Targeting ligands for flavivirus e protein and related conjugates, compositions, and methods of use

Abstract

Ligands that target Flavivirus; conjugates comprising radicals of such ligands; compositions comprising the conjugates; methods of use of the ligands and / or conjugates to target active agents to the Flavivirus E protein; and methods of use of the conjugates to treat and prevent Flavivirus infection.

Description

TARGETING LIGANDS FOR FLAVIVIRUS E PROTEIN AND RELATED CONJUGATES, COMPOSITIONS, AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of priority from U.S. Appl. No. 63 / 709,802, filed October 21, 2024, which is incorporated by reference as if fully set forth herein.TECHNICAL FIELDThis disclosure relates to radicals of ligands that target Flavivirus E protein, conjugates comprising the ligands, compositions comprising the conjugates, methods of use of the radicals of ligands to target active agents to the Flavivirus E protein, and methods of use of the conjugates to treat and prevent Flavivirus infection.BACKGROUNDDengue is the most prevalent arthropod-borne viral (arboviral) disease in humans and remains a global health problem. Dengue fever is a febrile disease caused by one of the four dengue virus serotypes, namely DEN-1, DEN-2, DEN-3 and DEN-4, which belong to the family Flaviviridae. The virus is transmitted to humans primarily by the mosquito Aedes aegypti.Before 1970, only nine countries had experienced severe Dengue epidemics. Dengue is now endemic in more than 100 countries in regions monitored by the WHO in Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. The Americas, South-East Asia, and the Western Pacific region remain the most seriously affected.Dengue affects an estimated 390 million people annually, of which 96 million display clinical signs of the disease. According to the WHO, the total number of global cases reported increased from 505,430 in 2000 to 5.2 million in 2019. The largest number of dengue cases reported to date was in 2023. The WHO monitored regions of the Americas reported 4.5 million cases, with 2,300 deaths. A high number of cases were also reported in Asia: Bangladesh (321,000), Malaysia (111,400), Thailand (150,000), and Viet Nam (369,000). Altogether, 2023 resulted in over 6.5 million dengue infections reported.Infections produce a range of clinical manifestations, from mild flu-like symptoms to more severe, and sometimes fatal, hemorrhagic disease. Typical symptoms include fever, severe headache, muscle and joint pains, and rashes. According to the WHO, there are fourmajor clinical manifestations of DHF: (1) high fever, (2) hemorrhagic phenomena, (3) thrombocytopenia, and (4) leakage of plasma.A quarter of infected individuals require hospitalization. Of those, 3-6% may progress to Dengue hemorrhagic fever (DHF) or Dengue shock syndrome (DSS), which can be fatal. DSS is defined as DHF plus weak rapid pulse, and narrow pulse pressure or hypotension with cold, clammy skin and restlessness. The severity of DHF can be reduced with early detection and intervention, but subjects in shock are at high risk of death.The annual death toll based on WHO estimates was around 12,500 in 2012; however, it is believed that this number is severely under representative due to the underreporting of the majority of cases.Previously infected people remain susceptible to infection because there are four different serotypes of the Dengue virus, and infection with one of these serotypes provides immunity to only that serotype. It is believed that DHF is more likely to occur in subjects who have secondary Dengue infections.Yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis, St Louis encephalitis, and Zika virus also belong to the family Flaviviridae. Mosquito-borne infection with WNV can be asymptomatic, or it can cause flu-like symptoms in some individuals. In some cases, it causes neurological disorders and encephalitis; in severe cases, it can result in death. Mosquito-borne infection with YFV can cause severe symptoms in infected individuals. Mosquito-borne infection with JEV can be asymptomatic, or it can cause flu-like symptoms, with some cases developing into encephalitis. The acute encephalitis stage of the disease is characterized by convulsions, neck stiffness and other symptoms.In view of the foregoing, there remains an unmet need for an effective way to treat and prevent Flavivirus infection. It is an object of the present disclosure to provide materials and methods for the treatment and prevention of Flavivirus infection. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description.SUMMARYProvided is a conjugate of the Formula I:Formula Ior a pharmaceutically acceptable salt thereof, wherein T is a radical of a ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell; L is a linker; and Ai and A2 are each, independently, a radical of a hapten. In embodiments of T, T isFormula II or Formula III (where points of attachment to L are represented by:F ormul a II Formula lll wherein: each R is independently hydrogen or a Ci-Ce alkyl (e.g., methyl); each Ri is independently hydrogen, a Ci-Ce alkyl carbonyl (e.g., CH3CO-), or; R2 is hydrogen or heterocyclyl alkyl (e.g., pyridinyl alkyl); X is hydrogen or halogen (e.g., Cl, Br, I, or F); each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; or R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, wherein alkyl is optionally substituted with hydroxyl; P is CH2 or NH; n is 0 or 1; Q is CH or N; and Y is CH or N. In embodiments of the conjugate of Formula I, Ai and A2 are bound to the same atom on L; in some instances, the same atom is not a carbon atom. In embodiments of the conjugate of Formula I, Ai and A2 are bound to a different atom on L. In embodiments of the conjugate of Formula I, Ai and A2 are each independently selected from a rhamnose fragment, an a-galactose fragment, a dinitrophenyl fragment, or a trinitrophenyl fragment. In some embodiments of the conjugate of Formula I, Ai is a rhamnose fragment. In some embodiments of the conjugate of Formula I, Ai is a dinitrophenyl fragment or a trinitrophenyl fragment. In some embodiments of the conjugate of Formula I, L comprises a chain of atoms from 3 atoms to 60 atoms in length. In some embodiments of the conjugate of Formula I, L comprises one or more peptide fragments, such as one or more lysine fragments, such as a lysine fragment of the formula:, wherein A2 is attached to the lysine fragment via a linker. In some embodiments of the conjugate of Formula I, L comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36, such as a PEGn fragment, wherein n = 14-36. In embodiments of the conjugate of Formula I, L comprises an alkylamido fragment or an alkylamidoalkyl fragment, such as alkylamidoalkyl fragment comprising the fragment - CH2CH2C(O)N(H)(CH2CH2)- or the fragment -CH2CH2C(O)N(CH2CH2)2. In embodiments of the conjugate, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl. In embodiments of the conjugate of Formula I, T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n = 0, Q is N, Y is CH, and X is Cl. In embodiments of the conjugate of Formula I, T Formula III wherein Ri is hydrogen, each R is hydrogen, n = 0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, Y is CH, and X is Cl. In embodiments of the conjugate of Formula I, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl (e.g., hydroxy ethyl), Y is CH, and X is Cl. In embodiments of the conjugate of Formula I, T is Formula III, wherein each R is methyl, R3, R4, and X are each hydrogen, P isNH, n=l, Q is CH, Y is N, and RI is. In embodiments of the conjugate ofFormula I, T is Formula III, wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and Ri is methyl carbonyl. In embodiments of the conjugate of Formula I, T is Formula III, wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl. In embodiments of the conjugate of Formula I, T is Formula III, wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n = 0, Q is N, Y is CH, and X is Cl. In embodiments of the conjugate of Formula I, T is Formula III, wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.Also provided are compounds of Formula IV:L2-A1T — L1'Y3-A2Formula IV and pharmaceutically acceptable salts or solvates thereof, wherein T is a radical of a ligand for a target protein of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; and A1and A2are each, a radical of an independently selected hapten.Provided are compositions comprising one or more compounds of Formula IV:L2-A1T-L1' 3-A2Formula IV and pharmaceutically acceptable salts or solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof; wherein T is a radical of a ligand for a target protein of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; and A1and A2are each, a radical of an independently selected hapten.Provided are compositions for use in treating a Flavivirus infection, the compositions comprising one or more compounds of Formula IV:L2-A1T-L1' 3-A2Formula IV and pharmaceutically acceptable salts or solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof; wherein T is a radical of a ligand for a target protein of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; and A1and A2are each, a radical of an independently selected hapten.Provided are unit doses for use in treating a Flavivirus infection, the unit doses comprising a therapeutically effective amount of one or more compounds of Formula IV:L2-A1T-L1' 3-A2Formula IVand pharmaceutically acceptable salts or solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof; wherein T is a radical of a ligand for a target protein of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; and A1and A2are each, a radical of an independently selected hapten.Provided are methods for treating a Flavivirus infection in a host animal, the methods comprising administering a therapeutically effective amount of one or more compounds of Formula IV:L2-A1T-UY3-A2Formula IV and pharmaceutically acceptable salts or solvates thereof, compositions thereof optionally including one or more diluents, carriers, or excipients, or combinations thereof, or unit doses thereof to the host animal having a Flavivirus infection; wherein T is a radical of a ligand for a target protein of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; and A1and A2are each, a radical of an independently selected hapten.Provided are uses of one or more compounds of Formula IV:L2-A1T-UY3-A2Formula IV and pharmaceutically acceptable salts or solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof in the manufacture of a medicament for use in treating a Flavivirus infection in a host animal; wherein T is a radical of a ligand for a target protein of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; and A1and A2are each, a radical of an independently selected hapten.In embodiments of the conjugate of the Formula IV, T is Formula II or Formula III(where points of attachment to L are represented byFormula II Formula III wherein each R is independently hydrogen or a Ci-Ce alkyl (e.g., methyl); Ri is hydrogen, aCi-Ce alkyl carbonyl (e.g., CH3CO-), or; R2 is hydrogen or heterocyclyl alkyl (e.g., pyridinyl alkyl); X is hydrogen or halogen (e.g., Cl, Br, I, or F); each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; or R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is optionally substituted with a fragment selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, wherein alkyl is optionally substituted with hydroxyl; P is CH2 or NH; n is 0 or 1; Q is CH or N; and Y is CH or N. In embodiments of the conjugate of the Formula IV, L2and L3are bound to the same atom on L1; in some instances, the same atom is not a carbon atom. In embodiments of the conjugate of the Formula IV, L2and L3bound to a different atom on L1. In embodiments of the conjugate of the Formula IV, A1and A2are each independently selected from a rhamnose fragment, an a-galactoe fragment, a dinitrophenyl fragment, or a trinitrophenyl fragment. In embodiments of the conjugate of the Formula IV, wherein A1is a rhamnose fragment. In embodiments of the conjugate of the Formula IV, A1is a dinitrophenyl fragment or a trinitrophenyl fragment. In embodiments of the conjugate of the Formula IV, each of L1, L2, and L3independently comprises a chain of atoms from 3 atoms to 60 atoms in length. In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises one or more peptide fragments. In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises one or more lysine fragments, such as a lysine fragment of the formula:, wherein A2is attached to the lysinefragment via L2. In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36, such as a PEGn fragment, wherein n = 14-36. In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises an alkylamido fragment or an alkylamidoalkyl fragment, such as an alkylamidoalkyl fragment comprising the fragment - CH2CH2C(O)N(H)(CH2CH2)- or the fragment -CH2CH2C(O)N(CH2CH2)2. In embodiments,of the conjugate of the Formula IV, L comprises: wherein m is an integer from 0 to 20. In some embodiments thereof, L2comprisesOwherein p and q are each, independently, an integer from 0 to 20. In some embodiments of L1as set forth above, or L1and L2as set forthabove, L comprises wherein d is an integer from 0 to 20. InL3iAL2! embodiments of the conjugate of the Formula IV, the fragment?comprises a fragment of the formula:each, independently, an integer from 0 to 20. In embodiments of the conjugate of the FormulaIV, the fragmentcomprises a fragment of the formula:embodiments of the conjugate of the Formula IV, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n=0, Q is N, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is radical of Formula III wherein Ri is hydrogen, each R is hydrogen, n=0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula II wherein Ri andR2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl (e.g., hydroxy ethyl), Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is N, and Ri is. In embodiments of the conjugate of the Formula IV, T isFormula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, Ri is methyl carbonyl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n=0, Q is N, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.Further provided is a conjugate as shown below:or a pharmaceutically acceptable salt or solvate thereof.A pharmaceutical composition is also provided. In embodiments, the pharmaceutical composition comprises an above-described conjugate and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutical composition is formulated for oral administration. In embodiments, the pharmaceutical composition is formulated for subcutaneous or intravenous administration.Further provided is a method of treating a Flavivirus infection in a subject. The method comprises administering to the subject an effective amount of an above-described conjugate or an above-described pharmaceutical composition. The Flavivirus can be any Flavivirus, such as Dengue virus serotype 1, 2, 3 or 4, Yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), or Zika virus.Still further provided is a method of preventing a Flavivirus infection in a subject. The method comprises administering to the subject an effective amount of an abovedescribed conjugate or an above-described pharmaceutical composition. The Flavivirus can be any Flavivirus, such as Dengue virus serotype 1, 2, 3 or 4, Yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), or Zika virus.Even still further provided is any ligand for targeting a compound to which it is linked to an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell. In this regard, provided are conjugates of Formula I or Formula IV comprising radicals of such ligands, which target an envelope (E) protein on the surface of a Flavivirus or a Flavivirus- infected cell. In another illustrative embodiment, haptens in the conjugates recruit endogenous antibodies present in the host animal. In a related embodiment, a method of preparing a compound for targeting to an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell is provided. The method comprises attaching the ligandto the compound via a linker, whereupon the compound is prepared for targeting to the E protein.In another illustrative embodiment, compounds, compositions, and unit doses are provided for use in methods for treating a Flavivirus infection in a host animal, where the compounds, compositions, and unit doses are administered to the host animal, and afteradministration, A1and A2in the conjugates, or any epitope of the foregoing are each bound by one or more antibodies.In another illustrative embodiment, compounds, compositions, and unit doses are provided for use in methods for treating a Flavivirus infection in a host animal, where the compounds, compositions, and unit doses are administered to the host animal, and after administration, A1and A2in the conjugates, or any epitope of the foregoing are each bound by a different antibody.In another illustrative embodiment, each of L1, L2, and L3is independently selected, and each may comprise a single divalent atom, or a chain of atoms. In another illustrative embodiment, L2may be a bond attaching L1to A1. In another illustrative embodiment, L3may be a bond attaching L1to A2.The conjugates, compositions, and unit doses are provided for use in methods of preventing a Flavivirus infection. It is to be understood that such treatment includes prophylactic and preventative treatment of host animals, including host animals at risk of a Flavivirus infection, or host animals exposed to a Flavivirus or a Flavivirus infection, including when symptoms of a Flavivirus infection have not been observed. For example, the compounds, compositions, and unit doses are useful in preventing the onset of a Flavivirus infection, and / or decreasing the severity of later arising symptoms associated with a Flavivirus infection.FIGURESFig- 1 shows the mean total fluorescent signal for wild-type Dengue Virus 2 (WT DV2), virus treated with Compound 2 (positive control), virus treated with Compound 1, and mock treatment of virus.Fig. 2 shows the relative light units (RLU) for Compound 1+anti-DNP antibody, Compound 1+1 OOx Compound 2+anti-DNP antibody, DV2 WT+anti-DNP antibody, and DV2 WT-anti-DNA antibody at various drug concentrations (molar) in an antibodydependent cellular cytotoxicity assay.Fig- 3 shows the average percent change in viremia (%) over time (days 2-5) for Compound 1 and vehicle (control).Fig- 4 shows the results of experiments where BHK cells were infected with DV2, or Vero cells were infected with ZIKV, or Huh7 cells were infected with KUNV, or YFV17D, each at an MOI of 5 for 36 hours in the presence of PBS (WT Control), Compound 2 or Experimental Compounds, each at a starting concentration of 50 pM. Animmunofluorescence assay was then used to determine the ratio between infected cells to non-infected cells via an Opera Phenix high resolution cell imager. One-Way ANOVA was used to determine statistical significance between WT infection and treatment. The table in Fig. 4 shows ECso values of each of the tested compounds against DV2.Fig. 5 The ability for Compound 1 or 12 to present its dual haptens to the surrounding environment when bound to DV2 was determined via ADCC assay with clarified virus particles (1x106 PFU / well). A) Results show that Compound 1 elicits a robust and site-specific activation of effector (i.e., NK) cells with an EC50 value of 391 nM. These results suggest that the dual haptens attached to Compound 1 are not obstructed from interacting with immune cells, confirming our mechanism of action. B) Moreover, Compound 12 exhibited even greater effector cell activation, with an ECso value of 3.68 nM, nearly a 100-fold increase in effector cell activation compared to Compound 1. C) Table of ECso values for all tested compounds.Fig- 6 shows the results of an immunofluorescence assay of DV2 infected cells demonstrates the specificity of Compound Ito the flavivirus E protein, as Compound 1 was shown to be out competed by the addition of lOOx Compound 2. These results suggest that Compound 1 co-localizes with DV2 E protein while retaining hapten presentation to the external environment.Fig. 7 AG129 mice lacking INF a / p and y were infected with 1x106 mouse adapted dengue virus serotype 2 strain D2S20. The first dose of Compound 1 was given 24 hours post infection. Blood samples (serum) and body weights were obtained daily. A) Compound 1 treatment resulted in 100% of mice surviving while only 40% of vehicle treated mice survived. B) NS1 levels in the blood serum of infected mice were significantly blunted by Compound 1 treatment. AUC analysis showed that Compound 1 treatment significantly reduced blood NS1 levels (Student’s t test ** = P value of 0.004). C) DV2 RNA in infected mouse blood further confirmed a blunted infection with Compound 1 treatment. AUC analysis displayed a high degree of significance (Student’s t test **** = P value of <0.001).DETAILED DESCRIPTIONWhile the concepts of the present disclosure are illustrated and described in detail in the description herein, results in the description are to be considered as exemplary and not restrictive in character; it being understood that only the illustrative embodiments are shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected.More specifically, a targeted therapeutic strategy with a dual mechanism of action that elicits host immune response against a target (e.g., a Flavivirus and a Flavivirus-infected cell) is disclosed. The strategy employs conjugates, which can be trivalent such that they comprise a targeting ligand bound (e.g., via a linker) to two haptens that bind to naturally occurring antibodies (e.g., in humans). Once recruited, these anti-hapten antibodies bind and activate the innate immune system against the target. Pharmaceutical compositions comprising such conjugates and methods comprising the administration of such conjugates and compositions are also provided.The conjugates hereof can be small molecule ligand-targeted drug conjugates that combine a receptor-specific ligand with two haptens and one or more linkers. Accordingly, the conjugates can be a trivalent drug that can target a Flavivirus or Flavirus-infected cell via the targeting ligand, e.g., a ligand that targets a Flavivirus envelope (E) protein, and also bind two antibodies in a subject via the dual payload. The general scheme is to provide a specific targeting ligand conjugated to an effective payload of two haptens to treat and prevent infections with a Flavivirus. The targeting ligand can specifically recognize a target (e.g., the E protein of a Flavivirus, which can be exclusively expressed on the surface of an infected cell). In certain embodiments, the haptens are selected to activate the innate immune system of the subject (e.g., adjacent to the targeted cell) to recruit immune cells and / or otherwise leverage the subject’s own immune system against the Flavivirus.Provided is a conjugate of the Formula I:AiT— Lzor a pharmaceutically acceptable salt thereof, wherein T is a radical of a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell; L is a linker; and Ai and A2 are each, independently, a hapten fragment. In embodiments of T, T isFormula II or Formula III (where points of attachment to L are represented by:Formula II Formula III wherein each R is independently hydrogen or a Ci-Ce alkyl (e.g., methyl); Ri is hydrogen, aCi-Ce alkyl carbonyl (e.g., CH3CO-), or; R2 is hydrogen or heterocyclyl alkyl (e.g., pyridinyl alkyl); X is hydrogen or halogen (e.g., Cl, Br, I, or F); each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; or R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, wherein alkyl is optionally substituted with hydroxyl; P is CH2 or NH; n is 0 or 1; Q is CH or N; and Y is CH or N.In embodiments of the conjugate of Formula I, Ai and A2 are bound to the same atom on L; in some instances, the same atom is not a carbon atom. In embodiments of the conjugate of Formula I, Ai and A2 are bound to a different atom on L.In embodiments of the conjugate of Formula I, Ai and A2 are each independently selected from a rhamnose fragment, an a-galactose fragment, a dinitrophenyl fragment, or a trinitrophenyl fragment. For example, A1can be a DNP fragment and A2can be a rhamnose fragment or vice versa. In some embodiments of the conjugate of Formula I, Ai is a rhamnose fragment. In some embodiments of the conjugate of Formula I, Ai is a dinitrophenyl fragment or a trinitrophenyl fragment.In some embodiments of the conjugate of Formula I, L comprises a chain of atoms from 3 atoms to 60 atoms in length. In many embodiments, L can comprise a chain of atoms from about 4 A to about 72 A in length. The chain of atoms is part of the backbone of the conjugate of Formula I. The “backbone” of the linker L is the shortest chain of contiguous atoms forming a covalently bonded connection between T and L on one side of the conjugate of Formula I and L and A1and A2on the other side of the conjugate of Formula I. A1and A2can be attached to L at the same location or at a different location.In many embodiments, L comprises one or more linker groups, each linker group may comprise one or more of a polyethylene glycol (PEG) fragment, an alkyl group, a sugar fragment, and / or a peptide fragment.In some embodiments, the linker comprises a hydrophilic substituent, such as a substituent that comprises one or more amino acid fragments (which are the same or different), an alkyl chain, a polyethylene glycol (PEG) fragment, or a combination of an any of the foregoing, in some embodiments, the linker comprises an oligomer of peptidoglycan fragments, glycan fragments, or anion of amino acids.For a linker that comprises one or more PEG fragments, all carbon and oxygen atoms of the one or more PEG fragments are part of the backbone of the linker L unless otherwise specified.In many embodiments, L has a chain of atoms at least 3 atoms in length, at least 7 atoms in length, at least 10 atoms in length, at least 14 atoms in length, or at least 20 atoms in length. In many embodiments, L has a chain of between 3 and 7 atoms in length, between 7 and 10 atoms in length, between 10 and 14 atoms in length, between 14 and 20 atoms in length, between 20 and 30 atoms in length, between 30 and 40 atoms in length, between 40 and 50 atoms in length, or between 50 and 60 atoms in length. In many embodiments, L has a chain of at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 atoms in length. The use of the word “between” is inclusive of the endpoints meaning that between 3 and 5 atoms in a chain length includes 3 atoms and includes 5 atoms.In many embodiments, L comprises one or more peptide fragments, each of which is independently optionally substituted. In some embodiments, L is an amino acid fragment of the formulathree carbon atoms in the linker backbone as presented wherein R can be H, alkyl, arylalkyl, -alkyl-S-alkyl or arylalkyl or the sidechain of any naturally- or non-naturally occurring amino acid. Examples of R include H (making the fragment a, glycine fragment), alkyl (such that fragment may be a fragment of alanine, valine, isoleucine, and leucine among others), -alkyl-S-alkyl (such that the fragment may be methionine among others), arylalkyl (such that the fragment may be phenylalanine, tyrosine, and tryptophan among others). The carbon atom to which R isattached can be chiral and can have any suitable relative configuration, such as a D- or L- configuration.In some embodiments of the conjugate of Formula I, L comprises one or more peptide fragments, such as one or more lysine fragments, such as a lysine fragment of the formula:, wherein A2 is attached to the lysine fragment via a linker.In some embodiments of the conjugate of Formula I, L comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36, such as a PEGn fragment, wherein n = 14-36. In embodiments of the conjugate of Formula I, L comprises an alkylamido fragment or an alkylamidoalkyl fragment, such as alkylamidoalkyl fragment comprising the fragment - CH2CH2C(O)N(H)(CH2CH2)- or the fragment -CH2CH2C(O)N(CH2CH2)2.In many embodiments, the atoms used in forming L comprise one or more chains of carbon atoms forming alkylene groups, one or more chains of carbon and oxygen atoms. It is to be understood that the bonds connecting atoms in the chain can be either saturated or unsaturated, such that for example, alkanes, alkenes, alkynes, cycloalkanes, arylenes, imides, and the like can be divalent radicals that are included in L. In each of the foregoing, the atoms of L in the chain can be substituted or unsubstituted. In many embodiments the substitutions are:In addition, the atoms forming the linker may also be cyclized to form saturated or unsaturated divalent cyclic radicals in the linker, such as radicals of the formulae:wherein each X1is independently CH2, NR’, or O wherein R’ is alkyl or hydrogen and each X2is independently S, O, N, NH, CR” whereinR” is alkyl or hydrogen. Examples of such radicals include:In some embodiments, L comprises suitable substituents that change the hydrophobicity or hydrophilicity of L. Thus, for example, L can have hydrophobic side chain group, such as an alkyl, cycloalkyl, aryl, arylalkyl, or like group, each of which is optionally substituted. In some embodiments, L comprises one or more amino acid fragments, such as hydrophobic amino acid side chains, including phenylalanine (Phe) and tyrosine (Tyr) fragments, and further including substituted variants thereof, and analogs and derivatives of such side chains. Other examples of L include alkylene-amino- alkylenecarbonyl, alkylene-thio-(carbonylalkylsuccinimid-3-yl) moieties, as further illustrated by the following formulae:wherein x and y are each independently 1, 2, 3, 4, or 5 , where the asterisk identifies points of attachment either to other linker moieties or to G or mFc.In many embodiments, the backbone atoms in the linker may contain the following atoms - carbon, nitrogen, oxygen, phosphorous, and sulfur. These atoms may be substituted with a number of different substituents including -CH2-, -C(O)— N(H)-, - NfR.1)= wherein R1is, for example, H, alkyl, and alkylaryl, and -0-P(0)(0H)0-).In these and other embodiments, L comprises one or more of chains of carbon atoms forming alkyl groups, chains of carbon and oxygen atoms forming polyoxyalkyl groups, chains of carbon and nitrogen atoms forming polyamines, and others, including rings, such as those that form aryl and heterocyclyl groups (e.g., triazoles, and oxazoles).In addition, the bonds connecting atoms in the backbone of L can be either saturated or unsaturated, such that for example, alkanes, alkenes, alkynes, cycloalkanes, arylenes, imides, can be divalent radicals that are included in L. Further, such atoms in the chain of L may be substituted or unsubstituted.Additional examples of radical groups which may be present in L include 1- alkylsuccinimid-3-yl, carbonyl, thionocarbonyl, alkyl, cycloalkyl, alkylcycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, carbonylalkylcarbonyl, l-alkylsuccinimid-3-yl, 1- (carbonylalkyl)succinimid-3-yl, alkylsulfoxyl, sulfonylalkyl, alkylsulfoxylalkyl, alkylsulfonylalkyl, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydrofuranyl, 1- (carbonyltetrahydro-2H-pyranyl)succinimid-3-yl, and 1- (carbonyltetrahydrofuranyl)succinimid-3-yl, wherein each group can be substituted or unsubstituted. Any of the aforementioned groups may be the linker L or may be included as a portion of L. In some embodiments, one or more of the aforementioned groups can be used in combination (or more than once) (e.g., -alkyl-C(O)-alkyl) and may further comprise an additional nitrogen (e.g., alkyl-C(O)-NH-, -NH-alkyl-C(O)- or -NH-alkyl-), oxygen (e.g., -alkyl-O-alkyl-) or sulfur (e.g., -alkyl-S-alkyl-). Examples of such L groups are alkylcarbonyl, cycloalkylcarbonyl, carbonylalkylcarbonyl, l-(carbonylalkyl)succinimid- 3-yl, and succinimid-3-ylthiol, wherein each group can be substituted or unsubstituted.In some embodiments, L can be formed via click chemistry / click chemistry- derived methods. For example, L can be derived from copper-catalyzed azide-alkyne cycloaddition (CuAAC), strain promoted azide-alkyne cycloaddition (SPAAC), inverse electron demand Diels-Alder reaction (IEDDA), and Staudinger ligation (SL). For example, T can be of the formula T-N3. T-N3 can then be reacted with an alkyne as shown in Scheme 1 :Scheme 1In Scheme 1, the wavy line connected to T and to A ' / A2represents a linkage between T and A' / A2and the groups to which they are attached. It should be appreciated that in Scheme 1, the triazole would be considered to be part of L if L is click chemistry-derived.In many embodiments, L comprises pegylated-, alkyl-, sugar-, and peptide-based linkers; bivalently covalently attached to T and AVA2.For example, L may be an amide,wherein x is an integer from 0 to 50 and y is an integer from 0 to 50In other examples, the linker L can comprise:wherein each of R2and R3is independently H or Ci-6 alkyl; and z is an integer from 1 to 8.In some embodiments, L comprises one or more spacer linkers wherein the spacer linker is bound to a linker backbone atom. In some embodiments, spacer linkers are hydrophilic spacer linkers comprising a plurality of hydroxyl functional groups. A spacer linker may comprise any stable arrangement of atoms. For example, a spacer linker may comprise one or more L’ where each L’ is independently selected from an amide, ester, urea, carbonate, carbamate, disulfide, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl (e.g., polyethylene glycol), cycloalkyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof. In some embodiments, a spacer linker comprises any one or more of the following units: an amide, ester, urea, carbonate, carbamate, disulfide, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof. In some embodiments, a spacer linker comprises a glycosylated amino acid. In some embodiments, a spacer comprises one or more monosaccharide, disaccharide, polysaccharide, glycan, or peptidoglycan. In some embodiments, a spacer comprises one or more units such as ethylene (e.g., polyethylene), ethylene glycol (e.g., PEG), ethanolamine, ethylenediamine, and the like (e.g., propylene glycol, propanolamine, or propylenediamine). In some embodiments, a spacer linker comprises an oligopeptide, polypeptide, a rigid functionality, peptidoglycan, oligoproline, oligopiperidine, or anycombination thereof. In some embodiments, a spacer linker comprises an oligoethylene glycol or a PEG. In some embodiments, a spacer linker comprises an oligoethylene glycol. In some embodiments, a spacer linker comprises a PEG. In some embodiments, a spacer linker comprises an oligopeptide or polypeptide. In some embodiments, a spacer linker comprises an oligopeptide. In some embodiments, a spacer linker comprises a polypeptide. In some embodiments, a spacer linker comprises a peptidoglycan. In some embodiments, a spacer linker does not comprise a glycan. In some embodiments, a spacer linker does not comprise a sugar.In some embodiments, a rigid functionality is an oligoproline or oligopiperidine. In some embodiments, a rigid functionality is an oligoproline. In some embodiments, a rigid functionality is an oligopiperidine. In some embodiments, a rigid functionality is an oligophenyl. In some embodiments, a rigid functionality is an oligoalkyne.In some embodiments, an oligoproline or oligopiperidine has about two up to and including about fifty, about two to about forty, about two to about thirty, about two to about twenty, about two to about fifteen, about two to about ten, or about two to about six repeating units (e.g., prolines or piperidines).In one example, L can comprise (-CH2CH2-O-)n, where n is an integer between and including 1 and 36 (e.g., 1 to 2, 2 to 6, 3 to 8, 6 to 12, and 4 to 10) a peptide, an alkylamido fragment (e.g., C(O)N(H)C2-Ci8 alkyl- or C2-C18 alkyl-C(O)N(H)-), an alkylamidoalkyl fragment (e.g., a C2-C18 alkyl-C(O)N(C2-Ci8 alkyl)2 or a C2-C18 alkyl-C(O)N(H)-C2-Ci8 alkyl group, such as a -CH2CH2C(O)N(CH2CH2)2 or a -CH2CH2C(O)N(H)(CH2CH2)- fragment), a peptidoglycan, or a combination of two or more of the foregoing. L can be a branched linker and at least two of the haptens can be connected to different branches of the linker, wherein the different branches optionally extend from different atoms of the linker.In embodiments of the conjugate, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl.In embodiments of the conjugate of Formula I, T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n = 0, Q is N, Y is CH, and X is Cl.In embodiments of the conjugate of Formula I, T is Formula III wherein Ri is hydrogen, each R is hydrogen, n = 0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl.In embodiments of the conjugate of Formula I, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl (e.g., hydroxy ethyl), Y is CH, and X is Cl.In embodiments of the conjugate of Formula I, T is Formula III, wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is N, and Ri isIn embodiments of the conjugate of Formula I, T is Formula III, wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and Ri is methyl carbonyl.In embodiments of the conjugate of Formula I, T is Formula III, wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.In embodiments of the conjugate of Formula I, T is Formula III, wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n = 0, Q is N, Y is CH, and X is Cl.In embodiments of the conjugate of Formula I, T is Formula III, wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.Also provided is a conjugate of the Formula IV:L3-A1T-lY2-A2or a pharmaceutically acceptable salt thereof, wherein T is a radical of a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell; L'-L3are each, independently, a linker, wherein L^L3independently have the same definitions as L above; and A1and A2are each a radical of an independently selected hapten.In embodiments of the conjugate of the Formula IV, T is Formula II or Formula III(where points of attachment to L are represented by:Formula II Formula III wherein each R is independently hydrogen or a Ci-Ce alkyl (e.g., methyl); Ri is hydrogen, aCi-Ce alkyl carbonyl (e.g., CH3CO-), or; R2 is hydrogen or heterocyclyl alkyl (e.g., pyridinyl alkyl); X is hydrogen or halogen (e.g., Cl, Br, I, or F); each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; or R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, wherein alkyl is optionally substituted with hydroxyl; P is CH2 or NH; n is 0 or 1; Q is CH or N; and Y is CH or N.In embodiments of the conjugate of the Formula IV, L2and L3are bound to the same atom on L1; in some instances, the same atom is not a carbon atom. In embodiments of the conjugate of the Formula IV, L2and L3bound to a different atom on L1.In embodiments of the conjugate of the Formula IV, A1and A2are each independently selected from a rhamnose fragment, an a-galactose fragment, a dinitrophenyl fragment, or a trinitrophenyl fragment. For example, A1can be a DNP fragment and A2can be a rhamnose fragment or vice versa. In embodiments of the conjugate of the Formula IV, wherein A1is a rhamnose fragment. In embodiments of the conjugate of the Formula IV, A1is a dinitrophenyl fragment or a trinitrophenyl fragment.In embodiments of the conjugate of the Formula IV, each of L1, L2, and L3independently comprises a chain of atoms from 3 atoms to 60 atoms in length. In many embodiments, L can comprise a chain of atoms from about 4 A to about 72 A in length. The chain of atoms is part of the backbone of the conjugate of Formula I. The “backbone” of the linker L is the shortest chain of contiguous atoms forming a covalently bonded connection between T and L on one side of the conjugate of Formula I and L and A1and A2on the other side of the conjugate of Formula I. A1and A2can be attached to L at the same location or at a different location.In many embodiments, L comprises one or more linker groups, each linker group may comprise one or more of a polyethylene glycol (PEG) fragment, an alkyl group, a sugar fragment, and / or a peptide fragment.In some embodiments, the linker comprises a hydrophilic substituent, such as a substituent that comprises one or more amino acid fragments (which are the same or different), an alkyl chain, a polyethylene glycol (PEG) fragment, or a combination of anany of the foregoing, in some embodiments, the linker comprises an oligomer of peptidoglycan fragments, glycan fragments, or anion of amino acids.For a linker that comprises one or more PEG moieties, all carbon and oxygen atoms of the one or more PEG moieties are part of the backbone of the linker L unless otherwise specified.In many embodiments, L has a chain of atoms at least 3 atoms in length, at least 7 atoms in length, at least 10 atoms in length, at least 14 atoms in length, or at least 20 atoms in length. In many embodiments, L has a chain of between 3 and 7 atoms in length, between 7 and 10 atoms in length, between 10 and 14 atoms in length, between 14 and 20 atoms in length, between 20 and 30 atoms in length, between 30 and 40 atoms in length, between 40 and 50 atoms in length, or between 50 and 60 atoms in length. In many embodiments, L has a chain of at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 , 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 atoms in length. The use of the word “between” is inclusive of the endpoints meaning that between 3 and 5 atoms in a chain length includes 3 atoms and includes 5 atoms.In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises one or more peptide fragments. In some embodiments, one or more of L1, L2, andL3is an amino acid fragment of the formulathree carbon atoms in the linker backbone as presented wherein R can be H, alkyl, arylalkyl, -alkyl-S-alkyl or arylalkyl or the side-chain of any naturally- or non-naturally occurring amino acid. Examples of R include H (making the fragment a, glycine fragment), alkyl (such that fragment may be a fragment of alanine, valine, isoleucine, and leucine among others), -alkyl-S-alkyl (such that the fragment may be methionine among others), arylalkyl (such that the fragment may be phenylalanine, tyrosine, and tryptophan among others). The carbon atom to which R is attached can be chiral and can have any suitable relative configuration, such as a D- or L- configuration.In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises one or more lysine fragments, such as a lysine fragment of the formula:, wherein A2is attached to the lysine fragment via L2. In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36, such as a PEGn fragment, wherein n = 14-36. In embodiments of the conjugate of the Formula IV, L1, L2, or L3each, independently, comprises an alkylamido fragment or an alkylamidoalkyl fragment, such as an alkylamidoalkyl fragment comprising:-CH2CH2C(O)N(H)(CH2CH2)- or -CH2CH2C(O)N(CH2CH2)2. In embodiments of the, i .conjugate of the Formula IV, L1comprises: wherein m is an integer from 0 to 20. In some embodiments thereof, L2comprisesOwherein p and q are each, independently, an integer from 0 to 20. In some embodiments of L1as set forth above, or L1and L2as set forthabove, L3comprises wherein d is an integer from 0 to 20. In embodiments of the conjugate of the Formula IV, the fragmentcomprises a fragment of the formula:each, independently, an integer from 0 to 20. In embodiments of the conjugate of the FormulaIV, the fragmentcomprises a fragment of the formula:embodiments of the conjugate of the Formula IV, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n=0, Q is N, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein Ri is hydrogen, each R is hydrogen, n=0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl (e.g., hydroxy ethyl), Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is N, and Ri is. In embodiments of the conjugate of the Formula IV, T isFormula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, Ri is methyl carbonyl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n=0, Q is N, Y is CH, and X is Cl. In embodiments of the conjugate of the Formula IV, T is Formula III wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.Further provided is a conjugate as shown below:orOne or more -OH groups of the conjugate can be independently replaced with a thiol, a phosphate, or a phosphanate ester. One or more of the -OH groups can be replaced with -OC(=O)R4, wherein R4is an alkyl group. One or more of the -OH groups can be replaced with-OC(=O)R4, wherein R4is a Ci-Ce alkyl group. An amine (-NH2) group can be replaced with -OC(=O)R4, and R4can be an alkyl group. The amine (-NH2) group can be replaced with -OC(=O)R4, and R4can be a Ci-Ce alkyl group. The carboxyl (-C00H) group can be replaced with -OC(=O)R4, wherein R4is an alkyl group. The carboxyl (-C00H) group can be replaced with -OC(=O)R4, wherein R4is a Ci-Ce alkyl group.With regard to the above, an alkyl group is a saturated, straight chain or branched non-cyclic hydrocarbon, an example of which is a Ci-Ce alkyl having from 1 to 6 carbon atoms. In some embodiments, the alkyl group has monovalency. Examples of alkyl groups with monovalency include -CH3, -CH2CH3, and the like. Monovalent alkyls may be found on substitutions in the chain of linker, L, for example. In some embodiments, the alkyl group has bivalency, such as when found in the chain of the linker, L. Examples of alkyl groups with bivalency include, but are not limited to, -CH2-, -CH2CH2-, and the like.Also with regard to the above, a heterocyclyl group is a substituted or an unsubstituted aromatic or non-aromatic ring compound containing three or more ring members, one or more (e.g., 1, 2 or 3) of which is a heteroatom, such as, but not limited to, N, O, and S. A heterocyclyl group can be a cycloheteroalkyl group or a heteroaryl group or, if polycyclic, a combination threof. A hetrocyclyl group can include three to around 20 ring members, such as three to around 15 ring members, such as 3-8 carbon atoms, 3-6 carbon atoms, 3-5 carbon atims, and 6-8 arbon atoms. A heterocyclyl group designed as a C2- heterocyclyl can be a 5-membered ring with two carbons and three heteroatoms, a 6- membered ring with two carbons and four heteroatoms, etc. Likewise, a C4-heterocyclylgroup can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl can include one or more double bonds, such as 3,6-dihydro-2H-pyran and 3,4-dihydro-2H-pyran, either of which can be substituted.In certain embodiments, processes for making the conjugates hereof are provided as set forth in the examples described herein and such processes otherwise known in the art.Optionally, the conjugate hereof is complexed with antibodies in vivo. Such complexation can be with different antibodies per hapten. Optionally, the conjugate hereof is complexed with antibodies in vivo. Such complexation can be with different antibodies per hapten.Conjugates may contain chiral centers and as such may exist in different isomeric forms. The term “isomers” refers to different conjugates that have the same molecular formula but differ in arrangement and configuration of the atoms.“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. A single stereoisomer with known relative and absolute configuration of two chiral centers can be designated using the conventional RS system (e.g., (1 S,2S)); a single stereoisomer with known relative configuration but unknown absolute configuration can be designated with stars (e.g., (1R*,2R*)); and a racemate with two letters (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1 S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)).“Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a conjugate is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved conjugates whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, resolved conjugates can be defined by the respective retention times for the corresponding enantiomers / diastereomers via chiral high-performance liquid chromatography (HPLC).Certain conjugates may contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.Geometric isomers may occur when a conjugate contains a double bond or some other feature that provides a certain amount of structural rigidity. If the conjugate contains adouble bond, the substituent may be E or Z configuration. If the conjugate contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or / ra / r.s-configuration.Conformational isomers (or conformers) are isomers that can differ by rotations about one or more “a” bonds. Rotamers are conformers that differ by rotation about only a single “a” bond.The term “atropisomer” refers to a structural isomer based on axial or planar chirality resulting from restricted rotation in the molecule.Unless specified otherwise, the conjugates are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp, using the appropriate solvent or mixture of solvents to achieve good separation).The conjugates can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare the conjugates and intermediates made therein are contemplated. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization.Pharmaceutically acceptable salts of the compounds and conjugates of the disclosure may be formed by using methods and procedures known by those of ordinary skill in the pharmaceutical arts. “Pharmaceutically acceptable salts” refer to derivatives of the conjugates wherein the parent compound is modified by making an acid salt or a base salt thereof. Substitution with heavier isotopes, particularly deuterium (i.e., H2or D), may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, or improved therapeutic index and the disclosure herein includes isotopically substituted compounds and conjugates, such as with deuterium.“Stable compound” and “stable structure” are meant to indicate a conjugate that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or prophylactic agent.“Solvate” means compounds complexed with a solvent molecule. It is appreciated that compounds described herein may form such complexes with solvents by simply mixing the compounds with a solvent or dissolving the compounds in a solvent. It is appreciated thatwhere the compounds are to be used as pharmaceuticals, such solvents are pharmaceutically acceptable solvents. It is further appreciated that where the compounds are to be used as pharmaceuticals, the relative amount of solvent that forms the solvate should be less than established guidelines for such pharmaceutical uses, such as less than International Conference on Harmonization (ICH) Guidelines. It is to be understood that the solvates may be isolated from excess solvent by evaporation, precipitation, and / or crystallization. In some embodiments, the solvates are amorphous, and in other embodiments, the solvates are crystalline. When the solvent is water, the solvate is termed a “hydrate”.In view of the above, also provided is a pharmaceutical composition. In embodiments, the pharmaceutical composition comprises an above-described conjugate and a pharmaceutically acceptable excipient. Pharmaceutical compositions may be prepared by combining one or more conjugates with a pharmaceutically acceptable excipient and, optionally, one or more additional pharmaceutically active agents in accordance with methods known in the art. Pharmaceutical compositions may be configured for oral or parenteral delivery.The conjugates and compositions may be administered as a therapy, wherein the subject has the flavivirus infection at the time the compound or composition is administered, or the compound or composition may be administered as prophylaxis, to prevent or delay onset of the flavivirus infection, wherein the subject does not have the flavivirus infection at the time the compound or composition is administered.Optionally, for therapy, the method may include the step of identifying the subject as having the flavivirus infection, before administering the conjugate or composition. Subjects with a flavivirus infection may be identified by methods known in the art, such as by assaying a biological sample (e.g., blood, serum, or plasma) obtained from the subject for the presence of flavivirus nucleic acids or flavivirus proteins. Such assays may involve, for example, the use of reverse transcriptase-polymerase chain reaction (RT-PCR), immunological assay, or Plaque-reduction neutralization testing (PRNT).In view of the above, further provided is a method of treating a Flavivirus infection in a subject. The method comprises administering to the subject an effective amount of an above-described conjugate or an above-described pharmaceutical composition. The Flavivirus can be any Flavivirus, such as Dengue virus serotype 1, 2, 3 or 4, Yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), or Zika virus.Still further provided is a method of preventing a Flavivirus infection in a subject. The method comprises administering to the subject an effective amount of an above-described conjugate or an above-described pharmaceutical composition. The Flavivirus can be any Flavivirus, such as Dengue virus serotype 1, 2, 3 or 4, Yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), or Zika virus.The Flavivirus infection can be due to Zika virus, West Nile virus, Dengue virus (e.g., type 1, 2, 3, or 4), tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, or yellow fever virus. Other members of the genus can be found in Kuno G. et al., Journal of Virology, 1998, “Phylogeny of the Genus Flavivirus, ” 72(I):73-83, which is incorporated herein by reference for its teachings regarding same. In some embodiments, the Flavivirus is Zika virus. The Zika virus may be any origin or lineage (e.g., African, Asian, American, Brazilian). Examples of Zika virus strains include but are not limited to MR766 (1947 Uganda strain), FSS13025 (2010 Cambodian strain), PRVABC59 (2015 Puerto Rican strain), GZ01 / 2016 (2016 Chinese strain (ex Venezuela)), H / PF / 2013 (2013 French Polynesian strain), IBH30656 (1968 Nigerian strain), Paraiba 2015 (2015 Brazilian strain), PLCal ZV (2013 Canadian strain (ex Thailand)), SMGC-1 (2016 Chinese strain), SPH 2015 (2015 Brazilian strain), and SZ01 (2016 Chinese strain).The methods of the invention may be used to treat an existing Flavivirus infection in a subject, or the methods of the invention may be used prophylactically to prevent a Flavivirus infection in a subject. As used herein, in this context, the term “prevent” or “prevention” is inclusive of delaying the onset of infection and / or one or more symptoms of infection, and precluding the occurrence or reoccurrence of infection and / or one or more symptoms of infection. Thus, in some embodiments, the subject has the flavivirus infection at the time the at least one compound is administered, and the at least one compound is administered as therapy.In some embodiments, the methods further comprise, prior to administering the conjugate (or pharmaceutical composition comprising same) to the subject, identifying the subject as having the Flavivirus infection. The identifying step may comprise assaying a biological sample (e.g., blood, saliva, or urine) obtained from the subject for the presence of flavivirus nucleic acids or flavivirus proteins (e.g., Zika virus nucleic acids or Zika virus proteins, or dengue virus nucleic acids or dengue virus proteins). In some embodiments, assaying includes the use of reverse transcriptase-polymerase chain reaction (RT-PCR), immunological assay (e.g., ELISA), or Plaque-reduction neutralization testing (PRNT).A method of preparing a compound for targeting to an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell is also provided. The method comprisesattaching a radical of the molecule to the compound via a linker, whereupon the compound is prepared for targeting to the E protein.The following clauses represent various embodiments of the disclosure.Clauses: 1. A conjugate of the formulaL2-A1T — IJ Y3-A2or a pharmaceutically acceptable salts or solvates thereof, whereinT is a radical of a ligand for a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell; L1, L2, and L3are each, an independently selected linker; andA1and A2are each, a radical of an independently selected hapten.2. A ligand having the following structure:3. The conjugate of clause 1, wherein T is a radical of the ligand of clause 2, wherein A1and A2are each the same radical of an independently selected hapten.4. The conjugate of clause 1, wherein T is a radical of the ligand of clause 2, wherein A1and A2are each a different radical of an independently selected hapten.5. The conjugate of clause 1, 3 or 4, wherein the radical of an independently selected hapten is selected from fragments of a rhamnose, a nitrophenyl, a nitrophenol, anitroaniline, a dinitrophenyl (DNP), a dinitrophenol, a dinitroaniline, a trinitrophenyl (TNP), a trinitrophenol, a trinitroaniline, chloronitrophenyl, a chloronitrophenol, a chloronitroaniline, an iodonitrophenyl, an iodonitrophenol, an iodonitroaniline, a nitrotyrosine, an hydroxynitrotyrosine, an aminonitrotyrosine, 4-hydroxy-3 -nitrophenyl acetic acid, an a- galactose , a sulfated Gal, a phosphorylcholine, a bacterial antigen, a viral antigen, or, in embodiments, A1and A2are each an independently selected fragment rhamnose, a- galactosyl fragment, dinitrobenzene, dinitroaniline, trinitrobenzene, and dinitroaniline.6. The conjugate of any preceding clause wherein A1and / or A2is dinitrophenyl (DNP), a dinitrophenol fragment, or a dinitroaniline fragment.7. The conjugate of any preceding clause wherein A1and / or A2is a rhamnose fragment, including L-rhamnose.8. The conjugate of any preceding clause wherein one of A1and A2is a L- rhamnose fragment; and the other of A1and A2is a dinitroaniline fragment.9. The conjugate of any preceding clause wherein the radical of an independently selected hapten has an epitope that has an endogenous Ab.10. The conjugate of any preceding clause wherein L2and L3are attached to the same atom of L1.11. The conjugate of any preceding clause wherein L2and L3are bound to the same atom on L1.12. The conjugate of any preceding clause wherein L2and L3are bound to the same non-carbon atom on L1.13. The conjugate of any preceding clause wherein L2and L3are bound to the same nitrogen atom on L1.14. The conjugate of any preceding clause wherein L2and L3are attached to different atoms of L1.15. The conjugate of any preceding clause wherein one or more of L1, L2, and L3is a single divalent atom selected from N, O, P, and S, where N and P are optionally substituted.16. The conjugate of any preceding clause wherein one or more of L1, L2, and L3is a chain of atoms, where the length of each chain is independently selected and in the range of about 2 to about 60.17. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes ethoxy, ethylamino, ethylene glycol, aza-ethylene glycol, (PEG)n, or aza-(PEG)n, or a combination thereof, where n is in the range from 2 to about 36.18. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes (PEG)n, or aza-(PEG)n, or a combination thereof, where n is 2-36.19. The conjugate of any preceding clause wherein each of L1, L2, and L3includes or also includes ethoxy, ethylamino, ethylene glycol, aza-ethylene glycol, (PEG)n, or aza- (PEG)n, or a combination thereof, where n is 2-36.20. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes O-alkyl-O, N-alkyl-N, C(O)-alkyl-C(O), or NC(O)-alkyl-C(O)N, or a combination thereof.21. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes O-alkyl-C(O), N-alkyl-C(O), O-alkyl-N-alkyl-C(O), N-alkyl-O- alkyl-C(O), or C(O)alkyl-C(O), or a combination thereof.22. The conjugate of any preceding clause wherein L1includes or also includes O- alkyl-C(O)N-diyl, O-alkyl-O-alkyl-C(O)N-diyl, or N-alkyl-O-alkyl-O-alkyl-C(O)N-diyl.23. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes one or more amino acids.24. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes one or more hydrophilic amino acids selected from Arg, Asn, Asp, Cys, Glu, Gin, His, Lys, Met, Orn, Ser, or Thr, including the naturally occurring L-enantiomers of each of the foregoing.25 The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes one or more hydrophilic amino acids selected from P-NH2-Ala, Arg, Asn, Asp, Cys, Glu, Gin, His, Lys, Met, Orn, Ser, or Thr, including the naturally occurring L- enantiomers of each of the foregoing.26. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes one or more amino acids selected from glycine, serine, proline, ornithine, and lysine.27. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes an ornithine or lysine, including L-omithine and L-lysine.28. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a lysine, including L-lysine.29. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a proline, including L-proline.30. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a (Pro)n, including (L-Pro)n, where n is 1-6.31. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a (Pro)3, including (L-Pro)3.32. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a (Pro)3-Lys, including (L-Pro)3-(L-Lys).33. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a (Pro)e, including (L-Pro)e.34. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a (Pro)e-Lys, including (L-Pro)e-(L-Lys).35. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes glycine and serine, including L-serine.36. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)n, including [Gly-(L-Ser)]n, where n is 1-3.37. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)2, including [Gly-(L-Ser)]2.38. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)2-Lys, including [Gly-(L-Ser)]2-(L-Lys).39. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)3, including [Gly-(L-Ser)]3.40. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)3-Lys, including [Gly-(L-Ser)]3-(L-Lys).41. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a C(O), C(O)O, C(0)NH, 0C(0)NH, or NHC(0)NH group.42. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes l,2,3-triazol-l,4-diyl, l,2,3-triazol-l,4-diyl, or a combination thereof.43. The conjugate of any preceding clause wherein one or more of L1, L2, and L3includes or also includes a maleimid-diyl or thiomaleimid-N,S-diyl.44. The conjugate of any preceding clause wherein L2and / or L3are hydrophilic.45. The conjugate of any preceding clause wherein L1includes a region that is capable of forming an a-helical conformation.56. The conjugate of any preceding clause wherein the extended conformation ofL2and / or L3is at least 8 A, 9 A, 10 A, 11 A, 12 A, 13 A, 14 A, 15 A, 20 A, 25 A, 30 A, 35 A, or 40 A, in length.47. The conjugate of any preceding clause wherein L2and / or L3includes or also includes (PEG)n or aza-(PEG)n, where n is in the range from about 3 to about 36, from about 4 to about 36, from about 5 to about 36, from about 6 to about 36, or from about 7 to about 36.48. The conjugate of any preceding clause wherein L2and / or L3includes or also includes one or more divalent cycloalkyl, including adamantyl, heterocyclyl, including maleimidyl, aryl, heteroaryl including triazolyl, , stilbene, oligoproline, or oligopiperidine groups..49. The conjugate of any preceding clause wherein the extended conformation of T-L1is at least 5 A, 6 A, 7 A, 8 A, 9 A, 10 A, 11 A, or 12 A in length.50. The conjugate of any preceding clause wherein L1includes or also includes (PEG)nor aza-(PEG)n, where n is in the range from about 3 to about 36, from about 4 to about 36, from about 5 to about 36, or from about 6 to about 36.51. A conjugate of formula:or a pharmaceutically acceptable salt or solvate thereof.The foregoing illustrative conjugates, as defined by clauses 1-51 may be included in any of the compositions, unit doses, uses, or methods described herein.DEFINITIONS

