Pentacyclic derivatives as zika virus inhibitors

Abstract

To provide a method for treating a disease.SOLUTION: There are provided herein compounds of Formula (I): wherein the various substituents are defined herein. There are provided herein compounds and methods for the treatment or prevention of Zika virus infection. As described and demonstrated in detail herein, the present invention surprisingly achieves a remarkable effect that could not have been readily anticipated by the man skilled in the art from the prior art.SELECTED DRAWING: None

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 incorporated herein 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 caused outbreaks of major public health concern. Outbreaks of Zika virus disease have been documented in Africa, the Americas, Asia, and the Pacific. Zika virus entry into the Western Hemisphere is believed to have occurred in Haiti and Brazil in 2014–2015, where it 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 significant concern, Zika virus infection is now strongly associated with microcephaly and intrauterine growth restriction in fetuses of women infected with the virus during pregnancy. Zika infection during pregnancy can also result in pregnancy complications such as miscarriage, stillbirth, and preterm birth.

[0003] Currently, there is no vaccine to prevent Zika virus disease, therefore, there is a need for therapeutic or prophylactic interventions to treat or prevent Zika virus disease, particularly 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 independently halo, C 1~6 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, pharmaceutically acceptable salt or solvate thereof.

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

[0011] [ka] [In the formula, R 1 Ha, Halo, C 1~10 Alkyl, C 3~12 is 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)(alkoxycarbonyl), -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 Ha, Halo, C 1~6 Alkyl, C 4~7 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, together with a pharmaceutically acceptable excipient.

[0016] In another embodiment of the present invention, a method for treating Zika virus infection in a subject in need of treatment is provided. A method for treating a viral infection, comprising administering to the subject a compound of formula (I):

[0017] [ka] [In the formula, R 1 Ha, Halo, C 1~10 Alkyl, C 3~12 is 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)(alkoxycarbonyl), -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 Ha, Halo, C1~6 Alkyl, C 4~7 provided that the compound is cycloalkyl or cyano; or a pharmaceutically 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 woman.

[0025] In another embodiment, the compound is mixed with a pharmaceutically acceptable excipient in a pharmaceutical composition.

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

[0027] [ka] [In the formula, R 1 Ha, Halo, C 1~10 Alkyl, C 3~12 is 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)(alkoxycarbonyl), -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 Ha, Halo, C 1~6 Alkyl, C 4~7 provided that the compound is cycloalkyl or cyano; or a pharmaceutically 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 woman.

[0035] In another embodiment, the compound is mixed with a pharmaceutically 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 INVENTION

[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 present invention as defined by the embodiments.

[0037] The compounds described herein may be, for example, 3 It will be understood that whenever an alkyl group is substituted with more than one of the same groups indicating "alkyl," 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, if W is absent, then M is connected to M.

[0039] "Alkyl" refers to a C1-C2 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, -CH2CH2CH 2CH2CH3), 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)(CH2CH2C H3)), 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 2C2-C containing double bonds 18 It is a hydrocarbon. Examples include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), cyclopentenyl (-C5H7), and 5-hexenyl (-CHCHCHCHCH=CH).

[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 (-CH-), 1,2-ethyl (-CHCH-), 1,3-propyl (-CHCHCH-), 1,4-butyl (-CHCHCHCH-), 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 (-CHC≡C-), and 4-pentynyl (-CHCHCHC≡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 "(Aryl)" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom of the aryl group 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, and the alkyl portion, including, for example, the alkanyl, alkenyl, or alkynyl group of the arylalkyl group, contains 1 to 6 carbon atoms, and the aryl portion contains 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 polycarbocycles, 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 substituted with a heteroatom (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)2NR n R p , S(O)2R x or (C1-10)alkoxy, wherein each (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C1-10)alkanoyl, and (C1-10)alkoxy is optionally substituted with one or more halo.

[0051] "Substituted alkyl," "substituted aryl," and "substituted arylalkyl" refer to alkyl, aryl, and alkyl groups in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. and arylalkyl, respectively. Typical substituents include, but are not limited to, halo (e.g., F, Cl, Br, I), -R, -OR, -SR, -NR, -CF, -CCl, -OCF, -CN, -NO, -N(R)C(=O)R, -C(=O)R, -OC(=O)R, -C(O)OR, -C(=O)NRR, -S(=O)R, -S(=O)OR, -S(=O)R, -OS(=O)OR, -S(=O)NRR, 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 in a compound of Formula I (e.g., 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 or double bond.

