Pentacyclic derivatives as inhibitors of zika virus

Abstract

Provided herein are compounds of Formula (I): wherein the various substituents are as defined herein.

Description

[0001] Cross-references to related applications

[0002] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 191,678, filed May 21, 2021, pursuant to 35 U.S.SC §119(e). The entire contents of the foregoing application are incorporated herein by reference. Background Technology

[0003] Zika virus, a mosquito-borne, single-stranded, positive-sense RNA flavivirus, has risen from relative obscurity to become an epidemic causing significant public health problems. Outbreaks of Zika virus disease have been recorded in Africa, the Americas, Asia, and the Pacific. The introduction of Zika virus into the Western Hemisphere is believed to have occurred in Haiti and Brazil in 2014–2015, and it rapidly spread to 33 or more countries. Historically, symptomatic Zika virus infection in humans has been described as a self-limiting, mild, febrile illness associated with rash, arthralgia, and conjunctivitis. However, recent Zika virus infection has also been associated with neurological complications, including Guillain-Barré syndrome and meningoencephalitis. Of particular concern is the strong association now between Zika virus infection and microcephaly and intrauterine growth retardation in fetuses of women infected during pregnancy. Zika infection during pregnancy can also lead to pregnancy complications such as miscarriage, stillbirth, and preterm birth.

[0004] There is currently no vaccine to prevent Zika virus disease. Therefore, treatment or preventative measures are needed to treat or prevent Zika virus disease, especially among women of childbearing age. Summary of the Invention

[0005] This article provides compounds and methods for treating or preventing Zika virus infection.

[0006] In one embodiment, these compounds typically have formula (I):

[0007]

[0008] in:

[0009] R 1a and R 1b Each is independently a halogen group, C 1-6 Alkyl or cycloalkyl;

[0010] P 1a Choose from the following groups:

[0011] as well as

[0012] P 1bChoose from the following groups:

[0013] as well as

[0014] V 1a and V 1b Each person independently selects a group consisting of the following items:

[0015]

[0016] E 1a and E 1b Each is independently -N(H)(C 1-6 alkoxycarbonyl), N(H)(C 3-12 cycloalkylcarbonyl), N(H)(C 1-6 alkyl carbonyl) or -N(H)(C 3-12 Cycloalkoxycarbonyl; or its stereoisomers, pharmaceutically acceptable salts or solvates.

[0017] In another embodiment, a pharmaceutical composition is provided comprising a compound of formula (I):

[0018]

[0019] in:

[0020] R 1 It is a halogen group, C 1-10 Alkyl, C 3-12 cycloalkyl or cyano groups;

[0021] P 1a and P 1b Each is selected independently from:

[0022] as well as

[0023] V 1a and V 1b Each is selected independently from:

[0024]

[0025] E 1a and E 1b Each is independently -N(H)(C 1-6 Alkoxycarbonyl), N(H) (cycloalkylcarbonyl), N(H) (alkylcarbonyl) or -N(H) (cycloalkoxycarbonyl);

[0026] The prerequisite is that when P 1a yes And V1a and V 1b All When, then R 1 It is a halogen group, C 1-6 Alkyl, C 4-7 Cycloalkyl or cyano; or pharmaceutically acceptable salts, stereoisomers or solvates thereof, and pharmaceutically acceptable excipients.

[0027] In another embodiment of the invention, a method for treating Zika virus infection in a subject in need is provided, the method comprising administering a compound of formula (I) to the subject:

[0028]

[0029] in:

[0030] R 1 It is a halogen group, C 1-10 Alkyl, C 3-12 cycloalkyl or cyano groups;

[0031] P 1a and P 1b Each is selected independently from:

[0032]

[0033] V 1a and V 1b Each is selected independently from:

[0034]

[0035] E 1a and E 1b Each is independently -N(H)(C 1-6 Alkoxycarbonyl), N(H) (cycloalkylcarbonyl), N(H) (alkylcarbonyl) or -N(H) (cycloalkoxycarbonyl);

[0036] The prerequisite is that when P 1a yes And V 1a and V 1b All When, then R 1 It is a halogen group, C 1-6 Alkyl, C 4-7 Cycloalkyl or cyano; or pharmaceutically acceptable salts, stereoisomers or solvates thereof.

[0037] In another implementation, the subjects are humans.

[0038] In another implementation, the subjects are women of childbearing age.

[0039] In another implementation, the subject is a pregnant woman.

[0040] In another embodiment, the compound is mixed in a pharmaceutical composition with a pharmaceutically acceptable excipient.

[0041] In another embodiment, a method for preventing Zika virus infection is provided, the method comprising administering a compound of formula (I) to a subject in need:

[0042]

[0043] in:

[0044] R 1 It is a halogen group, C 1-10 Alkyl, C 3-12 cycloalkyl or cyano groups;

[0045] P 1a and P 1b Each is selected independently from:

[0046]

[0047] V 1a and V 1b Each is selected independently from:

[0048]

[0049] E 1a and E 1b Each is independently -N(H)(C 1-6 Alkoxycarbonyl), N(H) (cycloalkylcarbonyl), N(H) (alkylcarbonyl) or -N(H) (cycloalkoxycarbonyl);

[0050] The prerequisite is that when P 1a yes And V 1a and V 1b All When, then R 1 It is a halogen group, C 1-6 Alkyl, C 4-7 Cycloalkyl or cyano; or pharmaceutically acceptable salts, stereoisomers or solvates thereof.

[0051] In another implementation, the subjects are humans.

[0052] In another implementation, the subjects are women of childbearing age.

[0053] In another implementation, the subject is a pregnant woman.

[0054] In another embodiment, the compound is mixed in a pharmaceutical composition with a pharmaceutically acceptable excipient. Other and further embodiments will be apparent to those skilled in the art, and the appended claims are intended to cover minor modifications. Detailed Implementation

[0055] Reference will now be made specifically to particular embodiments of the invention, examples of which are shown in the appended structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the embodiments.

[0056] Whenever the compound described herein is referred to by more than one of the same designated groups (e.g., "R1" or "A") 3 When substitution is performed, it should be understood that these groups can be the same or different, that is, each group is chosen independently.

[0057] "Non-existent": Some groups are defined as such that they can not exist. When a group is non-existent, it becomes a bonding group. Otherwise, two groups bonded to a non-existent group are linked to each other by a bond. For example, when W is non-existent, M is bonded to M.

[0058] "alkyl" refers to a C1-C group containing normal, secondary, tertiary, or cyclic carbon atoms. 18 Hydrocarbons. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl ( n -Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl ( n -Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i -Bu, isobutyl, -CH2CH(CH3)2), 2-butyl ( s -Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3) ), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3) and cyclopropylmethyl

[0059] "Alkenyl" refers to a group containing ortho-, secondary-, tertiary-, or cyclic carbon atoms and having at least one unsaturated site (i.e., carbon-carbon, sp). 2 C2-C (double bond) 18 Hydrocarbons. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0060] "Alkyne" is a C2-C group containing a normal, secondary, tertiary, or cyclic carbon atom and having at least one unsaturated site (i.e., a carbon-carbon, sp triple bond). 18 Hydrocarbons. Examples include, but are not limited to, ethynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0061] "Alkylene" refers to a saturated, branched, straight-chain, or cyclic hydrocarbon group with 1 to 18 carbon atoms, and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0062] "Ideinyl" refers to an unsaturated, branched, straight-chain, or cyclic hydrocarbon group with 2 to 18 carbon atoms, and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent olefin. Typical ideinyl groups include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0063] "Imyynyl" refers to an unsaturated, branched, straight-chain, or cyclic hydrocarbon group with 2 to 18 carbon atoms, and having two monovalent group centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Typical ynyl groups include, but are not limited to, ethynyl (-C≡C-), propynyl (-CH2C≡C-), and 4-pentynyl (-CH2CH2CH2C≡CH).

[0064] "Aryl" refers to a monovalent aromatic hydrocarbon group with 6 to 20 carbon atoms, derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, etc.

[0065] "Arylalkyl" refers to an acyclic alkyl group in which the carbon atom (usually terminal or sp) is... 3 In an arylalkyl group, one hydrogen atom bonded to a carbon atom is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, and 2-naphthophenylethyl-1-yl. An arylalkyl group contains 6 to 20 carbon atoms; for example, the alkyl portion (including alkyl, alkenyl, or alkynyl groups) of an arylalkyl group has 1 to 6 carbon atoms, and the aryl portion has 5 to 14 carbon atoms.

[0066] The term "polycyclic ring" refers to a saturated or unsaturated polycyclic ring system having 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, the term includes bicyclic [4,5], [5,5], [5,6], or [6,6] ring systems, as well as the following bridged ring systems:

[0067] as well as

[0068] (i.e., polycyclic rings of formula (I) such as [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]), which can be linked to the remainder of the compound of formula (I) at any synthetically feasible position. Similar to other polycyclic rings, these representative bicyclic and fused ring systems may optionally include one or more double bonds in the ring system.

[0069] The term "polyheterocycle" refers to a multicarbon ring as defined herein, in which one or more carbon atoms are surrounded by heteroatoms (e.g., O, S, S(O), S(O)2, N). + (O - )R x or NR x ) replace; where each R x Independently, it is H, (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C1-10)alkanoyl, or 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 by one or more halogen groups).