[0001] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation.

[0002] It is to be understood that in every instance disclosed herein, the recitation of a range of integers for any variable describes the recited range, every individual member in the range, and every possible subrange for that variable. For example, the recitation that n is an integer from 0 to 8, describes that range, the individual and selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n is 0, or n is 1, or n is 2, etc. In addition, the recitation that n is an integer from 0 to 8 also describes each and every subrange, each of which may for the basis of a further embodiment, such as n is an integer from 1 to 8, from 1 to 7, from 1 to 6, from 2 to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc.

[0003] It is also to be understood that unless otherwise indicated the recitation of a numerical value necessarily reflects the relative precision of the numerical value. For example, the recitation of a number with a specified precision based on significant figures necessarily includes a range of values that would match that number after appropriate rounding. For example, the recitation of the number 1 with a single significant figure is understood to properly refer to a range of values from 0.5 to 1.4. Similarly, the recitation of the number 1.0 with two significant figures is understood to properly refer to a range of values from 0.95 to 1.04. The relative precision of the numerical value can be further indicated by modifying with the term “about” to indicate that the modified number has lower precision.

[0004] As used herein, the term “about” when used with numerical values or limits generally means that the number is approximate and that, as recited, it is understood to include a range of values. For example, a real number that is recited with a single significant figure, would by definition include a so-called rounding range; the number about 5 would at the very least include the range 4.5-5.4, as each of those values rounds to 5. The same is to be understood for real numbers expressed with additional significant figures, where the corresponding rounding range applies to the last significant figure. Integers are to be understood to at least include the values ±1 for single-digit numbers, ±10 for two-digit numbers, etc. Depending upon the context and the variable recited, the term “about” is also interpreted to contemplate a range based on a percentage of the recited number, such as about 5 construed to include 5±10% or 5 ±20%. Notwithstanding the foregoing, it is understood that the range of values, unless otherwise indicated, should not be interpreted to include a negative range for a positively recited number, and vice-versa. In addition, depending up on the context, the recited number, unless otherwise indicated, should not be interpreted to include a value of zero when used in conjunction with an added component.

[0005] The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0006] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.

[0007] As used herein the term “radical” with reference to, for example, ligand for a target protein or hapten, refers to a ligand for a target protein or hapten, respectively, as described herein, where one or more atoms or groups, such as a hydrogen atom, or an alkyl group on a heteroatom, and the like, is removed to provide a radical for covalent linking or conjugation to the polyvalent linkers L1, L2, and L3. When the one or more groups are replaced with a different one or more groups then the resulting compound is an analog of the ligand.Illustrative analogs include, but are not limited to, those compounds that share functional and in some cases structural similarity to those compounds described herein. It is to be understood that such radicals can also be formed on acid, ester, or amide groups, such as carboxy, phosphoryl, and sulfuryl acids, by removing the OH, ester, or amide group. It is also to be understood that such radicals can be formed by removing other fragments, such as halo, alkoxy, amino, heterocyclyl, or heteroaryl groups.

[0008] “Alkyl” or “alkyl group” is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms (Ci-Cio alkyl), from 1 to 8 carbons (Ci-Cs alkyl), from 1 to 6 (Ci-Ce alkyl), 1 to 4 (C1-C4 alkyl), 1 to 3 (Ci- C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms. In some embodiments, the alkyl group has monovalency. Examples of alkyl groups with monovalency include -CH3, -CH2CH3, and the like. Monovalent alkyls may be found on substitutions in the chain of linker, L, for example. In some embodiments, the alkyl group has bivalency, such as when found in the chain of thelinker, L. Examples of alkyl groups with bivalency include, but are not limited to, -CH2-, - CH2CH2-, and the like. In some embodiments, the alkyl group is a saturated alkyl group. In some embodiments, an alkyl group is an unsaturated alkyl group, also termed an alkenyl group or an alkynyl group.

[0009] The term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain, or combination(s) thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quartemized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, without limitation, — CH2— CH2— O— CH3, — CH2— CH2— NH— CH3, — CH2— CH2— N(CH3)— CH3, — CH2— S— CH2— CH?, — CH2— CH2— S(O)— CH3, — CH2— CH2— S(O)2— CH?, — CH2=CH— O— CH3, — Si(CH3)3, — CH2— CH=N— OCH3, — CH=CH— N(CH3)— CH3, — O — CH3, — O — CH2 — CH3, and — CN. Up to two heteroatoms may be consecutive, such as, for example, — CH2 — NH — OCH3.

[0010] As used herein, the term “aryl” includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted. Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term “heteroaryl” includes aromatic heterocyclic groups, each of which may be optionally substituted. Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.

[0011] The term “optionally substituted” as used herein includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted. Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid is optionally substituted.

[0012] Illustrative substituents include, but are not limited to, a radical -(CH2)xZx, where x isan integer from 0-6 and Zxis selected from halogen, hydroxy, alkanoyloxy, including Ci-Ce alkanoyloxy, optionally substituted aroyloxy, alkyl, including Ci-Ce alkyl, alkoxy, including Ci-Ce alkoxy, cycloalkyl, including Cs-Cs cycloalkyl, cycloalkoxy, including Cs-Cs cycloalkoxy, alkenyl, including C2-C6 alkenyl, alkynyl, including C2-C6 alkynyl, haloalkyl, including Ci-Ce haloalkyl, haloalkoxy, including Ci-Ce haloalkoxy, halocycloalkyl, including C3-C8 halocycloalkyl, halocycloalkoxy, including Cs-Cs halocycloalkoxy, amino, Ci-Ce alkylamino, (Ci-Ce alkyl)(Ci-Ce alkyl)amino, alkylcarbonylamino, N-(Ci-Ce alkyl)alkylcarbonylamino, aminoalkyl, Ci-Ce alkylaminoalkyl, (Ci-Ce alkyl)(Ci-Ce alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(Ci-Ce alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or Zxis selected from -CO2R4and -CONR5R6, where R4, R5, and R6are each independently selected in each occurrence from hydrogen, Ci-Ce alkyl, aryl-Ci-Ce alkyl, and heteroaryl-Ci-Ce alkyl.

[0013] The compounds described herein can be used for both human clinical medicine and veterinary applications. Thus, the host animal treated with the compounds described herein can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal. The present invention can be applied to host animals including, but not limited to, humans, laboratory animals such rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.

[0014] The term “therapeutically effective amount” as used herein, refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In one aspect, the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used incombination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.

[0015] The conjugates and compositions may be delivered by suitable methods of delivery including, for example but not limited to, intranasally, orally, and intravenously. The method can further comprise administering autologous antibodies or allogeneic Immunoglobulin G (IgG) antibodies.

[0016] In each of the foregoing and each of the following embodiments, unless otherwise indicated, it is also to be understood that the transitional phrase “consisting essentially of’ means that the scope of the corresponding composition, unit dose, method or use is understood to encompass the specified compounds or recited steps, and those that do not materially affect the basic and novel characteristics of the invention described herein. For example, a method described herein that consists essentially of a single compound, or genus of compounds, is understood to represent a monotherapy for the recited disease. Though the monotherapy may include co-administration of one or more carriers, vehicles, diluents, adjuvants, excipients, and the like, and combinations thereof, and / or include coadministration of one or more additional active pharmaceutical ingredients, those latter additional active pharmaceutical ingredients are to be understood to be for treating diseases and / or symptoms distinct from treating the underlying conditions described herein, such as the treatment of the viral infection itself. Illustrative additional active pharmaceutical ingredients may include, for example, active ingredients for treating pain, inflammation, cough, congestion, and the like.

[0017] The disclosure also includes the following Embodiments, which are listed in no particular order of importance:

[0018] Embodiment 1 relates to a conjugate of the Formula I:or a pharmaceutically acceptable salt thereof, wherein:T is a radical of a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell;L is a linker; and Ai and A2 are each a radical of an independently selected hapten.

[0019] Embodiment 2 relates to the conjugate of Embodiment 1, wherein T is Formula II orFormula III (where points of attachment to L are represented byFormula II Formula III or pharmaceutically acceptable salt thereof; wherein: each R is independently hydrogen or a Ci-Ce alkyl (e.g., methyl);Ri is hydrogen, a Ci-Ce alkyl carbonyl,R2 is hydrogen or heterocyclyl alkyl;X is hydrogen or halogen; each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; or R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is optionally substituted with a group selected from a Ci- Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, wherein alkyl is optionally substituted with hydroxyl;P is CH2or NH; n is 0 or 1;Q is CH or N; andY is CH or N.

[0020] Embodiment 3 relates to the conjugate of Embodiment 1, or pharmaceutically acceptable salt thereof, wherein T is:group and the thioxothiazolidin-4-one is E or Z. In some embodiments, the bond between the tetrahydrofuranly group and the thioxothiazolidin-4-one is Z.

[0021] Embodiment 4 relates to the conjugate of any one of Embodiments 1-3, wherein Ai and A2 are bound to the same atom on L.

[0022] Embodiment 5 relates to the conjugate of Embodiment 4, or pharmaceutically acceptable salt thereof, wherein the same atom is not a carbon atom.

[0023] Embodiment 6 relates to the conjugate of any one of Embodiments 1-5, or pharmaceutically acceptable salt thereof, wherein Ai and A2 are bound to a different atom on L.

[0024] Embodiment 7 relates to the conjugate of any one of Embodiments 1-6, or pharmaceutically acceptable salt thereof, wherein Ai and A2 are each independently selected from a rhamnose fragment, an a-galactose fragment, a dinitrophenyl fragment, and a trinitrophenyl fragment.

[0025] Embodiment 8 relates to the conjugate of any one of Embodiments 1-7, or pharmaceutically acceptable salt thereof, wherein Ai is a rhamnose fragment.

[0026] Embodiment 9 relates to the conjugate of any one of Embodiments 1-7, or pharmaceutically acceptable salt thereof, wherein Ai is a dinitrophenyl fragment or a trinitrophenyl fragment.

[0027] Embodiment 10 relates to the conjugate of any one of Embodiments 1-7, or pharmaceutically acceptable salt thereof, wherein L comprises a chain of atoms from 3 atoms to 60 atoms in length.

[0028] Embodiment 11 relates to the conjugate of any one of Embodiments 1-10, or pharmaceutically acceptable salt thereof, wherein L comprises one or more peptide fragments.

[0029] Embodiment 12 relates to the conjugate of Embodiment 11, or pharmaceuticallyacceptable salt thereof, wherein L comprises one or more lysine fragments.

[0030] Embodiment 13 relates to the conjugate of Embodiment 12, or pharmaceutically acceptable salt thereof, wherein L comprises a lysine fragment of the formula:attached to the lysine fragment via a linker.

[0031] Embodiment 14 relates to the conjugate of any one of Embodiments 1-13, or pharmaceutically acceptable salt thereof, wherein L comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36.

[0032] Embodiment 15 relates to the conjugate of Embodiment 14, or pharmaceutically acceptable salt thereof, wherein n = 14-36.

[0033] Embodiment 16 relates to the conjugate of any one of Embodiments 1-13, or pharmaceutically acceptable salt thereof, wherein L comprises an alkylamido fragment or an alkylamidoalkyl fragment.

[0034] Embodiment 17 relates to the conjugate of Embodiment 16, or pharmaceutically acceptable salt thereof, wherein the alkylamidoalkyl fragment comprises the fragment -CH2CH2C(O)N(H)(CH2CH2)- or the fragment -CH2CH2C(O)N(CH2CH2)2.

[0035] Embodiment 18 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula II wherein Ri and R2are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, Y is CH, and X is Cl.

[0036] Embodiment 19 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n = 0, Q is N, Y is CH, and X is Cl.

[0037] Embodiment 20 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein Ri is hydrogen, each R is hydrogen, n = 0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl.

[0038] Embodiment 21 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula II wherein Ri and R2arehydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl, Y is CH, and X is Cl.

[0039] Embodiment 22 relates to the conjugate of Embodiment 21, or pharmaceutically acceptable salt thereof, wherein the hydroxy Ci-Ce alkyl is hydroxy ethyl.

[0040] Embodiment 23 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl,R3, R4, and X are each hydrogen,

[0041] Embodiment 24 relates to the conjugate of any one of Embodiments 2 and 4-1716, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and Ri is methyl carbonyl.

[0042] Embodiment 25 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.

[0043] Embodiment 26 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n = 0, Q is N, Y is CH, and X is Cl.

[0044] Embodiment 27 relates to the conjugate of any one of Embodiments 2 and 4-17, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.

[0045] Embodiment 28 relates to a conjugate of the Formula IV:or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, wherein:T is a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell;LCL3are each, independently, a linker; and A1and A2are each a radical of an independently selected hapten.

[0046] Embodiment 29 relates to the conjugate of Embodiment 28, or pharmaceutically acceptable salt thereof, wherein T is Formula II or Formula III (where points of attachment toL are representedFormula II Formula III wherein: each R is independently hydrogen or a Ci-Ce alkyl; Ri is hydrogen, a Ci-Ce alkyl carbonyl,R2 is hydrogen or heterocyclyl alkyl;X is hydrogen or halogen; each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; orR3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with hydroxyl;P is CH2or NH; n is 0 or 1;Q is CH or N; andY is CH or N.

[0047] Embodiment 30 relates to the conjugate of Embodiment 28, or pharmaceutically acceptable salt thereof, wherein T comprises:group and the thioxothiazolidin-4-one is E or Z. In some embodiments, the bond between the tetrahydrofuranly group and the thioxothiazolidin-4-one is Z.

[0048] Embodiment 31 relates to the conjugate of any one of Embodiments 28-30, or pharmaceutically acceptable salt thereof, wherein L2and L3are bound to the same atom on L1.

[0049] Embodiment 32 relates to the conjugate of Embodiment 30, or pharmaceutically acceptable salt thereof, wherein the same atom is not a carbon atom.

[0050] Embodiment 33 relates to the conjugate of any one of Embodiments 28-30, or pharmaceutically acceptable salt thereof, wherein L2and L3bound to a different atom on L1.

[0051] Embodiment 34 relates to the conjugate of any one of Embodiments 28-33, or pharmaceutically acceptable salt thereof, wherein A1and A2are each independently selected from a rhamnose fragment, an a-galactosyl fragment, a dinitrophenyl fragment, and a trinitrophenyl fragment.

[0052] Embodiment 35 relates to the conjugate of any one of Embodiments 28-34, or pharmaceutically acceptable salt thereof, wherein A1is a rhamnose fragment.

[0053] Embodiment 36 relates to the conjugate of any one of Embodiments 28-34, or pharmaceutically acceptable salt thereof, wherein A1is a dinitrophenyl fragment or a trinitrophenyl fragment.

[0054] Embodiment 37 relates to the conjugate of any one of Embodiments 28-36, or pharmaceutically acceptable salt thereof, wherein each of L1, L2, and L3independently comprises a chain of atoms from 3 atoms to 60 atoms in length.

[0055] Embodiment 38 relates to the conjugate of any one of Embodiments 28-36, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises one or more peptide fragments.

[0056] Embodiment 39 relates to the conjugate of Embodiment 38, or pharmaceuticallyacceptable salt thereof, wherein L1, L2, or L3each, independently, comprises one or more lysine fragments.

[0057] Embodiment 40 relates to the conjugate of Embodiment 38, or pharmaceutically acceptable salt thereof, wherein L1comprises a lysine fragment of the formula:attached to the lysine fragment via L2.

[0058] Embodiment 41 relates to the conjugate of any one of Embodiments 28-40, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36.

[0059] Embodiment 42 relates to the conjugate of Embodiment 41, or pharmaceutically acceptable salt thereof, wherein n = 14-36.

[0060] Embodiment 43 relates to the conjugate of any one of Embodiments 28-41, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises an alkylamido fragment or an alkylamidoalkyl fragment.

[0061] Embodiment 44 relates to the conjugate of Embodiment 43, or pharmaceutically acceptable salt thereof, wherein the alkylamidoalkyl fragment comprises the fragment-CH2CH2C(O)N(H)(CH2CH2)- or the fragment -CH2CH2C(O)N(CH2CH2)2.

[0062] Embodiment 45 relates to the conjugate of any one of Embodiments 28-44, or pharmaceutically acceptable salt thereof, wherein L1comprises:

[0063] Embodiment 46 relates to the conjugate of Embodiment 45, or pharmaceutically acceptable salt thereof, wherein L2comprises:wherein p and q are each, independently, an integer from 0 to 20.

[0064] Embodiment 47 relates to the conjugate of Embodiments 45 or 46, or pharmaceutically acceptable salt thereof, wherein L3comprises:wherein d is an integer from 0 to 20.

[0065] Embodiment 48 relates to the conjugate any one of 28-47, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:wherein m, p, d, and q are each, independently, an integer from 0 to 20.

[0066] Embodiment 49 relates to the conjugate any one of 28-48, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:

[0067] Embodiment 50 relates to the conjugate of any one of Embodiments 28-44, or pharmaceutically acceptable salt thereof, wherein L1comprises:wherein m is an integer from 0 to 20.

[0068] Embodiment 51 relates to the conjugate of Embodiment 50, or pharmaceutically acceptable salt thereof, wherein L2comprises:1 - 1 1 wherein p and q are each, independently, an integer from 0 to 20.

[0069] Embodiment 52 relates to the conjugate of Embodiment 50 or 51, or pharmaceutically acceptable salt thereof, wherein L3comprises:wherein d is an integer from 0 to 20.

[0070] Embodiment 53 relates to the conjugate any one of 28-44, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:wherein m, p, d, and q are each, independently, an integer from 0 to 20.