[0055] [ka] teeth,

[0056] [ka] It could be.

[0057] As used herein, "haloalkyl" includes alkyl groups substituted with one or more halogens (e.g., 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, "heterocycle" includes, by way of example and not limitation, those heterocycles 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, "heterocycle" includes "carbocycle" 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-quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, furan 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 limitation, the carbon-bonded heterocycle is bonded at the 2-, 3-, 4-, 5-, or 6-position of pyridine, the 3-, 4-, 5-, or 6-position of pyridazine, the 2-, 4-, 5-, or 6-position of pyrimidine, the 2-, 3-, 5-, or 6-position of pyrazine, the 2-, 3-, 4-, or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of isoxazole, pyrazole, or isothiazole, the 2- or 3-position of aziridine, the 2-, 3-, or 4-position of azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of 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-bonded 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-bonded heterocycles include 1-aziridyl, 1-azetedyl, 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 to 7 carbon atoms as a monocycle, about 7 to 12 carbon atoms as a bicycle, and up to about 25 carbon atoms as a polycycle. Monocyclic carbocycles typically have 3 to 6 ring atoms, and even more typically 5 or 6 ring atoms. Bicyclic carbocycles typically have 7 to 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 possess the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that possess the property of non-superimposability of their mirror image partners. Refers to a molecule that can be superimposed on a partner.

[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 separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0067] "Enantiomers" refer 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 are generally those set forth in 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. 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 one another. A specific stereoisomer can be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can 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 in the above.

[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 is a phenyl group. 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 can be substituted with alkoxy, ...aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, , 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) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl, oxo, and -P(O)OR2, wherein 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 further optionally substituted with one or two additional groups independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and —NR X R Y is optionally further substituted with one or two 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] As used herein, the term "aryloxycarbonyl" refers to a carbonyl refers to an aryloxy group attached to the parent molecular moiety through an aryloxy 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 the 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 further optionally substituted with 1, 2, or 3 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 is further optionally substituted with one or two 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 1, 2, 3, or 4 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 zero to two double bonds, and a 6- and 7-membered ring has zero to three 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; the alkyl portion of the arylalkyl and heterocyclylalkyl is 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] As used herein, the term "heterocyclylalkoxycarbonyl" means It 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 further optionally substituted with one or two additional groups independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and —NR X R Y is optionally further substituted with one or two 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 -NO2.

[0129] As used herein, "-NR a R b" refers to two groups, R a and R b R a and R b are 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 2 -alkyl group attached to the parent molecular moiety through a carbonyl group. a R b Refers to the base.

[0132] As used herein, "-NR c R d " refers to two groups, R c and R d R c and R d is hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, aryl aryl alkyl, 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 Rf ) carbonyl, (NR e R f ) sulfonyl, -C(NCN)OR', and -C(NCN)NR X R Y and R' is selected from alkyl and unsubstituted phenyl, and the alkyl portion of the arylalkyl, arylalkylcarbonyl, heterocyclylalkyl, and heterocyclylalkylcarbonyl is independently selected from one -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, wherein the heterocyclyl is further optionally substituted with 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 2 -alkyl group attached to the parent molecular moiety through a carbonyl group. 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 an alkyl group attached to the parent molecular moiety through a carbonyl group. e R f ) refers to an alkyl group.

[0139] As used herein, "(NR e R f The term "carbonyl" refers to an -NR 2 -alkyl group attached to the parent molecular moiety through a carbonyl group. e R f Refers to the base.

[0140] As used herein, "(NR e R f The term "sulfonyl" refers to an -NR 2 - group attached to the parent molecular moiety through a sulfonyl group. e R f Refers to the base.

