Conjugates, compositions and methods for treating RSV infection

Abstract

Conjugate compounds comprising (i) a ligand, which targets a protein of RSV or an RSV-infected cell, (ii) two or more haptens, and (iii) linkers connecting the ligand and one or more haptens; pharmaceutical compositions comprising the conjugate compounds; and methods of delivering the agent to RSV or an RSV-infected cell for therapy are described herein.

Description

Docket No. 1165.071132WO01CONJUGATES, COMPOSITIONS AND METHODS FOR TREATING RSV INFECTIONPRIORITY CLAIM

[0000] This patent application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 789,866 (filed April 16, 2025) and 63 / 984,020 (filed February 16, 2026), both of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0001] The present disclosure relates to a conjugate comprising (i) a ligand, which targets a protein on the surface of a virus or a virus-infected cell, (ii) one or more haptens, and (iii) linkers connecting the ligand and one or more haptens, and the use of the conjugate, such as a composition comprising the conjugate, to deliver the agent to a human in need thereof for RSV treatment.BACKGROUND

[0002] Respiratory syncytial virus (RSV) is a respiratory virus that causes cold-like symptoms and can lead to serious lung infections, particularly in pediatric and geriatric patients and immunocompromised adults.

[0003] The F glycoprotein (“F protein”) is a class I fusion protein that mediates viral entry of RSV into a cell by fusing the viral envelope with a host cell membrane. The F protein consists of two disulfide-linked subunits - Fl and F2. The Fl subunit contains a hydrophobic fusion peptide at its N terminus followed by two heptad repeats - HR1 and HR2, which are separated by an intervening region of about 300 amino acids. The G glycoprotein (“G protein”) exists in both membrane-bound and secreted forms, and is primarily responsible for viral attachment to host cells.

[0004] High-risk pediatric patients can be treated prophylactically with antibodies, such as the monoclonal antibody palivizumab, to reduce the incidence and severity of RSV infection. While ribavirin is approved for the treatment of severe RSV infection, its clinical efficacy is suboptimal.

[0005] However, there is an unmet need to treat RSV infection both prophylactically and after infection in a host animal.SUMMARY

[0006] Described herein are non-antibody, small-molecule compounds capable of preventing and treating RSV infection in a host animal. Also described herein are compositions and unit doses comprising the compounds, and methods and uses for using the compounds, compositions, andDocket No. 1165.071132WO01unit doses for preventing and treating RSV infection in a host animal. The compounds described herein comprise (i) a ligand capable of targeting a protein on the surface of a virus or a virus-infected cell, (ii) one or more haptens capable of recruiting antibodies, and (iii) linkers connecting the ligand and one or more haptens to form a conjugate. Such conjugates include the compounds of Formula I and Formula II as described herein.

[0007] Described herein are compounds of Formula I:L2-A1T-L1-Q\3-A2Formula Iand pharmaceutically acceptable salts and solvates thereof, wherein:T is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;L1, L2, and L3are each, an independently selected linker;Q comprises an optionally substituted trivalent nitrogen atom; andA1and A2are each, a radical of an independently selected hapten.

[0008] Described herein are compounds of Formula I:L2— A1T-L1-Q\3-A2Formula Iand pharmaceutically acceptable salts and solvates thereof, whereinT is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;L1, L2, and L3are each an independently selected linker;Q comprises an optionally substituted trivalent nitrogen atom, an optionally substituted trivalent group, or an optionally substituted CH; andA1and A2are each a radical of an independently selected hapten.

[0009] Described herein are compositions comprising one or more compounds of Formula I:L2-A1T-L1-Q\3-A2Formula I and / orpharmaceutically acceptable salts and solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof.Docket No. 1165.071132WO01

[0010] Described herein are compositions for use in treating RSV infection, the compositions comprising one or more compounds of Formula I:L2-A1T-L1-Q\3-A2Formula I and / orpharmaceutically acceptable salts and solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof.