[0071] Embodiment 54 relates to the conjugate any one of 28-44, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:

[0072] Embodiment 55 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl.

[0073] Embodiment 56 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n=0, Q is N, Y is CH, and X is Cl.

[0074] Embodiment 57 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein Ri is hydrogen, each R is hydrogen, n=0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, Y is CH, and X is Cl.

[0075] Embodiment 58 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl, Y is CH, and X is Cl.

[0076] Embodiment 59 relates to the conjugate of Embodiment 58, or pharmaceutically acceptable salt thereof, wherein the hydroxy Ci-Ce alkyl is hydroxy ethyl.

[0077] Embodiment 60 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen,

[0078] Embodiment 61 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and Ri is methyl carbonyl.

[0079] Embodiment 62 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.

[0080] Embodiment 63 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n=0, Q is N, Y is CH, and X is Cl.

[0081] Embodiment 64 relates to the conjugate any one of 28-54, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.

[0082] Embodiment 65 relates to a conjugate of the Formula IV:or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, wherein:T is a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell;LCL4are each, independently, a linker;A1and A2are each a radical of an independently selected hapten; andE1is T or a pharmacokinetic enhancer.

[0083] As used herein, the term “pharmacokinetic enhancer” refers to a pharmaceutically acceptable moiety or domain covalently linked (“conjugated” or “fused”) to the compounds described herein that prevents, delays or mitigates in vivo proteolytic degradation or other activity-diminishing chemical modification of the compounds described herein, increases half-life (serum half-life and / or therapeutic half-life), and / or improves or alters other pharmacokinetic or biophysical properties including but not limited to increasing the rate ofabsorption, reducing toxicity, improving solubility, reducing aggregation, increasing biological activity and / or target selectivity of the compounds described herein, and / or reducing immunogenicity of the compounds described herein, compared to a comparator such as a compound analogous to the compounds described herein lacking such an enhancer. Thus, for example, E1can be or comprise an albumin binder, such as:wherein R12-R21 are each independently selected from hydrogen, methyl, and fluorine. In other embodiments, E1can be or comprise a group of the formula:

[0084] Embodiment 66 relates to the conjugate of Embodiment 65, or pharmaceutically acceptable salt thereof, wherein T is Formula II or Formula III (where points of attachment toL are representedFormula II Formula III wherein: each R is independently hydrogen or a Ci-Ce alkyl; Ri is hydrogen, a Ci-Ce alkyl carbonyl,R2 is hydrogen or heterocyclyl alkyl;X is hydrogen or halogen; each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; orR3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with hydroxyl;P is CH2or NH; n is 0 or 1;Q is CH or N; andY is CH or N.

[0085] Embodiment 67 relates to the conjugate of Embodiment 65, or pharmaceutically acceptable salt thereof, wherein T comprises:, w ere n t e =~= etween the tetrahydrofuranly group and the thioxothiazolidin-4-one is E or Z. In some embodiments, the bond between the tetrahydrofuranly group and the thioxothiazolidin-4-one is Z.

[0086] Embodiment 68 relates to the conjugate any one of 65-67, or pharmaceutically acceptable salt thereof, wherein L2and L3are bound to the same atom on L1.

[0087] Embodiment 69 relates to the conjugate of Embodiment 68, or pharmaceutically acceptable salt thereof, wherein the same atom is not a carbon atom.

[0088] Embodiment 70 relates to the conjugate any one of 65-67, or pharmaceutically acceptable salt thereof, wherein L2and L3bound to a different atom on L1.

[0089] Embodiment 71 relates to the conjugate any one of 65-70, or pharmaceutically acceptable salt thereof, wherein A1and A2are each independently selected from a rhamnose fragment, an a-galactose fragment, a dinitrophenyl fragment, and a trinitrophenyl fragment.

[0090] Embodiment 72 relates to the conjugate any one of 64-69, or pharmaceutically acceptable salt thereof, wherein A1is a rhamnose fragment.

[0091] Embodiment 73 relates to the conjugate any one of 64-69, or pharmaceutically acceptable salt thereof, wherein A1is a dinitrophenyl fragment or a trinitrophenyl fragment.

[0092] Embodiment 74 relates to the conjugate any one of 65-73, or pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, and L4independently comprises a chain of atoms from 3 atoms to 60 atoms in length.

[0093] Embodiment 75 relates to the conjugate any one of 65-70, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises one or more peptide fragments.

[0094] Embodiment 76 relates to the conjugate of Embodiment 75, or pharmaceutically acceptable salt thereof, wherein L1, L2, L3or L4each, independently, comprises one or more lysine fragments.

[0095] Embodiment 77 relates to the conjugate of Embodiment 76, or pharmaceuticallyacceptable salt thereof, wherein L1comprises a lysine fragment of the formula:attached to the lysine fragment via L2.

[0096] Embodiment 78 relates to the conjugate any one of 65-77, or pharmaceutically acceptable salt thereof, wherein L1, L2, L3or L4each, independently, comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36.

[0097] Embodiment 79 relates to the conjugate of Embodiment 78, or pharmaceutically acceptable salt thereof, wherein n = 14-36.

[0098] Embodiment 80 relates to the conjugate any one of 65-77, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises an alkylamido fragment or an alkylamidoalkyl fragment.

[0099] Embodiment 81 relates to the conjugate any one of 65-80, or pharmaceutically acceptable salt thereof, wherein L1or L4comprises:wherein m is an integer from 0 to 20.

[0100] Embodiment 82 relates to the conjugate of Embodiment 81, or pharmaceutically acceptable salt thereof, wherein L2comprises:wherein p and q are each, independently, an integer from 0 to 20.

[0101] Embodiment 83 relates to the conjugate of Embodiment 81 or 82, or pharmaceutically acceptable salt thereof, wherein L3comprises:wherein d is an integer from 0 to 20.

[0102] Embodiment 84 relates to the conjugate of any one of Embodiments 65-83, orpharmaceutically acceptable salt thereof, wherein L4comprises

[0103] Embodiment 85 relates to the conjugate of any one of Embodiments 65-84, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:wherein m, p, and d are each, independently, an integer from 0 to 20.

[0104] Embodiment 86 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, Y is CH, and X is Cl.

[0105] Embodiment 87 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein Ri, R3, and R4 are hydrogen, each R is hydrogen, n=0, Q is N, Y is CH, and X is Cl.

[0106] Embodiment 88 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein Ri is hydrogen, each R is hydrogen, n=0, Q is N, R3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, Y is CH, and X is Cl.

[0107] Embodiment 89 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula II wherein Ri and R2 are hydrogen, R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, which is substituted with a hydroxy Ci-Ce alkyl, Y is CH, and X is Cl.

[0108] Embodiment 90 relates to the conjugate of Embodiment 89, or pharmaceutically acceptable salt thereof, wherein the hydroxy Ci-Ce alkyl is hydroxy ethyl.

[0109] Embodiment 91 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen,

[0110] Embodiment 92 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, R3, R4, and X are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and Ri is methyl carbonyl.

[0111] Embodiment 93 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is methyl, Ri, R3, and R4 are each hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.

[0112] Embodiment 94 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein each R is hydrogen, Ri, R3, and R4 are each hydrogen, n=0, Q is N, Y is CH, and X is Cl.

[0113] Embodiment 95 relates to the conjugate any one of 65-85, or pharmaceutically acceptable salt thereof, wherein T is Formula III wherein R3 and R4, together with the carbon atom to which they are attached, form a 6-membered aryl ring, each R is methyl, Ri is hydrogen, P is NH, n=l, Q is CH, Y is CH, and X is Cl.

[0114] Embodiment 96 relates to a conjugate of formula:or a pharmaceutically acceptable salt thereof.

[0115] Embodiment 97 relates to a pharmaceutical composition comprising a conjugate of any one of Embodiments 1-96 and a pharmaceutically acceptable excipient.

[0116] Embodiment 98 relates to the pharmaceutical composition of Embodiment 97 formulated for oral administration.

[0117] Embodiment 99 relates to the pharmaceutical composition of Embodiment 97 formulated for subcutaneous or intravenous administration.

[0118] Embodiment 100 relates to the pharmaceutical composition of Embodiment 97 formulated for oral administration.

[0119] Embodiment 101 relates to a method of treating a Flavivirus infection in a subject comprising administering to the subject an effective amount of the conjugate of any one of Embodiments 1-96 or the pharmaceutical composition of any one of Embodiments 97-100.

[0120] Embodiment 102 relates to the method of Embodiment 101, or pharmaceutically acceptable salt thereof, wherein the Flavivirus is Dengue virus serotype 1, 2, 3 or 4, Yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), or Zika virus.