[0070] "Substituted alkyl", "substituted aryl", and "substituted arylalkyl" refer to alkyl, aryl, and arylalkyl groups in which one or more hydrogen atoms are independently substituted by non-hydrogen substituents, respectively. Typical substituents include, but are not limited to: halogens (e.g., F, Cl, Br, I), -R, -OR, -SR, -NR2, -CF3, -CCl3, -OCF3, -CN, -NO2, -N(R)C(=O)R, -C(=O)R, -OC(=O)R, -C(O)OR, -C(=O)NRR, -S(=O)R, -S(=O)2OR, -S(=O)2R, -OS(=O)2OR, -S(=O)2NRR, and each R is independently -H, alkyl, aryl, arylalkyl, or heterocyclic. Alkylene, alkenylene, and alkyneyl groups may also be substituted similarly.

[0071] The term "optionally substituted" in relation to a specific part of a compound of formula I (e.g., an optionally substituted aryl group) refers to a part having 0, 1, 2 or more substituents.

[0072] The symbol in the ring structure " ---- " indicates that the key is a single or double key. In the non-restrictive example, It can be

[0073] As used herein, “haloalkyl” includes an alkyl group substituted with one or more halogens (e.g., F, Cl, Br, or I). Representative examples of haloalkyl groups include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.

[0074] As used herein, “heterocyclic” includes, by way of example and not limitation, the heterocyclic compounds described in the following: Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WABenjamin, 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), particularly Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention, "heterocycle" includes "carbon ring" as defined herein, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms have been substituted with heteroatoms (e.g., O, N or S).

[0075] Examples of heterocycles include, by way of example and not limitation, the following: pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, sulfoxylated tetrahydrothiophenyl, pyrimidinyl, furanyl, thiophene, pyrroleyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thionaphthyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl, 2-pyrrolidinoneyl, pyrrolinyl, tetra Hydrofuranyl, Tetrahydroquinolinyl, Tetrahydroisoquinolinyl, Decahydroquinolinyl, Octahydroisoquinolinyl, Azoalkyl, Triazinyl, 6H-1,2,5-Thiadiazinyl, 2H,6H-1,5,2-Dithiazinyl, Thiopheneyl, Thianthyl, Pyranyl, Isobenzofuranyl, Chromenyl, Xanthenyl, Phenoxathinyl, 2H-Pyrroleyl, Isothiazolyl, Isoxazolyl, Pyrazinyl, Pyridazinyl, Indoleyl Dolazinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purine, 4H-quinolinyl, phthalazinyl, naphridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, β-carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenanthrolinyl Thiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazoalkyl, imidazolinyl, pyrazolyl, pyrazolyl, piperazinyl, indololinyl, isoydinolinyl, quininecycloyl, morpholinyl, oxazolyl, benzotriazolyl, benzoisooxazolyl, oxindolyl, benzooxazolyl, isatinoyl, and bis(tetrahydrofuranyl):

[0076]

[0077] By way of example and not limitation, carbon-bonded heterocycles are bonded at the following positions: 2, 3, 4, 5, or 6 of pyridine; 3, 4, 5, or 6 of pyridazine; 2, 4, 5, or 6 of pyrimidine; 2, 3, 5, or 6 of pyrazine; 2, 3, 4, or 5 of furan, tetrahydrofuran, thiophene, thiocyclopentazone, pyrrole, or tetrahydropyrrole; 2, 4, or 5 of oxazole, imidazole, or thiazole; 3, 4, or 5 of isoxazole, pyrazole, or isothiazole; 2 or 3 of aziridine; 2, 3, or 4 of aziridine; 2, 3, 4, 5, 6, 7, or 8 of quinoline; or 1, 3, 4, 5, 6, 7, or 8 of isoquinoline. More typically, carbon-bonded heterocycles include 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl, 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.

[0078] By way of example and not limitation, nitrogen-bonded heterocycles are bonded at the following positions: 1-position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrroleoline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indolone, or 1H-indazole; 2-position of isoindole or isoindoline; 4-position of morpholine; and 9-position of carbazole or β-carbline. More typically, nitrogen-bonded heterocycles include 1-aziridinepropyl, 1-aziridinebutyl, 1-pyrroleyl, 1-imidazoyl, 1-pyrazolyl, and 1-piperidinyl.

[0079] A “carbocyclic ring” refers to a saturated, unsaturated, or aromatic ring having up to about 25 carbon atoms. Typically, carbocyclic rings have about 3 to 7 carbon atoms as a monocyclic ring, about 7 to 12 carbon atoms as a bicyclic ring, and up to about 25 carbon atoms as a polycyclic ring. Monocyclic carbocyclic rings typically have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocyclic rings typically have 7 to 12 ring atoms, for example, arranged in bicyclic [4,5], [5,5], [5,6], or [6,6] systems; or have 9 or 10 ring atoms arranged in bicyclic [5,6] or [6,6] systems. The term carbocyclic ring includes “cycloalkyl,” which is a saturated or unsaturated carbocyclic ring. Examples of monocyclic carbocyclic compounds 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.

[0080] The term "chirality" refers to a molecule that has a non-overlapping property with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0081] The term "stereoisomer" refers to compounds that have the same chemical composition but whose atoms or groups are arranged differently in space.

[0082] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.

[0083] "Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0084] The term “treatment” includes, to the extent that it relates to a disease or condition, preventing the occurrence of a disease or condition, suppressing a disease or condition, eliminating a disease or condition, and / or alleviating one or more symptoms of a disease or condition.

[0085] The stereochemical definitions and conventions used in this article generally follow SPParker's editing, McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of polarized light. In describing optically active compounds, prefixes (D and L) or (R and S) are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to indicate the plane polarization rotation symbol of the compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur without stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity. This invention includes all stereoisomers of the compounds described herein.

[0086] As used herein, the term "alkenyl" refers to a straight-chain or branched group containing two to six carbon atoms with at least one carbon-carbon double bond.

[0087] As used herein, the term "alkenyl group" refers to an alkenyl group that is partially connected to the parent molecule via an oxygen atom.

[0088] As used herein, the term "olefin carbonyl" refers to an olefin group that is partially connected to the parent molecule via a carbonyl group.

[0089] As used herein, the term "alkoxy" refers to an alkyl group that is partially attached to the parent molecule via an oxygen atom.

[0090] As used herein, the term "alkoxyalkyl" refers to an alkyl group that is substituted with one, two, or three alkoxy groups.

[0091] As used herein, the term "alkoxyalkyl carbonyl" refers to an alkoxyalkyl group that is partially linked to the parent molecule via a carbonyl group.

[0092] As used herein, the term "alkoxycarbonyl" refers to an alkoxy group that is partially attached to the parent molecule via a carbonyl group.

[0093] As used herein, the term "alkoxycarbonylalkyl" refers to an alkyl group that is substituted by one, two, or three alkoxycarbonyl groups.

[0094] As used herein, the term "alkyl" refers to a group derived from a straight-chain or branched saturated hydrocarbon containing one to six carbon atoms.

[0095] As used herein, the term "alkyl carbonyl" refers to an alkyl group that is partially attached to the parent molecule via a carbonyl group.

[0096] As used herein, the term "alkyl carbonyl alkyl" refers to an alkyl group that is substituted by one, two, or three alkyl carbonyl groups.

[0097] As used herein, the term "alkylcarbonyloxy group" refers to an alkyl carbonyl group that is partially attached to the parent molecule via an oxygen atom.

[0098] As used herein, the term "alkylthioalkyl" refers to an alkyl group that is partially linked to the parent molecule via a sulfur atom.

[0099] As used herein, the term "alkylsulfonyl" refers to an alkyl group that is partially attached to the parent molecule via a sulfonyl group.

[0100] As used herein, the term "aryl" refers to a phenyl group or a bicyclic fused ring system in which one or both rings are phenyl groups. A bicyclic fused ring system consists of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbon ring. The aryl groups of this disclosure can be partially attached to the parent molecule via any substituted 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 this disclosure are optionally substituted by one, two, three, four, or five substituents independently selected from: alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, secondary aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halogen, haloalkoxy, haloalkyl, heterocyclic, heterocyclic alkyl, heterocyclic carbonyl, hydroxy, hydroxyalkyl, nitro, -NR X R Y 、-(NR X R Y )alkyl, oxo, and -P(O)OR2, wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl portion of the arylalkyl and heterocyclic alkyl groups is unsubstituted, and wherein the secondary aryl group, the aryl portion of the arylalkyl group, the aryl portion of the arylcarbonyl group, the heterocyclic group, and the heterocyclic alkyl and heterocyclic carbonyl groups are further optionally substituted by one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and nitro groups.

[0101] As used herein, the term "aryl alkenyl" refers to an alkenyl group that is substituted by one, two, or three aryl groups.

[0102] As used herein, the term "arylalkoxy" refers to an aryl group that is partially attached to the parent molecule via an alkoxy group.

[0103] As used herein, the term "arylalkoxyalkyl" refers to an alkyl group that is substituted with one, two, or three arylalkoxy groups.

[0104] As used herein, the term "arylalkoxyalkyl carbonyl" refers to an arylalkoxyalkyl group that is partially linked to the parent molecule via a carbonyl group.

[0105] As used herein, the term "arylalkoxycarbonyl" refers to an arylalkoxy group that is partially attached to the parent molecule via a carbonyl group.

