Tetracyclic compounds for the treatment of zika virus infection

Abstract

Provided herein are compounds and methods for treating or preventing Zika virus infection. For example, compounds of Formula (I): wherein the variable substituents are as described herein. (I)

Description

[0001] This application is a divisional application of Chinese invention patent application filed on May 19, 2022, with application number 202280035878.1 and invention title "Tetracyclic Compound for Treating Zika Virus Infection". Cross-references to related applications

[0002] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 191,634, filed May 21, 2021, pursuant to 35 USC §119(e). The entire contents of the foregoing application are incorporated herein by reference. Background Technology

[0003] Zika virus is a mosquito-borne, single-stranded, positive-sense RNA flavivirus that has gone from relatively obscure to an epidemic of significant public health concern. 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. Notably, Zika virus infection is now closely associated with microcephaly and intrauterine growth retardation in fetuses of women infected during pregnancy. Zika infection during pregnancy can also cause pregnancy complications such as loss of pregnancy, stillbirth, and preterm birth.

[0004] There is currently no vaccine to prevent Zika virus disease. Therefore, there is a need for therapeutic or preventative interventions to treat or prevent Zika virus disease, particularly among women of childbearing age. Summary of the Invention

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

[0006] For example, compounds of formula (I): (I) in: R 1a and R 1b Each is independently a halogen group, C 1-6 Alkyl or cycloalkyl; P 1a Choose from the following groups: P 1b Choose from the following groups: 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 cycloalkyl carbonyl), N(H)(C 1-6 alkyl carbonyl) or -N(H)(C 3-12 (cycloalkoxycarbonyl); or their stereoisomers, pharmaceutically acceptable salts or solvates.

[0007] In another implementation, the subject is a human being.

[0008] In another implementation, the subjects are women of childbearing age.

[0009] In another implementation, the subjects are pregnant women.

[0010] In another embodiment, the compound is mixed with a pharmaceutically acceptable excipient in the pharmaceutical composition.

[0011] In another implementation, a method for preventing Zika virus infection is provided, the method comprising administering a compound of formula (Ia) to a subject in need of such protection. (Ia) in: R 1a and R 1b Each is independently a halogen group, C 1-10 Alkyl, C 3-12 cycloalkyl or cyano; P 1a and P 1b Each is selected independently from: V 1a and V 1b Each is selected independently from: E 1a and E 1b Each is independently -N(H)(C 1-6 Alkoxycarbonyl), N(H) (cycloalkylcarbonyl), N(H) (alkylcarbonyl) or -N(H) (cycloalkoxycarbonyl); The condition is when P 1a for V 1a and V 1b Both are When, then R 1 Halogenated, C 1-6 Alkyl, C 4-7 Cycloalkyl or cyano; or their pharmaceutically acceptable salts, stereoisomers or solvates.

[0012] In another implementation, the subject is a human being.

[0013] In another implementation, the subjects are women of childbearing age.

[0014] In another implementation, the subjects are pregnant women.

[0015] In another embodiment, the compound is mixed with a pharmaceutically acceptable excipient in the pharmaceutical composition. Other and further embodiments will be apparent to those skilled in the art, and minor modifications are intended to be covered by the appended claims. Detailed Implementation

[0016] definition "Alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon. For example, alkyl groups can have 1 to 6 carbons (i.e., C64-C ... 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C44) 1-4 Alkyl groups. Examples of alkyl groups include, but are not limited to, 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)CH2CH2CH2) CH3), 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) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0017] "Alkoxy" refers to an alkyl group having an oxygen atom attached to the alkyl group at the junction: alkyl-O-. Like alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C... 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups may be further substituted by various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0018] "Alkoxyalkyl" refers to a compound in which an alkoxy group is attached to an alkyl group, which in turn is attached to the remainder of the compound, making the alkyl group divalent. Alkoxyalkyl groups can have any suitable number of carbons, such as 2 to 6 (C6+). 2-6 alkoxyalkyl), 2 to 5 (C 2-5 alkoxyalkyl), 2 to 4 (C 2-4 alkoxyalkyl), or 2 to 3 (C 2-3 Alkoxyalkyl). Alkoxy and alkyl are defined as above, wherein the alkyl is divalent and may include, but is not limited to, methoxymethyl (CH3OCH2-), methoxyethyl (CH3OCH2CH2-), etc.

[0019] As used in this article, "halogen" or "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0020] "Cycloalkyl" refers to a compound having 3 to 12 cyclic carbon atoms (i.e., C64 ... 3-12 A cycloalkyl group (e.g., 3 to 12 cyclic atoms, 3 to 10 cyclic atoms, 3 to 8 cyclic atoms, 3 to 6 cyclic atoms, 3 to 5 cyclic atoms, or 3 to 4 cyclic atoms) is a single saturated or partially unsaturated all-carbon ring. The term "cycloalkyl" also includes multiple fused, saturated, and partially unsaturated all-carbon ring systems (e.g., ring systems comprising 2 or 3 carbon rings). When valence requirements permit, the rings of a polyfused ring system may be linked to each other via fusion, spirocyclic, and bridging bonds. Non-limiting examples of monocyclic cycloalkyl groups 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, and 1-cyclohex-3-enyl.

[0021] As used herein, “composition” is intended to cover products containing a specified amount of a specified ingredient and any product formed directly or indirectly from a combination of the specified amounts of the specified ingredients. “Pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and be harmful to the recipient.

[0022] "Pharmaceutically effective amount" means the amount of the compound of this disclosure in a formulation or combination thereof that provides the desired therapeutic or pharmaceutical outcome.

[0023] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

[0024] As used herein, “treatment” refers to a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and / or the lessening of the severity of symptoms and / or the prevention of the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or lessening the severity of a disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as causing the disappearance of clinical symptoms, improving the disease state, delaying the progression of the disease, improving quality of life, and / or prolonging survival.

[0025] As used herein, "therapeutic effective amount" or "effective amount" means an amount capable of effectively evoking the desired biological or medical response, including amounts of such a treatment sufficient to affect the disease when administered to a subject to treat that disease. Effective amounts may vary depending on the compound, the subject's disease and its severity, and age, weight, etc. Effective amounts may include a range of amounts. As understood in the art, an effective amount may be one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. Effective amounts may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered if, in combination with one or more other agents, a desired or beneficial outcome can be achieved or realized. The appropriate dose of any co-administered compound may optionally be reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0026] "Administration" refers to oral administration to a subject, as a suppository, local contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal or subcutaneous administration, intrathecal administration, or implantation of a slow-release device (e.g., a micro-osmotic pump). Administration may be performed according to a schedule based on the specified administration frequency, dosage, and other factors.

[0027] "Subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some implementations, the subject is a human.

[0028] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0029] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possess the desired pharmacological activity of a free base. These salts can be derived from inorganic acids, organic acids, or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propargylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, etc. Alkyne-1,4-diacidate, hexyne-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in *Remington: The Science and Practice of Pharmacy*, 21st edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0030] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4. + Salts of (where X is a C1-C4 alkyl group). Also includes base addition salts, such as sodium or potassium salts.

[0031] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n hydrogen atoms bonded to a carbon atom may be substituted with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and are therefore used to increase the half-life of compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been substituted with deuterium.

[0032] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Using positron-emitting isotopes such as 11 C 18 F, 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0033] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may include one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and compounds that can be defined according to absolute stereochemistry (…). R )-or( S(D)- or other stereoisomers defined for amino acids as (D)- or (L)-. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), ( R )-and( S (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When a compound is expressed in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomeric or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a “non-racemic mixture” is a mixture of stereoisomers in a ratio not equal to 1:1.

[0034] A "racemate" is a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0035] One or more “stereoisomers” refer to compounds with different chiralities of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or has asymmetric substituted double bonds, the compound may exist in stereoisomeric form and can therefore be prepared as individual stereoisomers or as mixtures. Unless otherwise specified, this specification is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and isolating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th Edition, J. March, John Wiley and Sons, New York, 1992).