[0121] Embodiment 103 relates to a method of preparing a compound for targeting to an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell, which method comprises attaching the ligand:whereupon the compound is prepared for targeting to the E protein.EXAMPLESThe following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention in any way.LIST OF ABBREVIATIONSExample 1: Synthesis of Compound 1(S)-2-(3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanamido)-6-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamideSynthesis of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline (1)Synthesis of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline was done following the known synthetic procedure reported in Antimicrobial Agents and Chemotherapy (2009), 53(5), 1823-1831.Synthesis of tert-butyl 3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoate (3)To a solution of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline (1, 0.220 g, 0.616 mmol) in DMSO (10 mL), tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propionate (2, BLDPharma, 0.216 g, 0.924 mmol) and tri ethylamine (GLR, 257 pL, 3 eq., 1.85 mmol) were added and the reaction mixture was stirred at 80 °C for 16 h. Progress of the reaction was monitored by TLC. After completion, reaction mixture was diluted with ice water and extracted with EtOAc. The organic layer was washed with ice water (three times) and thecombined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to get crude. Crude was purified by silica gel column chromatography using 2-5% methanol / dichloromethane as eluent to afford tert-butyl 3-(2-(2-((4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoate (3) as a yellow semi-solid. Yield: 0.240 g, 64 %. LC-MS (ESI) m / z 554.4 [M+l]+.Synthesis of 3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoic acid (4)To a solution of tert-butyl 3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoate (3, 0.240 g, 0.433 mmol) in DCM (4 mL) maintained at 0° C was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at 0° C - room temperature for 6 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated and dried to afford 3-(2-(2-((4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoic acid (4) as yellow solid. Yield: 0.210 g, 97 %. LC-MS (ESI) m / z 498.2 [M+l]+.Synthesis of (2R,3R,4R,5S,6S)-2-(((S)-24-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin- 2-yl)amino)-14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16-dioxo- 3,6,9,19,22-pentaoxa-12,15-diazatetracosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (6)To a solution of 3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoic acid (4, 0.2 g, 0.402 mmol) in N,N-dimethylformamide (3.0 mL), were added 2-methyl-2,6,8-triaza-6,7-decadiene — hydrogen chloride (1 / 1) (0.154 g, 0.803 mmol) and lH-l,2,3-benzotriazol-l-ol (0.081 g, 0.602 mmol). The reaction mixture was stirred at RT for 30 min., (2R,3R,4R,5S,6S)-2-(((S)-14-amino-25-((2,4- dinitrophenyl)amino)-13,20-dioxo-3,6,9,23-tetraoxa-12,19-diazapentacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (5. 0.351 g, 0.402 mmol) and N-ethyl- bis(isopropyl)amine (0.350 mL, 2.01 mmol) ware added at 0° C. The reaction mixture was stirred at RT for 12 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SC>4 and concentrated under reduced pressure to get crude. Crude was purified by column chromatography using 50-70% EtOAc / Heptane as eluent to afford (2R,3R,4R,5S,6S)-2-(((S)-24-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)- 14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16-dioxo-3,6,9,19,22-pentaoxa-12,15-diazatetracosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (6) as sticky yellow . Yield: 0.170 g, 31.24 %. LC-MS (ESI) m / z 1354.45 [M+l]+.Synthesis of (S)-2-(3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanamido)-6-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide (Compound 1)To a solution of (2R,3R,4R,5S,6S)-2-(((S)-24-((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16-dioxo-3 ,6,9, 19,22-pentaoxa- 12, 15- diazatetracosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (6, 0.110 g, 0.081 mmol) in methanol (4 mL), 25% w / v sodium methoxide solution in methanol (35.1 pL, 0.162 mmol) was added at 0° C. The reaction mixture was stirred at RT for 1 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with Dowex H+(pH=5), filter through sintered funnel. The filtrate was concentrated and dried to get the crude which was purified with prep-HPLC using ACN: H2O buffered with with 0.1% TFAto afford (S)-2-(3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanamido)-6-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide (Compound 1) as yellow solid. Yield: 0.044 g, 44%. LC-MS (ESI) m / z 1228.9 [M+l]+.JH NMR (400 MHz, DMSO-t / 6): 6 8.82-8.79 (m, 2H), 8.28 (d, J= 8.6 Hz, 1H), 8.22 (dd, J = 2.48 Hz, 9.44 Hz, 1H), 7.96-7.88 (m, 3H), 7.82-7.76 (m, 3H), 7.73-7.69 (m, 2H), 7.54 (d, J = 8.4 Hz, 3H), 7.29-7.20 (m, 3H), 4.72 (t, J= 5.64 Hz, 2H), 4.54 (d, J= 7.04 Hz, 2H), 4.19 (m, 1H), 3.64-3.32 (m, 35H), 3.19-3.15 (m, 3H), 2.96-2.94 (m, 2H), 2.39-2.27 (m, 4H), 1.32-1.30 (m, 1H), 1.23-1.18 (m, 5H), 1.12 (d, J= 6.16 Hz, 3H).Example 2: Synthesis of Compound 24-(5-(4-chlorophenyl)thiophen-2-yl)-N-(pyridin-3-ylmethyl)quinazolin-2-amine (Compound2)Synthesis of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline (1)Synthesis of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline was done following the literature reported procedure in Antimicrobial Agents and Chemotherapy (2009), 53(5), 1823-1831.Synthesis of 4-(5-(4-chlorophenyl)thiophen-2-yl)-N-(pyridin-3-ylmethyl)quinazolin-2-amine (Compound 2)To a solution of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline (1, 0.20 g, 0.308 mmol) and [(3-pyridyl)methyl]amine (2, Spectrochem, 0.083 g, 0.770 mmol) in DMSO (5 mL), triethylamine (111 pL, 0.770 mmol) was added. The reaction mixture was stirred at 80°C for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice water and extracted with EtOAc. The organic layer was washed with ice water (three times) and combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to get crude. The crude was purified by silica gel column chromatography using 0-2% methanol / dichloromethane as eluent to afford 4-(5-(4- chl orophenyl)thi ophen-2 -yl)-N-(pyri din-3 -ylmethyl)quinazolin-2-amine (Compound 2) asyellow solid. Yield: 0.090 g, 68 %. LC-MS (ESI) m / z 429.05 [M+l]+. 'HNMR (400 MHz, DMSO-t / e): 6 8.66 (d, J= 1.6 Hz, 1H), 8.44-8.82 (dd, J= 1.64 Hz, 4.76 Hz, 1H), 8.31 (d, J = 8.08 Hz, 1H), 8.02-7.99 (m, 2H), 7.83-7.81 (m, 3H), 7.76-7.72 (m, 2H) 7.57-7.54 (m, 3H), 7.36-7.34 (m, 2H), 4.65 (d, J= 6.24 Hz, 2H).Example 3: Synthesis of Compound 5(E)-2-(benzofuran-2-yl)-N-(4-(((S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16-dioxo-l-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9-trioxa-12,15-diazanonadecan-19- yl)oxy)-3-(trifluoromethyl)phenyl)-2-oxoacetohydrazonoyl cyanide (Compound 5)Synthesis of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenoxy)butanoate (A-3)In a 30 mL reaction vial, l-fluoro-4-nitro-2-(trifluoromethyl)benzene (CombiBlock, 0.1 g, 433 pmol), tert-butyl 4-hydroxybutanoate (Angene, 105 mg, 1.5 eq., 655 pmol) andDipotassium carbonate (TCI chemicals, 135 mg, 2.3 eq., 974 pmol) were dissolved in dimethylformamide (5 mL, 64.6 mmol). The resultant mixture was stirred for 18 h at 95° C. The reaction mixture was quenched with NH4CI and extracted with EtOAc (3 xl5 mL). The combined organic layer was then washed with water, brine and dried over sodium sulfate. The combined organic layer was filtered and concentrated under vacuo to afford a dark green sticky solid. This was further purified using flash column chromatography using EtOAc / Heptane eluent mixture to afford tert-butyl 4-(4-nitro-2- (trifluoromethyl)phenoxy)butanoate (A-3) as a white solid. Yield: 114 mg, 75%; LC-MS (ESI) m / z = 407.95 [M+OAc]’.Synthesis of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenoxy)butanoate (A-4)In a 50 mL flask, palladium (10% on C) (GLR, 622 mg, 3 eq., 5.84 mmol) was added under an inert atmosphere. The flask was evacuated three times and backfilled with N2. Subsequently, tert-butyl 4-[4-nitro-2-(trifluoromethyl)phenoxy]butyrate (680 mg, 1.95 mmol) dissolved in methanol (16.5 mL, 406 mmol) was added to the reaction vessel dropwise. Subsequently, the flask was evacuated, backfilled with hydrogen gas (in a latex rubber bladder) and left to stir at RT for 16h. The reaction was monitored to completion by TLC. Upon completion, the reaction mixture was filtered over a pad of celite in a sintered funnel (50 mL), the celite was thoroughly washed with MeOH (3 x 15 mL). The combined filtrate was then concentrated under vacuo to obtain a pale-yellow liquid crude. The crude liquid containing tert-butyl 4- (4-amino-2-(trifluoromethyl)phenoxy)butanoate (A-4) was used as such for the next step without further purification. Yield: 580 mg, 93 %.JH NMR (400 MHz, CDCh): 8 7.03 (bs, 1H), 6.95 - 6.86 (m, 2H), 4.03 (t, J = 6.0 Hz, 2H), 2.46 (t, J = 6.0 Hz, 2H), 2.07-2.05 (m, 2H), 1.48 (s, 9H).Synthesis of tert-butyl (E)-4-(4-(2-(2-(benzofuran-2-yl)-l-cyano-2- oxoethylidene)hydrazineyl)-2-(trifluoromethyl)phenoxy)butanoate (A-6)To a solution of tert-butyl 4-(4-amino-2-(trifluoromethyl)phenoxy)butanoate (140 mg, 438 pmol) in 6 N hydrochloric acid (JDH chemicals, 4 mL) was added dropwise a solution of sodium nitrite (36.3 mg, 1.2 eq., 526 pmol) in water (1 mL) at 0 °C. After stirring at room temperature for 30 min, a mixture of sodium acetate (50 mg, 610 pmol) and 3-(l-benzofuran-2-yl)-3-oxopropiononitrile (BLD Pharma, 89.3 mg, 482 pmol) in 1,4-di oxane (2 mL) was added to the reaction mixture. After stirringfor 48h, the reaction mixture was diluted with EtOAc and washed with sat. NaHCCh and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using EtOAc / Heptane eluent system to afford the desired product tert-butyl (E)-4-(4-(2-(2- (benzofuran-2-yl)- 1 -cyano-2-oxoethylidene)hydrazineyl)-2- (trifluoromethyl)phenoxy)butanoate (A-6) as an orange solid. Yield: 45 mg, 20 %. LC-MS (ESI) m / z = 513.90 [M-l]’.Synthesis of (E)-4-(4-(2-(2-(benzofuran-2-yl)-l-cyano-2-oxoethylidene)hydrazineyl)-2- (trifluoromethyl)phenoxy)butanoic acid (A-7)In a 25 mL flask, tert-butyl (E)-4-(4-(2-(2-(benzofuran-2-yl)-l-cyano-2- oxoethylidene)hydrazineyl)-2-(trifluoromethyl)phenoxy)butanoate (40 mg, 77.6 pmol) was dissolved in dichloromethane (5 mL, 78.1 mmol). To this solution, trifluoroacetic acid (TCI chemicals, 0.2 mL, 2.6 mmol) was added dropwise at 0 °C. Subsequently, the reaction mixture was allowed to stir at RT for 4h. Upon completion, the reaction mixture was concentrated in vacuo to dryness. The crude orange solid containing the desired product (E)- 4-(4-(2-(2-(benzofuran-2-yl)-l-cyano-2-oxoethylidene)hydrazineyl)-2- (trifluoromethyl)phenoxy)butanoic acid (A-7) was then used for next steps without further purification. Yield: 35 mg, 97 %. LC-MS (ESI) m / z 460.0 = [M+l]+.Synthesis of (2R,3R,4R,6S)-2-((14-(4-(4-(2-((E)-2-(benzofuran-2-yl)-l-cyano-2- oxoethylidene)hydrazineyl)-2-(trifluoromethyl)phenoxy)butanamido)-25-((2,4- dinitrophenyl)amino)-13,20-dioxo-3,6,9,23-tetraoxa-12,19-diazapentacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (A-9)In a 25 mL flask, (E)-4-(4-(2-(2-(benzofuran-2-yl)-l-cyano-2- oxoethylidene)hydrazineyl)-2-(trifluoromethyl)phenoxy)butanoic acid (35 mg, 73.9 pmol) was dissolved in 2 mL of DMF. To this solution, l,l,3,3-tetramethyl-2-(3H-l,2,3,4- tetraazainden-3-yl)-3 -isoureaium hexafluoridophosphate(l-) (GLR, 42.2 mg, 1.5 eq., Il l pmol) and (2R,3R,4R,6S)-4,5-diacetoxy-2-[2-(2-{2-[2-(l-amino-5-{3-[2-(2,4- dinitrophenylamino)ethoxy]propionylamino}pentylcarbonylamino)ethoxy]ethoxy}ethoxy)eth oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate (64.7 mg, 73.9 pmol) were added and the resultant mixture was allowed to stir at 0 °C for 15 min. Subsequently, N- ethylbis(isopropyl)amine (GLR, 0.3 mL, 3 eq., 222 pmol) was added to the mixture dropwise and the reaction pH was set between 9-10. The resultant mixture was allowed to stir at RT tillcompletion (TLC control). Subsequently, the mixture was washed with water (2 x 10 mL), brine and dried over sodium sulfate. The combined organic layers were concentrated, and the crude residue was purified by flash chromatography (SiO2) to afford the product (2R,3R,4R,6S)-2-((14-(4-(4-(2-((E)-2-(benzofuran-2-yl)-l-cyano- 2-oxoethylidene)hydrazineyl)-2-(trifluoromethyl)phenoxy)butanamido)-25-((2,4- dinitrophenyl)amino)-13,20-dioxo-3,6,9,23-tetraoxa-12,19-diazapentacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (A-9) as a yellow solid. Yield: 30 mg, 31 %. LC-MS (ESI) m / z = 1316.10 [M+l]+.(E)-2-(benzofuran-2-yl)-N-(4-(((S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16-dioxo-l-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9-trioxa-12,15-diazanonadecan-19- yl)oxy)-3-(trifluoromethyl)phenyl)-2-oxoacetohydrazonoyl cyanide (Compound 5) In a 10 mL flask, product (2R,3R,4R,6S)-2-((14-(4-(4-(2-((E)-2-(benzofuran- 2-yl)- 1 -cyano-2-oxoethylidene)hydrazineyl)-2- (trifluoromethyl)phenoxy)butanamido)-25-((2,4-dinitrophenyl)amino)-13,20-dioxo- 3,6,9,23-tetraoxa-12,19-diazapentacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5- triyl triacetate (65 mg, 49.4 pmol) was dissolved in 5 mL of MeOH. To this mixture, 0.5 mL of 5% (w / w) NaOH solution in water was added dropwise to set the pH of the solution between 9-11. The resultant clear yellow solution was then stirred at RT for 30 min under TLC control. Upon completion, the mixture was diluted with 50 mL of water and lyophilized. The lyophilized crude yellow solid was then purified by reverse phase HPLC using a ACN / water buffer with 0.1% TFA as a elution gradient to afford (E)-2-(benzofuran-2-yl)-N-(4-((14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16-dioxo- 1 -(((2R,3R,4R, 5R,6S)- 3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9-trioxa-12,15- diazanonadecan-19-yl)oxy)-3-(trifluoromethyl)phenyl)-2-oxoacetohydrazonoyl cyanide (Compounds 5) as a bright yellow solid. Yield: 10 mg, 18 %. LC-MS (ESI) m / z = 1190.5 [M+l]+. 'HNMR (400 MHz, CDCh): 6 8.82-8.79 (m, 2H), 8.21 (dd, J= 9.5 Hz, J= 2.8 Hz, 1H), 7.96-7.92 (m, 3H), 7.86-7.84 (m, 2H), 7.79-7.72 (m, 3H), 7.55 (t, J= 7.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.22 (d, J= 9.7 Hz, 1H), 4.80-4.50 (m, 4H), 4.23-4.10 (m, 4H), 3.68-2.90 (m, 38H), 2.49-2.33 (m, 6H), 1.95 (m, 3H), 1.61- 1.11 (m, 12H).Example 4: Synthesis of Compound 10(S)-6-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)-2-(3-(2-(2-(4-((Z)-5-((5-(l- fluoro-4-hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin-3- yl)butanamido)ethoxy)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide(Compound 10)Synthesis of l-(benzyloxy)-4-fluoronaphthalene (B-2)In a 100 mL flask, 2g of 4-fluoronaphthalen-l-ol (BLD Pharma, 1 g, 6.17 mmol), benzyl bromide (Spectrochem, 949 mg, 5.55 mmol), K2CO3 (TCI, 1.28 g, 9.25 mmol) were suspended in dry acetonitrile (20 mL). This mixture was then refluxed at 80 °C for 2h. Upon completion, the reaction mixture was filtered through a pad of celite. The filtrate was then evaporated to dryness to obtain a pink crude liquid. The crude liquid was then diluted with 150 mL of 10% EtOAc / Heptanes, washed with water, IN NaOH and brine. The combined organic layers were then passed through a l” pad of silica gel. The elute was collected and evaporated to obtain the desired product l-(benzyloxy)-4-fluoronaphthalene (B-2). Yield: 1.25 g, 72 %. 'H NMR (400 MHz, DMSO-t / 6): 6 8.24 (d, J = 8.12 Hz, 1H), 8.01 (d, J = 8.12 Hz, 1H), 7.65 (m, 2H), 7.56 (m, 2H), 7.44 (m, 2H), 7.37 (m, 1H), 7.26 (m, 1H), 7.02 (dd, J = 8.44 Hz, J = 4.00 Hz, 2H), 5.30 (s, 2H).Synthesis of (4-(benzyloxy)-l -fluoronaphthal en-2-yl)boronic acid (B-3)In a 50 mL flask, 2,2,6,6-Tetramethylpiperidine (Chempure, 672 mg, 4.76 mmol) was dissolved in dry THF under an inert, dry atmosphere and stirred at -40 °C for 5 min. To this solution, n-BuLi (Hychem, 279 mg, 4.36 mmol) was added dropwise and the resultant mixture was stirred at -40 °C for Ih. Subsequently, the reaction mixture was cooled to -78 °C, triisopropyl borate (Avra, 745 mg, 3.96 mmol) was added and the mixture was stirred at -78 °C for 30 min. Compound l-(benzyloxy)-4-fluoronaphthalene (500 mg, 1.98 mmol) was dissolved in dry THF was then added to the reaction mixture dropwise at -78 °C and the reaction mixture was then stirred at 0 °C for 8h. Upon completion, the reaction mixture was quenched IN HC1 and allowed to stir at rt for Ih. Next, the reaction mixture was diluted with DCM, washed with water and brine. The combined organic layers were then evaporated to obtain a pale yellow residue. The residue was further purified using column chromatography using DCM / MeOH eluents to obtain the desired product (4-(benzyloxy)-l -fluoronaphthal en-2-yl)boronic acid (B- 3) as a colorless solid. Yield: 325 mg, 51 %. LC-MS (ESI) m / z = 355 [M + OAc]'.Synthesis of 5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2-carbaldehy de (B-5)In a 30 mL vial, compound (4-(benzyloxy)-l -fluoronaphthal en-2-yl)boronic acid (1 g, 3.2 mmol), 5-bromo-furan-2 carbaldehyde (TCI, 1.06 g, 6.1 mmol), potassium carbonate (TCI, 1.77 g, 12.8 mmol) were dissolved in 12 mL of Dioxane / Water (4: 1 v / v). The resultant solution was then sparged with N2 gas for 10 min. Subsequently, Pd(dppf)C12*DCM (Johnson Matthey, 230 mg, 320 pmol) was added to the reaction mixture under an inert atmosphere and the vial was sealed and stirred at 90 °C for 3h. Upon completion, the reaction mixture was filteredthrough a pad of celite, the filtrate evaporated to dryness to obtain a crude black residue. The crude residue was then purified using column chromatography using DCM / MeOH eluents to obtain the desired product 5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2-carbaldehy de (B-5) as pale yellow solid. Yield: 550 mg g, 41 %. LC-MS (ESI) m / z = 347.10 [M+l]+.Synthesis of (Z)-4-(5-((5-(4-(benzyloxy)-l-fluoronaphthalen-2-yl)furan-2-yl)methylene)-4- oxo-2-thioxothiazolidin-3-yl)butanoic acid (B-7)In a 100 mL flask, 5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2-carbaldehy de (601 mg, 1.58 mmol), 4-(4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (Angene, 315 mg, 1.44 mmol) were suspended in EtOH (10 mL) and refluxed at 85 °C till solution turns a clear yellow. To this refluxing solution, 3 drops of Piperidine (GLR) were added and the resultant solution was refluxed at 85 °C for Ih. Upon completion (TLC control), the reaction mixture was cooled down which led to the precipitation of an orange solid. The orange solid was then filtered, washed with cold water, 5 mL of IN HC1 and 10 ml of cold EtOH. The residue was air dried till a firm, free-flowing solid formed. The resultant orange solid containing the desired product (Z)-4-(5-((5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2 -yl)methyl ene)-4-oxo-2- thioxothiazolidin-3-yl)butanoic acid (B-7) was used as such for further reactions. Yield: 730 mg, 93 %. LC-MS (ESI) m / z 548.0 = [M+l]+.Synthesis of tert-butyl (Z)-3-(2-(2-(4-(5-((5-(4-(benzyloxy)-l-fluoronaphthalen-2-yl)furan-2- yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanamido)ethoxy)ethoxy)propanoate (B-9)To a solution of (Z)-4-(5-((5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2- yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (350 mg, 0.639 mmol ) and tertbutyl 3-(2-(2-aminoethoxy)ethoxy)propanoate (BLD, 224 mg, 0.959 mmol) in N,N- dimethylformamide (8 mL), PyBOP (GLR, 499 mg, 0.959 mmol) was added and left to stir at 0 °C for 15 mins. To this solution, N-ethylbis(isopropyl)amine (GLR, 330 mg, 2.56 mmol) was added at 0°C, the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, reaction mixture was diluted with ice water and extracted with DCM, the organic layer was dried over Na2SC>4 and concentrated under reduced pressure to get crude. Crude was purified by column chromatography using 5-7.5% methanol / dichloromethane as eluent to afford tert-butyl (Z)-3- (2-(2-(4-(5-((5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2-yl)methylene)-4-oxo-2- thioxothiazolidin-3-yl)butanamido)ethoxy)ethoxy)propanoate (B-9) as a orange solid. Yield: 550 mg, 95%. LC-MS (ESI) m / z = 763.0 [M+l]+.Synthesis of (Z)-3-(2-(2-(4-(5-((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2- yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanamido)ethoxy)ethoxy)propanoic acid (B- 10)In a 50 mL flask, under an inert atmosphere tert-butyl (Z)-3-(2-(2-(4-(5-((5-(4- (benzyloxy)-l-fluoronaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin-3 - yl)butanamido)ethoxy)ethoxy)propanoate (300 mg, 0.393 mmol) was dissolved in DCM (10 mL) and stirred at -78 °C for 10 mins. To this solution, BCh (Spectrochem, 230 mg, 1.97 mmol) was added dropwise and stirred at -78 °C for 2h. Upon completion, the reaction mixture was quenched with water and the resultant mixture was stirred at rt for Ih. The mixture was then diluted with DCM, washed with water and brine. The combined organic layers were dried over sodium sulfate and evaporated to obtain a crude red residue. The crude was further purified using DCM / THF (98:2 v / v) and MeOH / EtiN (99: 1 v / v) as eluents to obtain the desired product (Z)-3-(2-(2-(4-(5-((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2- thioxothiazolidin-3-yl)butanamido)ethoxy)ethoxy)propanoic acid (B-10) as dark red solid. Yield: 0.310 g, 79 %. LC-MS (ESI) m / z = 617.0 [M+l]+.Synthesis of (2R,3R,4R,5S,6S)-2-(((S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-29-((Z)-5-((5-(l-fluoro-4- hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin-3 -yl)- 13, 16, 26- trioxo-3,6,9,19,22-pentaoxa-12,15,25-triazanonacosyl)oxy)-6-methyltetrahydro-2H-pyran- 3 ,4,5-triyl triacetate (B-12)To a solution of (Z)-3-(2-(2-(4-(5-((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2- yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanamido)ethoxy)ethoxy)propanoic acid (0.144 g, 163 p) and (2R,3R,4R,5S,6S)-2-(((S)-14-amino-25-((2,4-dinitrophenyl)amino)- 13,20-dioxo-3,6,9,23-tetraoxa-12,19-diazapentacosyl)oxy)-6-methyltetrahydro-2H-pyran- 3 ,4, 5-triyl triacetate (130 mg, 149 p) in N,N-dimethylformamide (Acros, 5 mL), PyBOP (GLR, 116 mg, 223 pmol)was added and left to stir at 0 °C for 15 mins. To this solution, N- ethylbis(isopropyl)amine (GLR, 78 mg, 594 pmol) was added at 0°C, the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS, After completion, reaction mixture was diluted with ice water and extracted with DCM, the organic layer was dried over Na2SC>4 and concentrated under reduced pressure afforded a red crude solid. The crude solid was purified by column chromatography using 5-7.5% methanol / di chloromethane as eluent to afford the desired product (2R,3R,4R,5S,6S)-2-(((S)-14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-29-((Z)-5-((5-(l-fluoro-4- hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin-3 -yl)- 13, 16, 26- trioxo-3,6,9,19,22-pentaoxa-12,15,25-triazanonacosyl)oxy)-6-methyltetrahydro-2H-pyran- 3 ,4,5-triyl triacetate (B-12) as a red liquid. Yield: 0.290 g, 53 %. LC-MS (ESI) m / z = 1472.95 [M+l]+Synthesis of (S)-6-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)-2-(3-(2-(2-(4-((Z)- 5-((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin- 3-yl)butanamido)ethoxy)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide (Compound 10)To a solution of compound (2R,3R,4R,5S,6S)-2-(((S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-29-((Z)-5-((5-(l-fluoro-4- hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin-3 -yl)- 13, 16, 26- trioxo-3,6,9,19,22-pentaoxa-12,15,25-triazanonacosyl)oxy)-6-methyltetrahydro-2H-pyran- 3,4,5-triyl triacetate (200 mg, 136 pmol) in methanol (3 mL), sodium methoxide (Spectrochem, 36.7 mg, 679 pmol) was added dropwise and the pH of the solution was set between 9-10. The resultant mixture was stirred at rt for 2h. Upon completion, the reaction mixture was neutralized to pH= 7 using Amberlite™ IRC 120 H, hydrogen form (Merck) and filtered. The filtrate was evaporated under vacuo to obtain a crude red solid. The crude red solid was purified by reversephase HPLC using ACN / Water eluents and the fractions were lyophilized to obtain the desired compound (S)-6-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)-2-(3-(2-(2-(4-((Z)-5- ((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothi azolidin-3- yl)butanamido)ethoxy)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide (Compound 10) as a red solid. Yield: 16 mg, 99 %. LC-MS (ESI) m / z 1347.35 [M+l]+. 