[0141] As used herein, "-NR X R Y " refers to two groups, R X and R Y 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 ) independently selected from carbonyl, and 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 inhibitor 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 with the prodrug compounds of the present 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. The prodrug moiety may include an active metabolite 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 acyloxyalkyl ester is a substituted aryl. 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. Patent Nos. 4,816,570, 4,968,788, 5,663,159, and 5,792,756. Subsequently, acyloxyalkyl esters were 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 present invention combinations. 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, particularly phenyl esters, have been reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37:498). Phenyl esters containing a carboxylic acid 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, ortho- or para-substituted groups can promote hydrolysis. Benzyl analogs bearing acylated or alkylated phenols can generate phenolic compounds through the action of enzymes, such as esterases and oxidases, which can then be cleaved by benzyl CO-coupling to generate phosphate and quinone methide intermediates. 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 containing carboxylic acid ester-containing groups attached to the benzyl methylene have been described (Glazier WO 91 / 19721). Thio-containing prodrugs have been reported to be useful for the 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 then decomposes 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] A "protecting group" refers to a moiety of a compound that masks or alters 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 utilized to mask the reactivity of certain functional groups to aid in the efficiency of desired chemical reactions, e.g., to create and break chemical bonds in an orderly and planned manner. Protection of a compound's functional group alters 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 may 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 protecting groups is to convert parent drugs into prodrugs, whereby the parent drug is released upon in vivo conversion of the prodrug. Because active prodrugs may be absorbed more effectively than the parent drug, prodrugs may have greater in vivo efficacy 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, although 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 synthetic procedures, i.e., routes or methods, for preparing compounds of the present invention. In most cases, the decisions regarding which groups to protect, when to protect, and the nature of the chemical protecting group "PG" depend on the chemical nature of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive, or other conditions) and the intended direction of synthesis. When a compound is substituted with multiple PGs, the PGs do not need to be, and generally are not, the same. Generally, PGs are used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups, thus preventing side reactions or otherwise facilitating synthetic efficiency. The order of deprotection to obtain free deprotected groups depends on the intended direction of synthesis and the reaction conditions encountered, and can occur in any order as determined by one of ordinary skill in the art.

[0157] Various functional groups in the compounds of the present invention can be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functional groups) include "ether- or ester-forming groups." Ether- or ester-forming groups can function as chemical protecting groups in the synthetic schemes described herein. However, as will be appreciated by those skilled in the art, some hydroxyl- and thio-protecting groups are not ether- or ester-forming groups, 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"). Kocienski, Philip J.; Protecting See also "Protecting Groups: An Overview" (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, In the form, each of these may occur independently no more than 12 times. Compounds described herein may contain groups with the same designated group, e.g., "R 1 " or "R 3 ", it is understood that whenever substituted with more than one of the groups, the groups can be the same or different, i.e., each group is independently selected. The wavy line indicates 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. Generally, the term "isolated and purified" means that the compound is substantially free of biological material (e.g., blood, tissue, cells, etc.). In one specific 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 from biological material; in another specific embodiment, the term means that the compound or complex of the present invention is at least about 75% free by weight from biological material; in another specific embodiment, the term means that the compound or complex of the present invention is at least about 90% free by weight from biological material; in another specific embodiment, the term means that the compound or complex of the present invention is at least about 98% free by weight from biological material; and in another embodiment, the term means that the compound or complex of the present invention is at least about 99% free by weight from biological material. In another specific embodiment, the present invention provides synthetically prepared (e.g., ex vivo) compounds or complexes of the present invention.

[0161] stereoisomer The compounds of the present invention may have chiral centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Additionally, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, chiral centers apparent 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 within the scope of the present invention. Racemic mixtures can be 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 materials. 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 hydroxyl groups of compounds include Na + and NX4 + (X is independently selected from H or a C1-C4 alkyl group).

[0164] For therapeutic use, 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 physiologically unacceptable acids or bases may also find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the present invention.

[0165] Metal salts are typically prepared by reacting the metal hydroxide with a compound herein. Examples of metal salts prepared in this manner include 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] Additionally, salts may be formed from the acid addition of certain organic and inorganic acids, such as HCl, HBr, HSO, HPO, or organic sulfonic acids, to a basic center, typically an amine, or to an acidic group. Finally, it should be understood that the compositions herein include the compounds of the invention in their non-ionized and zwitterionic forms, as well as combinations with a stoichiometric amount of water in hydrates.