[0036] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-ketone and imine-enamine tautomers, or tautomers containing heteroaryl groups that are simultaneously attached to the ring atoms of the ring-NH- and ring=N-, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of chemical groups are for convenience; chemical groups may be depicted without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate the attachment points of groups. Dashed lines indicate optional bonds. Unless chemically or structurally required, the order in which chemical groups are written or the points where they connect to the rest of the molecule do not indicate or imply directionality. For example, the group “-SO2CH2-” is equivalent to “-CH2SO2-”, and both can be attached in either direction. Similarly, “arylalkyl” groups may, for example, be attached to the rest of the molecule at the aryl or alkyl portion of the group. Prefixes such as “C…” u-v "or (C u -C v The ) indicates that the following group has u to v carbon atoms. For example, "C 1-6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0038] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0039] The in vivo metabolites of the compounds described herein also fall within the scope of this document, and to some extent, such products are novel and unobservable relative to the prior art. These products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, this includes methods for generating novel and unobservable compounds by means of exposing the compound to mammals for a period sufficient to produce its metabolites. Such products are typically identified by processes such as the preparation of radiolabels (e.g.,...). 14 C or 3 Compound H is administered parenterally to animals (such as rats, mice, guinea pigs, monkeys, or humans) at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (typically about 30 seconds to about 30 hours) and for the separation of its metabolites from urine, blood, or other biological samples. These products are readily separated because they are labeled (other products are separated using antibodies capable of binding to epitopes that survive in the metabolites). The metabolite structure is determined in a conventional manner (e.g., by MS or NMR analysis). Typically, the analysis of metabolites is performed in the same manner as routine drug metabolism studies well known to those skilled in the art.

[0040] pharmaceutical preparations In some embodiments, this disclosure provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. This document also provides a pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0041] In some embodiments, the compounds disclosed herein are formulated with conventional carriers and excipients, which will be selected according to conventional practice. Tablets may contain excipients, flow aids, fillers, binders, etc. Aqueous formulations may be prepared aseptically and may be isotonic, for example, when intended for delivery via non-oral administration. In some embodiments, the formulation may optionally contain excipients, such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the formulation is from about 3 to about 11, for example from about 7 to about 10.

[0042] In one embodiment, a pharmaceutical composition is provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents and pharmaceutically acceptable excipients.

[0043] In one embodiment, a kit is provided comprising a combination of the compound of the present disclosure or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0044] In some embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In other embodiments, the compound of this disclosure or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0045] In some embodiments, when the compounds of this disclosure are combined with one or more additional therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential manner. When administered sequentially, the combination may be administered in two or more doses.

[0046] In some embodiments, the compounds of this disclosure are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as as a solid dosage form for oral administration.

[0047] In some embodiments, the compounds disclosed herein are administered in combination with one or more additional therapeutic agents.

[0048] To prolong the effects of the compounds disclosed herein, it is generally desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound depends on its dissolution rate, and subsequently on the crystal size and crystal form. Alternatively, delayed absorption of the compound in a parenteral administration form can be achieved by dissolving or suspending the compound in an oil medium. Injectable reservoir forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer, such as poly(lactide-polyglycolic acid). The rate of compound release can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0049] Application route One or more of the compounds of formula (I) or their pharmaceutically acceptable salts (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, pulmonary, local (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that the route may be varied depending on, for example, the condition of the recipient. In some embodiments, the compounds disclosed herein are orally bioavailable and can be administered orally.

[0050] The compounds disclosed herein (also referred to herein as the active ingredients) may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that the route may be changed depending on, for example, the condition of the recipient. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0051] The compounds disclosed herein can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer.

[0052] The dosage or frequency of administration of the disclosed compounds may be adjusted during treatment based on the judgment of the physician administering the medication.

[0053] The compound can be administered to a subject (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0054] The compound may be administered by any available route and method, such as by oral or parenteral (e.g., intravenous) administration. Therapeuticly effective amounts of the compound may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day, or such as from about 0.3 mg / day to about 30 mg / day, or such as from about 30 mg / day to about 300 mg / day.

[0055] The compounds of this disclosure may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., about 1 mg to about 1000 mg of the compound). Therapeuticly effective amounts may include about 1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose. Other therapeutically effective amounts of the compounds of this disclosure are about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg per dose. Other therapeutically effective amounts of the disclosed compounds are about 100 mg per dose, or about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, or about 500 mg per dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 16 hours, or about every 24 hours. A single dose may also be administered every 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about every 7 days. A single dose may also be administered every 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, a single dose may be administered about once a week. A single dose can also be administered approximately once a month.

[0056] Other therapeutically effective amounts of the disclosed compounds are about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg per dose.

[0057] The dosage frequency of the disclosed compound can be determined according to the needs of each patient and can be, for example, once daily or twice daily or more. Administration of the compound continues as long as necessary to treat the disease or condition. For example, the compound can be administered to a person with cancer for a period of approximately 20 days to approximately 180 days, or for a period of approximately 20 days to approximately 90 days, or for a period of approximately 30 days to approximately 60 days.

[0058] Administration may be intermittent, with the patient receiving a daily dose of the disclosed compound for a period of several days or more, followed by a period of several days or more without receiving the daily dose of the compound. For example, the patient may receive a dose of the compound every other day or three times a week. Again, as an example, the patient may receive a daily dose of the compound for a period of approximately 1 day to approximately 14 days, followed by a period of approximately 7 days to approximately 21 days without receiving the compound, and then resume receiving the daily dose of the compound for a subsequent period (e.g., approximately 1 day to approximately 14 days). The alternating periods of compound administration followed by non-administration may be repeated as needed to treat the patient's clinical needs.

[0059] List of abbreviations and acronyms.

[0060] Example The following embodiments are included to demonstrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that function fully in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, those skilled in the art will understand that, based on this disclosure, many changes can be made to the specific implementations of the disclosure without departing from the spirit and scope of this disclosure and still obtaining similar or analogous results.

[0061] Experimental Procedure General Plan Option 1 : The compound of Formula 1.4 can be obtained according to the method shown in Scheme 1. Dibromobutanone 1.1 can be esterified with 2 equivalents of a suitable Boc-protected proline coupling coupler, and subsequently condensed with ammonium acetate to form a diimidazole 1.2. Halogenation at the imidazole position using a known halogenating agent (e.g., NCS, NBS, etc.) can form an intermediate 1.3, which can be purified to the final product after Boc deprotection and subsequent amide coupling with a suitable agent (e.g., HATU, EDCI, etc.). Alternatively, the halogenation and amide formation steps can be performed in reverse order to obtain the final product 1.4.

[0062] Option 2 : The compound of Formula 2.2 can be obtained according to the method shown in Scheme 2. Using a dihaloimidazole 1.3, palladium-mediated cross-coupling with a suitable alkyl or aryl-boronic acid or boronic ester yields intermediate 2.1, which can be purified to the final product 2.2 by Boc deprotection and amide coupling. Alternatively, the palladium-mediated cross-coupling and amide coupling steps can be performed in reverse order to obtain the final product 2.2.

[0063] Option 3 : The compound of formula 3.4 can be obtained according to the method shown in scheme 3. Monohalogenation of 1.2 with a suitable halogenating agent in 1 equivalent can form intermediate 3.1, which can be converted to intermediate 3.2 via palladium-mediated cross-coupling with alkyl or arylboronic acid or borate ester. Monohalogenation of imidazole with a suitable halogenating agent can give intermediate 3.3, which can be deprotected and coupled with an amide to give the final product 3.4.

[0064] Option 4 : Alkylimidazoles can also be prepared as shown in Scheme 4. Esterification of proline derivative 4.1 and a suitable bromoketone 4.2 yields ester intermediate 4.3, which can be condensed to give imidazole 4.4, which can be halogenated to give 4.5. Palladium-mediated cross-coupling with diboronate 4.6 yields intermediate 4.7. Subsequent Boc deprotection and amide coupling yield the final product 4.8. Example procedures and compound examples Program 1: Di-tert-butyl6,6'-((5,10-dihydro-2,7-diyl)bis(1H-imidazol-5, 2-Diyl))(6S,6'S)-bis(5-azaspiro[2,4]heptane-5-carboxylic acid ester) A THF (25 mL) suspension of 1,1'-(5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(2-bromoethane-1-one) (2.00 g, 4.42 mmol), (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid (2.67 g, 11.1 mmol), and cesium carbonate (1.81 g, 5.55 mmol) was heated overnight at 40 °C. The reactants were diluted with EtOAc (30 mL) and water (25 mL). A brown solution was partitioned and 1 N HCl (20 mL) was added to the organic extract. The aqueous layer was back-extracted with EtOAc (10 mL). The combined organics were dried over sodium sulfate and concentrated.

[0065] The crude residue and a suspension of ammonium acetate (17.34 g, 225 mmol) in toluene (50 mL) and isopropanol (6 mL) were heated under reflux for 18 hours. The reaction mixture was diluted with EtOAc and washed three times with NaHCO3 solution. The organic extract was dried over sodium sulfate, concentrated, and purified by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM) to obtain the desired product.