'H NMR (400 MHz, DMSO-t / e): 6 10.82 (s, 1H), 8.83-8.81 (m, 2H), 8.21 (dd, J= 9.5 Hz, J= 2.7 Hz, 1H), 8.17 (d, J= 8.5 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.94-7.91 (m, 3H), 7.79 (t, J= 5.5 Hz, 1H), 7.71 (s, 1H), 7.67 (m, 1H), 7.61 (m, 1H), 7.45 (d, J= 3.8 Hz, 1H), 7.33 (d, J= 5.9 Hz, 1H), 7.26 (t, J= 3.4 Hz, 1H), 7.23 (d, J= 9.6 Hz, 1H), 4.74 (t, J= 4.3 Hz, 2H), 4.56-4.55 (m, 2H), 4.21-4.16 (m, 1H), 4.06 (t, J= 7.2 Hz, 2H), 3.65-3.55 (m, 11H), 3.52-3.41 (m, 16H), 3.38- 3.28 (m, 6H), 3.23-3.13 (m, 5H), 2.96-2.95 (m, 2H), 2.38-2.27 (m, 4H), 2.15 (t, J= 7.6 Hz, 2H), 1.90-1.11 (m, 12H) ppm.19F NMR (400 MHz, DMSO-t / e): -132.29 ppm.Example 5: Synthesis of Compound 12 l-((4-(5-(4-chlorophenyl)thi ophen-2 -yl)quinazolin-2-yl)amino)-27-(26-((4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)- N-(25-((2,4-dinitrophenyl)amino)-13,20-dioxo-l-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6- methyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,6, 9,23 -tetraoxa- 12,19 - di azapentacosan- 14-yl)-3,6,9,12,15,18,21,24,30,33,36-undecaoxa-27-azanonatriacontan-39-amide (Compound 12)Synthesis of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (C-2)To the stirred solution of methyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (BLD Pharm, C-l, 0.5 g, 2.12 mmol) in dichloromethane (8.0 mL), triethylamine (0.92 mL, 6.36 mmol) was added at 0°C. After 10 minutes, -toluenesulfonyl chloride (0.60 g, 3.17 mmol) was added pinch wise to the reaction mixture at the same temperature and the reaction mixture was stirred at room temperature for next 12 h. Progress of the reaction was monitored by LCMS and after completion, the reaction mixture was concentrated under reduced pressure to get crude. The crude was further purified by silica gel column chromatography eluting in 5% MeOH / DCM to afford methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (C-2) as a yellowish liquid. Yield: 0.55 g, 66.56 %; LCMS m / z 408.75 [M+NH4]+.Synthesis of methyl 32-(2,2-dimethyl-4-oxo-3,8,ll,14,17,20,23,26,29-nonaoxa-5- azahentriacontan-31 -yl)-2,2-dimethyl-4-oxo-3 ,8, 11,1 ,17,20,23 ,26,29,35,38,41 -dodecaoxa- 5,32-diazatetratetracontan-44-oate (C-4)To the stirred solution of di-tert-butyl (3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51- hexadecaoxa-27-azatripentacontane-l,53-diyl)dicarbamate (Broad Pharm, 3, 0.20 g, 0.20 mmol) in dimethyl formamide (5.0 mL), triethylamine (0.08 mL, 0.60 mmol) was added at ambient temperature. After 10 mins, methyl 3-(2-(2-(2- (tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (C-2, 0.38 g, 1.0 mmol) was added to the reaction mixture and the reaction mixture was stirred at 60°C for 16 h. Completion of the reaction was monitored by TLC and ELSD-LCMS. After completion, the reaction mixture was evaporated to dryness to get crude. The crude was further purified by silica gel column chromatography eluting in 5% MeOH / DCM to afford methyl 32-(2,2-dimethyl-4-oxo-3,8,ll,14,17,20,23,26,29-nonaoxa-5-azahentriacontan-31-yl)-2,2-dimethyl-4-oxo- 3,8,ll,14,17,20,23,26,29,35,38,41-dodecaoxa-5,32-diazatetratetracontan-44-oate (C-4) as a pale yellow viscous liquid. Yield: (0.16 g, 65.7 %); LCMS (ELSD) m / z 1226.65 [M+H]+.Synthesis of methyl l-amino-27-(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosyl)- 3,6,9,12,15,18,21,24,30,33,36-undecaoxa-27-azanonatriacontan-39-oate (C-5)To the stirred solution of 32-(2,2-dimethyl-4-oxo-3,8,ll,14,17,20,23,26,29-nonaoxa-5- azahentriacontan-31 -yl)-2,2-dimethyl-4-oxo-3 ,8, 11,14,17,20,23 ,26,29,35,38,41 -dodecaoxa- 5,32-diazatetratetracontan-44-oate (C-4, 0.10 g, 0.08 mmol) in anhydrous dichloromethane (TCI, 5.0 mL), trifluoroacetic acid (GLR, 3.0 mL) was added at 0°C and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by LCMS. After completion, solvent was concentrated and dried under reduced pressure to get methyl 1-amino-27-(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosyl)-3,6,9,12,15,18,21,24,30,33,36- undecaoxa-27-azanonatriacontan-39-oate (C-5) as a light yellowish liquid which was used for the next reaction. Yield: 0.08 g, Crude; LCMS (ESI) m / z 1026.10 [M+H]+.Synthesis of methyl l-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-27-(26- ((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24- octaoxahexacosyl)-3 ,6,9, 12,15,18,21 ,24,30,33 ,36-undecaoxa-27-azanonatriacontan-39-oate (C-7)To the stirred solution of methyl l-amino-27-(26-amino-3,6,9,12,15,18,21,24- octaoxahexacosyl)-3,6,9,12,15,18,21,24,30,33,36-undecaoxa-27-azanonatriacontan-39-oate (C-5, 0.07 g, 0.07 mmol) in anhydrous dimethyl sulfoxide (TCI, 2.0 mL), 2-chloro-4-(5-(4- chlorophenyl)thiophen-2-yl)quinazoline (C-6, 0.05 g, 0.14 mmol) and potassium carbonate (TCI, 0.047 g, 0.34 mmol) were added at 0°C and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was evaporated to dryness under reduced pressure to get crude material methyl l-((4-(5-(4-chlorophenyl)thi ophen-2 -yl)quinazolin-2-yl)amino)-27-(26-((4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)- 3,6,9,12,15,18,21,24,30,33,36-undecaoxa-27-azanonatriacontan-39-oate (C-7) as a light yellowish solid which was used for the next reaction without further purification. Yield: 0.09 g, Crude; LCMS m / z 1668.10 [M+H]+.Synthesis of (2R,3R,4R,6S)-2-((l-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)-27-(26-((4-(5-(4-chlorophenyl)thi ophen-2 -yl)quinazolin-2-yl)amino)- 3,6,9,12,15,18,21 ,24-octaoxahexacosyl)-41 -(4-(3 -(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-39,42-dioxo- 3,6,9,12,15,18,21,24,30,33,36,46,49,52-tetradecaoxa-27,40,43-triazatetrapentacontan-54- yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (C-9)To the stirred solution of methyl l-((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-27-(26-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)-3,6,9,12,15,18,21,24,30,33,36- undecaoxa-27-azanonatriacontan-39-oate (C-7, 0.08 g, 0.05 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL), was added solution of sodium hydroxide (0.05 mL) [prepared by dissolving 0.58 gm of sodium hydroxide in water (14.5 mL)] at ambient temperature over a period of 5 mins to adjust the pH=12. Homogeneous mass wasobserved and stirred for 4 h at that temperature. The completion of the reaction was confirmed by TLC and LCMS. After that, pH of the reaction mass was slowly adjusted to 7, by using Dowex 50XW8 (H+) resin. The reaction mass was filtered through sintered funnel. The organic layer was evaporated to dryness to get crude (0.06 g) which was used for the next step. To the stirred solution of the crude (0.06 g, 0.036 mmol) and (2R,3R,4R,5S,6S)-2-((43-((2,4- dinitrophenyl)amino)-13,38-dioxo-3,6,9,16,19,22,28,31,34,41-decaoxa-12,25,37- triazatritetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (C-8, 0.035 g, 0.04 mmol) in M / f-di methyl form am ide (2.0 mL), (Benzotriazol- 1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (GLR, 0.02 g, 0.04 mmol) was added at 0°C. After 10 minutes ethylbi s(propan-2-yl)amine (0.03 mL, 0.12 mmol) was added dropwise to the reaction mixture at the same temperature and the reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure to get crude which was further purified by LH20 sephadex gel eluting in MeOH to afford (2R,3R,4R,6S)-2-((l-((4-(5-(4- chlorophenyl)thi ophen-2 -yl)quinazolin-2-yl)amino)-27-(26-((4-(5-(4-chlorophenyl)thi ophen- 2-yl)quinazolin-2-yl)amino)-3 ,6,9, 12,15,18,21 ,24-octaoxahexacosyl)-41 -(4-(3 -(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-39,42-dioxo- 3,6,9,12,15,18,21,24,30,33,36,46,49,52-tetradecaoxa-27,40,43-triazatetrapentacontan-54- yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (C-9) as a yellowish liquid. Yield: 60 mg, 49.82 % over two steps; LCMS (ESI) m / z 1255.50 [M / 2+H]+.Synthesis of l-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-27-(26-((4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)- N-(25-((2,4-dinitrophenyl)amino)-13,20-dioxo-l-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6- methyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,6, 9,23 -tetraoxa- 12,19 - di azapentacosan- 14-yl)- 3,6,9,12,15,18,21,24,30,33,36-undecaoxa-27-azanonatriacontan-39-amide (Compound 12)To the stirred solution of (2R,3R,4R,6S)-2-((l-((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-27-(26-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)-3 ,6,9, 12,15,18,21 ,24-octaoxahexacosyl)-41 -(4-(3 -(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-39,42-dioxo- 3,6,9,12,15,18,21,24,30,33,36,46,49,52-tetradecaoxa-27,40,43-triazatetrapentacontan-54- yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (C-9, 0.06 g, 0.024 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL), was added solution of sodium hydroxide (0.05 mL) [prepared by dissolving 0.58 gm of sodium hydroxide in water (14.5 mL)] at ambienttemperature over a period of 5 mins to adjust the pH >10. The reaction mixture was stirred for 4 h at that temperature. The completion of the reaction was confirmed by LCMS. After that, the reaction mass pH was slowly adjusted to 7, by using Dowex 50XW8 (H+) resin. The reaction mass was filtered through sintered funnel. The organic layer was evaporated to dryness to get crude which was purified by prep HPLC purification using water / acetonitrile in 0.1% TFA to afford l-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-27-(26-((4-(5- (4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24- octaoxahexacosyl)-N-(25-((2,4-dinitrophenyl)amino)-13,20-dioxo-l-(((2R,3R,4R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,23-tetraoxa-12,19-diazapentacosan- 14-yl)-3,6,9,12,15,18,21,24,30,33,36-undecaoxa-27-azanonatriacontan-39-amide (Compound 12) as a yellowish solid. Yield: 0.014 g, 24.57 %; LCMS (ESI) m / z 2385.02 [M+H]+. 'HNMR (400 MHz, DMSO-tfc): 9.12 (brs, 1H), 8.36 (d, J= 2.6 Hz, 1H), 8.81 (s, 1H), 8.31 (brs, 2H), 8.22 (dd, Jj = 2.64 Hz, 9.56 Hz, 1H), 8.17 (brs, 2H), 8.02-7.90 (m, 2H), 7.82- 7.74 (m, 9H), 7.58-7.53 (m, 6H), 7.45-7.33 (m, 2H), 7.26 (dd, J = 9.6 Hz, 1H), 4.56 (s, 1H), 4.22-4.16 (m, 2H), 3.79-3.72 (m, 10H), 3.65-3.63 (m, 20H), 3.60-3.45 (68H), 3.39-3.35 (m, 12H), 3.25-3.13 (m, 4H), 2.96-2.94 (m, 2H), 2.39-2.27 (m, 4H), 1.57-1.55 (m, 1H), 1.46-1.42 (m, 1H), 1.39-1.30 (m, 2H), 1.26-1.16 (m, 2H), 1.11 (d, J= 6.16 Hz, 3H).Example 6: Synthesis of Compound 13(S)-2-(3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-((R)-l-hydroxyethyl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanamido)-6-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide(Compound 13)Synthesis of 7-bromo-2-chloro-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazoline (D-3)A solution of [5-(p-chlorophenyl)-2-thienyl]boranediol (BLD Pharm; D-l, 0.5 g, 1.68 mmol), 7-bromo-2,4-dichloroquinazoline (Angene; D-2, 0.51 g, 1.84 mmol), dipotassium carbonate (0.46 g, 3.35 mmol) in Dioxane / Water (4: 1 v / v) (10 mL), was purged with N2 gas for 10 min. Subsequently, Pd(dppf)C12*DCM (BLD Pharm; 68.4 mg, 0.084 mmol) was added to the reaction mixture under an inert atmosphere and the reaction mixture was stirred at 90 °C for 3h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was filtered through a pad of celite. The filtrate was evaporated to dryness to obtain a crude black residue. The crude residue was further purified by silica gel column chromatography using 2-5% methanol / dichloromethane as eluent to obtain the desired product 7-bromo-2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline (D-3) as a yellow solid. Yield: 310 mg, 39.51% ; LC-MS (ESI) m / z 434.80 [M+H]+. Synthesis of tert-butyl 3-(2-(2-((7-bromo-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoate (D-5)To the stirred solution of 7-bromo-2-chloro-4-[5-(p-chlorophenyl)-2- thienyl]quinazoline (3, 0.2 g, 0.46 mmol) and tert-butyl 3-[2-(2- aminoethoxy)ethoxy]propionate (BLD Pharm; D-4, 160.4 mg, 0.68 mmol) in dimethyl sulfoxide (7 mL), triethylamine (0.16 mL, 1.14 mmol) was added and the reaction mixture was stirred at 90 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x50mL). The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuum to afford crude. The crude material was further purified by silica gel column chromatography using 70% Ethyl acetate in Heptane as eluent to afford tert-butyl 3- (2-(2-((7-bromo-4-(5-(4-chl orophenyl)thi ophen-2 -yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoate (D-5) as ayellow semi-solid. Yield: 180 mg, 48.01 %. LC- MS (ESI) m / z 631.90 [M + H]+.Synthesis of tert-butyl 3-(2-(2-((7-acetyl-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoate (D-6)A solution of tert-butyl 3-(2-(2-((7-bromo-4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoate (D-5, 0.23 g, 0.26 mmol) and Tributyl(l- ethoxyvinyl)tin (TCI; 88.5 pL, 0.26 mmol) in 1,4 dioxane (8 mL), was purged with N2 gas for 10 min. Subsequently, Pd(PPh3)4 (TCI; 30 mg, 0.26 mmol) was added to the reaction mixture under an inert atmosphere and the reaction mixture was stirred at 90 °C for 4h. Progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with 2N HC1 (3mL) and left to stir at ambient temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2x50mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a dark brown residue. The residue was further purified by silica gel column chromatography using 2-5% methanol / dichloromethane as eluent to afford the desired product tert-butyl 3-(2-(2-((7-acetyl- 4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoate (D-6) as a pale yellow solid. Yield: 150 mg, 67.78 %. LC-MS (ESI) m / z 596.05 [M+H]+.Synthesis of tert-butyl (R)-3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-(l- hydroxyethyl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoate (7)To the stirred ice cold solution of tert-butyl 3-(2-(2-((7-acetyl-4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoate (D-6, 0.14 g, 0.24 mmol) in acetonitrile (5 mL), RuCl(p-cymene)[(R,R)-Ts-DPEN] (BLD Pharm; 15.6 mg, 22.14 pmol) was added at same temperature. The reaction mixture was then stirred at same temperature for 30 min. Subsequently, a mixture of N-ethyldiisopropylamine (0.24 mL, 1.40 mmol) and formic acid (0.08 mL, 2.34 mmol) in acetonitrile (1.0 mL) was added to the reaction mixture at same temperature. The resultant mixture was stirred at ambient temperature for another 12 h. Progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was evaporated to dryness to get orange residue. The crude was further purified by silica gel column chromatography using 80% Ethyl acetate / Heptane as eluent to afford tert-butyl (R)-3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-(l-hydroxyethyl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoate (D-7) as a yellow solid. Yield: 120 mg; 85.43 %. LC-MS (ESI) m / z 598.15 [M+H]+.Synthesis of (R)-3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-(l- hydroxyethyl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoic acid (D-8)To an ice cold solution of tert-butyl (R)-3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)- 7-(l -hydroxy ethyl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoate (7, 0.12 g, 0.20 mmol) in di chloromethane (5 mL), trifluoroacetic acid (1.0 mL) was added and the resultant mixture was stirred at ambient temperature for 2h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was evaporated under reduced pressure and triturated with diethyl ether (2x5 mL) to afford crude yellow liquid containing (R)-3-(2-(2-((4- (5-(4-chlorophenyl)thiophen-2-yl)-7-(l -hydroxy ethyl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanoic acid (D-8). Yield: 100 mg, crude; LC-MS (ESI) m / z 542.15 [M+H]+.Synthesis of (2R,3R,4R,5S,6S)-2-(((S)-24-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-((R)-l- hydroxyethyl)quinazolin-2-yl)amino)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16-dioxo-3 ,6,9, 19,22-pentaoxa- 12, 15- diazatetracosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (D-10)To the stirred solution of (R)-3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-(l- hydroxyethyl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanoic acid (D-8, 0.07 g, 0.10 mmol) and (2R,3R,4R,5S,6S)-2-(((S)-14-amino-25-((2,4-dinitrophenyl)amino)-13,20-dioxo- 3,6,9,23-tetraoxa-12,19-diazapentacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (D-9, 0.08 g, 0.09 mmol) in dichloromethane (2 mL), triethylamine (0.05 mL, 0.4 mmol) was added and stirred at 0°C for 15 mins. Propylphosphonic anhydride (50% solution in Ethyl Acetate) (BLD pharm; 0.13 g, 0.41 mmol) was added at 0°C to it and the reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was diluted with ice cold water (50 mL) and extracted with dichloromethane (2x50 mL), the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford a red crude solid. The crude solid was purified by silica gel column chromatography using 5-7.5% methanol / di chloromethane as eluent to afford the desired product (2R,3R,4R,5S,6S)-2-(((S)- 24-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-((R)-l-hydroxyethyl)quinazolin-2-yl)amino)-14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16-dioxo-3,6,9,19,22- pentaoxa-12,15-diazatetracosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (D-10) as a yellow solid. Yield: 35 mg, 14.41 %. LC-MS (ESI) m / z 1398.05 [M+H]+Synthesis of (S)-2-(3-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-((R)-l- hydroxyethyl)quinazolin-2-yl)amino)ethoxy)ethoxy)propanamido)-6-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide (Compound 13)To the stirred solution of (2R,3R,4R,5S,6S)-2-(((S)-24-((4-(5-(4- chlorophenyl)thi ophen-2 -yl)-7-((R)-l-hydroxyethyl)quinazolin-2-yl)amino)-14-(4-(3-(2- ((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16-dioxo-3,6,9,19,22-pentaoxa- 12,15-diazatetracosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (D-10, 35 mg, 13.5 pmol) in methanol (3 mL), 25% (w / w) solution of sodium methoxide in methanol was added dropwise to adjust the pH >10. The resultant mixture was stirred at ambient temperature for 2h. Progress of the reaction was monitored by LCMS. Upon completion, pH of the reaction mass was slowly adjusted to 7, by using Dowex 50XW8 (H+) resin and filtered through sintered funnel. The organic layer was evaporated to dryness to get crude which was further purified by prep HPLC purification using water / acetonitrile in 0.1% TFAto afford (S)-2-(3-(2- (2-((4-(5-(4-chlorophenyl)thiophen-2-yl)-7-((R)-l-hydroxyethyl)quinazolin-2- yl)amino)ethoxy)ethoxy)propanamido)-6-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)-N-(2-(2-(2-(2-(((2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)hexanamide (Compound 13) as a yellow solid. Yield: 7 mg, 22 %. LC-MS (ESI) m / z 1272.80 [M+H]+. 'H NMR (400 MHz, DMSO-t / e): 8 8.82-8.79 (m, 2H), 8.32 (s, 1H), 8.21 (dd, J= 9.0, 3.0 Hz, 1H), 8.05 - 7.76 (m, 7H), 7.54 (m, 3H), 7.35 (s, 1H), 7.22 (d, J= 9.0 Hz, 1H), 4.87 (s, 1H), 4.55 (s, 1H), 4.21 (m, 1H), 3.64 - 3.14 (m, 31H), 2.95 (m, 2H), 2.37-2.27 (m, 4H), 1.58 - 1.40 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H), 1.39 - 1.15 (m, 5H), 1.11 (d, J = 6.4 Hz, 3H) ppm.19F NMR (400 MHz, DMSO-tL): -73.87 ppm.Example 7: Synthesis of Compound 143,3-dimethyl-l-(6-oxo-6-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)hexyl)-2-((lE,3E)-5-((E)-l,3,3-trimethylindolin-2- ylidene)penta-l,3-dien-l-yl)-3H-indol-l-ium 2,2,2-trifluoroacetate (Compound 14)Synthesis of 2-chloro-4-(5-phenylthiophen-2-yl)quinazoline (E-3)To a stirred solution of 4,4,5,5-tetramethyl-2-(5-phenylthiophen-2-yl)-l,3,2- dioxaborolane (Angene; E-l, 0.60 g, 2.10 mmol) in 10 mL mixture of Dioxane / Water (4: 1 v / v), 2,4-dichloroquinazoline (Angene; 2, 0.54 g, 2.73 mmol) and potassium carbonate (0.87 g, 6.29 mmol) were added at rt and the reaction mixture was degassed over 10 mins. After degassing, (l,l'-Bis(diphenylphosphino)ferrocene)palladium (II) dichloride (BLD, 0.17 g, 0.21 mmol) was added to it at rt. The resultant solution was again degassed by bubbling argon for next 10 min. The vial was sealed and stirred at 90 °C for 3h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled and filtered through a short pad of celite. The filtrate was extracted with saturated brine solution (30 mL) and aqueous layer was extracted twice with ethyl acetate (2 x 80 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated under vaccuo. The crude residue was further purified by column chromatography using 70% ethyl acetate in Heptane as eluent to obtain 2- chloro-4-(5-phenylthiophen-2-yl)quinazoline as a yellow solid (E-3). Yield: 0.40 g, 59.11 %. LC-MS (ESI) m / z 323.00 [M+H]+.Synthesis of tert-butyl (2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamate (E-5)To a stirred solution of 2-chloro-4-(5-phenylthiophen-2-yl)quinazoline (E-3, 0.16 g, 0.48 mmol) and tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (BLD Pharm; E-4, 0.25 g, 0.96 mmol) in Dimethyl sulfoxide (5.0 mL), Triethylamine (0.30 mL, 1.44 mmol) was added at rt and the reaction mixture was heated at 100°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was again washed with ice cold water (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude material, which was further purified using silica gel chromatography using 70% Ethyl acetate in Heptane as eluent to afford tert-butyl (2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamate (E-5) product as a yellow semi-solid. Yield: 130 mg, 49.06 %. LC-MS (ESI) m / z 535.10 [M + H]+.Synthesis of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-phenylthiophen-2-yl)quinazolin-2- amine (E-6)To a stirred solution of tert-butyl (2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamate (E-5, 0.10 g, 0.18 mmol), in anhydrous Dichloromethane (TCI, 5.0 mL), Trifluoroacetic acid (GLR, 1.5 mL) was added at 0°C and the reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion solvent was concentrated and dried under reduced pressure to get crude which was further triturated using Pentane / Ether solution to obtain N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-phenylthiophen-2-yl)quinazolin-2-amine (E-6) as a light yellowish liquid which was used for the next reaction without further purification. Yield: 0.08 g, Crude; LCMS (ESI) m / z 435.05 [M+H]+.Synthesis of 3,3-dimethyl-l-(6-oxo-6-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)hexyl)-2-((lE,3E)-5-((E)-l,3,3-trimethylindolin-2- ylidene)penta- 1 ,3 -dien- 1 -yl)-3H-indol- 1 -ium 2,2,2-trifluoroacetate (E-7)To a stirred solution of 2-{2-[2-(2-aminoethoxy)ethoxy]ethylamino}-4-(5-phenyl-2- thienyl)quinazoline (E-6, 0.08 g, 0.18 mmol) and Lumiprobe NHS-Cy5 (BLD pharm; E-6, 0.10 g, 0.15 mmol) in Tetrahydrofuran (3 mL), N-ethyldiisopropylamine (0.17 mL, 0.90 mmol) was added dropwise to the reaction mixture and was stirred at ambient temperature for 4 h. Progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum to get crude which was further purified by prep HPLC using TFA buffer to afford 3,3- dimethyl-l-(6-oxo-6-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)hexyl)-2-((lE,3E)-5-((E)-l,3,3-trimethylindolin-2- ylidene)penta-l,3-dien-l-yl)-3H-indol-l-ium 2,2,2-trifluoroacetate (E-7) as a bluish solid. Yield: 37 mg, 22.33%. LC-MS (ESI) m / z 899.47 [M + H]+. 'H-NMR (400 MHz, DMSO-de) 6 8.33-8.27 (m, 3H), 8.00 (brs, 1H), 7.81-7.77 (m, 4H), 7.70 (d, J= 4.0 Hz, 1H), 7.60-7.50 (m, 3H), 7.48 (t, J= 7.5 Hz, 1H), 7.41-7.32 (m, 6H), 7.20 (m, 2H), 6.53 (t, J= 12.0 Hz, 1H), 6.25 (t, J= 14.0 Hz, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.63-3.41 (m, 13H), 3.17-3.14 (m, 2H), 2.04 (t, J = 7.2 Hz, 2H), 1.66-1.65 (m, 14H), 1.53-1.49 (m, 2H), 1.32-1.31 (m, 2H).Example 8: Synthesis of Compound 182-((E)-4-((14S,19S)-14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,24,27 ,30, 33,36, 39-nonaoxa-12, 15,20- triazadotetracontan-42-amido)-2-sulfostyryl)-5-nitrobenzenesulfonic acid (Compound 18)Synthesis of (E)-6,6'-(ethene-l,2-diyl)bis(3-nitrobenzenesulfonic acid) (F-2)A stirred solution of sodium (E)-6,6'-(ethene-l,2-diyl)bis(3-nitrobenzenesulfonate) (1, 0.11 g, 0.23 mmol) in water (2 mL) was heated to 50°C. The resultant mixture was charged with 1 N HC1 (1 mL) dropwise to adjust pH to 4 at same temperature; The reaction medium was stirred for 2 h at same temperature and the progress of the reaction was monitored by TLC.The reaction mixture was evaporated to dryness to obtain the crude. The crude was diluted with 20% MeOH in DCM and the insoluble solids were filtered. The filtrate was evaporated to dryness to afford (E)-6,6'-(ethene-l,2-diyl)bis(3-nitrobenzenesulfonic acid) (F-2) as yellowish solid. Yield: 100 mg; crude. LC-MS (ESI) m / z 428.75 [M-H]’.Synthesis of (E)-5-amino-2-(4-nitro-2-sulfostyryl)benzenesulfonic acid (F-3)A stirred solution of (E)-6,6'-(ethene-l,2-diyl)bis(3-nitrobenzenesulfonic acid) (0.1 g, 0.23 mmol) was dissolved in water (4 mL) at 50°C. The resulting mixture was charged with 25% ammonium hydroxide (0.45 mL) solution at same temperature till pH of the reaction was raised to 8. Sodium hydrogensulfide (39.1 mg, 0.70 mmol) was added to the reaction mixture and the temperature was raised to 60°C. The reaction mixture was stirred for 30 minutes at same temperature. After completion by TLC, the reaction mixture was evaporated to dryness to afford the desired compound as brown colored solid crude material. Yield: 60 mg; crude. 