[0011] Described herein are unit doses for use in treating RSV infection, the unit doses comprising a therapeutically effective amount of one or more compounds of Formula I:,L2-A1T- L1— Q3-A2Formula Iand / orpharmaceutically acceptable salts and solvates thereof, and optionally including one or more diluents, carriers, or excipients, or combinations thereof.

[0012] Described herein are methods for treating RSV infection, the methods comprising administering a therapeutically effective amount of one or more compounds of Formula I:L2-A1T-L1-Q\3-A2Formula Iand / or pharmaceutically acceptable salts and solvates thereof, compositions thereof optionally including one or more diluents, carriers, or excipients, or combinations thereof, or unit doses thereof to a host to a host animal having an RSV infection.

[0013] Described herein are uses of one or more compounds of Formula I:,L2-A1T- L1— Q\3-A2Formula Iand pharmaceutically acceptable salts and 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 an RSV infection in a host animal.

[0014] In a first illustrative embodiment, T is a radical of an RSV fusion (F) glycoprotein. In a second illustrative embodiment, T is a radical of an RSV attachment glycoprotein (G).

[0015] In another illustrative embodiment, each of L1, L2, and L3is independently selected, andDocket No. 1165.071132WO01each may comprise a bond, single divalent atom, or a chain of atoms.

[0016] In another illustrative embodiment, the haptens included in the compounds, compositions, and unit doses described herein recruit endogenous antibodies present in the host animal.

[0017] In another illustrative embodiment, compounds, compositions, and unit doses described herein are used in methods for treating RSV infection in a host animal, where the compounds, compositions, and unit doses are administered to the host animal, and after administration A1and A2, or any epitope of the foregoing are each bound by one or more antibodies.

[0018] In another illustrative embodiment, compounds, compositions, and unit doses described herein are used in methods for treating RSV infection in a host animal, where the compounds, compositions, and unit doses are administered to the host animal, and after administration A1and A2, or any epitope of the foregoing are each bound by a different antibody.

[0019] The compounds, compositions, unit doses, methods, and uses described herein are useful in treating RSV infection. It is to be understood that such treatment includes prophylactic and preventative treatment of host animals, including host animals at risk of RSV infection, or host animals exposed to RSV infection, including when symptoms of RSV infection have not been observed. For example, the compounds, compositions, unit doses, methods, and uses described herein are useful in preventing the onset of RSV infection, and / or decreasing the severity of later arising symptoms associated with RSV infection.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 is a scheme showing an example of a synthetic method for making the compound of Example 2.

[0021] FIG. 2 is a scheme showing an example of a synthetic method for making the compound of Example 1.

[0022] FIG. 3 shows structures for compounds according to the disclosure.

[0023] FIG. 4 is an immunofluorescence assay (IF A) image showing binding specificity of IpM of Compound 5 and 1 pM of Compound 5 + lOOx TMC353121.

[0024] FIG. 5 is a graph showing late-stage infection efficacy of Compound 5 In Vitro. The graph shows Compound 5 ECso values versus RSV long strain time of addition results.

[0025] FIGS. 6A- 6D are graphs showing activation efficacy of Compound 5 against an immunological panel. FIG. 6A shows activation efficacy of Compound 5 in Antibody Dependent Cellular Cytotoxicity (ADCC) assays when bound to RSV infected cells. FIG. 6B shows activation efficacy of Compound 5 in ADCC assays when bound to RSV virus. FIG. 6C shows activation efficacy of Compound 5 in Antibody Dependent Cellular Phagocytosis (ADCP) assays when bound to RSV infected cells. FIG. 6D shows activation efficacy ofDocket No. 1165.071132WO01Compound 5 in Compliment Dependent Cytotoxicity (CDC) assays when bound to RSV infected cells.

[0026] FIGS. 7A-7B are bar graphs showing dosing window of Compound 5 in mice. The graphs compare the effect of Compound 5 on RSV titer compared to vehicle, Ziresovir, and uninfected control, in upper respiratory tract infection (FIG. 7A) and lower respiratory tract infection (FIG. 7B).