[0106] As used herein, the term "arylalkyl" refers to an alkyl group substituted with one, two, or three aryl groups. The alkyl moiety of an arylalkyl group is further optionally replaced by one or two groups independently selected from alkoxy, alkylcarbonyloxy, halogen, haloalkoxy, haloalkyl, heterocyclic, hydroxyl, and -NR groups. c R dThe additional groups are substituted, wherein the heterocyclic group is optionally further replaced by one or two independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halogen, haloalkoxy, haloalkyl, hydroxyl and -NR. X R Y Substituents of the substituents;

[0107] As used herein, the term "arylalkylcarbonyl" refers to an arylalkyl group that is partially linked to the parent molecule via a carbonyl group.

[0108] As used herein, the term "aryl carbonyl" refers to an aryl group that is partially attached to the parent molecule via a carbonyl group.

[0109] As used in this article, the term "aryloxy group" refers to an aryl group that is partially attached to the parent molecule via an oxygen atom.

[0110] As used herein, the term "aryloxyalkyl" refers to an alkyl group that is substituted with one, two, or three aryloxy groups.

[0111] As used herein, the term "aryloxycarbonyl" refers to an aryloxy group that is partially attached to the parent molecule via a carbonyl group.

[0112] As used herein, the term "arylthioalkyl" refers to an aryl group that is partially attached to the parent molecule via a sulfur atom.

[0113] As used herein, the term "arylsulfonyl" refers to an aryl group that is partially attached to the parent molecule via a sulfonyl group.

[0114] As used herein, the terms “Cap” and “cap” refer to a group located on a nitrogen atom of a terminal nitrogen-containing ring. It should be understood that “Cap” and “cap” can also refer to reagents used to attach groups to segments of terminal nitrogen-containing rings or final products.

[0115] As used in this article, the term "carbonyl" refers to -C(=O)-.

[0116] As used in this article, the term "carboxyl group" refers to -CO2H.

[0117] As used in this article, the term "cyano" refers to -CN.

[0118] As used herein, the term "cyanoalkyl" refers to an alkyl group having at least one -CN substituent.

[0119] As used herein, the term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring system having three to seven carbon atoms and zero heteroatoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups of this disclosure are optionally selected independently by one, two, three, four, or five groups selected from alkoxy, alkyl, aryl, cyano, haloyl, haloalkoxy, haloalkyl, heterocyclic, hydroxy, hydroxyalkyl, nitro, and -NR. x R y The substituents are replaced, wherein the aryl and heterocyclic groups are further optionally replaced by one, two or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy and nitro groups.

[0120] As used herein, the term "(cycloalkyl)alkenyl" refers to an alkenyl group that is substituted with one, two, or three cycloalkyl groups.

[0121] As used herein, the term "(cycloalkyl)alkyl" refers to an alkyl group substituted with one, two, or three cycloalkyl groups. The alkyl moiety of a (cycloalkyl)alkyl group is further optionally replaced by one or two groups independently selected from hydroxyl and -NR. c R d The group is substituted.

[0122] As used herein, the term "cycloalkyloxy" refers to a cycloalkyl group that is partially connected to the parent molecule via an oxygen atom.

[0123] As used herein, the term "cycloalkyloxyalkyl" refers to an alkyl group that is substituted by one, two, or three cycloalkyloxy groups.

[0124] As used herein, the term "cycloalkylsulfonyl" refers to a cycloalkyl group that is partially linked to the parent molecule via a sulfonyl group.

[0125] As used in this article, the term "formyl" refers to -CHO.

[0126] As used herein, the terms “halogen” and “halogen” refer to F, Cl, Br, or I.

[0127] As used herein, the term "haloalkoxy" refers to a haloalkyl group that is partially attached to the parent molecule via an oxygen atom.

[0128] As used herein, the term "haloalkoxycarbonyl" refers to a haloalkoxy group that is partially attached to the parent molecule via a carbonyl group.

[0129] As used herein, the term "haloalkyl" refers to an alkyl group that is substituted with one, two, three, or four halogen atoms.

[0130] As used herein, the term "haloalkylthioalkyl" refers to a haloalkyl group that is partially attached to the parent molecule via a sulfur atom.

[0131] As used herein, the term "heterocyclic group" refers to a four-, five-, six-, or seven-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, and sulfur. Four-membered rings have zero double bonds, five-membered rings have zero to two double bonds, and six- and seven-membered rings have zero to three double bonds. The term "heterocyclic group" also includes bicyclic groups in which the heterocyclic ring is fused to another monocyclic heterocyclic group or a four- to six-membered aromatic or non-aromatic carbon ring; and bridging bicyclic groups such as 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl, and 2-azabicyclo[2.2.2]oct-3-yl. The heterocyclic groups of this disclosure can be linked to a parent molecule moiety via any carbon or nitrogen atom in the group. Examples of heterocyclic groups include, but are not limited to, benzothiophene, furanyl, imidazolyl, indololinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazine, piperidinyl, pyrazolyl, pyridinyl, pyrroloalkyl, pyrrolopyridinyl, pyrrolo, thiazolyl, thiophene, thiomorpholinyl, 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl, and 2-azabicyclo[2.2.2]oct-3-yl. The heterocyclic groups of this disclosure are optionally selected from one, two, three, four, or five independently from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halogen, haloalkoxy, haloalkyl, secondary heterocyclic group, heterocyclic alkyl, heterocyclic carbonyl, hydroxy, hydroxyalkyl, nitro, -NR X R Y 、-(NR X R Y The alkyl and oxo groups are substituted, wherein the alkyl portion of the arylalkyl and heterocyclic alkyl groups is unsubstituted, and wherein the aryl, the aryl portion of the arylalkyl, the aryl portion of the arylcarbonyl, the secondary heterocyclic group, and the heterocyclic portion of the heterocyclic alkyl and heterocyclic carbonyl groups are optionally further substituted by one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl, and nitro groups.

[0132] As used herein, the term "heterocyclic alkenyl" refers to an alkenyl group that is substituted by one, two, or three heterocyclic groups.

[0133] As used herein, the term "heterocyclic alkoxy" refers to a heterocyclic group that is partially connected to the parent molecule via an alkoxy group.

[0134] As used herein, the term "heterocyclic alkoxy carbonyl" refers to a heterocyclic alkoxy group that is partially connected to the parent molecule via a carbonyl group.

[0135] As used herein, the term "heterocyclic alkyl" refers to an alkyl group substituted with one, two, or three heterocyclic groups. The alkyl moiety of the heterocyclic alkyl group is further optionally replaced by one or two groups independently selected from alkoxy, alkylcarbonyloxy, aryl, halogen, haloalkoxy, haloalkyl, hydroxy, and -NR. c R d The additional groups are substituted, wherein the aryl group is further optionally replaced by one or two independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halogen, haloalkoxy, haloalkyl, hydroxyl and -NR. X R Y Substituents are substituted.

[0136] As used herein, the term "heterocyclic alkyl carbonyl" refers to a heterocyclic alkyl group that is partially connected to the parent molecule via a carbonyl group.

[0137] As used herein, the term "heterocyclic carbonyl" refers to a heterocyclic group that is partially connected to the parent molecule via a carbonyl group.

[0138] As used herein, the term "heterocyclic hydroxyl group" refers to a heterocyclic group that is partially connected to the parent molecule via an oxygen atom.

[0139] As used herein, the term "heterocyclic oxyalkyl" refers to an alkyl group that is substituted by one, two, or three heterocyclic oxy groups.

[0140] As used herein, the term "heterocyclic oxycarbonyl" refers to a heterocyclic oxy group that is partially connected to the parent molecule via a carbonyl group.

[0141] As used in this article, the term "hydroxyl group" refers to -OH.

[0142] As used herein, the term "hydroxyalkyl" refers to an alkyl group that is substituted with one, two, or three hydroxyl groups.

[0143] As used herein, the term "hydroxyalkyl carbonyl" refers to a hydroxyalkyl group that is partially linked to the parent molecule via a carbonyl group.

[0144] As used in this article, the term "nitro" refers to -NO2.

[0145] As used in this article, the term "-NR" a R b "" refers to two groups R that are partially connected to the parent molecule through a nitrogen atom. a and R b R a and R b It is independently selected from hydrogen, alkenyl and alkyl.

[0146] As used in this article, the term "(NR)" a R b "alkyl" refers to an alkyl group consisting of one, two, or three -NR groups. a R b Alkyl groups substituted with radicals.

[0147] As used in this article, the term "(NR)" a R b "Carbonyl" refers to the -NR group that is partially connected to the parent molecule through a carbonyl group. a R b Group.

[0148] As used in this article, the term "-NR" c R d” It refers to two groups R that are partially connected to the parent molecule through a nitrogen atom. c and R d R c and R d Independently selected from hydrogen, olefin carbonyl, alkoxyalkyl carbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclic, heterocyclic alkoxycarbonyl, heterocyclic alkyl, heterocyclic alkylcarbonyl, heterocyclic carbonyl, heterocyclic oxycarbonyl, hydroxyalkylcarbonyl, (NR) e R f )alkyl, (NR e R f )alkyl carbonyl, (NR e R f Carbonyl group, (NR) e R f )sulfonyl, -C(NCN)OR' and -C(NCN)NR X R Y R' is selected from alkyl and unsubstituted phenyl, and the alkyl moiety of arylalkyl, arylalkylcarbonyl, heterocyclic alkyl and heterocyclic alkylcarbonyl is further optionally surrounded by a -NR. e R f Group substitution; and wherein the aryl moiety of the aryl group, the aryl moiety of the arylalkoxycarbonyl group, the arylalkyl group, the arylalkylcarbonyl group, the arylcarbonyl group, the aryloxycarbonyl group and the arylsulfonyl group, the heterocyclic group and the heterocyclic alkoxycarbonyl group, the heterocyclic alkyl group, the heterocyclic alkylcarbonyl group, the heterocyclic carbonyl group and the heterocyclic oxycarbonyl group are further optionally substituted by one, two or three substituents independently selected from alkoxy, alkyl, cyano, halogen, haloalkoxy, haloalkyl and nitro groups.