[0167] Also included within the scope of the present invention are salts of the parent compound with one or more amino acids. Any natural or unnatural amino acid is suitable, particularly the naturally occurring amino acids found as protein components, although the amino acids typically have side chains with basic or acidic groups, such as lysine, arginine, or glutamic acid, or neutral groups, such as 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 can 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. When labeled, compounds that bind substantially irreversibly are useful as probes for detecting Zika virus. Accordingly, the present invention relates to a method for detecting NS3 in a sample suspected of containing Zika virus, comprising treating the sample with a composition comprising a compound of the present invention linked 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 includes, or is 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, particularly recombinant cells that synthesize the desired glycoprotein, etc. Typically, the sample is suspected of containing Zika virus. The sample can 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 treatment step of the present invention may involve adding a compound of the present invention to a sample, or it may involve adding a compound of the present invention to a sample. The method includes adding a precursor of the substance to the sample. The adding step includes any of the administration methods described above.

[0171] If desired, the activity of the Zika virus after application of the compound can be observed by any method, including direct and indirect methods for detecting Zika virus activity. Quantitative, qualitative, and semi-qualitative methods for 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 present 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 those of cell culture assays, and therefore cell-based assays should typically be the primary screening tool.

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

[0175] While it is possible for the active ingredient to be administered alone, it may be preferable to present it as a pharmaceutical formulation. 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] A tablet is made by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets are formed by compressing or molding the active ingredient in a free-flowing form such as powder or granules in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent. They can be prepared by compression. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored, and can optionally be formulated so as 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, formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount, for example, 0.075 to 20% w / w (including active ingredient in the range of 0.1% to 20% in 0.1% w / w increments, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and 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 include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide 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 contain an emulsifier (otherwise known as an emulsion), but desirably contains a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[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. Creams should preferably be non-greasy, non-staining, and washable products with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, 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, may also be used, the last three being preferred esters. These may be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0184] Pharmaceutical formulations according to the present invention comprise one or more compounds of the present invention together with one or more pharmaceutically acceptable carriers or additives, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral administration, 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 administration 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 pharmaceutically acceptable additives suitable for the manufacture of tablets are acceptable. These additives 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; binders 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] Aqueous suspensions of the present invention contain the active ingredient in admixture with additives suitable for the manufacture of aqueous suspensions. Such additives 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., heptadecathethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoates, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0187] Oil suspensions can be prepared 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 adding antioxidants such as ascorbic acid.

[0188] Dispersible powders and granules of the present invention suitable for preparation of 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 additives, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0189] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can 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 Condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate, are also included. Emulsions 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 demulcents, preservatives, flavorings, or coloring agents.

[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 described 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. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, 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 a carrier material 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 to 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 from about 3 to 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 comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising 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 particle sizes in the range of, for example, 0.1 to 500 micrometers (including particle sizes in the range of 0.1 to 500 micrometers in micrometer increments, 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 may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. 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 present 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] A veterinary carrier is a substance useful for the purpose of administering the composition and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

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

[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-((methoxycarbo Nyl)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 hours. The reaction was diluted with 75 mL of HCl and HCl. Quenched with EtOAc and 60 mL of water. Partitioned the brown solution. Added 50 mL of 1N HCl. Back-extracted the aqueous phase with 2 x 40 mL of EtOAc. Dry the combined organic phases 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 equivalents) were slowly added. Stirred for 30 minutes, 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. Concentration gave 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) gave 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 the 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). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) afforded 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-di 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 the 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° C. for 3 h. The reaction was concentrated to dryness.

[0218] To a solution of the 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). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) afforded 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 NaHCO (9.9 mg, 0.228 mmol) in DCM / acetone (1 mL each) was added N-fluorobenzenesulfonimide (26.18 mg, 0.083 mmol). The mixture was stirred at 40 °C for 1.5 h. The reaction mixture was cooled to 0°C and 10 drops of TFA was 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] Procedure 4, Example 31 Methyl((S)-1-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-5-methyl-1-(propionyl-L-valyl)pyrrolidin-2-yl)-1,1 1-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 minutes. The reaction was diluted with EtOAc and washed with saturated NaHCO solution. The organic extract was dried over sodium sulfate and purified by normal phase SiO 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 tert-Butyl (2S,5S)-2- in DCM (4 mL) and MeOH (1 mL) To a solution of (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) was added 4M hydrochloric acid (4M in dioxane) (0.300 mL). The reaction was heated to 40° C. for 5 hours. The reaction was concentrated to dryness. Proceed to the following step, assuming 100% yield.