[0027] FIGS. 8A-8B are bar graphs showing dosing window of Compound 5 in mice. FIG. 8A compares the effect of Compound 5 dosed subcutaneous (SC) at either 24hpi, 48hpi, 72hpi, 96hpi, 120hpi, 144hpi, or 168hpi to vehicle on RSV titer levels in nasal turbinates. FIG. 8B shows the effect of Compound 5 versus vehicle at 24hpi, 48hpi, 72hpi, and 96hpi on concentration of cytokines IL-ip, IP- 10, MCP-1, and TNF-a.

[0028] FIGS. 9A-9F are various graphs showing the efficacy of Compound 5 in neonatal lamb. Lambs were randomly assigned to four different groups, including a Vehicle treated Group (PBS) (n=7), two Compound 5 treatment groups - Low-Dose: 2.25 pmol / kg (n = 7) and High-Dose: 6.75 pmol / kg (n = 7) - and a single Mock infected group (n = 6). Lambs were infected with RSV on Day 0 and then treated 24hpi (Day 1) with Vehicle (Group 1), Compound 5 Low-Dose (Group 2), Compound 5 High-Dose (Group 3). The Vehicle group, serving as a positive RSV control group, was infected with RSV but received treatment with Vehicle 24hpi. The Mock RSV infected group (Group 4) served as the negative RSV control group and was aerosolized with RSV-free, Hep-2 cell-conditioned media. It received no treatment. FIG. 9A shows viral titer and viral RNA levels in lung tissue for Compound 5 (high and low dose) and vehicle treated groups, as well as for the Mock RSV infected group (non-infected). FIG. 9B shows viral titer and viral RNA levels in bronchioalveolar Lavage Fluid (BALF) for Compound 5 (high and low dose) and vehicle treated groups, as well as for the Mock RSV infected group (non-infected). FIG. 9C and 9D shows lung damage scores for Compound 5 (high and low dose) and vehicle treated groups, as well as for the Mock RSV infected group (non-infected). FIG. 9D shows resting respiratory rate for Compound 5 (high and low dose) and vehicle treated groups, as well as for the Mock RSV infected group (non-infected). FIG. 9E is a bar graph showing % of RSV induced lung lesions for vehicle and Compound 5 treated lungs, as well as non-infected lungs. FIG. 9F shows the morphology of Compound 5 or vehicle treated neonatal lamb lungs, as well as non-infected neonatal lamb lung.

[0029] FIGS. 10A-10D are graphs showing anti-infection efficacy of Compounds 6, 7, 12, and 13 In Vitro. The ability of Compound 6, 7, 12, and 13 to halt lethal infection was examined byDocket No. 1165.071132WO01cytopathic effect (CPE) assay. FIG. 10A shows anti-infection efficacy of Compound 6. FIG.10B shows anti-infection efficacy of Compound 7. FIG. IOC shows anti-infection efficacy of Compound 12. FIG. 10D shows anti-infection efficacy of Compound 13.

[0030] FIGS. 11A-11C are graphs showing immunological profiles of Compounds 6, 7, and 12-16. FIG. 11A shows activation efficacy of Compounds 6 and 7 in Antibody Dependent Cellular Cytotoxicity (ADCC) assays when bound to RSV infected cells while in the presence of anti-hapten antibodies. FIG. 11B shows activation efficacy of Compound 12 in ADCC assays when bound to RSV infected cells while in the presence of anti-hapten antibodies. FIG. 11C shows activation efficacy of Compounds 13-16 in ADCC assays when bound to RSV infected cells while in the presence of anti-hapten antibodies.