[0149] As used in this article, the term "(NR)" cR d "Alkenyl" refers to an group consisting of one, two, or three -NR groups. c R d Alkenyl groups substituted with radicals.

[0150] As used in this article, the term "(NR)" c R d "alkyl" refers to an alkyl group consisting of one, two, or three -NR groups. c R d Alkyl groups substituted with radicals. (NR) c R d The alkyl moiety of the alkyl group is further optionally surrounded by one or two groups selected from alkoxy, alkoxyalkyl carbonyl, alkoxycarbonyl, alkylthioalkyl, arylalkoxyalkyl carbonyl, carboxyl, heterocyclic, heterocyclic carbonyl, hydroxyl, and (NR) e R f The carbonyl group is substituted with an additional group; wherein the heterocyclic group is further optionally substituted by one, two, three, four or five substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl and nitro.

[0151] As used in this article, the term "(NR)" c R d "Carbonyl" refers to the -NR group that is partially connected to the parent molecule through a carbonyl group. c R d Group.

[0152] As used in this article, the term "-NR" e R f "" refers to two groups R that are partially connected to the parent molecule through a nitrogen atom. e and R f R e and R f Independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl)alkyl, unsubstituted heterocyclic, unsubstituted heterocyclic alkyl, -(NR X R Y )alkyl and -(NR X R Y Carbonyl group.

[0153] As used in this article, the term "(NR)" e R f "alkyl" refers to an alkyl group consisting of one, two, or three -NR groups. e R f Alkyl groups substituted with radicals.

[0154] As used in this article, the term "(NR)" e R f"alkyl carbonyl" refers to a group that is partially connected to the parent molecule via a carbonyl group. e R f )alkyl group.

[0155] As used in this article, the term "(NR)" e R f "Carbonyl" refers to the -NR group that is partially connected to the parent molecule through a carbonyl group. e R f Group.

[0156] As used in this article, the term "(NR)" e R f "Sulfonyl group" refers to -NR group that is partially linked to the parent molecule through a sulfonyl group. e R f Group.

[0157] As used in this article, the term "-NR" X R Y "" refers to two groups R that are partially connected to the parent molecule through a nitrogen atom. X and R Y R X and R Y Independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclic and (NR) X 'R Y ') carbonyl group, where R X 'and R Y 'Independently selected from hydrogen and alkyl groups.'

[0158] As used in this article, the term "(NR)" X R Y "alkyl" refers to an alkyl group consisting of one, two, or three -NR groups. X R Y Alkyl groups substituted with radicals.

[0159] As used in this article, the term "oxo" refers to =O.

[0160] As used in this article, the term "sulfonyl" refers to -SO2-.

[0161] As used herein, the term "trialkylsilyl" refers to -SiR3, where R is an alkyl group. The R groups may be the same or different.

[0162] As used herein, the term “trialkylsilylalkyl” refers to an alkyl group that is substituted by one, two, or three trialkylsilyl groups.

[0163] As used herein, the term "trialkylsilylalkoxy" refers to a trialkylsilylalkyl group that is partially linked to the parent molecule via an oxygen atom.

[0164] As used herein, the term “trialkylsilylalkoxyalkyl” refers to an alkyl group that is substituted by one, two, or three trialkylsilylalkoxy groups.

[0165] prodrug

[0166] As used herein, the term "prodrug" refers to any compound of the present invention ("active inhibitory compound") that, when applied to a biological system, produces an inhibitory effect on Zika virus activity. This compound can be formed from a prodrug through: (i) spontaneous chemical reactions, (ii) enzyme-catalyzed chemical reactions, (iii) photolysis, and / or (iv) metabolic chemical reactions.

[0167] "Prodrug fraction" refers to the unstable functional group that is isolated from the active inhibitory compound systemically within the cell during metabolism through hydrolysis, enzymatic cleavage, or other processes. (Bundgaard, Hans, "Design and Application of Prodrugs") 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 of the prodrug compounds of the present invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. The prodrug moiety can be used to enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy. The prodrug moiety may include an active metabolite or the drug itself.

[0168] Exemplary prodrug moieties include hydrolysis-sensitive or unstable acyloxymethyl esters -CH2OC(=O)R 99 and acyloxymethyl carbonate -CH2OC(=O)OR 99 , where R 99 It is a C1-C6 alkyl, a C1-C6 substituted alkyl, or a C6-C 20 Aryl or C6-C 20Substituted aryl groups. Acyloxyalkyl esters were first used as a prodrug strategy for carboxylic acids, and then applied to phosphate esters and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; and U.S. Patents 4,816,570, 4,968,788, 5,663,159, and 5,792,756. Subsequently, acyloxyalkyl esters were used to deliver phosphonates across cell membranes and improve oral bioavailability. Similar variants of acyloxyalkyl esters (alkoxycarbonyloxyalkyl esters (carbonates)) can also be used as prodrug moieties in compounds combined in this invention to enhance oral bioavailability. An exemplary acyloxymethyl ester is neopentyloxymethoxy(POM)-CH2OC(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moieties are neopentyloxymethyl carbonate(POC)-CH2OC(=O)OC(CH3)3.

[0169] Aryl esters, particularly phenyl esters, with phosphorus groups have been reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37:498). Phenyl esters containing carboxylic acid esters ortho to phosphate esters have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters have been reported to produce parent phosphonic acids. In some cases, substituents at the ortho or para positions can accelerate hydrolysis. Benzyl analogs of acylated or alkylated phenols can be converted into phenolic compounds by enzymatic action (e.g., esterases, oxidases, etc.), which then undergo cleavage at the benzyl CO bond to generate phosphate and quinone methylation intermediates. Examples of such prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. II 2345; Glazier WO 91 / 19721. Other benzyl prodrugs containing carboxylic acid ester groups linked to benzyl methylene groups have also been described (Glazier WO 91 / 19721). Sulfur-containing prodrugs have been reported for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group, wherein the thiol group is esterified by an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide yields a free thio intermediate, which subsequently decomposes into phosphoric acid and cyclic sulfides (Puech et al. (1993) Antiviral Res., 22:155-174; Benzaria et al. (1996) J. Med. Chem. 39:4958).

[0170] Protecting group

[0171] In the context of this invention, the protecting group includes a prodrug moiety and a chemical protecting group.

[0172] A "protecting group" is a compound moiety that masks or alters the properties of functional groups or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example... Protective Groups in Organic Chemistry Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. Functional group protection of a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by commonly used analytical tools. Chemically protected intermediates can themselves be biologically active or inactive.

[0173] Protected compounds can also exhibit alterations both in vitro and in vivo, and in some cases, optimized properties, such as cross-membrane penetration and resistance to enzymatic degradation or chelation. In this role, the protected compound with the intended therapeutic effect may be referred to as a prodrug. Another function of the protecting group is to convert the parent drug into a prodrug, thereby releasing the parent drug during prodrug conversion in vivo. Because the active prodrug may be absorbed more efficiently than the parent drug, the prodrug may have greater potency in vivo. In the case of chemical intermediates, the protecting group is removed in vitro; in the case of prodrugs, the protecting group is removed in vivo. For chemical intermediates, the physiological acceptability of the resulting product (e.g., an alcohol) after deprotection is not particularly important, but generally, it is preferable if these products are pharmacologically harmless.

[0174] Protecting groups are available, generally known, and used, and are optionally used to prevent side reactions with the protecting group during the synthetic procedure (i.e., the route or method for preparing the compounds of the present invention). In most cases, the decision regarding which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will depend on the chemical nature of the reaction to be protected (e.g., acidic, basic, oxidative, reducing, or other conditions) and the intended synthetic direction. If the compound is substituted by multiple PGs, the PGs are not required and are generally not identical. Typically, PGs will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups to prevent side reactions or otherwise promote synthetic efficiency. The deprotection sequence that produces free deprotected groups depends on the intended synthetic direction and the reaction conditions encountered, and can occur in any order determined by a person skilled in the art.

[0175] Various functional groups of the compounds of this invention can be protected. For example, protecting groups of the -OH group (whether hydroxyl, carboxylic acid, phosphoric acid, or other functional groups) include "ether or ester forming groups". In the synthetic embodiments described herein, ether or ester forming groups can act as chemical protecting groups. However, as those skilled in the art will understand, some hydroxyl and thio groups are not ether or ester forming groups and are included in amides, as described below.

[0176] Protective Groups in Organic Synthesis Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”) describes a very large number of hydroxyl protecting groups and amide forming groups, as well as the corresponding chemical cleavage reactions. See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), the entire contents of which are incorporated herein by reference. Specifically, Chapter 1, Protecting Groups: An Overview, pp. 1–20; Chapter 2, Hydroxyl Protecting Groups, pp. 21–94; Chapter 3, Diol Protecting Groups, pp. 95–117; Chapter 4, Carboxyl Protecting Groups, pp. 118–154; Chapter 5, Carbonyl Protecting Groups, pp. 155–184. For protecting groups of carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other protecting groups of acids, see Greene as described below.

