate was added to each well of the assay plate. For the Nano-Glo assay system, 50 μL of diluted substrate (50-fold dilution from stock in assay buffer) was added. 8) The plate was incubated at room temperature for 5 minutes. 9) Optimally, cell viability is measured using the Promega Cell-titer Glo kit (only used if ZIKV-Rlu was used for infection). 10) Luciferase signals were read using Cytation5 with a gain value of 120-150.

[0260] Data analysis The luciferase signal from the DMSO-treated group (untreated control) was set as 100%. The relative luciferase signal was obtained by normalizing the luciferase signal from each dilution treatment group to that of the control group. b. Relative luciferase signal (Y-axis) was plotted against the log10 values ​​of compound concentration (X-axis) in the software GraphPad Prism8 and curves were fitted using a non-linear regression model (log(inhibitor) vs. response - variable slope (4 parameters), lower bound constrained to 0 and upper bound constrained to 100). c.EC 50 The values ​​are reported below.

[0261] Biological assays were performed to measure activity against ZIKV. As summarized in Table 3, the test compounds are inhibitors of ZIKV.

[0262] Biological assays were performed to measure activity against ZIKV. As summarized in Table 4, the test compounds are inhibitors of ZIKV.

[0263] [Table 4]

[0264] The above description of the specific embodiments fully reveals the general nature of the present invention, and by applying the knowledge of those skilled in the art, such specific embodiments can be easily modified and / or adapted to various applications without undue experimentation and without departing from the general concept of the present disclosure. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phrases or terms used herein are for the purpose of description and not for the purpose of limitation, and that the terms or terms used herein should be interpreted by those skilled in the art in light of the teaching and guidance.

Claims

1. Formula (I): 【Chemical 34】 [In the formula, R １ Fluoro, chloro, C １～１０ alkyl, C4-7 cycloalkyl or cyano; P １ａ and P １ｂ are each independently 【Chemistry 35】 is selected from the group consisting of V １ａ and V １ｂ are each independently 【Chemical Formula 36】 is selected from the group consisting of E １ａ and E １ｂ are each independently -N(H)(C １～６ Alkoxycarbonyl ), N(H)(C ３～１２ cycloalkylcarbonyl), N(H)(C １～６ alkylcarbonyl), or -N(H)(C ３～１２ or a pharma- ceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

2. R １ is fluoro or chloro, or a pharma- ceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

3. R １ is chloro, or a pharma- ceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

4. V １ａ teeth 【Chemical 39】 2. The compound of claim 1, wherein:

5. V １ａ and V １ｂ Both are 【Chemistry 40】 2. The compound of claim 1, wherein:

6. P １ａ teeth 【Chemistry 41】 2. The compound of claim 1, wherein:

7. P １ａ teeth 【Chemistry 42】 And P １ｂ teeth 【Chemistry 43】 2. The compound of claim 1, wherein:

8. P １ａ teeth 【Chemistry 44】 2. The compound of claim 1, wherein:

9. P １ａ and P １ｂ Both are 【Chemistry 45】 2. The compound of claim 1, wherein:

10. methyl ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-(O-(tert-butyl)-N-(methoxycarbonyl)-L-threonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((S)-6-(4-chloro-5-(2-((S)-5-((methoxycarbonyl)-L-valyl)-5-azaspiro[2.4]heptan-6-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3S)-1-((S)-6-(4-chloro-5-(2-((S)-5-((methoxycarbonyl)-L-isoleucyl)-5-azaspiro[2.4]heptan-6-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((S)-1-((S)-6-(4-chloro-5-(2-((S)-5-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-azaspiro[2.4]heptan-6-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-valyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-bromo-2-((2S,4S)-1-((methoxycarbonyl)-L-valyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-2-((2S,5S)-2-(9-(4-chloro-2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate, methyl ((S)-2-((2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate, methyl ((S)-2-((2S,5S)-2-(9-(4-cyclopropyl-2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate, methyl ((S)-2-((2S,5S)-2-(9-(4-chloro-2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-ethylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-cyano-2-((2S,4S)-1-((methoxycarbonyl)-L-valyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, Methyl ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochloro Meno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-2-((2S,5S)-2-(9-(4-chloro-2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-cyano-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-bromo-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-cyclopropyl-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-alloisoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-4-(methoxymethyl)-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, Methyl((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazole- 2-yl)-5-methylpyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3R)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-alloisoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((methoxycarbonyl)-L-isoleucyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((2S,3R)-1-((S)-2-(4-chloro-5-(2-((S)-1-((methoxycarbonyl)-L-alloisoleucyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, Methyl((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4-fluoro-3,3 -dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(9-(4-fluoro-2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((methoxycarbonyl)-L-valyl)octahydrocyclopenta[b]pyrrol-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((methoxycarbonyl)-L-isoleucyl)octahydrocyclopenta[b]pyrrol-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((S)-2-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)octahydrocyclopenta[b]pyrrol-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate, methyl ((S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydrocyclopenta[b]pyrrol-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((2S,3R)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-alloisoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4-fluoro-3,3-dimethyl-1-oxobutan-2-yl)carbamate, methyl ((S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate, methyl ((2S,3S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, methyl ((S)-4,4,4-trifluoro-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)pyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, Methyl ((2S,3R)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-alloisoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate, and 1. A compound selected from the group consisting of methyl ((S)-4-fluoro-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, or a pharma- ceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

11. formula: 【Chemistry 46】 or a pharma- ceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, together with at least one pharma- ceutically acceptable excipient.

13. A composition comprising a compound according to claims 1 to 11 for treating a subject infected with Zika virus.

14. 12. A composition comprising a compound according to claims 1 to 11 for preventing Zika virus infection in a subject in need thereof.

15. 12. Use of a compound according to claims 1 to 11 in the manufacture of a medicament for treating or preventing Zika virus infection.

16. 12. A composition comprising a compound according to claims 1 to 11 for use in the treatment or prevention of Zika virus infection.

17. Use of the composition described in claim 12 in the manufacture of a medicine for treating or preventing Zika virus infection.

18. The composition of claim 12 for use in the treatment or prevention of Zika virus infection.

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