[0066] ES / MS: 733.81 (M + ).

[0067] 1H NMR (400MHz, methanol-d4) δ 7.35 (d, J = 15.9Hz, 2H), 7.19 (d, J =13.3Hz, 4H), 5.27 (s, 4H), 5.17 – 4.99 (m, 2H), 3.59 (dd, J = 25.6, 10.2Hz, 2H), 3.49 – 3.37 (m, 1H), 2.45 (s, 1H), 2.28 (q, J = 10.9, 10.0Hz, 1H), 1.88 (d, J = 9.3Hz, 1H), 1.48 (d, J = 7.6Hz, 6H), 1.35 – 1.09 (m, 17H), 0.81 –0.32 (m, 7H).

[0068] Example 59 of Program 2: Dimethyl((2S,2'S)-((6S,6'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) bis(4-chloro-1H-imidazol-5,2-diyl))bis(5-azaspiro[2,4]heptane-6,5-diyl))bis(3-methyl-1-oxobutane Alkyl-1,2-dimethyl)dicarbamate Di-tert-butyl6,6'-((5,10-dihydroxonop[5,4,3-cde]xon-2,7-diyl)bis(4-chloro-1H-imidazolium) azole-5,2-diyl)(6S,6'S)-bis(5-azaspiro[2,4]heptane-5-carboxylic acid ester) To a suspension of di-tert-butyl 6,6'-((5,10-dihydro-xantho[5,4,3-cde]xanthoen-2,7-diyl)bis(1H-imidazol-5,2-diyl))(6S,6'S)-bis(5-azaspiro[2,4]heptane-5-carboxylic acid ester) (662 mg, 0.903 mmol) in MeOH (15 mL), 20 drops of AcOH and palau'chlor (416 mg, 1.99 mmol) were added. The brown slurry was stirred overnight at room temperature. The reactants were diluted with DCM, washed with saturated NaHCO3 solution, and dried over sodium sulfate. Purification was performed by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM) to obtain the desired product.

[0069] ES / MS: 801.2 (M + ).

[0070] ¹H NMR (400MHz, methanol-d⁴) δ 7.22 (s, 4H), 5.34 (s, 5H), 5.08 – 4.91 (m, 3H), 3.69 (d, J = 10.4Hz, 2H), 3.50 (d, J = 17.3Hz, 1H), 2.34 (s, 1H), 2.24 – 2.11 (m, 3H), 1.48 (s, 8H), 1.33 – 1.20 (m, 22H), 0.74 (d, J = 16.8Hz, 2H), 0.64 (d, J = 14.0Hz, 9H).

[0071] Dimethyl((2S,2'S)-((6S,6'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) bis(4-chloro-1H-imidazol-5,2-diyl))bis(5-azaspiro[2,4]heptane-6,5-diyl))bis(3-methyl-1-oxobutane Alkyl-1,2-diyl))dicarbamate (Example 59) Add hydrochloric acid (4M dioxane solution, 400 µl) to a solution of di-tert-butyl 6,6'-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))(6S,6'S)-bis(5-azaspiro[2,4]heptane-5-carboxylic acid ester) (50.2 mg, 0.0626 mmol) in DCM (5 mL) and MeOH (1.5 mL). Heat the reaction mixture to 40 °C overnight. Concentrate the reaction mixture to dryness.

[0072] To a 2 mL solution of crude residue, Moc-L-valine (24.4 mg, 0.139 mmol), and HATU (52.3 mg, 0.138 mmol) in DMF, N,N-diisopropylethylamine (130 µl, 0.746 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was then cooled to 0 °C. 10 drops of TFA were added. The mixture was analyzed by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain the product as bis(trifluoroacetate).

[0073] ES / MS: 915.5 (M + ).

[0074] 1H NMR (400MHz, methanol-d4) δ 7.34 – 7.12 (m, 4H), 5.46 (d, J = 7.4Hz, 0H), 5.31 (d, J = 7.8Hz, 4H), 5.20 (td, J = 8.0, 2.0Hz, 2H), 4.14 (dd, J =7.6, 1.6Hz, 2H), 3.99 (d, J = 9.8Hz, 2H), 3.76 (dd, J = 16.5, 10.8Hz, 2H), 3.67 (s, 4H), 3.58 (s, 1H), 2.65 (dd, J = 12.7, 7.4Hz, 0H), 2.41 (dd, J =12.7, 8.3Hz, 2H), 2.16 – 1.94 (m, 4H), 1.31 (d, J = 3.8Hz, 0H), 1.03 (t, J =6.3Hz, 2H), 0.95 (dd, J = 14.7, 6.7Hz, 10H), 0.84 (q, J = 7.2, 6.6Hz, 1H), 0.76 (p, J = 4.9Hz, 3H), 0.72 – 0.56 (m, 2H), 0.48 (s, 0H).

[0075] Example 23 of Program 3 : Dimethyl((1S,1'S)-((2S,2'S)-((5,10-dihydroxenobenz[5,4,3-cde]xenobenz-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate Dimethyl((1S,1'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) bis(1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))diamino Formate Add 1.5 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of di-tert-butyl 2,2'-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (150 mg, 0.220 mmol) (obtained by substituting (tert-butoxycarbonyl)-L-proline with (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid as described in Procedure 1) and MeOH. Heat the reaction mixture to 40 °C for 1 hour. Concentrate the reaction mixture to dryness.

[0076] To a DMF (3 mL) solution of crude (S)-2-((methoxycarbonyl)amino)-2-phenylacetic acid (98.2 mg, 0.469 mmol) and COMU (199 mg, 0.465 mmol), N,N-diisopropylethylamine (300 µl, 1.72 mmol) was added. The purple solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with NaHCO3 solution and brine. The organic extract was dried over sodium sulfate and purified by normal-phase SiO2 chromatography (eluent: MeOH / ethyl acetate) to obtain the desired product.

[0077] ES / MS: 863.26 (M + ).

[0078] Dimethyl((1S,1'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)) Carbamate (Example 23) To a MeOH (3 mL) suspension of dimethyl((1S,1'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate (72.3 mg, 0.084 mmol), 3 drops of AcOH and n-chlorosuccinimide (24.2 mg, 0.181 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. 100 μL of TFA was added. The mixture was analyzed by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain the product as bis(trifluoroacetate).

[0079] ES / MS: 933.4 (M + ).

[0080] 1H NMR (400MHz, methanol-d4) δ 7.40 (s, 2H), 7.34 (d, J = 1.8Hz, 9H), 7.22– 7.16 (m, 4H), 5.51 (s, 2H), 5.33 (d, J = 5.9Hz, 6H), 5.20 – 5.09 (m, 3H),3.86 (s, 3H), 3.63 (d, J = 7.6Hz, 8H), 3.47 – 3.37 (m, 2H), 2.32 (dd, J =13.3, 6.4Hz, 1H), 2.19 (d, J = 6.4Hz, 1H), 2.12 – 1.96 (m, 4H), 1.89 (s, 1H).

[0081] Program 4 : Di-tert-butyl-2,2'-((5,10-dihydro-xonop[5,4,3-cde]xon-2,7-diyl)bis(4-bromo-1H-imidazolium) azole-5,2-diyl)(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) At 0 °C, N-bromosuccinimide (277 mg, 1.556 mmol) was added to a slurry of di-tert-butyl 2,2'-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (500 mg, 0.734 mmol) (obtained by substituting (tert-butoxycarbonyl)-L-proline with (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid as described in Procedure 1). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. 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 / DCM) to obtain the desired product.

[0082] ES / MS: 838.9 (M + ).

[0083] 1H NMR (400MHz, methanol-d4) δ 7.19 (d, J = 8.0Hz, 4H), 5.31 (s, 5H), 4.77(s, 3H), 3.67 (d, J = 9.5Hz, 4H), 3.49 (s, 3H), 2.68 (s, 38H), 2.36 (s, 3H), 2.00 (s, 24H), 1.46 (s, 10H), 1.25 (d, J = 2.6Hz, 25H).