[0177] As an example rather than a limitation, R 1 R 3 R A1 R A3 and X A In some embodiments, these are recursive substituents. Typically, each of these recursive substituents may independently appear 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 times in a given embodiment. More typically, each of these recursive substituents may independently appear 12 times or fewer times in a given embodiment. Whenever the compound described herein is subjected to more than one of the same designated groups (e.g., "R"), 1 "or "R 3When substitution occurs, it should be understood that these groups can be the same or different, meaning each group is chosen independently. The wavy lines indicate the sites where covalent bonds are attached to adjacent groups, parts, or atoms.

[0178] In one embodiment of the invention, the compound is in an 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 invention, this term means that the compound or conjugate of the invention is free of at least about 50% by weight of biological material; in another specific embodiment, this term means that the compound or conjugate of the invention is free of at least about 75% by weight of biological material; in another specific embodiment, this term means that the compound or conjugate of the invention is free of at least about 90% by weight of biological material; in another specific embodiment, this term means that the compound or conjugate of the invention is free of at least about 98% by weight of biological material; and in yet another embodiment, this term means that the compound or conjugate of the invention is free of at least about 99% by weight of biological material. In another specific embodiment, the invention provides compounds or conjugates of the invention that have been synthesized (e.g., in vitro).

[0179] Stereoisomers

[0180] The compounds of this invention may have a chiral center, such as a chiral carbon or phosphorus atom. Therefore, the compounds of this invention comprise racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and transisomers. Furthermore, the compounds of this invention comprise optical isomers enriched or resolved at any or all asymmetric, chiral atoms. In other words, the chiral center, as apparent from the description, is provided as a chiral isomer or a racemic mixture. Both racemic mixtures and diastereomer mixtures, as well as isolated or synthesized individual optical isomers (substantially free of their enantiomers or diastereomer conjugates), are within the scope of this invention. Racemic mixtures are isolated into their individual, substantially optically pure isomers using well-known techniques, such as, for example, separating diastereomers formed with optically active auxiliaries (e.g., acids or bases), and then converting the diastereomers back into the optically active substance. In most cases, the desired optical isomers are synthesized via stereospecific reactions, starting from a suitable stereoisomer of the desired starting material.

[0181] In some cases, the compounds of the present invention may also exist as tautomers. Although only one delocalized resonance structure can be described, all such forms are considered within the scope of the present invention. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazolium systems, olefin-amine tautomers may exist, and all their possible tautomer forms are within the scope of the present invention.

[0182] Salts and hydrates

[0183] Examples of physiologically acceptable salts of the compounds of the present invention include those derived from suitable bases, such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and Nx4. + Salts of compounds containing (where X is a C1-C4 alkyl group). Physiologically acceptable salts of hydrogen atoms or amino groups include salts of the following acids: organic carboxylic acids, such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, ethanesulfonic acid, lactobionic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and aminosulfonic acid. Physiologically acceptable salts of compounds containing hydroxyl groups include the anion of said compound with a suitable cation such as Na+. + and NX4 + (where X is independently selected from a combination of H or C1-C4 alkyl groups).

[0184] For therapeutic purposes, the salts of the active ingredients of the compounds of the present invention will generally be physiologically acceptable, i.e., they will be salts derived from physiologically acceptable acids or bases. However, salts of physiologically unacceptable acids or bases may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts (whether or not derived from physiologically acceptable acids or bases) are within the scope of the present invention.

[0185] Metal salts are typically prepared by reacting a metal hydroxide with the compounds of this invention. An example of a metal salt prepared in this manner is one containing Li. + Na + and K + Salts with low solubility can be precipitated from solutions of salts with high solubility by adding a suitable metal compound.

[0186] Additionally, salts can be formed by the addition of certain organic and inorganic acids (e.g., HCl, HBr, H2SO4, H3PO4, 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 non-ionic and zwitterionic forms of the compounds of the present invention combined with a stoichiometric amount of water in the hydrate.

[0187] Salts of the parent compound and one or more amino acids are also included within the scope of this invention. Any natural or non-natural amino acid is suitable, especially naturally occurring amino acids found as protein components, although amino acids are generally those with side chains having basic or acidic groups (e.g., lysine, arginine, or glutamic acid) or neutral groups (such as glycine, serine, threonine, alanine, isoleucine, or leucine).

[0188] Methods to suppress Zika virus

[0189] Another aspect of the present invention relates to a method for inhibiting the activity of Zika virus, the method comprising the step of treating a sample suspected of containing Zika virus with a compound or composition of the present invention.

[0190] The compounds of this invention can act as inhibitors of Zika virus, as intermediates for such inhibitors, or have other uses as described below. Inhibitors typically bind to sites on the surface or in the cavities of the liver. Compounds bound in the liver can bind reversibly to varying degrees. Those compounds that bind substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, compounds that bind substantially irreversibly are used as probes for detecting Zika virus. Therefore, the present invention relates to a method for detecting NS3 in samples suspected of containing Zika virus, the method comprising the steps of: treating the sample suspected of containing Zika virus with a composition comprising a compound of the present invention bound to a label; and observing the effect of the sample on the labeling activity. Suitable labels are well known in the diagnostic field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups, and chromogens. The compounds herein are labeled in a conventional manner using functional groups such as hydroxyl or amino groups. In one embodiment, the present invention provides compounds of formula (I) that comprise or are bound to or linked to one or more detectable labels. In the context of this invention, samples suspected of containing Zika virus include natural or artificial materials, such as living organisms; tissue or cell cultures; biological samples, such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); laboratory samples; food, water, or air samples; biological product samples, such as cell extracts, particularly recombinant cells for synthesizing desired glycoproteins; and so on. Typically, the sample will be suspected of containing Zika virus. The sample can be contained in any medium, including water and organic solvent / water mixtures. Samples include living organisms such as humans, and artificial materials such as cell cultures.

[0191] The processing steps of this invention include adding the compound of this invention to a sample, or the step includes adding a precursor of the composition to the sample. The addition step includes any application method as described above.

[0192] If necessary, the activity of Zika virus after compound application can be observed by any method, including direct and indirect methods for detecting Zika virus activity. Quantitative, qualitative, and semi-quantitative methods for determining Zika virus activity are all acceptable. One of the screening methods described above is typically used; however, any other method, such as observing the physiological characteristics of a living organism, is also applicable.

[0193] Many organisms contain the Zika virus. The compounds of this invention can be used to treat or prevent diseases associated with Zika virus activation in animals or humans.

[0194] However, when screening for compounds that can inhibit Zika virus activity, it should be remembered that enzyme assay results may not always correlate with cell culture assays. Therefore, cell-based assays should generally be the primary screening tool.

[0195] pharmaceutical preparations

[0196] The compounds of this invention are formulated using conventional carriers and excipients, which will be selected according to conventional practice. Tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and will generally be isotonic when intended for delivery by non-oral administration. All formulations will optionally contain excipients, such as... Handbook of Pharmaceutical Excipients The excipients described in (1986) include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextrin), hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the formulation is from about 3 to about 11, but is typically from about 7 to 10.

[0197] While the active ingredients can be administered alone, it may be preferred to provide them as pharmaceutical formulations. The veterinary and human formulations of the present invention each comprise at least one active ingredient as defined above, together with one or more acceptable carriers and optional other therapeutic ingredients. The carrier must be "acceptable," meaning it is compatible with the other components of the formulation and physiologically harmless to the recipient.

[0198] These formulations include those suitable for the aforementioned routes of administration. The formulations are readily available in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical field. Techniques and formulations are commonly found in… Remington' s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the step of associating an active ingredient with a carrier that constitutes one or more auxiliary ingredients. Generally, formulations are prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then, if desired, shaping the product.

[0199] The formulations of the present invention suitable for oral administration can be provided as discrete units such as capsules, granules, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient can also be administered as pills, granules, or pastes.

[0200] Tablets are made by compression or molding, optionally using one or more excipients. Compressed tablets are prepared by compressing an 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, surfactant, or dispersant. Molded tablets are prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored, and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0201] For application to the eyes or other external tissues (e.g., the mouth and skin), the formulation is preferably applied as a topical ointment or cream containing active ingredients in amounts, for example, from 0.075% w / w to 20% w / w (including active ingredients in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably from 0.2% w / w to 15% w / w, and most preferably from 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredients may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream with an oil-in-water emulsion base.

[0202] If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may ideally include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0203] The oil phase of the emulsion of the present invention can be composed of known components in a known manner. While this phase may consist only of emulsifiers (or simply emulsifiers), it ideally includes at least one emulsifier with fats or oils, or a mixture of both. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also preferable to include both oils and fats. Emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

[0204] Emulsifiers and emulsion stabilizers suitable for the formulations of this invention include 60. 80. Cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0205] The appropriate oil or fat is selected for the formulation based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched monoalkyl or dialkyl esters can be used, such as diisohexyl adipate, isohexadecanoyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched esters known as Crodamol CAP, the last three being preferred esters. These esters can 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, can be used.

[0206] Pharmaceutical formulations according to the invention comprise one or more compounds of the invention, as well as one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when intended for oral use, they can be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or can be coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0207] Formulations intended for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium phosphate or kaolin) or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0208] The aqueous suspension of the present invention contains an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefinic oxygen and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and metaesters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0209] Oily suspensions can be prepared by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0210] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by adding water, provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0211] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0212] The pharmaceutical compositions of the present invention may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or prepared as lyophilized powders. Acceptable solvents and media that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

[0213] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of the active material, compounded with an appropriate and convenient amount of carrier material, which may vary between approximately 5% to approximately 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosage amounts. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 μg to 500 μg of the active ingredient per milliliter of solution to allow for the infusion of an appropriate volume at a rate of approximately 30 mL / hr.