[0224] To a solution of the 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). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) afforded 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] Procedure 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 SiO 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 under Ar / Vac 3x. Pd / C (10%, 19 mg, 17.85 μmol) was added and stirred overnight at room temperature under 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 = 8.2 Hz, 1H), 7.92 (s, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.60-7.51 (m, 2H), 7.36 (d, J = 1.5 Hz, 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° C. for 6 hours. The reaction was concentrated to dryness.

[0229] To a solution of the 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). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0°C, and 0.2 mL of TFA was added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) afforded the product as the bis-trifluoroacetate salt. ES / MS:861.5(M + ). 1H NMR (400MHz, methanol-d4) δ 8.62 (d, J = 11.4Hz, 1H), 8.26-8.18 (m, 1H), 8.04-7.91 (m, 2H), 7.6 7(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,2H),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] Procedure 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 by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product as the trifluoroacetate salt. ES / MS:993.6(M + ). 1H NMR (400MHz, methanol-d4) δ 8.65-8.47 (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] Procedure 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 (methyl-1-benzoyl)-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 the 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] Procedure 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)Cl (1.17 mg, 0.00159 mmol), Zn powder (0.521 mg, 0.00796 mmol), and Zn(CN) (5.61 mg, 0.0478 mmol) was degassed with argon for 2 minutes. The reaction was heated in a microwave at 180 °C for 15 minutes. The reaction mixture was filtered and purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product as the 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 chemistries where necessary.

[0237] [Table 1]

[0238] 1H NMR Proton NMR data are 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 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, Cat. 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 microplate (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 acid solution 100x (Gibco, catalog number 11140050) + 1% penicillin-streptomycin (10,000 U / mL) (Gibco, catalog number 15140122). Assay medium: 2% FBS, 2% GlutaMAX™ supplement (Gibco DMEM medium (Gibco, Cat#31053028) supplemented with 1% sodium pyruvate solution (Gibco, Cat#11360070), 1% MEM non-essential amino acid solution 100x, and 1% penicillin-streptomycin (10,000U / 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 strain)

[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. Cell preparation Human hepatocellular carcinoma cell line (Huh7) cells were detached from a T-175 flask using trypsin-EDTA solution and 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 3 x 10 cells were collected. 5 Diluted to a density of 100 cells / mL. Cells were seeded into white opaque 96-well plates (assay plates) at 50 μL cells per well. The plates were gently shaken to ensure that the cells adhered evenly to the plate. The seeded cells were incubated in a humidified incubator (37°C, 5% CO2).

[0256] Day 2 infection 1) Nine serially (2-fold or 3-fold) concentrated compounds were prepared in a clear V-bottom 96-well plate (compound plate) 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 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 400x more 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 approximately 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, measure cell viability using the Promega Cell-titer Glo kit (only used if ZIKV-Rlu was used for infection). 10) Luciferase signals were read using Cytation 5 with a gain value of 120-150.

[0260] Data analysis a, 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-treated group to that of the control group. b. Relative luciferase signal (Y-axis) was plotted against the log10 value of compound concentration (X-axis) in the software GraphPad Prism8, and curves were fitted using a nonlinear 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 foregoing description of specific embodiments sufficiently reveals the general nature of the present invention, and by applying the knowledge of those skilled in the art, such specific embodiments can be readily adapted for various applications without undue experimentation and without departing from the general concepts of the present disclosure. Modifications and / or adaptations are possible. Therefore, such adaptations and modifications are 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 phraseology or terminology herein is for the purpose of description and not of limitation, and that the terminology or terminology herein should be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0265] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula (I): [ka] [In the formula, R 1 Ha, Halo, C 1~10 Alkyl, C 3~12 is cycloalkyl or cyano; P 1a and P 1b are each independently [ka] is selected from the group consisting of V 1a and V 1b are each independently

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Claims

[Claim 1] The invention described in the specification.

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