[0031] FIGS. 12A-12E are graphs showing efficacy of Compounds 7, 12, and 13 at various doses and routes of administration for reducing RSV titer in both upper and lower respiratory tract infections in mice. FIG. 12A shows nasal turbinates viral titer for vehicle and Compounds 7 and 12 administered at various doses and routes of administration. FIG. 12B shows lung viral titer for vehicle and Compounds 7 and 12 administered at various doses and routes of administration. FIG. 12C shows nasal turbinates RNA for vehicle and Compounds 7 and 12 administered at various doses and routes of administration. FIG. 12D shows nasal turbinates viral titer for vehicle, Ziresovir, and Compounds 7 and 13 administered at various doses. FIG.12E shows lung viral titer for vehicle, Ziresovir, and Compounds 7 and 13 administered at various doses.

[0032] FIG. 13 shows structures for compounds according to the disclosure.DETAILED DESCRIPTION

[0033] All headings, captions, and numbering sequences used in this specification are for convenience of reference only and shall in no way define, limit, or describe the scope or intent of this invention or any part thereof.

[0034] The following enumerated clauses serve to further illustrate the invention described herein. The clauses describe various features and aspects of the ligands and haptens, and various combinations of those features and aspects in the many embodiments of the invention. The following enumerated clauses illustrate many embodiments of the invention and are not to be construed as limiting the scope of the invention in any way.1. A compound of the formulaL2— A1T-L1-Q\3-A2Docket No. 1165.071132WO01Formula Iand pharmaceutically acceptable salts and solvates thereof, whereinT is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;L1, L2, and L3are each an independently selected linker;Q comprises a trivalent nitrogen atom; andA1and A2are each a radical of an independently selected hapten.1 A. A compound of the formula,L2-A1Formula Iand pharmaceutically acceptable salts and solvates thereof, whereinT is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;L1, L2, and L3are each an independently selected linker;Q comprises an optionally substituted trivalent nitrogen atom, an optionally substituted trivalent group, or an optionally substituted CH; andA1and A2are each a radical of an independently selected hapten.2. The compound of clause 1, wherein L1, L2, and L3taken together do not compriseNH0wherein m, p, d, and q are each, independently, an integer from 0 to 20, such as from 1 to 20, 0 to 15, 1 to 10, 2 to 10, 2 to 8 or 3 to 9.3. The compound of clause 1 or 2 of the formula(PEG2)n— A1T— X1-(PEG1)m-X2- X3-^'(PEG3)Z— A2Formula IIDocket No. 1165.071132WO01and pharmaceutically acceptable salts and solvates thereof, wherein:T is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;PEG1, PEG2, and PEG3are each, independently groups of the formula OCH2CH2;PEG2optionally comprises a C(O)NHCH2CH2 group between two adjacent OCH2CH2 groups (e g., -OCH2CH2C(O)NHCH2CH2OCH2CH2-);PEG3optionally comprises a NHC(O)CH2CH2 group between two adjacent OCH2CH2 groups (e g., -OCH2CH2NHC(O)CH2CH2OCH2CH2-);n, m, and z are each, independently 3 to 36;X1is alkylene, such as ethylene (-CH2CH2-);X2is absent or a group selected from:‘ , wherein t is 2 to 10;, wherein g is 2 to 10, wherein g is 2 to 10; or, wherein r is 2 to 10;X3is absent or carbonyl (C(O)); andA1and A2are each, a radical of an independently selected hapten.4. The compound of any preceding clause, wherein the target protein is an RSV fusion (F) glycoprotein.5. The compound of any preceding clause, wherein the target protein is an RSV attachment glycoprotein (G).6. The compound of any preceding clause, wherein the ligand is an inhibitor of RSV fusion (F) glycoprotein.7. The compound of any preceding clause, wherein the ligand is an inhibitor of RSV attachment glycoprotein (G).8. The compound of any preceding clause, wherein the ligand is of the formulaDocket No. 1165.071132WO01where X is CH2, O, S, or SO2; n is 1 or 2 with the proviso that if X is not CH2, n is 2; and Y is alkyl, halo, CN, alkoxy, alkyl-OH, or H.9. The compound of any preceding clause, wherein the ligand is TMC353121or an analog or derivative thereof, such as compounds disclosed in WO 2005 / 058869, WO 2005 / 058871, WO 20025 / 058874, and the like.10. The