[0084] Example 17 of Program 5 : Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) Bis(4-cyclopropyl-1H-imidazol-5,2-diyl)) Bis(pyrrolidine-2,1-diyl)) Bis(3-methyl-1-oxobutane-1,2-diyl) dicarbamate Di-tert-butyl-2,2'-((5,10-dihydro-xono[5,4,3-cde]xon-2,7-diyl)bis(4-cyclopropyl- 1H-Imidazol-5,2-diyl)(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) A solution of di-tert-butyl 2,2'-((5,10-dihydroxyleno[5,4,3-cde]xylen-2,7-diyl)bis(4-bromo-1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (199 mg, 0.237 mmol), cyclopropylboronic acid (168 mg, 1.956 mmol), palladium acetate (6.7 mg, 0.03 mmol), butyl di-1-adamantylphosphine (minimum 95%) (26 mg, 0.073 mmol), and potassium carbonate (310 mg, 2.243 mmol) in dioxane (6 mL) and water (3 mL) was degassed with argon for 10 minutes, 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 / hexane) to obtain the desired product.

[0085] ES / MS: 761.1 (M + ).

[0086] Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) Bis(4-cyclopropyl-1H-imidazol-5,2-diyl)) Bis(pyrrolidine-2,1-diyl)) Bis(3-methyl-1-oxobutane-1,2-diyl) Dicarbamate (Example 17) Add 350 µl of 4 M hydrochloric acid (4 M dioxane solution) to a solution of di-tert-butyl 2,2'-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl)bis(4-cyclopropyl-1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (32 mg, 0.04 mmol) in DCM (2 mL) and MeOH (0.5 mL). Stir the reaction mixture at room temperature for 90 min, then heat at 40 °C for 3 h. Concentrate the reaction mixture to dryness.

[0087] N,N-diisopropylethylamine (50 µl, 0.29 mmol) was added to a 2 mL solution of crude material, Moc-L-valine (19.6 mg, 0.11 mmol), and HATU (38.2 mg, 0.1 mmol) in DMF. The reaction was stirred overnight at room temperature. The mixture was then analyzed by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain the product as bis(trifluoroacetate).

[0088] ES / MS: 875.2 (M + ).

[0089] 1H NMR (400MHz, methanol-d4) δ 7.85 (s, 1H), 7.24 (s, 1H), 7.21 (d, J =1.5Hz, 2H), 7.16 (s, 1H), 5.33 (d, J = 6.9Hz, 4H), 5.21 (t, J = 7.5Hz, 1H), 5.14 – 5.00 (m, 1H), 4.28 – 4.16 (m, 2H), 3.99 (d, J = 8.1Hz, 1H), 3.84 (d, J= 9.4Hz, 2H), 3.64 (d, J = 4.2Hz, 5H), 2.56 (s, 1H), 2.44 – 2.21 (m, 1H),2.13 (dt, J = 13.3, 6.5Hz, 1H), 2.03 (q, J = 6.5Hz, 1H), 1.06 – 0.83 (m,12H).

[0090] Example 40 of Program 6 : Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydroxoneno[5,4,3-cde]xonene-2, 7-Diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxo) Butane-1,2-dimethyl)dicarbamate Di-tert-butyl5,5'-((5,10-dihydro-2,7-diyl)bis(4-(prop-1-ene-) 2-yl)-1H-imidazol-5,2-diyl))(2S,2'S,5S,5'S)-bis(2-methylpyrrolidine-1-carboxylic acid ester) A solution of di-tert-butyl 5,5'-((5,10-dihydro-xantho[5,4,3-cde]xanthoen-2,7-diyl)bis(4-bromo-1H-imidazol-5,2-diyl))(2S,2'S,5S,5'S)-bis(2-methylpyrrolidine-1-carboxylic acid ester) (371.7 mg, 0.429 mmol) (obtained as described in Procedure 4), pinacol isopropenylborate (700 µl, 3.724 mmol), palladium acetate (10 mg, 0.045 mmol), butyl di-1-adamantylphosphine (minimum 95%) (32 mg, 0.208 mmol), and potassium carbonate (474 ​​mg, 3.430 mmol) in toluene (6 mL) and water (3 mL) was degassed with argon for 10 minutes, 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 obtain the desired product.

[0091] ES / MS: 789.2 (M + ).

[0092] Di-tert-butyl5,5'-((5,10-dihydro-xonop[5,4,3-cde]xon-2,7-diyl)bis(4-isopropyl- 1H-Imidazol-5,2-diyl))(2S,2'S,5S,5'S)-bis(2-methylpyrrolidine-1-carboxylic acid ester) A solution of di-tert-butyl 5,5'-((5,10-dihydro-xantho[5,4,3-cde]xanthoen-2,7-diyl)bis(4-(prop-1-en-2-yl)-1H-imidazol-5,2-diyl))(2S,2'S,5S,5'S)-bis(2-methylpyrrolidine-1-carboxylic acid ester) (163 mg, 207 µmol) in EtOH (10 mL) was degassed three times with Ar / Vac. Pd / C (10%, 11 mg, 10.33 µmol) was added and the mixture was stirred in a hydrogen balloon at room temperature for 2 days. The suspension was filtered through a diatomaceous earth stopper and washed with DCM. Concentration was used to obtain the desired product, which was used directly in the next step without purification.

[0093] ES / MS: 793.2 (M + ).

[0094] 1H NMR (400MHz, methanol-d4) δ 6.92 (s, 4H), 5.27 (s, 4H), 4.02 (s, 4H), 3.60 (q, J = 7.0Hz, 4H), 2.22 (s, 8H), 2.18 – 2.06 (m, 2H), 1.74 (s, 4H), 1.44 – 1.26 (m, 43H), 1.19 (s, 34H), 1.26 – 1.13 (m, 6H).

[0095] Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydroxoneno[5,4,3-cde]xonene-2, 7-Diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxo) Butane-1,2-dimethyl)dicarbamate (Example 40) Add 1200 µl of 4 M hydrochloric acid (4 M dioxane solution) to a solution of di-tert-butyl 5,5'-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))(2S,2'S,5S,5'S)-bis(2-methylpyrrolidine-1-carboxylic acid ester) (137.7 mg, 0.092 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.

[0096] To a DMF (2 mL) solution of HCl salt (60 mg, 0.09 mmol), Moc-L-valine (33 mg, 0.188 mmol), and HATU (75 mg, 0.197 mmol), N,N-diisopropylethylamine (125 µl, 0.718 mmol) was added. The mixture was stirred overnight at room temperature. After cooling to 0 °C, 100 µL of TFA was added, and the mixture was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA was added to obtain the product as bis(trifluoroacetate).

[0097] ES / MS: 907.4 (M + ).

[0098] 1H NMR (400 MHz, methanol-d4) δ 7.09 (s, 1H), 7.02 (s, 1H), 6.96 (d, J = 8.5 Hz, 4H), 5.66 (d, J = 7.1 Hz, 1H), 5.37 (d, J = 3.6 Hz, 7H), 5.04 (dd, J = 10.9, 6.7 Hz, 3H), 4.75 (s, 1H), 4.11 – 4.04 (m, 4H), 3.70 (s, 3H), 3.65 (s, 8H), 3.30 – 3.21 (m, 1H), 2.70 (s, 1H), 2.51 – 2.43 (m, 3H), 2.35 (s, 4H), 2.29 (s, 4H), 2.28 (d, J = 24.2 Hz, 1H), 2.00 (d, J = 18.3 Hz, 2H), 1.97 (s, 6H), 1.54 (d, J = 6.6 Hz, 8H), 1.45 – 1.10 (m, 27H), 1.08 (d, J = 6.7 Hz, 4H), 1.05 – 0.89 (m, 12H), 0.86 (d, J = 6.8 Hz, 8H).

[0099] Program 7 Example 16 : Methyl((2S,3S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-L-isoleucyl) (2,4)-5-azaspiro[2,4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromenone[5,4,3-cde]chromenone-2-yl)- 4-Isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentane-2-yl)carbamic acid ester tert-Butyl(S)-6-(4-bromo-5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hepta-6- (yl)-1H-imidazol-5-yl)-5,10-dihydro-chromeno[5,4,3-cde]chromeno-2-yl)-1H-imidazol-2-yl)-5-azaspiro [2.4]Heptane-5-carboxylic acid ester At 0 °C, N-bromosuccinimide (160 mg, 0.899 mmol) was added to a DCM (10 mL) solution of di-tert-butyl 6,6'-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))(6S,6'S)-bis(5-azaspiro[2,4]heptane-5-carboxylic acid ester) (650 mg, 0.887 mmol). The reaction mixture was gradually warmed to room temperature. After 30 minutes, 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 / DCM) to obtain the desired product.

[0100] ES / MS: 813.1 (M + ).