[0214] Formulations suitable for application to the eyes include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solvent of the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5% w / w to 20% w / w, advantageously 0.5% w / w to 10% w / w, and particularly about 1.5% w / w.

[0215] Preparations suitable for topical application in the oral cavity include lozenges containing flavoring active ingredients, typically sucrose and gum arabic or tragacanth; tablets containing inert active ingredients, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredients in a suitable liquid carrier.

[0216] Formulations for rectal administration may be provided as suppositories with a suitable matrix, including, for example, cocoa butter or salicylates.

[0217] Formulations suitable for intrapulmonary or intranasal administration have particle sizes ranging from, for example, 0.1 micrometers to 500 micrometers (inclusive, increments of micrometers, such as 0.5 micrometers, 1 micrometer, 30 micrometers, 35 micrometers, etc.), and are administered via rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveolar sacs. 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 together with other therapeutic agents, such as compounds used to date for the treatment or prevention of conditions associated with Zika virus activity.

[0218] Preparations suitable for vaginal application may be provided in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, and contain, in addition to the active ingredient, a suitable carrier known in the art.

[0219] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0220] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose of the active ingredient as described above, or a suitable portion thereof.

[0221] It should 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 related to the type of formulation discussed, such as flavoring agents suitable for oral administration.

[0222] The present invention further provides a veterinary drug composition comprising at least one active ingredient as defined above and its veterinary drug carrier.

[0223] Veterinary drug carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials. They are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary drug compositions can be administered orally, parenterally, or via any other desired route.

[0224] The compounds of the present invention can also be formulated to provide controlled release of the active ingredient, thereby allowing for lower frequency of administration or improving the pharmacokinetic or toxicological characteristics of the active ingredient. Therefore, the present invention also provides compositions comprising one or more compounds of the present invention formulated for sustained or controlled release.

[0225] The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is used for prevention (low dose), the method of delivery, and the pharmaceutical formulation, and will be determined by clinicians using routine dose escalation studies.

[0226] Application route

[0227] One or more compounds of the present invention (referred to herein as the active ingredient) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0228] List of abbreviations and acronyms

[0229]

[0230]

[0231] Example procedures and compound examples

[0232] Example 24 of Program 1

[0233] ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methyl (oxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho [1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxo Methyl butyl-2-yl)carbamate

[0234]

[0235] (2S,5S)-5-methylpyrrolidine-1,2-dicarboxylic acid 2-(2-(9-(((2S,4S)-1-(tert-butoxycarbonyl)-4- Methylpyrrolidine-2-carbonyl)oxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromene-3-yl)-2-oxo 1-(tert-butyl) ester (ethyl)

[0236] 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 100 mL of THF was heated at 40°C for 24 hours. The reaction was quenched with 75 mL of EtOAc and 60 mL of water. The brown solution was partitioned. 50 mL of 1N HCl was added. The aqueous layer was back-extracted with 2 × 40 mL of EtOAc. The combined organic matter was dried over sodium sulfate.

[0237] ES / MS: 746.7 (M) + ).

[0238] (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,4,5, 11-Tetrahydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1- tert-butyl formate

[0239] A suspension of (2S,5S)-5-methylpyrrolidine-1,2-dicarboxylic acid 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) ester (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 overnight at 90°C. The reactants were partitioned with water. The aqueous layer was back-extracted with EtOAc. The combined organics were transferred to a 500 mL rb containing 30 mL MeOH. 5 g of diatomaceous earth, 25 mL of brine, and 13 mL of 6N NaOH (approximately 6 eq) were slowly added. Stir for 30 minutes, then filter through a diatomaceous earth stopper. Rinse with toluene and IPA (50 mL). Separate the organic extract and wash with water. Dry the organic extract with sodium sulfate and purify by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM) to obtain the desired product.

[0240] ES / MS: 707.3 (M + ).

[0241] 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).

[0242] (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-di Hydroisocyano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0243] To a solution of (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,4,5,11-tetrahydroisocyano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (4.51 g, 6.38 mmol) in DCM (60 mL), manganese dioxide (16.63 g, 191.32 mmol) was added. The reaction mixture was stirred at room temperature for 4 days and exposed to air. 150 mL of DCM and 30 g of diatomaceous earth were added. The mixture was filtered through a diatomaceous earth stopper. The solution was concentrated to obtain the desired product.

[0244] ES / MS: 705.3 (M + ).

[0245] 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 = 7.4Hz, 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).

[0246] (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-di Hydroisocyano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidine-1- tert-butyl formate

[0247] To a suspension of (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-carboxylic acid tert-butyl ester (999.3 mg, 1.418 mmol) in MeOH (40 mL), AcOH (0.05 mL, 0.873 mmol) and n-chlorosuccinimide (208.9 mg, 1.564 mmol) were added. The organic solution was stirred overnight at room temperature. The reactants were diluted with DCM, washed with saturated NaHCO3 solution, and dried over sodium sulfate. The desired product was obtained by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM).

[0248] ES / MS: 739.2 (M + ).

[0249] 1H NMR (400MHz, methanol-d4) δ8.43(s,1H),7.79(d,J=8.4Hz,1H),7.72(d,J=8.9Hz,1H) ,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).

[0250] ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methyl (oxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho [1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxo Methyl butyl-2-yl)carbamate

[0251] 50.1 mg, 0.068 mmol of tert-butyl 1-(2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (2S,5S)-1-( ... Methyl carbamate (S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate was dissolved in 0.475 mL of 4 M hydrochloric acid (4 M dioxane solution). The reaction mixture was heated to 40°C for 4 hours. The reaction mixture was then concentrated to dryness.

[0252] N,N-diisopropylethylamine (120 μl, 0.689 mmol) was added to a solution of hydrochloride (41.47 mg, 0.068 mmol), moc-trifluoro-L-tert-leucine (34.6 mg, 0.142 mmol), and HATU (55.5 mg, 0.146 mmol) in DMF (1.5 mL). The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and 0.2 mL of TFA was added. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product in the form of bis(trifluoroacetate).

[0253] ES / MS: 989.4 (M + ).

[0254] ¹H NMR (400 MHz, methanol-d⁴) δ 8.58 (d, J = 2.4 Hz, ¹H), 8.11 (t, J = 7.8 Hz, ¹H), 8.02–7.80 (m, ³H), 7.69–7.57 (m, ³H), 7.48 (dd, J = 26.1, 11.1 Hz, ¹H), 5.33–5.20 (m, 4H), 5.01–4.92 (m, ¹H), 4.78–4.57 (m, 2H), 3.68 (d, J = 8.1 Hz, 5H), 3.57 ( 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).

[0255] Example 10 of Program 2

[0256] ((S)-2-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetramethyl) (H-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyanate En[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-yl)-1-((2R, 6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate

[0257]

[0258] ((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-methylpyrrolidone-2-yl)-1,11-dihydroisocyanene[4', A solution of methyl carbamate (80.0 mg, 0.0834 mmol), n-bromosuccinimide (18.0 mg, 0.101 mmol), and acetic acid (2.5 mg, 0.0417 mmol) in methanol (1 mL) was stirred at room temperature for 30 minutes. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to the form of trifluoroacetate.

[0259] ES / MS: 1038.9 (M+ ).

[0260] ¹H NMR (400 MHz, methanol-d⁴) δ 8.59 (dd, J = 8.4, 3.5 Hz, 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, 5.3 Hz, 3H), 5.00 (dd, J = 9.9, 7.6 Hz, 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),2.9 0-2.74(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).

[0261] Example 33 of Program 3

[0262] ((S)-1-((2S,5S)-2-(4-Fluoro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valineyl)-5- Methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2- methyl 5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0263]

[0264] ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valinel)-5-methylpyridine) (P-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5- Methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0265] Add 1.0 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (100.1 mg, 0.142 mmol) in DCM (8 mL) and MeOH (2 mL). Heat the reaction mixture to 40°C for 3 hours. Concentrate the reaction mixture to dryness.

[0266] N,N-diisopropylethylamine (250 μl, 1.435 mmol) was added to a solution of hydrochloride (82.02 mg, 0.142 mmol), Moc-L-valine (52.8 mg, 0.301 mmol), and HATU (113.4 mg, 0.298 mmol) in DMF (2.0 mL). The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and 0.2 mL of TFA was added. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product in the form of bis(trifluoroacetate).

[0267] The product was washed with sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated to dryness to obtain the desired product.

[0268] ES / MS: 819.5 (M) + ).

[0269] 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).

[0270] ((S)-1-((2S,5S)-2-(4-Fluoro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valineyl)-5- Methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2- methyl 5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0271] N-fluorobenzenesulfonamide (26.18 mg, 0.083 mmol) was added to a slurry of ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valinel)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate (61.8 mg, 0.075 mmol) and NaHCO3 (9.9 mg, 0.228 mmol) in DCM / acetone (1 mL each). The mixture was stirred at 40°C for 1.5 h. The reaction mixture was cooled to 0°C and 10 drops of TFA were added. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to obtain the product in the form of bis(trifluoroacetate).

[0272] ES / MS: 837.4 (M) + ).