'H-NMR (400 MHz, DMSO-de) 6 8.56 (d, J = 16.8 Hz, 1H), 8.34 (d, J = 16.8 Hz, 1H), 8.17 (dd, J= 2.6, 8.0 Hz, 1H), 7.87 (d, J= 16.8 Hz, 1H), 7.76 (d, J= 9.2 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.12 (d, J= 2.4 Hz, 1H), 6.55 (dd, J= 2.4, 8.8 Hz, 1H), 5.54 (brs, 2H).Synthesis of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-phenylthiophen-2-yl)quinazolin-2- amine (F-4)N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-phenylthiophen-2-yl)quinazolin-2-amine (F-4) was the common intermediate used for Compound 14.Synthesis of tert-butyl (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxo-5-((2-(2-(2- ((4-(5-phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)amino)pentanoate (F- 6)To a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert- butoxy)-5-oxopentanoic acid (F-4, 0.70 g, 1.65 mmol) and N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-4-(5-phenylthiophen-2-yl)quinazolin-2-amine (F-5, 0.78 g, 1.86 mmol) in YY-di methyl form am ide (10 mL), O-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU; 0.68 g, 1.81 mmol) and N- ethyldiisopropylamine (1.00 mL, 4.95 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 4 h. Progress of the reaction was monitored by TLC. After completion of the reaction, solvent was concentrated under high vacuum to get the crude which was further purified by silica gel column chromatography using 2-5 % Methanol inDichloromethane gradient to afford tert-butyl (S)-4-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-5-oxo-5-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)pentanoate (F-6)as pale yellow liquid. Yield: 670 mg, 49.40%. LC-MS (ESI) m / z 842.10 [M+H]+.Synthesis of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxo-5-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)amino)pentanoic acid (7)To a stirred solution of tert-butyl (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 5-oxo-5-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)pentanoate (F-6, 0.50 g, 0.59 mmol) in Dichloromethane (10 mL), Trifluoroacetic acid (2.0 mL) was added at 0° C and the reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated to get crude which was triturated using pentane / ether solution to afford (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxo-5- ((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)pentanoic acid (F-7) as orange yellow gummy liquid. Yield: 350 mg, crude; LC-MS (ESI) m / z 786.10 [M +H]+.Synthesi s of (2R, 3R,4R, 6 S)-2-((( 14 S, 19 S)- 19-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16,20-trioxo-29-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,24,27-pentaoxa-12, 15,21- triazanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-9)To a stirred solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxo-5- ((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)pentanoic acid (7, 0.40 g, 0.51 mmol) and (2R,3R,4R,5S,6S)-2-(((S)-14-amino-25-((2,4-dinitrophenyl)amino)-13,20-dioxo-3,6,9,23- tetraoxa-12,19-diazapentacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-8, 0.49 g, 0.56 mmol) in YY-di methyl form am ide (10 mL), O-(7-Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 0.29 g, 0.56 mmol) and N- ethyldiisopropylamine (0.30 mL, 1.5 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, solvent was concentrated under high vacuum to get the crude that was purified by silica gel column chromatography using 2-5 % methanol in dichloromethane gradient to afford (2R,3R,4R,6S)-2-(((14S,19S)-19-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16,20-trioxo-29-((4-(5-phenylthiophen- 2-yl)quinazolin-2-yl)amino)-3,6,9,24,27-pentaoxa-12,15,21-triazanonacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-9) as pale yellow liquid. Yield: 350 mg, 41.86%. LC-MS (ESI) m / z 1641.90 [M+H]+.Synthesis of (2R,3R,4R,6S)-2-(((14S,19S)-19-amino-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16,20-trioxo-29-((4-(5-phenylthiophen- 2-yl)quinazolin-2-yl)amino)-3,6,9,24,27-pentaoxa-12,15,21-triazanonacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-10)To a stirred solution of (2R,3R,4R,6S)-2-(((14S,19S)-19-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16,20-trioxo-29-((4-(5-phenylthiophen- 2-yl)quinazolin-2-yl)amino)-3,6,9,24,27-pentaoxa-12,15,21-triazanonacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-9, 0.20 g, 0.12 mmol) in anhydrous N,N- dimethylformamide (2.0 mL), piperidine (2.0 mL) was added at ambient temperature and the reaction mixture was allowed to stir for 30 min. Progress of the reaction was monitored by LCMS. After completion, solvent was concentrated and dried under reduced pressure. The crude was further triturated with Diethyl Ether to afford (2R,3R,4R,6S)-2-(((14S,19S)-19- amino-14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16,20-trioxo- 29-((4-(5-phenylthiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,24,27-pentaoxa-12, 15,21- triazanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-10) as a light yellow liquid which was used for the next reaction. Yield: 0.15 g, 86.73%; LCMS (ESI) m / z 711.00 [M / 2+H]+.Synthesis of (2R,3R,4R,6S)-2-(((14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-44,44-dimethyl- 13,16,21 ,42-tetraoxo- 19- ((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-3,6,9,24,27,30,33,36,39,43-decaoxa-12,15,20- triazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-12)To a stirred solution of 2,2-dimethyl-4-oxo-3,7,10,13,16,19,22-heptaoxapentacosan- 25-oic acid (Angene; F-ll, 0.06 g, 0.14 mmol) and (2R,3R,4R,6S)-2-(((14S,19S)-19-amino- 14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)-13,16,20-trioxo-29-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,24,27-pentaoxa-12, 15,21-triazanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (10, 0.20 g, 0.14 mmol) in A,A-dimethylformamide (4 mL), benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP; 0.08 g, 0.14 mmol) and A-ethyldiisopropylamine (0.60 mL, 0.42 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC. After completion of reaction, solvent was concentrated under high vacuum to get the crude which was further purified by silica gel column chromatography using 5-10 % Methanol in Dichloromethane gradient to afford (2R,3R,4R,6S)-2-(((14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-44,44-dimethyl- 13,16,21 ,42-tetraoxo- 19- ((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-3,6,9,24,27,30,33,36,39,43-decaoxa-12,15,20- triazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-12) as pale yellow liquid. Yield: 100 mg, 38.58%. LC-MS (ESI) m / z 929.60 [M / 2+H]+.Synthesis of (14S, 19S)-14-(4-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l-(((2R,3R,4R,6S)-3,4,5-triacetoxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,24,27,30,33,36,39-nonaoxa-12,15,20- triazadotetracontan-42-oic acid (F-13)To a stirred solution of (2R,3R,4R,6S)-2-(((14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)-44,44-dimethyl- 13,16,21 ,42-tetraoxo- 19- ((2-(2-(2-((4-(5-phenylthiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-3,6,9,24,27,30,33,36,39,43-decaoxa-12,15,20- triazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (F-12, 0.10 g, 0.04 mmol) in Dichloromethane (2 mL), Trifluoroacetic acid (1.0 mL) was added at 0° C and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was evaporated to dryness to afford (14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l- (((2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)- 3,6,9,24,27,30,33,36,39-nonaoxa-12,15,20-triazadotetracontan-42-oic acid (F-13) as orange yellow gummy liquid. Yield: 70 mg, crude; LC-MS (ESI) m / z 893.05 [M / 2 +H]+.Synthesis of 2-((E)-4-((14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l- (((2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3.6.9.24.27.30.33.36.39-nonaoxa-12,15,20-triazadotetracontan-42-amido)-2-sulfostyryl)-5- nitrobenzenesulfonic acid (F-14)To a stirred solution of (14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l- (((2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3.6.9.24.27.30.33.36.39-nonaoxa-12,15,20-triazadotetracontan-42-oic acid (Angene; F-13,0.07 g, 0.04 mmol) and (E)-5-amino-2-(4-nitro-2-sulfostyryl)benzenesulfonic acid (F-3, 0.03 g, 0.07 mmol) in Y,Y-di methyl form am ide (4 mL), O-(7-Azabenzotriazo1-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU; 0.02 g, 0.04 mmol) and N- ethyldiisopropylamine (0.03 mL, 0.15 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, solvent was concentrated under high vacuum to get the crude 2-((E)-4-(( 14 S, 19 S)- 14-(4-(3 -(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l- (((2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3.6.9.24.27.30.33.36.39-nonaoxa-12,15,20-triazadotetracontan-42-amido)-2-sulfostyryl)-5- nitrobenzenesulfonic acid (F-14) as pale yellow liquid which was used for next reaction without doing further purification. Yield: 120 mg; crude LC-MS (ESI) m / z 1081.95 [M / 2-H]'.Synthesis of 2-((E)-4-((14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l- (((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,24,27,30,33,36,39-nonaoxa-12,15,20-triazadotetracontan-42-amido)-2-sulfostyryl)-5- nitrobenzenesulfonic acid (Compound 18)To a stirred solution of 2-((E)-4-((14S,19S)-14-(4-(3-(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l-(((2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)- 3,6,9,24,27,30,33,36,39-nonaoxa-12,15,20-triazadotetracontan-42-amido)-2-sulfostyryl)-5- nitrobenzenesulfonic acid (F-14, 0.12 g, 0.054 mmol) in Methanol:THF (8 mL;l :3), 5% NaOH aqueous solution (0.1 mL) was added dropwise till pH=12. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by Prep-HPLC using 0-50% acetonitrile in H2O with 0.1% ammonium acetate. Desired fractions were lyophilised to afford 2-((E)-4-(( 14 S, 19 S)- 14-(4-(3 -(2-((2,4- dinitrophenyl)amino)ethoxy)propanamido)butyl)- 13,16,21 -tri oxo- 19-((2-(2-(2-((4-(5- phenylthiophen-2-yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-l- (((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)- 3,6,9,24,27,30,33,36,39-nonaoxa-12,15,20-triazadotetracontan-42-amido)-2-sulfostyryl)-5- nitrobenzenesulfonic acid (Compound 18) as yellow sticky solid. Yield: 0.016 g, 14.16%; LCMS (ESI) m / z 1019.12 [M / 2+H]+ 1H-NMR (400 MHz, DMSO-d6s) 6 10.12 (brs, 1H), 8.83 (d, J= 2.4 Hz, 1H), 8.80 (brs, 1H), 8.56 (d, J= 2.4 Hz, 1H), 8.36-8.32 (m, 2H), 8.22 (dd, J = 8.8, 2.4 Hz, 1H), 8.08-8.04 (m, 1H), 8.00-7.89 (m, 5H), 7.85-7.71 (m, 8H), 7.57 (d, J= 8.8 Hz, 1H), 7.48 (t, J= 8.0 Hz, 2H), 7.42-7.38 (m, 1H), 7.31-7.28 (m, 1H), 7.23 (d, J= 10.0 Hz, 1H), 4.55 (s, 1H), 4.18-4.12 (m, 3H), 3.70-3.39 (m, 60H), 3.33-3.14 (m, 6H), 2.98-2.95 (m, 2H), 2.56-2.55 (m, 2H), 2.37 (t, J= 6.4 Hz, 2H), 2.31-2.27 (m, 2H), 2.12-2.10 (m, 2H), 1.91-1.81 (m, 1H), 1.70-1.68 (m, 1H), 1.54-1.42 (m, 1H), 1.31-1.29 (m, 2H), 1.22-1.19 (m, 2H), 1.14- 1.10 (m, 3H).Example 9: Synthesis of Compound 19(2R,3R,4R,6S)-2-((15-(l-(l-(l-(l-(l-(l-((l,71-bis((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-34,38-dioxo- 3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamoyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)-29-((2,4-dinitrophenyl)amino)-3,6,9,12,18,21,24,27-octaoxa-15- azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound 19).Synthesis of 2-chloro-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazoline (G-l)Common intermediate used for Compound 1Synthesis of tert-butyl (32-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)carbamate (G-3)To a stirred solution of 2-chloro-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazoline (1, 0.25 g, 0.7 mmol) and tert-butyl (32-amino-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)carbamate (BLD, 0.63 g, 1.05 mmol) in Dimethyl sulfoxide (2 mL), triethylamine (0.48 mL, 3.5 mmol) was added at ambient temperature and the reaction mixture was stirred at 90°C for 16 h. After completion of the reaction on the basis of TLC and LCMS, the reaction mixture was concentrated in high vacuum and then diluted with water (50 mL). The reaction mixture was extracted with ethyl acetate (2x50 ml). The combined organic layer was concentrated and dried to get crude. The crude was further purified by 10% MeOH in DCM to afford tert-butyl (32-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)carbamate (G-3) as yellowish gummy liquid. Yield: 0.5 g, 77.54 %; LCMS m / z 921.11 [M+H]+.Synthesis of Nl-(4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)-3.6.9.12.15.18.21.24.27.30-decaoxadotriacontane- 1 ,32-diamine (G-4)To a stirred solution of tert-butyl (32-((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)carbamate (G-3, 0.35 g, 0.39 mmol) in Dichloromethane (5 mL), Trifluoroacetic acid (1.5 mL) was added at 0°C. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored on the basis of TLC and LCMS. After completion, solvent was evaporated. The resultant crude was triturated with Pentane and Ether and dried to get crude Nl-(4-(5 -(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontane-l,32-diamine (G-4) as yellowish liquid. The crude was used for the next step without further purification. Yield: 0.3 g, Crude; LCMS m / z 821.05 [M+H]+.Synthesis of tert-butyl (l,71-bis((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)- 34,38-dioxo-3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamate (G-6)To a stirred solution of 3-((tert-butoxycarbonyl)amino)pentanedioic acid (Angene; 31 mg, 0.12 mmol) and Nl-(4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)-3.6.9.12.15.18.21.24.27.30-decaoxadotriacontane-l,32-diamine (G-4, 0.30 mg, 0.37 mmol) inN, Y-di methyl formamide (4 mL), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC;O.12 g, 0.627 mmol) and 1 -Hydroxybenzotriazole (HOBt; 0.096 g, 0.627 mmol) were added at 0°C followed by the addition of N-ethyldiisopropylamine (0.11 mL, 0.62 mmol). The reaction mixture was allowed to stir at ambient temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2x30 mL). The combinedorganic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude was further purified over silica gel column chromatography using 10% Methanol in Dichloromethane as eluent to afford tert-butyl (1,71- bis((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-34,38-dioxo-3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamate (G-6). Yield: 0.18 g, 77.43%; LCMS m / z 1852.00 [M+H]+.Synthesi s of 3 -amino-N 1 ,N5 -bis(32-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)pentanediamide (G-7)To the stirred solution of tert-butyl (l,71-bis((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-34,38-dioxo-3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamate (G-6 80 mg, 0.043 mmol) in Dichloromethane (3 mL), Trifluoroacetic acid (1 mL) was added dropwise at 0°C and allowed to stir for 2 h at ambient temperature. Progress of the reaction was monitored by TLC and LCMS. After completion solvent was evaporated. The resultant crude was triturated with Pentane and Ether and dried to afford 3-amino-Nl,N5-bis(32-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)- 3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)pentanediamide (G-7). Crude was used for the next step without further purification. Yield: 0.075 g, Crude; LCMS m / z 1752.70 [M+H]+.Synthesis of (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(l-(l-(l-(piperidine- 4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)-3,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (G-8)Synthesis of (2R,3R,4R,6S)-2-((15-(l-(l-(l-(l-(l-(l-((l,71-bis((4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-34,38-dioxo-3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamoyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)-29-((2,4-dinitrophenyl)amino)-3,6,9,12,18,21,24,27-octaoxa-15- azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (G-9)To a stirred solution of 3-amino-Nl,N5-bis(32-((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)pentanediamide (G-7, 0.075 g, 0.042 mmol) in AA-dimethylformamide (3 mL), Triethylamine (0.15 mL, 1.07 mmol) was added and the resulting mixture was stirred at RT for 10 min. After that, Carbonyldiimidazole (GLR, 37.4 mg, 0.231 mmol) was added to the reaction mixture and stirred at ambient temperature. After 1 h, the solution of (2R,3R,4R,6S)-2-((29-((2,4- dinitrophenyl)amino)- 15 -( 1 -( 1 -( 1 -( 1 -( 1 -(piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)-3,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6-methyltetrahydro-2H- pyran-3,4,5-triyl triacetate (G-8, 73.5 mg, 0.047 mmol) in AA-dimethylformamide (1 mL) was added to the reaction mixture at ambient temperature and stirred at same temperature for another 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was concentrated in vacuo to get the crude as (2R,3R,4R,6S)-2-((15-(l-(l- ( 1 -( 1 -( 1 -( 1 -(( 1 , 71 -bi s((4-(5 -(4-chl orophenyl)thi ophen-2 -yl)quinazolin-2-yl)amino)-34,38- dioxo-3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamoyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)-29-((2,4-dinitrophenyl)amino)-3,6,9,12,18,21,24,27-octaoxa-15- azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (G-9). Crude was forwarded to next step without purification. Yield: 140 mg, Crude; LCMS (ESI) m / z 1671.45 [M / 2+H]+.Synthesi s of N 1 ,N5 -bis(32-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)- 3,6,9,12,15,18,21 ,24,27,30-decaoxadotriacontyl)-3 -(4-(4-(4-(4-(4-(4-(( 14-((2,4- dinitrophenyl)amino)-3 ,6,9,12-tetraoxatetradecyl)( 14-(((2R,3R,4R, 6 S)-3 ,4, 5 -trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)carbamoyl)piperidine-l- carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 - carbonyl)piperidine-l-carboxamido)pentanediamide (Compound 19)To a stirred ice cold solution of (2R,3R,4R,6S)-2-((15-(l-(l-(l-(l-(l-(l-((l,71-bis((4- (5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-34,38-dioxo- 3,6,9,12,15,18,21,24,27,30,42,45,48,51,54,57,60,63,66,69-icosaoxa-33,39- diazahenheptacontan-36-yl)carbamoyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)-29-((2,4-dinitrophenyl)amino)-3,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (G-9, 0.14 g, 0.042 mmol) in methanol (5 mL), 5% NaOH aqueous solution (0.2 ml ) was added dropwise till pH=12. The reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was neutralized to pH=7 using Amberlite™ H+resin and filtered. The filtrate was evaporated under vacuum to obtain a crude. The crude was further purified by Prep-HPLC using 0-50% Acetonitrile in H2O with 0.1% ammonium acetate. Desired fractions were lyophilised to afford Nl,N5-bis(32-((4-(5- (4-chlorophenyl)thiophen-2-yl)quinazolin-2-yl)amino)-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)-3 -(4-(4-(4-(4-(4-(4-(( 14-((2,4-dinitrophenyl)amino)-3 ,6,9,12- tetraoxatetradecyl)(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)oxy)-3,6,9,12-tetraoxatetradecyl)carbamoyl)piperidine-l-carbonyl)piperidine-l- carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 - carboxamido)pentanediamide (Compound 19) as yellow sticky solid. Yield: 0.03 g, 22.05 %; LCMS (ESI) m / z 1608.24 [M / 2+H]+. LC-HRMS m / z 3213.5 [M+H]+.Example 10: Synthesis of Compound 20 l-(6-((2-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-2-((lE,3E)-5-((E)-l,3,3- trimethylindolin-2-ylidene)penta- 1 ,3-dien- 1 -yl)-3H-indol- 1 -ium 2,2,2-trifluoroacetateSynthesis of (5-(4-chlorophenyl)thiophen-2-yl)boronic acid (H-2)To a solution of 2-bromo-5-(4-chlorophenyl)thiophene (H-l, 1 g, 3.66 mmol) in Tetrahydrofuran (10 mL) at -78°C, 2.5M n-butyl lithium solution in Tetrahydrofuran (3.43 ml, 5.48 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 30 min. Trimethoxyborane (3.26 mL, 29.2 mmol) was added to the mixture at -78°C after 30 min and the reaction mixture was allowed to come to room temperature. The progress of the reaction was monitored by TLC. After 1 h, 1N HC1 (10 mL) was added dropwise to acidify the reaction mixture till pH = 4. The reaction mixture was extracted with DCM (2x50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude (5-(4-chlorophenyl)thiophen-2-yl)boronic acid (H- 2) as a colorless semi solid. Yield: 0.8 g, Crude; LCMS m / z 569.35 [M+H]+. 7H NMR (400 MHz, DMSO-t / 6): 8.28 (brs, 1H), 7.74-7.64 (m, 2H), 7.60-7.53 (m, 1H), 7.46 (d, J= 8.2 Hz, 2H).Synthesis of (5-(4-chlorophenyl)thiophen-2-yl)boronic acid (H-4)To a stirred solution of (5-(4-chlorophenyl)thiophen-2-yl)boronic acid (H-2, 750 mg, 2.52 mmol) in 1,4 dioxane (4.5 mL) and water (0.5 mL), 2,4-dichloroquinazoline (H-3, 0.2 g, 1.01 mmol) and K2CO3 (0.35 g, 2.52 mmol) were added consecutively at rt. The reactionmixture was degassed with Argon over 20 mins. (1,1'- Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (BLD, 68.4 mg, 83.9 pmol) was added to the reaction mixture at rt and the resulting suspension was again degassed for next 10 min. The reaction mixture was further stirred at 90°C for next 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with water and was extracted with ethyl acetate (2x50 ml). Combined organic layer was dried over sodium sulfate, filtered and evaporated to dryness to get the crude, which was further purified by 10% ethyl acetate in Heptane to afford 2- chloro-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazoline (H-4) as a pale yellow colored solid. Yield: 0.26 g, 82.45 %; LCMS m / z 356.80 [M+H]+.Synthesis of tert-butyl (2-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamate (H-6)To a solution of 2-chloro-4-[5-(p-chlorophenyl)-2-thienyl]quinazoline (H-4, 0.16 g, 0.45 mmol) and tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate ( BLD; H-5, 0.17 g, 0.67 mmol) in Dimethyl sulfoxide (1 mL), triethylamine (0.30 mL, 2.24 mmol) was added at ambient temperature and the reaction mixture was stirred at 100°C for 16 h. Progress of the reaction was monitored by TLC and LCMS analysis. After completion, the reaction mixture was diluted with ice cold water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with ice cold water (2 x 50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude. This crude was further purified by silica gel column chromatography using 5-10% MeOH in DCM to afford tert-butyl (2-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)carbamate (H-6) as colorless liquid. Yield: 0.2 g, 75.33 %; LCMS m / z 569.35 [M+H]+.Synthesis of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-amine (H-7)To a stirred solution of tert-butyl (2-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2- yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)carbamate (H-6, 0.17 g, 0.30 mmol) in Dichloromethane (5 mL), Trifluoroacetic acid (1.5 mL) was added at 0°C and the reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS analysis. After completion of the reaction, solvent was evaporated to drynessand the crude was triturated with Pentane / Ether solution and dried to get crude N-(2-(2-(2- aminoethoxy)ethoxy)ethyl)-4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2-amine (H-7) as colorless liquid. The crude was used for the next step without doing further purification. Yield: 0.14 g, Crude; LCMS (ELSD) m / z 468.98 [M+H]+.Synthesis of l-(6-((2-(2-(2-((4-(5-(4-chlorophenyl)thiophen-2-yl)quinazolin-2- yl)amino)ethoxy)ethoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-2-((lE,3E)-5-((E)-l,3,3- trimethylindolin-2-ylidene)penta- 1 ,3 -dien- 1 -yl)-3H-indol- 1 -ium 2,2,2-trifluoroacetate (Compound 20)To a stirred solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(5-(4- chlorophenyl)thiophen-2-yl)quinazolin-2-amine (7, 45 mg, 0.095 mmol) and Lumiprobe NHS-Cy5 (BLD; H-8, 55.7 mg, 0.095 mmol) in Tetrahydrofuran (1.5 mL), N- ethyldiisopropylamine (0.08 mL, 0.48 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 4 h. After completion of the reaction on basis of LCMS, the reaction mixture was concentrated and dried to get crude which was further purified by prep HPLC using water / acetonitrile in 0.1% TFA to afford l-(6-((2-(2-(2-((4-(5-(4- chlorophenyl)thi ophen-2 -yl)quinazolin-2-yl)amino)ethoxy)ethoxy)ethyl)amino)-6-oxohexyl)- 3,3-dimethyl-2-((lE,3E)-5-((E)-l,3,3-trimethylindolin-2-ylidene)penta-l,3-dien-l-yl)-3H- indol-l-ium 2,2,2-trifluoroacetate as bluish fluffy solid. Yield: 0.007 g, 7.8%; LCMS (ESI) m / z 933.56 [M+H]+. 