[0101] 1H NMR (400MHz, methanol-d4) δ 7.38 (d, J = 17.6Hz, 1H), 7.21 (d, J =14.2Hz, 4H), 5.30 (d, J = 3.3Hz, 4H), 3.66 (dd, J = 32.4, 10.3Hz, 1H), 2.70(s, 5H), 2.45 (s, 0H), 2.38 – 2.24 (m, 1H), 2.17 (d, J = 7.4Hz, 1H), 1.51 –1.40 (m, 5H), 1.31 – 1.27 (m, 14H), 0.84 – 0.49 (m, 8H).

[0102] tert-Butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hept-6-yl)-1H- (imidazol-5-yl)-5,10-dihydro-xoneno[5,4,3-cde]xoneno-2-yl)-4-(prop-1-en-2-yl)-1H-imidazol-2- (2,4)-5-azaspiro[2,4]heptane-5-carboxylic acid ester 355.4 mg, 0.438 mmol of tert-butyl(S)-6-(4-bromo-5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid ester. A solution of pinacol isopropenylborate (200 µl, 1.064 mmol), palladium acetate (11.8 mg, 0.053 mmol), butyl di-1-adamantylphosphine (34.1 mg, 0.095 mmol), and potassium carbonate (182 mg, 1.317 mmol) in dioxane (8 mL) and water (4 mL) was degassed with argon for 10 minutes, 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 obtain the desired product.

[0103] ES / MS: 773.4 (M + ).

[0104] ¹H NMR (400MHz, methanol-d⁴) δ 7.36 (d, J = 16.2Hz, 1H), 7.20 (d, J = 13.7Hz, 2H), 7.04 – 6.93 (m, 2H), 5.34 – 5.10 (m, 6H), 5.01 (dt, J = 34.5, 7.2Hz, 1H), 4.89 (s, 11H), 3.89 – 3.38 (m, 3H), 2.52 – 2.08 (m, 3H), 1.49 (s, 5H), 1.33 – 1.26 (m, 13H), 1.22 (s, 16H), 0.87 – 0.44 (m, 9H).

[0105] tert-Butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hept-6-yl)-1H- Imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-aza Spiro[2,4]heptane-5-carboxylic acid ester A solution of tert-butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-(prop-1-en-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid ester (291.2 mg, 376.74 µmol) in EtOH (15 mL) was degassed under argon and vacuum. Pd / C (10%, 25.8 mg, 24.4 µmol) was added and the mixture was stirred overnight with an H2 ball. The reactants were filtered through a diatomaceous earth stopper, washed with DCM, and the filtrate was concentrated to give tert-butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hept-6-yl)-4-chloro-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid ester, which was used without further purification, assuming a quantitative yield.

[0106] ES / MS: 755.6 (M + ).

[0107] 1H NMR (400MHz, methanol-d4) δ 7.36 (d, J = 15.7Hz, 1H), 7.21 (d, J =13.0Hz, 2H), 6.93 (d, J = 6.6Hz, 2H), 5.29 (s, 4H), 5.14 – 4.89 (m, 2H), 3.77(d, J = 10.3Hz, 1H), 3.59 – 3.34 (m, 1H), 2.43 – 1.94 (m, 3H), 1.49 (s, 4H), 1.39 – 1.24 (m, 17H), 1.22 (s, 12H), 0.83 – 0.44 (m, 8H).

[0108] tert-Butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hept-6-yl)-4- Chloro-1H-imidazol-5-yl)-5,10-dihydro-1H-imidazol-2-yl)-4-isopropyl-1H-imidazol-2-yl)- 5-azaspiro[2,4]heptane-5-carboxylic acid ester AcOH (50 μL) and palau' chloride (84.8 mg, 0.405 mmol) were added to a MeOH suspension (7 mL) of tert-butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-yl)-1H-imidazol-5-yl)-5,10-dihydro-xono[5,4,3-cde]xono-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid ester (275.4 mg, 0.355 mmol). The yellow solution was stirred overnight at room temperature. The reactants were diluted with DCM, washed with saturated NaHCO3 solution, and dried over sodium sulfate. The crude residue was purified by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM) to obtain the desired product.

[0109] ES / MS: 809.4 (M + ).

[0110] 1H NMR (400MHz, methanol-d4) δ 7.23 (d, J = 21.8Hz, 2H), 6.96 (d, J =5.4Hz, 2H), 5.32 (d, J = 3.8Hz, 4H), 3.75 (s, 17H), 2.18 (d, J = 7.6Hz, 2H), 1.48 (s, 6H), 1.32 (dq, J = 18.2, 4.0, 3.5Hz, 22H), 1.22 (s, 4H), 0.94 – 0.48 (m, 9H).

[0111] Methyl((2S,3S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-L-isoleucyl) (2,4)-5-azaspiro[2,4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromenone[5,4,3-cde]chromenone-2-yl)- 4-Isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentane-2-yl)carbamic acid Ester (Example 16) To tert-butyl(S)-6-(5-(7-(2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]hept-6-yl)-4- Chloro-1H-imidazol-5-yl)-5,10-dihydro-1H-imidazol-2-yl)-4-isopropyl-1H-imidazol-2-yl)- 5-azaspiro[2,4]heptane-5-carboxylic acid ester Add 1500 µl of hydrochloric acid (4 M dioxane solution) to an 8 mL solution of DCM (177 mg, 0.219 mmol). Stir the reaction mixture for 1 hour, then concentrate to dryness.

[0112] N,N-diisopropylethylamine (500 µl, 2.871 mmol) was added to a DMF (3 mL) suspension of crude residue (methoxycarbonyl)-L-isoleucine (92 mg, 0.487 mmol) and HATU (191 mg, 0.503 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3 solution, and brine. The organic extract was dried over sodium sulfate and analyzed by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain methyl ((2S,3S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-L-isoleucyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentane-2-yl)carbamate as a bis(trifluoroacetate) salt (Example xx).

[0113] ES / MS: 925.6 (M+H) + ).

[0114] 1H NMR (400MHz, methanol-d4) δ 7.40 – 7.16 (m, 2H), 7.09 – 6.89 (m, 2H), 5.42 – 5.22 (m, 5H), 5.18 (t, J = 8.0Hz, 1H), 4.15 (t, J = 8.9Hz, 2H), 4.03(dd, J = 29.7, 9.8Hz, 2H), 3.83 (dd, J = 24.2, 9.9Hz, 2H), 3.67 (d, J =3.8Hz, 5H), 3.59 – 3.47 (m, 1H), 2.48 (ddd, J = 36.0, 12.8, 9.1Hz, 2H), 2.17(dd, J = 12.9, 7.5Hz, 1H), 2.12 – 2.00 (m, 1H), 1.79 (d, J = 8.5Hz, 2H), 1.62– 1.47 (m, 2H), 1.46 – 1.30 (m, 6H), 1.17 (qd, J = 13.3, 8.1Hz, 2H), 1.06 –0.51 (m, 18H).

[0115] Example 24 of Program 8: Dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydroxoneno[5,4,3-cde]xonene-2, 7-diyl)bis(4-bromo-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1, 2-Dimethyl)2-dicarbamate Dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydroxoneno[5,4,3-cde]xonene-2, 7-diyl)bis(1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl) dicarbamate To a solution of di-tert-butyl 2,2'-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (246 mg, 0.361 mmol) (obtained by substituting (tert-butoxycarbonyl)-L-proline with (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid as described in Procedure 1) in DCM (4 mL) and MeOH (1 mL), 2.5 mL of 4 M hydrochloric acid (4 M dioxane solution) was added. The reaction mixture was heated to 40 °C for 1.5 hours. The reaction mixture was concentrated to dryness.

[0116] N,N-diisopropylethylamine (500 µl, 2.87 mmol) was added to a 3 mL solution of crude (methoxycarbonyl)-L-isoleucine (145 mg, 0.767 mmol) and HATU (289 mg, 0.761 mmol) in DMF. After 2 hours, the reaction mixture was diluted with EtOAc and washed with NaHCO3 solution and brine. The organic extract was dried over sodium sulfate and purified by normal-phase SiO2 chromatography (eluent: MeOH / ethyl acetate) to obtain the desired product.

[0117] ES / MS: 823.34 (M + ).

[0118] 1H NMR (400MHz, methanol-d4) δ 7.23 (d, J = 52.7Hz, 7H), 5.22 (s, 4H), 5.14 (t, J = 6.4Hz, 2H), 4.25 (d, J = 8.5Hz, 2H), 4.02 (s, 1H), 3.86 (s, 2H),3.64 (s, 5H), 2.32 (d, J = 18.0Hz, 4H), 2.00 (s, 3H), 1.76 (s, 2H), 1.53 (s,2H), 1.14 (s, 2H), 0.96 – 0.77 (m, 15H).