[0273] 1H NMR (400MHz, methanol-d4) δ8.58(d,J=9.8Hz,1H),8.21(d,J=4.8Hz,0H),8.06(dd,J=1 9.4,8.2Hz,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=8.0Hz, 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=26.3,6.7H z, 4H), 0.95 (t, J = 7.2Hz, 4H), 0.85 (dd, J = 6.8, 3.3Hz, 4H), 0.09 (d, J = 2.2Hz, 0H).

[0274] Example 31 of Program 4

[0275] ((S)-1-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-5-methyl-1-(propionyl-L-valine)pyrene) (P-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5- Methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0276]

[0277] (2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1H-imidazolium (-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-methyl tert-butyl ester

[0278] At 0°C, N-bromosuccinimide (138.9 mg, 0.780 mmol) was added to a slurry of (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (500.3 mg, 0.710 mmol) in DCM (20 mL). The reaction mixture was gradually warmed to room temperature and stirred for 30 min. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic extract was dried over sodium sulfate and purified by normal-phase SiO2 chromatography (eluent: ethyl acetate / hexane) to obtain the desired product.

[0279] ES / MS: 785.2 (M + ).

[0280] ¹H NMR (400 MHz, methanol-d⁴) δ 8.43 (s, OH), 8.06 (d, J = 8.3 Hz, OH), 7.96 (s, ¹H), 7.79 (d, J = 8.2 Hz, OH), 7.72 (d, J = 8.9 Hz, OH), 7.58 (d, J = 15.7 Hz, 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).

[0281] ((S)-1-((2S,5S)-2-(4-bromo-5-(2-((2S,5S)-5-methyl-1-(propionyl-L-valine)pyrene) (P-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5- Methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0282] Add 0.300 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of (2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (32.6 mg, 0.042 mmol) in DCM (4 mL) and MeOH (1 mL). Heat the reaction mixture to 40 °C for 5 hours. Concentrate the reaction mixture to dryness. Proceed to the following steps, assuming 100% yield.

[0283] N,N-diisopropylethylamine (80 μl, 0.459 mmol) was added to a solution of hydrochloride (27.30 mg, 0.045 mmol), Moc-L-valine (17.9 mg, 0.095 mmol), and HATU (36.4 mg, 0.096 mmol) in DMF (1.5 mL). The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and 0.2 mL of TFA was added. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product in the form of bis(trifluoroacetate).

[0284] ES / MS: 899.3 (M + ).

[0285] 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),2.79( 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=18.5,11.3,4.9 Hz,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).

[0286] Example 43 of Program 5

[0287] ((S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine) (2-yl)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H- Imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0288]

[0289] (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-di Hydroisocyano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-(prop-1-en-2-yl)-1H-imidazol-2-yl)-5- tert-butyl methylpyrrolidone-1-carboxylate

[0290] (2S,5S)-2-(9-(4-bromo-2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (323.1 mg, 0.412 mmol), and pinacol isopropenylboronic acid A solution of 95% ester (310 μl, 1.649 mmol), palladium acetate (9.5 mg, 0.042 mmol), at least 95% butyldi-1-adamantylphosphine (29.8 mg, 0.083 mmol), and potassium carbonate (228.9 mg, 1.656 mmol) in dioxane (12.8 mL) and water (6.4 mL) was degassed with argon for 10 min and then heated overnight at 100 °C. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and purified by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM) to give the desired product.

[0291] ES / MS: 745.5 (M) + ).

[0292] ¹H NMR (400 MHz, methanol-d⁴) δ 8.39 (s, ¹H), 7.97 (d, J = 8.1 Hz, ¹H), 7.84 (s, ¹H), 7.69 (d, J = 8.8 Hz, 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).

[0293] (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-di Hydroisocyano[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrole tert-butyl alkyl-1-carboxylate

[0294] A solution of (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-(prop-1-en-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (266.1 mg, 344 μmol) in EtOH (15 mL) was degassed with Ar / Vac 3×. Pd / C (10%, 19 mg, 17.85 μmol) was added, and the mixture was stirred overnight in a hydrogen balloon at room temperature. The reaction mixture was filtered through a diatomaceous earth stopper and washed with DCM. The mixture was concentrated and used directly in the next step without purification.

[0295] ES / MS: 747.3 (M) + ).

[0296] 1H NMR (400MHz, methanol-d4) δ8.40(s,1H),8.01(d,J=8.2Hz,1H),7.92(s,1H),7.70(d,J=8.9Hz,1H), 7.60-7.51(m,2H),7.36(d,J=1.5Hz,1H),5.21(s,2H),5.07(s,1H),4.09(s,1H),4.02(s,1H) ,3.60(q,J=7.0Hz,5H),3.27(t,J=6.8Hz,0H),2.37(d,J=7.8Hz,1H),2.29(s,2H),2.21(s,2H ), 2.26-2.05 (m, 1H), 1.45 (dd, J = 23.7, 6.3Hz, 6H), 1.36-1.22 (m, 7H), 1.17 (t, J = 7.1Hz, 10H).

[0297] ((S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine) (2-yl)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H- Imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate

[0298] Add 0.5 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of (2S,5S)-2-(5-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (50.6 mg, 0.068 mmol) in DCM (4 mL) and MeOH (1 mL). Heat the reaction mixture to 40 °C for 6 hours. Concentrate the reaction mixture to dryness.

[0299] N,N-diisopropylethylamine (120 μl, 0.684 mmol) was added to a solution of hydrochloride (41.98 mg, 0.068 mmol), Moc-L-valine (25.2 mg, 0.144 mmol), and HATU (54.4 mg, 0.143 mmol) in DMF (1.5 mL). The mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and 0.2 mL of TFA was added. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product in the form of bis(trifluoroacetate).

[0300] ES / MS: 861.5 (M) + ).

[0301] 1H NMR (400MHz, methanol-d4) δ8.62(d,J=11.4Hz,1H),8.26-8.18(m,1H),8.04-7.91(m,2H),7.67(d,J=8.8Hz,1H),7.66-7.54(m,1 H),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).

[0302] Program 6 Example 9

[0303] ((S)-2-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetramethyl) (H-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyanate En[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-yl)-1-((2R, 6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate

[0304]

[0305] ((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-methylpyrrolidone-2-yl)-1,11-dihydroisocyanene[4', A solution of methyl carbamate (40.0 mg, 0.0417 mmol), n-chlorosuccinimide (6.1 mg, 0.0459 mmol), and acetic acid (1.25 mg, 0.0209 mmol) in methanol (1 mL) was stirred at room temperature for 2 hours. The product was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to the form of trifluoroacetate.

[0306] ES / MS: 993.6 (M) + ).

[0307] ¹H NMR (400 MHz, 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 = 6.4 Hz, OH), 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).

[0308] Program 7 Example 18

[0309] ((2S,3S)-1-((2S,4S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine) (acyl)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)- 1H-Imidazol-2-yl)-4-(methoxymethyl)pyrrolidone-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

[0310]

[0311] ((2S,3S)-1-((2S,4S)-2-(4-bromo-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxopentan- Methyl 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) were heated overnight at 100 °C in a mixture of toluene / water (20 / 1 v / v, 2 mL). 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 anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product in the form of trifluoroacetate.

[0312] ES / MS: 903.5 (M + ).

[0313] 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,8 H),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).

[0314] Program 8 Example 16

[0315] ((2S,3S)-1-((2S,4S)-2-(4-cyano-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine) (2-yl)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H- Imidazol-2-yl)-4-(methoxymethyl)pyrrolidone-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate

[0316]

[0317] ((2S,3S)-1-((2S,4S)-2-(4-bromo-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl A mixture of methyl 1-oxopent-2-yl)carbamate (15 mg, 0.0159 mmol), Pd(dppf)Cl2 (1.17 mg, 0.00159 mmol), Zn powder (0.521 mg, 0.00796 mmol), and Zn(CN)2 (5.61 mg, 0.0478 mmol) in dimethylacetamide (0.3 mL) was degassed with argon for 2 min. The reaction mixture was heated in a microwave oven at 180°C for 15 min. The reaction mixture was filtered and purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product in the form of trifluoroacetate.

[0318] ES / MS: 889.4 (M + ).

[0319] 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).

[0320] Compound table

[0321] The following compounds were prepared as required using appropriate starting materials and appropriate protecting group chemicals according to the examples and procedures described herein and indicated in Table 1.

[0322] Table 1

[0323]

[0324]

[0325]

[0326]

[0327] 1H NMR

[0328] The proton NMR data are shown in Table 2.

[0329] Table 2 ( EC- Some integrations need to be fixed. Please check the main... xls surface)

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] Table 3

[0339]

[0340]

[0341]

[0342]

[0343]

[0344] Bioassay A protocol for ZIKV reporter virus-based antiviral screening on Huh7 cells.

[0345] 1. Cells

[0346] A cancer cell line derived from human hepatocytes (Huh7)

[0347] 2. Reagents

[0348] ViviRen TM Live cell substrate (Promega, catalog number E6492) or Nano Glo assay system (Promega: N1130).

[0349] White, opaque, 96-well TC-treated microplate (Corning, catalog number 3916)

[0350] 96-well transparent V-bottom TC-treated microplate (Corning, catalog number 3894)

[0351] 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).

[0352] Assay medium: supplemented with 2% FBS and 2% GlutaMAX TM Supplements (Gibco, catalog number 35050061), 1% sodium pyruvate solution (Gibco, catalog number 11360070), 1% MEM non-essential amino acid solution 100x and DMEM medium (Gibco, catalog number 31053028) containing 1% penicillin-streptomycin (10,000 U / mL).