'H NMR (400 MHz, DMSO-t / e): 8.33-8.26 (m, 3H), 7.96 (d, J= 3.6 Hz, 1H), 7.84-7.79 (m, 3H), 7.72-7.68 (m, 2H), 7.58 (dd, J= 7.24 Hz, 2.52 Hz, 2H), 7.54-7.51 (m, 3H), 7.37-7.29 (m, 4H), 7.27-7.19 (m, 4H), 6.99 (s, 1H), 6.52 (t, J= 12.36 Hz, 1H), 6.24 (t, J= 14.2 Hz, 2H), 4.04 (t, J = 6.96 Hz, 2H), ), 3.61-3.55 (m, 10H), 3.51-3.49 (m, 2H), 3.38-3.37 (m, 2H), 3.18-3.12 (m, 2H), 2.04 (t, J = 7.16 Hz, 2H), 1.75 (s, 1H), 1.65-1.64 (m, 14H), 1.57 (s, 3H), 1.53-1.47 (m, 3H), 1.41 (s, 1H), 1.34-1.25 (m, 2H), 1.22 (s, 1H).Example 11: Synthesis of Compound 22(Z)-4-(5-((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2- thioxothiazolidin-3-yl)butanoic acid (Compound 22).Synthesis of l-(benzyloxy)-4-fluoronaphthalene (1-2)In a 100 mL flask, 2g of 4-fluoronaphthalen-l-ol (BLD Pharma, 1 g, 6.17 mmol), benzyl bromide (Spectrochem, 949 mg, 5.55 mmol), K2CO3 (TCI, 1.28 g, 9.25 mmol) were suspended in dry acetonitrile (20 mL). This mixture was then refluxed at 80 °C for 2h. Upon completion, the reaction mixture was filtered through a pad of celite. The filtrate was then evaporated to dryness to obtain a pink crude liquid. The crude liquid was then diluted with 150 mL of 10% EtOAc / Heptanes, washed with water, IN NaOH and brine. The combined organic layers were then passed through a l” pad of silica gel. The elute was collected and evaporated to obtain the desired product l-(benzyloxy)-4-fluoronaphthalene (1-2). Yield: 1.25 g, 72 %. 'H NMR (400 MHz, DMSO-tL): 6 8.24 (d, J = 8.12 Hz, 1H), 8.01 (d, J = 8.12 Hz, 1H), 7.65 (m, 2H), 7.56 (m, 2H), 7.44 (m, 2H), 7.37 (m, 1H), 7.26 (m, 1H), 7.02 (dd, J = 8.44 Hz, J = 4.00 Hz, 2H), 5.30 (s, 2H).Synthesis of (4-(benzyloxy)-l -fluoronaphthal en-2-yl)boronic acid (1-3)In a 50 mL flask, 2,2,6,6-Tetramethylpiperidine (Chempure, 672 mg, 4.76 mmol) was dissolved in dry THF under an inert, dry atmosphere and stirred at -40 °C for 5 mins. To this solution, n-BuLi (Hychem, 279 mg, 4.36 mmol) was added dropwise and the resultant mixture was stirred at -40 °C for Ih. Subsequently, the reaction mixture was cooled to -78 °C, triisopropyl borate (Avra, 745 mg, 3.96 mmol) was added and the mixture was stirred at -78 °Cfor 30 min. Compound l-(benzyloxy)-4-fluoronaphthalene (500 mg, 1.98 mmol) was dissolved in dry THF was then added to the reaction mixture dropwise at -78 °C and the reaction mixture was then stirred at 0 °C for 8h. Upon completion, the reaction mixture was quenched IN HC1 and allowed to stir at rt for Ih. Next, the reaction mixture was diluted with DCM, washed with water and brine. The combined organic layers were then evaporated to obtain a pale yellow residue. The residue was further purified using column chromatography using DCM / MeOH eluents to obtain the desired product (4-(benzyloxy)-l -fluoronaphthal en-2-yl)boronic acid (I- 3) as a colorless solid. Yield: 325 mg, 51 %. LC-MS (ESI) m / z = 354.95 [M + OAc]'.Synthesis of 5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2-carbaldehy de (1-5)In a 30 mL vial, compound (4-(benzyloxy)-l -fluoronaphthal en-2-yl)boronic acid (1 g, 3.2 mmol), 5-bromo-furan-2 carbaldehyde (TCI, 1.06 g, 6.1 mmol), potassium carbonate (TCI, 1.77 g, 12.8 mmol) were dissolved in 12 mL of Dioxane / Water (4: 1 v / v). The resultant solution was then sparged with N2 gas for 10 min. Subsequently, Pd(dppf)C12*DCM (Johnson Matthey, 230 mg, 320 pmol) was added to the reaction mixture under an inert atmosphere and the vial was sealed and stirred at 90 °C for 3h. Upon completion, the reaction mixture was filtered through a pad of celite, the filtrate evaporated to dryness to obtain a crude black residue. The crude residue was then purified using column chromatography using DCM / MeOH eluents to obtain the desired product 5-(4-(benzyloxy)-l-fluoronaphthalen-2-yl)furan-2-carbaldehyde (I- 5) as pale yellow solid. Yield: 550 mg g, 41 %. LC-MS (ESI) m / z = 347.10 [M+l]+.Synthesis of (Z)-4-(5-((5-(4-(benzyloxy)-l-fluoronaphthalen-2-yl)furan-2-yl)methylene)-4- oxo-2-thioxothiazolidin-3-yl)butanoic acid (1-7)In a 100 mL flask, 5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2-carbaldehy de (601 mg, 1.58 mmol), 4-(4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (Angene, 315 mg, 1.44 mmol) were suspended in EtOH (10 mL) and refluxed at 85 °C till solution turns a clear yellow. To this refluxing solution, 3 drops of Piperidine (GLR) were added and the resultant solution was refluxed at 85 °C for Ih. Upon completion (TLC control), the reaction mixture was cooled down which led to the precipitation of an orange solid. The orange solid was then filtered, washed with cold water, 5 mL of IN HC1 and 10 ml of cold EtOH. The residue was air dried till a firm, free-flowing solid formed. The resultant orange solid containing the desired product (Z)-4-(5-((5-(4-(benzyloxy)-l -fluoronaphthal en-2-yl)furan-2 -yl)methyl ene)-4-oxo-2- thioxothiazolidin-3-yl)butanoic acid (1-7) was used as such for further reactions. Yield: 730 mg, 93 %. LC-MS (ESI) m / z 548.05 = [M+l]+.Synthesis of (Z)-4-(5-((5-(l-fluoro-4-hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo- 2-thioxothiazolidin-3-yl)butanoic acid (1-8)In a 50 mL flask, under an inert atmosphere (Z)-4-(5-((5-(4-(benzyloxy)-l- fluoronaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (75 mg, 0.137 mmol) was dissolved in DCM (5 mL) and stirred at -78 °C for 10 mins. To this solution, BCh (Spectrochem, 80.2 mg, 685 pmol) was added dropwise and stirred at -78 °C for 2h. Upon completion, the reaction mixture was quenched with water and the resultant mixture was stirred at rt for Ih. The mixture was then diluted with DCM, washed with water and brine. The combined organic layers were dried over sodium sulfate and evaporated to obtain a crude red residue. The crude red solid was purified by reverse-phase HPLC using ACN / W ater eluents and the fractions were lyophilized to obtain the desired compound (Z)-4-(5-((5-(l-fluoro-4- hydroxynaphthalen-2-yl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)butanoic acid (1-8) as dark red solid. Yield: 28 mg, 95 %. LC-MS (ESI) m / z = 458.3 [M+l]+. 'H NMR (400 MHz, DMSO-tL): 6 8.18 (d, J= 8.00 Hz, IH), 8.06 (d, J= 8.00 Hz, IH), 7.72 (s, IH), 7.67 (dt, J= 6.9 Hz, J = l.l Hz, IH), 7.61 (dt, J= 6.9 Hz , J=l.l Hz, IH), 7.46 (d, J=3.8 Hz, IH), 7.35 (d, J = 5.96 Hz, IH), 7.27 (t, J = 3.8 Hz, IH), 4.09 (t, J = 7.04 Hz, 2H), 2.28 (t, J = 7.16 Hz, 2H), 1.89 (m, 2H).Example 12: Antiviral Activity AssayCells, Viruses and ReagentsBaby Hamster Kidney cells (BHK - ATCC: CCL-10) were used for dengue virus serotype 1-4 (DV1 - Hawaii Strain - ATCC: VR-1856; DV2 - New Guinea Strain - ATCC: VR-1584; DV3 - H87 Strain - ATCC: VR-3380; DV4 - H241 Strain -ATCC: VR-1490) infection. Vero cells (ATCC: CCL-81) were used for Zika virus (ATCC - VR-1843) infection. Huh7 cells (gift from the Kuhn lab of Purdue) were used for Kunjin virus (KUNV) and Yellow Fever virus 17D (YFV-17D) infections (both gifts from the Kuhn lab of Purdue). BHK cell complete media: 2% Low IgG FBS Serum (Corning: MT35073CV), lx MEM (Fisher: MT10010CV) and lx PenStrep (Fisher: 15-140-148). Vero and Huh7 cell complete media: 2% Low IgG FBS, lx DMEM (Fisher: MT10013CV), and lx PenStrep. Cells were washed with lx PBS (Fisher: MT21040CV) unless otherwise specified.Cell-Based Flavivirus Infection (CFI) AssayBHK cells for DV2 infection, were each seeded at a density of 40,000 cells per well in 96 well, black walled, clear flat bottom plates (Thermo Scientific: 165305). The day after seeding, 50 pl of ten 5-fold serial dilutions of each Compound or Free Targeting Ligand (Compound 2) (from 200 pM to 102.4 pM) were added to specific wells. Cells were then infected with 50 pl of dengue 2 to a final MOI of 5 and final compound concentration of i the original concentration, and the cells were incubated at 37°C for 24 hours. After the incubation, cells were washed twice with PBS and were fixed with 4% paraformaldehyde for 20 minutes at 37°C. After fixation, cells were washed twice and were permeabilized with 0.5% Triton X-100 (Fisher: AAA16046AE) in lx PBS for 30 minutes at room temperature. Cells were washed twice and 100 pl of blocking buffer (BB - lx PBS, 2% FBS [Fisher: 10- 082-147], 0.05% Tween 20 [Fisher: AAJ20605AP]) was added to each well. Cells were incubated with the blocking buffer overnight at 4°C. The next day, cells were washed and 50 pl of Mouse anti-flavivirus E protein monoclonal antibody 4G2 (Fisher: NBP25270902) at a dilution of 1 :500 in BB was added to each well and incubated at 37°C for 1 hour. After washing twice, 50 pl of Goat anti-Mouse IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (Fisher: Al 1001) at a dilution of 1 :500 in BB was added to each well for 1 hour at 37°C. Cells were then washed twice, and lOOul of DAPI solution in BB (1 pg / ml working concentration [Invitrogen - 62248]) was added to each well. Cells were imaged using an Invitrogen™ EVOS™ M5000 Imaging System (Fisher - 12-563-631). Total Mean Fluorescence of Images was processed using Image J software (UCSF: ImageJ). Data was plotted and statistical significance was calculated using GraphPad Prism (version 10.3.1). The results are shown in Fig. 1. Compound 1 was found to reduce significantly viral infection by nearly 50% at 10 pM, similar to the free ligand, Compound 2, suggesting Compound 1 retained antiviral activity upon conjugation with linkers and haptens.Example 13: Immunofluorescence Assay (IFA)BHK cells for DV2 infection, were each seeded at a density of 0.1 x 106 cells per well in 12 well flat bottom plates. The next day, cells were infected with DV2 at an MOI of 1 in 250 pl of complete media for 1 hour at 37°C with rocking. After the incubation, complete media was added to the cells to bring the final volume to 1 ml. The infection was allowed to progress for 24 hours, after which the media was removed, and cells were washed twice. Cells were fixed with 500 pl of 4% Paraformaldehyde in PBS per well at 37°C for 20 minutes. The fixative was removed, and cells were washed twice with lx PBS. The cells were then permeabilized with 500 pl of 0.5% Triton X-100 per well for 30 minutes at room-temperature. After the incubation, the cells were washed twice and 500 pl of BB was added to each well and plates were incubated at 4°C overnight. Cells were washed twice, and 250 pL of: 10 pM Compound 1 or 10 pM Compound 1 + 10 mM of Targeting Ligand (TL), was added to specific wells and allowed to incubate overnight at 4°C . The next day, cells were washed twice with lx PBS and 250 pL of Mouse anti-flavivirus E protein monoclonal antibody 4G2 and Rabbit anti-DNP antibody (CF 750 Rabbit Anti -DNP - Biotium - 20869) each at a dilution of 1 :500 in BB, was added to each well and incubated at 37°C for 1 hour. After washing twice, 250 pl of Goat anti-Mouse IgG (H+L) Cross- Adsorbed Secondary Antibody, Alexa Fluor™ 488 (Fisher: Al 1001) at a dilution of 1 :500 in BB was added to each well for 1 hour at 37°C. Cells were then washed twice, and 500 pl of DAPI solution in BB was added to each well. Cells were imaged using an Invitrogen™ EVOS™ M5000 Imaging System (Fisher - 12-563-631) and overlays were created using Image J. Compound 1 was found to localize to infected cells only and not to uninfected cells. Compound 1 colocalized strongly with DV2 E protein expression, suggesting successful binding of the Compound 1 with DV2 E protein as hypothesized. This interaction was shown to be outcompeted by the presence of lOOx Free Ligand, suggesting that the Compound 1 does not bind promiscuously to non-target proteins. Moreover, no anti-DNP antibody signal was observed in non-infected cells incubated with Compound 1, further supporting the specificity of Compound 1.Example 14: Antibody-Dependent Cellular Cytotoxicity (ADCC) AssayClarified virus supernatant containing 1.87 x 107 PFU / ml of DV2 was used for the assay. The day of the assay, 25 pL per well of DV2 supernatant diluted to a final viral load of 1 x 106 PFU / ml in ADCC buffer (Promega: G7015A) was seeded into 96 well white-walled plates, and the ADCC assay was performed according to the manufacture’s suggestions (Promega: G7015). Briefly, serial 5-fold dilutions of Compound 1, 12 or 13, and Compound 1, 12, and 13 + lOOx Compound were made in ADCC media ranging from 400 pM down to 32 nM. After adding the 25 pL of DV2, 25 pL of ADCC media containing compounds was added to selected wells, and plates were incubated at 37°C for 30 minutes. Next, 25 pL of anti-DNP IgG antibodies (Aero Biosystems - DNP-M2-25mg) was added to selected wells at a concentration of 33.3 pg / ml in ADCC media and plates were incubated again at 37°C for 30 minutes. Finally, 25 pL of ADCC effector cells were then added to each well, and the plates were incubated at 37°C for 6 hours. After the 6-hour incubation, 70 pl of the luminescent reporter reagent was added to each well and the plates were read using a Spark® 10M Multimode Microplate Reader (Tecan). The EC50 curves were calculated usingGraphPad Prism (version 10.3.1). The results are shown in Fig. 2. Compound 1 was found to activate natural killer effector cells when bound to Dengue 2 virus in the presence of antihapten antibodies. This interaction was found to be specific for Compound 1, as it was shown to be outcompeted by free ligand, Compound 2. These results indicate that Compound 1 specifically bridges the immune system to Dengue 2 virus virions, supporting a dual hapten mechanism of action.Example 15: In vivo Efficacy StudyThe efficacy of Compound 1 to manage or delay dengue 2 virus viremia in animals was explored using eight-week-old AG129 mice (Jackson Laboratories) as a model system. In total, 10 mice were infected with lx 106 PFU / ml of DV2 on Day 0 via tail vein injection. In addition, the mice were also given 6g / kg of Human IVIG via intraperitoneal injection on day 0 and day 3 and day 6. Beginning on Day 1 (24 hours after infection), 5 mice were treated with 1.5 mg / kg of Compound 1 suspended in Phosphate buffered saline twice a day for 7 days via subcutaneous injection. The other 5 mice were given empty vehicle in parallel to the Compound 1 group. Blood samples were collected once daily via facial veins, and samples were used for downstream qRT-PCR and NS1 quantification assays. Body weight was also recorded at each treatment session. On Day 8 of the study, the animals were euthanized, and a final blood sample was collected via cardiac puncture. The brain, spleen, kidneys and liver of the mice were also harvested for qRT-PCR. The organ tissues for RNA analysis were automatically homogenized using a Fisherbrand Bead Mill 4 Mini Homogenizer (Fisher - 15-340-164). Viral RNA was extracted from the blood and organ samples following the product protocol of Zymo Quick- RNA MicroPrep kit (Zymo Research: R1051). RNA was then quantified with qRT-PCR with primers specific to DENV E protein and GAPDH (for organ samples) using Bio-Rad's iTaq Universal SYBR Green SuperMix (Bio-Rad: 1725121) and a Biorad CFX Connect Real-Time PCR System. Relative amounts of Viral RNA were standardized to the amount of the housekeeping gene GAPDH for the organ samples, or molecules of RNA / ml for the blood samples. NS1 quantification in blood samples was done by first separating the red blood cells from serum via centrifugation at 1,000 x g for 15 minutes at room temperature. An aliquot of 10 pl from each serum sample was used in an NS1 ELISA assay following the manufacturer’s recommendations (Eagle Biosciences: ARG81357). All graphs and AUC analyses were generated using GraphPad Prism 10. The results are shown in Fig. 3. The fold change of DV2 RNA in the blood samples of infected mice was found to be significantly reduced in the Compound 1-treated mice overthe four-day treatment period, suggesting that Compound 1 can prevent Dengue 2 virus viremia from increasing during treatment.Example 16: Addition of the linker and dual haptens does not impair Compound 1 and Compound 12s direct antiviral activity or ability to recruit immune cells.To determine if the various compounds retained their direct antiviral activity after modification (i.e., attaching the dual haptens via linker to the targeting ligand), a cell based flavivirus infection assay was performed. BHK cells were infected with dengue virus serotype 2 (DV2), and Vero cells were infected with Zika virus (ZIKV), each treated with Compound 1 and Compound 12 in either their Free Targeting Ligand (TL) or Dual Hapten (DH) forms. Immunofluorescence analysis showed that both the TL and DH forms of Compound 1 and Compound 12 reduced the infection rates of DV2 and ZIKV compared to untreated controls. Statistical analysis confirmed that the antiviral activity of Compound 1 and Compound 12 DH was about 10-fold that of the free ligand Compound 12, indicating that the addition of dual haptens did not impair antiviral function. Additionally, the retention of antiviral activity in all four serotypes of dengue (DV1-4), ZIKV, KUNV and YFV-17D infections (Figure ID) demonstrates that Compound 1 is effective across multiple flavivirus species, broadening its potential therapeutic applications.An antibody-dependent cellular cytotoxicity (ADCC) assay was used to evaluate whether Compounds could present their dual haptens to immune effector cells in the presence of DV2. In this assay, the Compound’s ability to activate natural killer (NK) cells was measured. Compound 1 and Compound 12 elicited strong activation of effector cells, with an EC50 value of 391 nM and 3.68 nM, respectively, demonstrating that the dual haptens remain accessible to immune cells at relatively low concentrations. These results confirm that the dual haptens on Compounds 1 and 12 remain accessible to immune cells, supporting the compound’s proposed mechanism of action, wherein the compounds bind to the E protein on flaviviruses and simultaneously recruit immune cells to the virions in the bloodstream. By doing so, Compounds 1 and 12 promote targeted cellular cytotoxicity against free floating virions, enhancing the potential for viral clearance and reduction in Viremia. This immune recruitment capability not only validates Compound 1 and 12 specificity and functionality but also suggests a dual therapeutic action — direct antiviral activity combined with immune- mediated cell clearance — that could be highly effective in treating flavivirus infections.The ability for Compound 1 or Compound 12 to present its dual haptens to the surrounding environment when bound to DV2 was determined via ADCC assay with clarifiedvirus particles (1x106 PFU / well). A) Results show that Compound 1 elicits a robust and site-specific activation of effector (i.e., NK) cells with an ECso value of 391 nM. These results suggest that the dual haptens attached to Compound 1 are not obstructed from interacting with immune cells, confirming our mechanism of action. B) Moreover, Compound 12 exhibited even greater effector cell activation, with an ECso value of 3.68 nM, nearly a 100-fold increase in effector cell activation compared to Compound 1. C) Table of ECso values for all tested compounds.Example 17: Compound 1 binds specifically to flavivirus E proteinConfirming the binding specificity of Compound 1 is essential to ensure that it minimizes off-target interactions when introduced into a biological system. An immunofluorescence assay was conducted on DV2-infected cells to assess Compound 1’s binding specificity to the E protein of flaviviruses. The assay demonstrated that Compound 1 co-localizes with the DV2 E protein, as evidenced by their overlapping signals in the fluorescence overlay. When the free ligand (lOOx FL) was added as a competitor, it effectively outcompeted Compound 1. Given the established specificity of the free ligand for the E protein (data not shown), this competitive binding confirms that Compound 1 also specifically targets the E protein of DV2. This competitive binding strongly supports the selective targeting capability of Compound 1 in flavivirus infection, reducing the likelihood of off-target interactions in a complex biological system. These findings highlight the potential of Compound 1 to precisely target viral particles in infected cells, thereby enhancing its safety profile for therapeutic applications.Example 18: In vivo efficacy of Compound 1 in an AG129 mouse modelAG129 mice lack interferon a / and y genes, which makes them highly susceptible to mouse-adapted dengue infections (Zellweger & Shresta, 2014). To evaluate the effectiveness of Compound 1 in reducing viremia and improving survival in this model, we treated AG129 mice with Compound 1 following infection with dengue virus serotype 2 (DV2). Mice were infected with IxlO6plaque-forming units (PFU) per ml of the mouse-adapted dengue strain D2S20 via tail vein injection. In addition to viral infection, mice were administered 6 g / kg of Human IVIG via intraperitoneal injection on day 0 and day 3 to facilitate the immunological engagement of Compound 1. 24 hours post infection, the treatment group (n=4) was given 1.8 mg / kg of Compound 1 suspended in PBS via subcutaneous injection. The treatment continued to be administered twice a day for 4 days. Blood samples and body weights weremeasured each day to monitor the infection process. Treatment with Compound 1 lead to 100% survival of the treatment group, while only 40% of the vehicle group (n=4) survived. The daily blood samples were analyzed using qRT-PCR to detect NS1 and DV2 RNA levels. Both NS1 and DV2 RNA levels were reduced with Compound 1 treatment, with statistical analysis of the area under the curve indicating p-values of 0.004 and <0.001, respectively. These findings confirm Compound 1’s in vivo antiviral efficacy and its potential to suppress dengue infection effectively.Our Bispecific Antigenic Immuno-Therapy molecules are a novel approach to treating viral infections with the power of the immune system. Initial results indicate that our bispecific molecules protect against DV2 and ZIKV infection in vitro. This suggests that our targeting ligands are still able to bind to flavivirus particles, disrupting some early stages of virus entry or fusion. In addition, effector cell activation suggests that the binding is specific, and the haptens linked to our targeting ligands are still accessible to antibodies and thus able to recruit an immune response. Positive in vivo data suggests that our mechanism of action is effective at protecting AG129 mice from lethal infection. Combination of the direct antiviral effect of Compound 1 with recruitment and activation of immune cells will likely lead to a more powerful overall effect than can be achieved with traditional antiviral approaches.While these early results are promising, further research is needed to optimize Compound 1’s efficacy and broaden its applicability. Future studies will focus on testing Compound 1 against additional dengue virus strains and a wider range of flaviviruses to confirm its broad-spectrum antiviral potential. Structural modifications to Compound 1 will also be explored to enhance binding affinity, stability, and efficacy. Importantly, in vivo studies will be conducted to determine whether Compound 1 treatment contributes to antibody-dependent enhancement (ADE), a critical consideration in dengue therapy development. Ensuring that Compound 1 does not induce ADE will be essential for advancing this therapy into clinical stages.The creation of this antiviral could have far-reaching implications for public health. A therapeutic agent capable of treating multiple flavivirus infections would not only save lives but also reduce the economic burden in regions heavily affected by these diseases. Given the increasing global spread of dengue and related viruses, the development of a versatile, immune-engaging antiviral like Compound 1 could be transformative in both clinical and public health contexts.All patents, patent application publications, journal articles, textbooks, and otherpublications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.The invention illustratively described herein may be suitably practiced in the absence of any element(s) or limitation(s), which is / are not specifically disclosed herein. Thus, for example, each instance herein of any of the terms “comprising,” “consisting essentially of,” and “consisting of’ may be replaced with either of the other two terms. Likewise, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods and / or steps of the type, which are described herein and / or which will become apparent to those ordinarily skilled in the art upon reading the disclosure. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. The following terms and phrases shall have the meaning indicated.In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section.