[0119] Dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydroxoneno[5,4,3-cde]xonene-2, 7-diyl)bis(4-bromo-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1, 2-Dimethyl)dicarbamate (Example 24) At 0 °C, 3 drops of AcOH and 24 mg of n-bromosuccinimide (0.135 mmol) were added to a MeOH (3 mL) suspension of dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydroxeno[5,4,3-cde]xeno-2,7-diyl)bis(1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate (50 mg, 0.061 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. 100 μL of TFA was added. The mixture was analyzed by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain the product as bis(trifluoroacetate).

[0120] ES / MS: 981.4 (M + ).

[0121] 1H NMR (400MHz, methanol-d4) δ 7.19 (d, J = 11.3Hz, 3H), 5.31 (s, 4H), 5.08 (t, J = 7.1Hz, 2H), 4.23 (d, J = 8.2Hz, 2H), 4.07 (dd, J = 17.0, 8.1Hz,2H), 3.83 (q, J = 7.5Hz, 2H), 3.64 (s, 5H), 3.53 (s, 1H), 2.39 (dd, J = 12.6,6.6Hz, 2H), 2.27 (dt, J = 12.0, 5.7Hz, 1H), 2.09 (ddt, J = 31.2, 13.4, 7.1Hz,2H), 1.77 (d, J = 9.3Hz, 2H), 1.53 (d, J = 11.4Hz, 2H), 1.14 (dt, J = 14.8,7.5Hz, 2H), 0.98 – 0.82 (m, 13H).

[0122] Example 76 of Program 9: Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) bis(4-(tert-butyl)-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2- Dicarbamate 1-(tert-butyl)2-(3,3-dimethyl-2-oxobutyl)(S)-pyrrolidine-1,2-dicarboxylic acid Triethylamine (1 mL, 7.17 mmol) was added to a CH3CN (20 mL) solution of 1-bromo-3,3-dimethylbut-2-one (0.750 mL, 5.58 mmol) and (tert-butoxycarbonyl)-L-proline (1.2 g, 5.58 mmol). The reaction mixture was stirred at room temperature over a period of time. The mixture was diluted with DCM and washed with 1N HCl. The organic extract was dried over sodium sulfate to give the desired product. tert-butyl(S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester A suspension of 1-(tert-butyl)-2-(3,3-dimethyl-2-oxobutyl)(S)-pyrrolidine-1,2-dicarboxylic acid (1.75 g, 5.58 mmol) and ammonium acetate (4.34 g, 56.3 mmol) in toluene (8 mL) and isopropanol (1 mL) was heated under reflux overnight. The reaction mixture was diluted with EtOAc and washed three times with NaHCO3 solution. The organic extract was dried over sodium sulfate and purified by normal-phase SiO2 chromatography (eluent: MeOH / ethyl acetate) to give the desired product.

[0123] ES / MS: 294.0 (M + ).

[0124] Multi-peak report 1H NMR (400MHz, chloroform-d) δ 6.57 (s, 1H), 4.90 (dd, J = 7.7, 2.5Hz, 1H), 3.50 – 3.26 (m, 2H), 2.90 (s, 1H), 2.17 – 2.04 (m, 3H), 1.93 (d, J = 12.0Hz, 2H), 1.47 (s, 10H), 1.26 (s, 11H).

[0125] tert-butyl(S)-2-(4-(tert-butyl)-5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester N-iodosuccinimide (0.534 g, 2.37 mmol) was added to a DCM (7 mL) solution of tert-butyl(S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester (0.458 g, 1.56 mmol). The mixture was stirred overnight at room temperature. The solution was concentrated and purified by normal-phase SiO2 chromatography (eluent: ethyl acetate / hexane) to give the desired product.

[0126] ES / MS: 420.1 (M + ).

[0127] ¹H NMR (400MHz, chloroform-d) δ 10.69 (s, 1H), 5.02 – 4.78 (m, 1H), 3.48 – 3.26 (m, 2H), 2.89 (s, 1H), 2.05 (d, J = 12.0Hz, 2H), 1.90 (q, J = 4.4Hz, 1H), 1.47 (s, 9H), 1.38 (s, 9H).

[0128] Di-tert-butyl-2,2'-((5,10-dihydroxenopheno[5,4,3-cde]xenophen-2,7-diyl)bis(4-tert-butyl- 1H-Imidazol-5,2-diyl)(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) In a 40 mL reaction flask, a suspension of 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronadien-2-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene (100 mg, 0.216 mmol), tert-butyl(S)-2-(4-(tert-butyl)-5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester (181 mg, 433 mmol), palladium acetate (2.5 mg, 0.011 mmol), butyldi-1-adamantylphosphine (minimum 95%) (9 mg, 0.025 mmol), and potassium carbonate (134 mg, 0.970 mmol) in dioxane (4 mL) and water (2 mL) was degassed with argon for 10 minutes, and then heated overnight at 100 °C. The reaction mixture was diluted with DCM and washed twice with brine. The product was dried over sodium sulfate, concentrated, and purified by normal-phase SiO2 chromatography (eluent: ethyl acetate / DCM) to obtain the desired product.

[0129] ES / MS: 793.3 (M + ).

[0130] 1 H NMR (400MHz, cd3od) δ 6.79 (d, J = 3.7Hz, 4H), 5.25 (s, 4H), 4.76 (s,2H), 3.63 (s, 3H), 3.47 (s, 3H), 2.41 – 2.18 (m, 2H), 1.89 (dd, J = 11.6,6.5Hz, 2H), 1.29 (s, 18H), 1.26 (d, J = 4.3Hz, 18H).

[0131] Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl) bis(4-(tert-butyl)-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2- Dicarbamate (Example 76) Add 1 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of di-tert-butyl 2,2'-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl)bis(4-tert-butyl-1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (112 mg, 0.141 mmol) in DCM and MeOH. Heat the reaction mixture to 40 °C for 1 hour. Concentrate the reaction mixture to dryness.

[0132] To a DMF (2 mL) solution of HCl salt (94 mg, 0.141 mmol), Moc-L-valine (50.9 mg, 0.291 mmol), and HATU (115 mg, 0.302 mmol), N,N-diisopropylethylamine (200 µl, 1.15 mmol) was added. The mixture was stirred at room temperature for 2 hours. Ten drops of TFA were then added. The solution was analyzed by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain the product as bis(trifluoroacetate).

[0133] ES / MS: 907.3 (M + ).

[0134] 1H NMR (400MHz, methanol-d4) δ 6.99 – 6.90 (m, 3H), 5.33 (d, J = 3.3Hz, 4H), 5.15 (t, J = 7.7Hz, 2H), 4.19 (d, J = 7.2Hz, 2H), 4.07 (s, 2H), 3.78 (q,J = 8.2Hz, 2H), 3.63 (d, J = 9.9Hz, 5H), 2.52 (d, J = 14.6Hz, 2H), 2.34 –1.87 (m, 8H), 1.33 (d, J = 13.3Hz, 18H), 0.90 (t, J = 6.3Hz, 9H).

[0135] Example 25 of Program 10: N,N'-((2S,2'S)-((2S,2'S)-((5,10-dihydroxoneno[5,4,3-cde]xoneno-2,7-diyl)bis (4-Chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))di Cyclopropane formamide Di-tert-butyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxenophenone[5,4,3-cde]xenophenone-2,7-di- bis(1H-imidazol-5,2-diyl) bis(pyrrolidine-2,1-diyl) bis(3-methyl-1-oxobutane-1,2-diyl) Carbamate Add 4.5 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of di-tert-butyl 2,2'-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-carboxylic acid ester) (447 mg, 0.657 mmol) (obtained by substituting (tert-butoxycarbonyl)-L-proline with (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid as described in Procedure 1) and MeOH (8 mL). Heat the reaction mixture to 40 °C for 1.5 hours. Concentrate the reaction mixture to dryness.

[0136] N,N-diisopropylethylamine (900 µl, 5.17 mmol) was added to a 5 mL solution of crude material, (tert-butyloxycarbonyl)-L-valine (302 mg, 1.39 mmol), and HATU (525 mg, 1.38 mmol) in DMF. The reaction mixture was stirred overnight at room temperature. The reactants were diluted with EtOAc and washed with NaHCO3 solution and brine. The organic extract was dried over sodium sulfate and purified by normal-phase SiO2 chromatography (eluent: MeOH / ethyl acetate) to obtain the desired product.