[0353] Trypsin-EDTA solution (Gibco, catalog number 25200056)

[0354] 3. Virus

[0355] Recombinant ZIKV strains possessing the Renilla luciferase gene (strain FSS-Rlu) or the Nano luciferase gene (strains PRV-Nano, Dakar-Nano).

[0356] 4. Instruments

[0357] BioTek Cytation 5 or other plate readers for chemical fluorescence detection models.

[0358] Eppendorf plate centrifuge

[0359] Plate shaker

[0360] Eppendorf multichannel pipette

[0361] program

[0362] Day 1: Cell Preparation

[0363] Human hepatocyte-derived cancer cell line (Huh7) was isolated from a T-175 flask using trypsin-EDTA solution. The isolated cells were then suspended in sterile 50 ml conical tubes in complete culture medium.

[0364] Centrifuge a 50ml conical tube at 1200 rpm for 3 minutes at room temperature.

[0365] Resuspend the cells in the assay medium. Count the cells and dilute them to 3 × 10⁶. 5 Density of cells per milliliter.

[0366] Seed cells at 50 μl cells / well in a white, opaque 96-well plate (assay plate). Gently shake the plate to ensure the cells adhere evenly.

[0367] The plated cells were incubated in a humid incubator (37°C and 5% CO2).

[0368] Day 2: Infection

[0369] 1) Nine series (2x or 3x) of concentrated compounds were prepared in 96-well clear V-bottom plates (compound plates) using 90% DMSO solution and DMSO control.

[0370] For example:

[0371]

[0372] 2) Dilute the reporter virus stock solution to 3 × 10⁻⁶ using assay medium. 4 The concentration of FFU (FFU: lesion-forming unit) / mL was determined. 200 μl of diluted virus was aliquoted into each well of a clear V-bottom 96-well plate (mixing plate).

[0373] 3) Add 1 μl of the above 400x concentrated compound dilution to each well of the mixing plate. Shake the plate on a plate shaker for 5 minutes.

[0374] 4) Add 50 μl of the compound-virus mixture to each well of the assay plate (MOI approximately 0.1). Gently shake the plate to thoroughly mix the virus.

[0375] Example of a format used for measuring plates

[0376]

[0377] Note: CC refers to cell control.

[0378] 5) Centrifuge the plate at 1000 rpm for 15 seconds.

[0379] 6) Incubate the plate at 37°C and 5% CO2 in a humidified incubator for 48 hours.

[0380] Day 4: Reading luciferase signals

[0381] 7) ViviRen TM The live cell substrate was diluted 3000x in the assay medium. 25 μl of the diluted substrate was added to each well of the assay plate.

[0382] For the Nano-Glo assay system, add 50 μl of diluted substrate (diluted 50x from the stock solution in assay buffer).

[0383] 8) Incubate the plate at room temperature for 5 minutes.

[0384] 9) Ideally, cell viability should be measured using the Promega Cell-titer Glo kit (only when ZIKV-Rlu is used for infection).

[0385] 10) Use Cytation 5 with a gain of 120-150 to read the luciferase signal.

[0386] Data Analysis

[0387] a. The luciferase signal from the DMSO treatment group (untreated control) was set to 100%. The relative luciferase signal was obtained by normalizing the luciferase signal from each diluted treatment group to the control luciferase signal.

[0388] b. In the software GraphPad Prism 8, the relative luciferase signal (Y-axis) was plotted as the log10 value of the compound concentration (X-axis), and a nonlinear regression model was used to fit the curve (log(inhibitor) versus response-variable slope (four parameters), with a bottom constraint of 0 and a top constraint of 100).

[0389] c.EC 50 The values ​​are reported below.

[0390] Bioassays were performed to measure activity against ZIKV. As summarized in Table 3, the tested compounds were inhibitors of ZIKV.

[0391] Bioassays were performed to measure activity against ZIKV. As summarized in Table 4, the test compounds were inhibitors of ZIKV.

[0392] Table 4

[0393]

[0394]

[0395] The foregoing description of the specific embodiments so fully reveals the general nature of the invention that others can readily modify and / or adapt such specific embodiments for various applications by applying knowledge of the art, without excessive experimentation and without departing from the general concept of this disclosure. Therefore, based on the teachings and guidance given herein, such adaptations and modifications are intended to be within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is for descriptive rather than limiting purposes, and that the terminology or terminology of this specification should be interpreted by those skilled in the art based on the teachings and guidance.

Claims

1. A compound of formula (I): (I) Among them: R 1 It is fluorine, chlorine, C 1-10 Alkyl, C 3-12 cycloalkyl or cyano groups; P 1a and P 1b Each person independently selects a group consisting of the following items: ； V 1a and V 1b Each person independently selects a group consisting of the following items: ； E 1a and E 1b Each is independently -N(H)(C 1-6 alkoxycarbonyl), N(H)(C 3-12 cycloalkylcarbonyl), N(H)(C 1-6 alkyl carbonyl) or -N(H)(C 3-12 (cycloalkoxycarbonyl); the prerequisite is that when P 1a yes And V 1a and V 1b All When, then R 1 It is a halogen group, C 1-10 Alkyl, C 4-7 cycloalkyl or cyano groups; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein R 1 It is either fluorine or chlorine.

3. The compound according to claim 1 or 2, wherein R 1 It is chlorine.

4. The compound according to any one of claims 1 to 3, wherein V 1a yes .

5. The compound according to any one of claims 1 to 4, wherein V 1a and V 1b All .

6. The compound according to any one of claims 1 to 5, wherein P 1a yes .

7. The compound according to any one of claims 1 to 5, wherein P 1a yes And P 1b yes .

8. The compound according to any one of claims 1 to 5, wherein P 1a yes .

9. The compound according to any one of claims 1 to 5 or 8, wherein P 1a and P 1b All .

10. A compound, said compound being selected from the group consisting of: ((S)-1-((2S,5S)-2-(5-(2-((2S,5S)-1-(O-(tert-butyl)-N-(methoxycarbonyl)-L-threonyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-chloro-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((S)-6-(4-chloro-5-(2-((S)-5-((methoxycarbonyl)-L-valine)-5-azaspiro[2.4]hept-6-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((2S,3S)-1-((S)-6-(4-chloro-5-(2-((S)-5-((methoxycarbonyl)-L-isoleucyl)-5-azaspiro[2.4]hept-6-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((S)-1-((S)-6-(4-chloro-5-(2-((S)-5-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-azaspiro[2.4]hept-6-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-valine)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-2-((2S,5S)-2-(9-(4-chloro-2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidone-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidone-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)methyl carbamate; ((S)-2-((2S,5S)-2-(9-(4-cyclopropyl-2-((2S,5S)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)-5-methylpyrrolidone-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidone-1-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)methyl carbamate; ((S)-2-((2S,5S)-2-(9-(4-chloro-2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-ethylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-cyano-2-((2S,4S)-1-((methoxycarbonyl)-L-valine)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-2-((2S,5S)-2-(9-(4-chloro-2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-cyano-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-cyclopropyl-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-chloro-2-((2S,4S)-4-(methoxymethyl)-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidone-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((2S,3S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((2S,3R)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((methoxycarbonyl)-L-valine)pyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((2S,3S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((methoxycarbonyl)-L-isoleucyl)pyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((2S,3R)-1-((S)-2-(4-chloro-5-(2-((S)-1-((methoxycarbonyl)-L-isoleucyl)pyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidine-1-yl)-3-methyl-1-oxopent-2-yl)carbamate; ((S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobut-2-yl)methyl carbamate; ((S)-1-((S)-2-(4-chloro-5-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobut-2-yl)methyl carbamate; ((S)-1-((2S,5S)-2-(4-chloro-5-(2-((2S,5S)-1-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4-fluoro-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(9-(4-fluoro-2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidone-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((methoxycarbonyl)-L-valine)octahydrocyclopentadieno[b]pyrrolo-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopentadieno[b]pyrrolo-1(2H)-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((2S,3S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((methoxycarbonyl)-L-isoleucyl)octahydrocyclopentadieno[b]pyrrolo-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopentadieno[b]pyrrolo-1(2H)-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((S)-2-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetyl)octahydrocyclopentadieno[b]pyrrolo-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopentadieno[b]pyrrolo-1(2H)-yl)-1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)methyl carbamate; ((S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(2-((2S,3aS,6aS)-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)octahydrocyclopentadieno[b]pyrrole-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)hexahydrocyclopentadieno[b]pyrrole-1(2H)-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((2S,3S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((2S,3R)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-cyclopropyl-5-(2-((2S,5S)-1-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-4-fluoro-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidone-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidone-1-yl)-3-methyl-1-oxobut-2-yl)carbamate; ((2S,3S)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; ((S)-4,4,4-trifluoro-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-5-methyl-1-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)pyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamate; ((2S,3R)-1-((2S,5S)-2-(4-isopropyl-5-(2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-yl)carbamate; and ((S)-4-fluoro-1-((2S,5S)-2-(5-(2-((2S,5S)-1-((S)-4-fluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-methylpyrrolidine-2-yl)-1,11-dihydroisocyaneno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)carbamate.

11. A compound having the following formula: Or, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

13. Use of the compounds according to claims 1 to 11 or the compositions according to claim 12 in the preparation of medicaments for treating or preventing Zika virus infection.

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