Claims

WHAT IS CLAIMED IS:

1. A conjugate of the Formula I:A1 T-k'A2or a pharmaceutically acceptable salt thereof, wherein:T is a radical of a targeting ligand for an envelope (E) protein on the surface of aFlavivirus or a Flavivirus-infected cell;L is a linker; and Ai and A2 are each a radical of an independently selected hapten.

2. The conjugate of claim 1, wherein T is Formula II or Formula III (where points of attachment to L are represented byFormula II Formula III or pharmaceutically acceptable salt thereof; wherein: each R is independently hydrogen or a Ci-Ce alkyl (e.g., methyl);RI is hydrogen, a Ci-Ce alkyl carbonyl,R2 is hydrogen or heterocyclyl alkyl;X is hydrogen or halogen; each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; orR3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is optionally substituted with a group selected from a Ci- Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, wherein alkyl is optionally substituted with hydroxyl;P is CJL or NH; n is 0 or 1;Q is CH or N; and Y is CH or N.

3. The conjugate of claim 1, or pharmaceutically acceptable salt thereof, wherein T is:group and the thioxothiazolidin-4-one is E or Z.

4. The conjugate of claim 2, or pharmaceutically acceptable salt thereof, wherein Ai and A2 are each independently selected from a rhamnose fragment, an a-galactose fragment, a dinitrophenyl fragment, and a trinitrophenyl fragment.

5. The conjugate of claim 1, or pharmaceutically acceptable salt thereof, wherein L comprises a chain of atoms from 3 atoms to 60 atoms in length.

6. The conjugate of claim 1, or pharmaceutically acceptable salt thereof, wherein L comprises one or more peptide fragments.

7. The conjugate of claim 6, or pharmaceutically acceptable salt thereof, wherein L comprises a lysine fragment of the formula:attached to the lysine fragment via a linker.

8. The conjugate of claim 1, or pharmaceutically acceptable salt thereof, wherein L comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36.

9. The conjugate of claim 1, or pharmaceutically acceptable salt thereof, wherein L comprises an alkylamido fragment or an alkylamidoalkyl fragment.

10. A conjugate of the Formula IV:L3-A1T-lY2-A2or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, wherein:T is a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell;LEL3are each, independently, a linker; and A1and A2are each, independently, a hapten.

11. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein T is Formula II or Formula III (where points of attachment to L are represented byFormula II Formula III wherein: each R is independently hydrogen or a Ci-Ce alkyl;RI is hydrogen, a Ci-Ce alkyl carbonyl,R.2 is hydrogen or heterocyclyl alkyl;X is hydrogen or halogen; each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; orR3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with hydroxyl;P is CH2or NH; n is 0 or 1;Q is CH or N; andY is CH or N.

12. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein T comprises:group and the thioxothiazolidin-4-one is E or Z. In some embodiments, the bond between the tetrahydrofuranly group and the thioxothiazolidin-4-one is Z.

13. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein A1and A2are each independently selected from a rhamnose fragment, an a- galactose fragment, a dinitrophenyl fragment, and a trinitrophenyl fragment.12114. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein each of L1, L2, and L3independently comprises a chain of atoms from 3 atoms to 60 atoms in length.

15. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises one or more peptide fragments.

16. The conjugate of claim 15, or pharmaceutically acceptable salt thereof, wherein L1comprises a lysine fragment of the formula:attached to the lysine fragment via L2.

17. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises a polyethylene glycok (PEGn) fragment, wherein n = 1-36.

18. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein L1, L2, or L3each, independently, comprises an alkylamido fragment or an alkylamidoalkyl fragment.

19. The conjugate of any claim 10, or pharmaceutically acceptable salt thereof, wherein L1comprises:wherein m is an integer from 0 to 20.

20. The conjugate of claim 19, or pharmaceutically acceptable salt thereof, wherein L2comprises:122wherein p and q are each, independently, an integer from 0 to 20.

21. The conjugate of claim 19 or 20, or pharmaceutically acceptable salt thereof, wherein L3comprises:wherein d is an integer from 0 to 20.

22. The conjugate of claim 10, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:123wherein m, p, d, and q are each, independently, an integer from 0 to 20.

23. A conjugate of the Formula IV:or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt thereof, wherein:T is a targeting ligand for an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell;L^L4are each, independently, a linker;A1and A2are each, independently, a hapten; andE1is T or a pharmacokinetic enhancer.

24. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein T is Formula II or Formula III (where points of attachment to L are represented bywherein: each R is independently hydrogen or a Ci-Ce alkyl;124RI is hydrogen, a Ci-Ce alkyl carbonyl,R.2 is hydrogen or heterocyclyl alkyl;X is hydrogen or halogen; each R3 and R4 is independently hydrogen or a Ci-Ce alkyl; orR3 and R4, together with the carbon atom to which they are attached, form a 6- membered aryl ring, which is optionally substituted with a group selected from a Ci-Ce alkyl, a hydroxy Ci-Ce alkyl, an aryl Ci-Ce alkyl, and hydroxyl, or pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with hydroxyl;P is CH2or NH; n is 0 or 1;Q is CH or N; andY is CH or N.

25. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein T comprises:group and the thioxothiazolidin-4-one is E or Z. In some embodiments, the bond between the tetrahydrofuranly group and the thioxothiazolidin-4-one is Z.

26. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein A1and A2are each independently selected from a rhamnose fragment, an a- galactosyl fragment, a dinitrophenyl fragment, and a trinitrophenyl fragment.

27. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, and L4independently comprises a chain of atoms from 3 atoms125to 60 atoms in length.

28. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, whereinL1, L2, or L3each, independently, comprises one or more peptide fragments.

29. The conjugate of claim 28, or pharmaceutically acceptable salt thereof, wherein L1comprises a lysine fragment of the formula:attached to the lysine fragment via L2.

30. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, whereinL1, L2, L3or L4each, independently, comprises a polyethylene glycoln (PEGn) fragment, wherein n = 1-36.

31. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein L1or L4comprises:wherein m is an integer from 0 to 20.

32. The conjugate of claim 31, or pharmaceutically acceptable salt thereof, wherein L2comprises:wherein p and q are each, independently, an integer from 0 to 20.

33. The conjugate of claim 31 or 32, or pharmaceutically acceptable salt thereof, wherein L3comprises:126wherein d is an integer from 0 to 20.

34. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein L4comprises -(Cffcjm-35. The conjugate of claim 23, or pharmaceutically acceptable salt thereof, wherein the fragment:comprises a fragment of the formula:127wherein m, p, and d are each, independently, an integer from 0 to 20.

36. A conjugate of formula:128or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a conjugate of claim 1, 23 or 36 and a pharmaceutically acceptable excipient.

38. A method of treating a Flavivirus infection in a subject comprising administering to the subject an effective amount of the conjugate of claim 1, 23 or 36 or the pharmaceutical composition of claim 37.

39. The method of claim 38, or pharmaceutically acceptable salt thereof, wherein the Flavivirus is Dengue virus serotype 1, 2, 3 or 4, Yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), or Zika virus.

0. A method of preparing a compound for targeting to an envelope (E) protein on the surface of a Flavivirus or a Flavivirus-infected cell, which method comprises attaching the ligand:to the compound via a linker, whereupon the compound is prepared for targeting to the E protein.132

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