[0137] ES / MS: 879.3 (M + ).

[0138] 1H NMR (400MHz, methanol-d4) δ 7.28 (s, 4H), 7.12 (d, J = 13.9Hz, 9H), 5.23 (s, 10H), 5.15 (t, J = 6.6Hz, 4H), 4.19 (d, J = 7.1Hz, 4H), 3.93 (s,1H), 3.86 (s, 5H), 2.40 – 2.11 (m, 14H), 2.00 (s, 8H), 1.44 (s, 39H), 1.33(s, 8H), 0.95 (dd, J = 14.9, 6.9Hz, 19H), 0.87 (d, J = 6.7Hz, 13H).

[0139] Di-tert-butyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxenophenone[5,4,3-cde]xenophenone-2,7-di- bis(4-chloro-1H-imidazol-5,2-diyl) bis(pyrrolidine-2,1-diyl) bis(3-methyl-1-oxobutane-1,2-diyl) dicarbamate To a suspension of di-tert-butyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxono[5,4,3-cde]xono-2,7-diyl)bis(1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (413 mg, 0.470 mmol) in MeOH (10 mL), 10 drops of AcOH and n-chlorosuccinimide (137 mg, 1.03 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with DCM, washed with saturated NaHCO3 solution, and dried over sodium sulfate. Purification was performed by normal-phase SiO2 chromatography (eluent: MeOH / ethyl acetate) to obtain the desired product.

[0140] ES / MS: 948.1 (M + ).

[0141] 1H NMR (400MHz, methanol-d4) δ 7.18 (dd, J = 26.2, 13.8Hz, 4H), 5.27 (s,5H), 5.06 (t, J = 6.8Hz, 2H), 4.17 (d, J = 7.2Hz, 2H), 3.95 (d, J = 7.9Hz,1H), 3.90 – 3.80 (m, 2H), 2.80 (s, 7H), 2.68 (s, 3H), 2.42 – 2.19 (m, 3H), 2.19 – 1.94 (m, 4H), 1.43 (s, 14H), 0.96 (dd, J = 12.7, 6.8Hz, 7H), 0.89 (d,J = 6.7Hz, 5H).

[0142] N,N'-((2S,2'S)-((2S,2'S)-((5,10-dihydroxoneno[5,4,3-cde]xoneno-2,7-diyl)bis (4-Chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))di Cyclopropane formamide (Example 25) Add 2.5 mL of 4 M hydrochloric acid (4 M dioxane solution) to a solution of di-tert-butyl((2S,2'S)-((2S,2'S)-((5,10-dihydroxenophenone[5,4,3-cde]xenophenone-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate (329 mg, 0.347 mmol) in DCM (8 mL) and MeOH (2 mL). Heat the reaction mixture to 40 °C for 2 hours. Concentrate the reaction mixture to dryness.

[0143] Add N,N-diisopropylethylamine (250 µl, 0.718 mmol) to a DMF (1.5 mL) solution of crude HCl salt (71.3 mg, 0.087 mmol), cyclopropionic acid (0.014 mL, 0.179 mmol), and HATU (72.8 mg, 0.191 mmol). Stir overnight at room temperature. Add 10 drops of TFA. Analyze by RP-HPLC (eluent: water / MeCN). Purified with 0.1% TFA to obtain the product as bis(trifluoroacetate).

[0144] ES / MS: 885.0 (M + ).

[0145] 1H NMR (400MHz, methanol-d4) δ 7.42 – 7.09 (m, 3H), 5.31 – 5.22 (m, 4H), 5.06 (dd, J = 7.8, 6.1Hz, 2H), 4.42 (d, J = 7.9Hz, 2H), 4.11 – 3.96 (m, 2H), 3.91 – 3.76 (m, 2H), 2.47 – 2.32 (m, 1H), 2.24 (dd, J = 11.6, 6.1Hz, 1H), 2.07 (ddd, J = 21.3, 13.8, 6.9Hz, 6H), 1.70 (ddd, J = 9.2, 7.2, 3.9Hz, 2H),1.03 (dd, J = 15.4, 6.8Hz, 2H), 0.96 (d, J = 6.9Hz, 9H), 0.88 – 0.72 (m, 6H).

[0146] Sihuanzhai Card Form Compound Table The following compounds were prepared as required using appropriate starting materials and appropriate protecting group chemicals, according to the embodiments and procedures described herein (and indicated in Table 1).

[0147] Table 1

[0148] 1H NMR The proton NMR data are shown in Table 2.

[0149] Table 2

[0150] The IUPAC name of the compound was provided by ChemBioDraw Ultra. Table 3. Chemical Names of IUPAC :

[0151] Bioassay Protocol for antiviral screening based on ZIKV reporter virus in Huh7 cells: 1. Cell A cancer cell line derived from human hepatocytes (Huh7) 2. Reagents ViviRen ™ Live cell substrate (Promega, catalog number E6492) or Nano Glo assay system (Promega: N1130). White, opaque 96-well TC-treated microplate (Corning, catalog number 3916) 96-well transparent V-bottom TC-treated microplate (Corning, catalog number 3894) Complete cell culture medium: DMEM (Gibco, catalog number 10569) supplemented with 10% FBS (HyClone, catalog number SH30071.03IH25-40) + 1% MEM non-essential amino acid solution 100x (Gibco, catalog number 11140050) + 1% penicillin-streptomycin (10,000 U / mL) (Gibco, catalog number 15140122).

[0152] Test medium: supplemented with 2% FBS and 2% GlutaMAX ™ 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).

[0153] Trypsin-EDTA solution (Gibco, catalog number 25200056) 3. Virus Recombinant ZIKV strains possessing the Renida luciferase gene (strain FSS-Rlu) or the nanoluciferase gene (strains PRV-Nano, Dakar-Nano) 4. Instruments BioTek Cytation 5 or other plate readers for chemiluminescence detection models.

[0154] Eppendorf plate centrifuge plate oscillator Eppendorf multichannel pipette program Day 1: Cell Preparation 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.

[0155] Centrifuge the 50ml conical tube at 1200 rpm for 3 minutes at room temperature.

[0156] Resuspend the cells in test medium. Count the cells and dilute them to 3 × 10⁶. 5 Density of cells / ml.

[0157] Dip cells at a rate of 50 µl cells / well in a white, opaque 96-well plate (assay plate). Gently shake the plate to ensure uniform cell adhesion.

[0158] The plated cells were cultured in a humidified incubator (37°C, 5% CO2).

[0159] Day 2: Infection 1) Nine series (2x or 3x) of concentrated compounds were prepared in a clear V-bottom 96-well plate (compound plate) using 90% DMSO solution and DMSO control.

[0160] For example:

[0161] 2) Dilute the reporter virus stock solution to 3 × 10⁻⁶ using test 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).

[0162] 3) Add 1 µl of the above 400× concentrated compound dilution from the compound plate to the respective well of the mixing plate. Shake the plate on a plate shaker for 5 minutes.

[0163] 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.

[0164] Exemplary format of the measuring plate :

[0165] Note: CC is used for cell control.

[0166] 5) Centrifuge the plate at 1000 rpm for 15 seconds.

[0167] 6) Incubate the plates in a humidified incubator at 37°C with 5% CO2 for 48 hours.

[0168] Day 4: Reading luciferase signals 7) ViviRen ™ The live cell substrate was diluted 3000x in the test medium. 25 µl of the diluted substrate was added to each well of the assay plate.

[0169] For the Nano-Glo assay system, add 50 µl of diluted substrate (diluted 50× times from the stock solution in assay buffer).

[0170] 8) Incubate the plate at room temperature for 5 minutes.

[0171] 9) Ideally, cell viability should be measured using the Promega Cell-titer Glo kit (only when ZIKV-Rlu is used for infection).

[0172] 10) Use Cytation 5 with a gain value of 120 to 150 to read the luciferase signal.

[0173] Data Analysis 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 signals from their respective dilution treatment groups to the control luciferase signal.

[0174] b. Plot the relative luciferase signal (Y-axis) against the log10 value (X-axis) of the compound concentration in the software GraphPad Prism 8, and fit the curve using a nonlinear regression model (log(inhibitor) against response - variable slope (four parameters) with bottom to 0 and top to 100 constraints).

[0175] c. EC 50 The values ​​are reported below.

[0176] Bioassays were performed to measure activity against ZIKV. As summarized in Table 4, the test compounds were inhibitors of ZIKV.

[0177] Table 4

[0178] The foregoing description of 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 or departing from the general conception of this disclosure. Therefore, based on the teachings and guidance presented herein, such modifications and alterations are intended to fall 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 will be interpreted by those skilled in the art based on the teachings and guidance.

Claims

1. A compound of formula (I): (I) in: R 1a and R 1b Each is independently a halogen group, C 1-6 Alkyl or cycloalkyl; P 1a Choose from the following groups: P 1b Choose from the following groups: 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 cycloalkyl carbonyl), N(H)(C 1-6 alkyl carbonyl) or -N(H)(C 3-12 (cycloalkoxycarbonyl); or their stereoisomers, pharmaceutically acceptable salts or solvates.

2. The compound according to claim 1, wherein R 1a and R 1b Both are halogen groups.

3. The compound according to claim 1, wherein R 1a and R 1b Both are chlorine.

4. The compound according to claim 1, wherein R 1a It is chlorine and R 1b Selected from C 1-6 Alkyl or C 3-12 Cycloalkyl.

5. The compound according to claim 1, wherein R 1a and R 1b Each independently is C 1-6 Alkyl or C 3-12 Cycloalkyl.

6. The compound according to any one of claims 1 to 5, wherein P 1a and P 1b Each was selected independently; 。 7. A compound, said compound being selected from the group consisting of: Dimethyl((2S,2'S)-((3R,3'R,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((3R,3'R,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3R,3'R,5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methoxypyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methoxypyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methoxypyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3,3-dimethylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3,3-dimethylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3,3-dimethylpyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((1S,1'S,3S,3'S,5S,5'S)-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((1S,1'S,3S,3'S,5S,5'S)-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((1S,1'S,3S,3'S,5S,5'S)-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydrocoryn[5,4,3-cde]coryn-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(piperidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(piperidine-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Methyl((S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-L-valine)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl ((2S,3S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-L-isoleucyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-cyclopropyl-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-ethyl-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydrocoryn[5,4,3-cde]coryn-2,7-diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-(((1S,1'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis(azanediyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((1S,1'S)-((2S,2'S,5S,5'S)-((5,10-dihydro-corben-[5,4,3-cde]corben-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(1-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoethane-2,1-diyl))dicarbamate; Methyl((2S,3S)-1-((S)-2-(5-(7-(4-chloro-2-((S)-1-((methoxycarbonyl)-L-isoleucyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((1S,1'S)-((2S,2'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-bromo-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; N,N'-((2S,2'S)-((2S,2'S)-((5,10-dihydrochrome[5,4,3-cde]chrome-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicyclopropaneformamide; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,3aS,3a'S,6aS,6a'S)-((5,10-dihydro-coryn[5,4,3-cde]coryn-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(hexahydrocyclopentadieno[b]pyrrole-2,1(2H)-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Methyl((S)-1-((2S,3aS,6aS)-2-(4-chloro-5-(7-(2-((2S,3aS,6aS)-1-((methoxycarbonyl)-L-valine)octahydrocyclopentadieno[b]pyrrolo-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromen[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)hexahydrocyclopentadieno[b]pyrrolo-1(2H)-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3R,3'R)-((2S,2'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3R,3'R)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydro-zirbenzirben-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,3aS,3a'S,6aS,6a'S)-((5,10-dihydro-coryn[5,4,3-cde]coryn-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(hexahydrocyclopentadieno[b]pyrrole-2,1(2H)-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S,3aS,3a'S,6aS,6a'S)-((5,10-dihydro-coryn[5,4,3-cde]coryn-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(hexahydrocyclopentadieno[b]pyrrole-2,1(2H)-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,3aS,3a'S,7aS,7a'S)-((5,10-dihydro-corben-[5,4,3-cde]corben-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(octahydro-1H-indole-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,3aS,3a'S,7aS,7a'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(octahydro-1H-indole-2,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S,3aS,3a'S,7aS,7a'S)-((5,10-dihydro-coryn[5,4,3-cde]coryn-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(octahydro-1H-indole-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Methyl((S)-1-((2S,5S)-2-(5-(7-(4-chloro-2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl((2S,3S)-1-((2S,5S)-2-(5-(7-(4-chloro-2-((2S,5S)-1-((methoxycarbonyl)-L-isoleucyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-(methoxymethyl)pyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((1R,1'R,3S,3'S,5R,5'R)-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-azabicyclo[3.1.0]hexane-3,2-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3R,3'R)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methoxy-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2R,2'R,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-(methoxymethyl)pyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3R,3'R,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((3R,3'R,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3R,3'R,5S,5'S)-((5,10-dihydro-zirbenzirben-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3,3-difluoropyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3,3-difluoropyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((5S,5'S)-((5,10-dihydro-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3,3-difluoropyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((6S,6'S)-((5,10-dihydro-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(5-azaspiro[2,4]heptane-6,5-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((6S,6'S)-((5,10-dihydro-xenophyllo[5,4,3-cde]xenophyllo-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(5-azaspiro[2,4]heptane-6,5-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((6S,6'S)-((5,10-dihydro-xono[5,4,3-cde]xono-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(5-azaspiro[2,4]heptane-6,5-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2R,2'R,5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2R,2'R,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydrocoryn[5,4,3-cde]coryn-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((2R,2'R,5S,5'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S,3S,3'S)-((2S,2'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-2,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Methyl((2S,3S)-1-((2S,4S)-2-(4-chloro-5-(7-(2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((2S,2'S,3S,3'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxopentane-1,2-diyl))dicarbamate; Methyl((S)-1-((2S,4S)-2-(4-bromo-5-(7-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-valine)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl((2S,3S)-1-((2S,4S)-2-(4-isopropyl-5-(7-(2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryn[5,4,3-cde]coryn-2,7-diyl)bis(4-(prop-1-en-2-yl)-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Dimethyl((2S,2'S)-((3S,3'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-isopropyl-1H-imidazol-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Methyl((2S,3S)-1-((2S,4S)-2-(5-(7-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-isoleucyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((2S,2'S)-((2S,2'S,5S,5'S)-((5,10-dihydrocoryneb[5,4,3-cde]coryneb-2,7-diyl)bis(4-chloro-1H-imidazol-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Methyl((S)-1-((2S,5S)-2-(4-chloro-5-(7-(2-((2S,5S)-1-((methoxycarbonyl)-L-valine)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydrocoryn[5,4,3-cde]coryn-2,7-diyl)bis(4-(tert-butyl)-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Methyl((S)-1-((S)-2-(5-(7-(4-chloro-2-((S)-1-((methoxycarbonyl)-L-valine)pyrrolidone-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)pyrrolidone-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl ((2S,3S)-1-((R)-6-(5-(7-(4-chloro-2-((R)-5-((methoxycarbonyl)-L-isoleucyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Dimethyl((2S,2'S)-((2S,2'S)-((5,10-dihydro-coreno[5,4,3-cde]coreno-2,7-diyl)bis(4-propyl-1H-imidazol-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate; Methyl((S)-1-((2S,4S)-2-(5-(7-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-valine)-4-methylpyrrolidone-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-4-methylpyrrolidone-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl((R)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-D-valine)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl((S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3,3-dimethyl-1-oxobutane-2-yl)carbamate; Methyl((S)-1-((2S,4S)-2-(5-(7-(4-chloro-2-((2S,4S)-1-((methoxycarbonyl)-L-valine)-4-methylpyrrolidone-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-4-methylpyrrolidone-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl((R)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-D-valine)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxobutane-2-yl)carbamate; Methyl((S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3,3-dimethyl-1-oxobutane-2-yl)carbamate; Methyl ((2S,3R)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((methoxycarbonyl)-L-isoleucyl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-3-methyl-1-oxopentane-2-yl)carbamate; Methyl((S)-1-((2S,4R)-2-(5-(7-(4-chloro-2-((2S,4R)-1-((methoxycarbonyl)-L-valine)-4-methylpyrrolidone-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromene[5,4,3-cde]chromene-2-yl)-4-isopropyl-1H-imidazol-2-yl)-4-methylpyrrolidone-1-yl)-3-methyl-1-oxobutane-2-yl)carbamate; and Methyl((S)-1-((S)-6-(5-(7-(4-chloro-2-((S)-5-((S)-4,4,4-trifluoro-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-5-azaspiro[2.4]hept-6-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeno-2-yl)-4-isopropyl-1H-imidazol-2-yl)-5-azaspiro[2.4]hept-5-yl)-4,4,4-trifluoro-3,3-dimethyl-1-oxobutane-2-yl)carbamate.

8. A compound having the following formula: ; or their pharmaceutically acceptable salts or solvates.

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