compound of any preceding clause, wherein the ligand isNH2 or or an analog or derivative thereof.11. The compound of any preceding clause, wherein the ligand isHOor an analog or derivative thereof.12. The compound of any preceding clause, wherein the ligand is of the formulaDocket No. 1165.071132WO01where Ri is NH2, NHRn, where Rn is alky, amino, hydroxyalkyl, OR, or OH; R2 is alkyl (C-l to C-4), halo, CN, N3, OR; R3 is alkyl (C-l to C-4); and R4is alkyl (C-l to C-4), halo, CN, N3, OR.13. The compound of any preceding clause, wherein the ligand is presatoviraor an analog or derivative thereof.14. The compound of any preceding clause, wherein the ligand is of the formulawherein Ra and Rb are independently selected from alkyl (C1-C4), alkoxyl (C1-C4), halo, cyano, and azido; and n is 1, 2, or 3.15. The compound of any preceding clause, wherein the ligand isDocket No. 1165.071132WO01NH2or an analog or derivative thereof.16. The compound of any preceding clause, wherein the ligand is susinatoviror an analog or derivative thereof.17. The compound of any preceding clause, wherein the ligand isor an analog or derivative thereof.18. The compound of any preceding clause, wherein the ligand is VP- 14637Docket No. 1165.071132WO01N~N N~Nor an analog or derivative thereof.19. The compound of any preceding clause, wherein the ligand is of RFI-641~ y N y6 bor an analog or derivative thereof.20. The compound of any preceding clause, wherein the ligand(risetovir, BMS 433771) or an analog or derivative thereof.21. The compound of any preceding clause, wherein the ligand is rilematovir, ziresovir, RSV-IN-1, RSV-IN-5, YM 53403, or BTA-9981, or an analog or derivative of the foregoing.22. The compound of any preceding clause, wherein the ligand is a peptide having SEQ ID NO: 1, or a fragment thereof.23. The compound of any preceding clause, wherein the ligand is a peptide having SEQ ID NO: 18, or a fragment thereof.Docket No. 1165.071132WO0124. The compound of any preceding clause, wherein the ligand is SEQ ID NO: 16 (T118).25. The compound of any preceding clause, wherein the ligand is SEQ ID NO: 34 (T205).26. The compound of any preceding clause, wherein the ligand is SEQ ID NO: 40 (VIQKI), or a substitution isomer selected from VIQKI-I456F (SEQ ID NO: 41)0 and VIQKI-I454F / I456F SEQ ID NO: 42).27. The compound of any preceding clause, wherein the ligand is not a folate.28. The compound of any preceding clause, wherein T is selected from the group consisting of radicals of the formulae29. The compound of any preceding clause, wherein A1and A2are the same hapten.30. The compound of any preceding clause, wherein A1and A2are different haptens.31. The compound of any preceding clause, wherein each hapten is independently selected from a rhamnose, a nitrophenyl, a nitrophenol, a nitroaniline, 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-galactosyl moiety, a sulfated Gal, a phosphorylcholine, a bacterial antigen, and a viral antigen.32. The compound of any preceding clause, wherein each hapten is selected from rhamnose, a-galactosyl moiety, dinitrobenzene, dinitroaniline, trinitrobenzene, and dinitroaniline.Docket No. 1165.071132WO0133. The compound of any preceding clause, wherein A1and / or A2is a radical of a dinitrophenyl (DNP), a dinitrophenol, or a dinitroaniline.34. The compound of any preceding clause, wherein A1and / or A2is a radical of a rhamnose, including L-rhamnose.35. The compound of any preceding clause, wherein one of A1and A2is a radical of L-rhamnose; and the other of A1and A2is a radical of a dinitroaniline.36. The compound of any preceding clause, wherein the hapten has an epitope that has an endogenous Ab, B or T cell.37. The compound of any preceding clause, wherein the hapten is not FITC.38. The compound of any preceding clause, wherein Q comprises N(CH2)3.39. The compound of any preceding clause, wherein Q comprises N(CH2CH2)3.40. The compound of any preceding clause, wherein Q comprises N(CH2CH2O)3.41. The compound of any preceding clause, wherein Q comprises C(O)-N(CH2)2.42. The compound of any preceding clause, wherein Q comprises C(O)-N(CH2CH2)2.43. The compound of any preceding clause, wherein Q comprises C(O)-N(CH2CH2O)2.44. The compound of any preceding clause, wherein Q comprises C(O)-N(CH2CH2O)2.45. The compound 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.46. The compound 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 60.47. The compound 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 36.48. The compound 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 2-36.49. The compound 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 2-36.50. The compound 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.Docket No. 1165.071132WO0151. The compound 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.52. The compound 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.53. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes one or more amino acids.54. The compound 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.55. The compound 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.56. The compound 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.57. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes an ornithine or lysine, including L-ornithine and L-lysine.58. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes a lysine, including L-lysine.59. The compound of any preceding clause, wherein one or more of L1, L2, and L3comprises one or more divalent piperidylcarbonyl radicals.60. The compound of any preceding clause, wherein one or more of L1, L2, and L3comprises one or more divalent isonipecotic acid radicals, or regio isomers thereof, including divalent nipecotic acid radicals and divalent pipecolic acid radicals.61. The compound of any preceding clause, wherein one or more of L1, L2, and L3comprises one or more divalent piperidinyl radicals.62. The compound of any preceding clause, wherein one or more of L1, L2, and L3comprises one or more divalent piperidin-4-yl radicals, divalent piperi din-3 -yl radicals, and / or divalent piperidin-2-yl radicals.63. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes a proline, including L-proline.Docket No. 1165.071132WO0164. The compound 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 1-6.65. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes a (Pro)3, including (L-Pro)3.66. The compound 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).67. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes a (Pro)e, including (L-Pro)e.68. The compound 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).69. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes glycine and serine, including L-serine.70. The compound 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 1-3.71. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)2, including [Gly-(L-Ser)]2.72. The compound 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).73. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes (Gly-Ser)3, including [Gly-(L-Ser)]3.74. The compound 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).75. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes C(O), C(O)O, C(O)NH, OC(O)NH, or NHC(O)NH.76. The compound of any preceding clause, wherein L1and L2each includes or also includes C(O)NH.77. The compound of any preceding clause, wherein L1and L2each includes or also includes (CH2CH2)C(O)NH(CH2CH2).78. The compound of any preceding clause, wherein L1and L2each includes or also includes O(CH2CH2)C(O)NH(CH2CH2)O.79. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes 1,2, 3 -triazol- 1,4-diyl, 1,2, 3 -triazol- 1,4-diyl, or a combination thereof.80. The compound of any preceding clause, wherein one or more of L1, L2, and L3includes or also includes a maleimid-diyl or thiomaleimid-N,S-diyl.Docket No. 1165.071132WO0181. The compound of any preceding clause, wherein L2and / or L3are hydrophilic.82. The compound of any preceding clause, wherein L1includes a region that is capable of forming an a-helical conformation.83. The compound of any preceding clause, wherein the extended conformation of L2and / 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.84. The compound of any preceding clause, wherein L2and / or L3includes 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, from about 6 to about 36, or from about 7 to about 36.85. The compound 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.86. The compound of any preceding clause, wherein the extended conformation of T-L1is at least 10 A, 12 A, 15 A, 20 A, 25 A, 30 A, 35 A, 40 A, 45 A, or 50 A in length.87. The compound of any preceding clause, wherein L1includes or also includes a linear, unbranched chain of atoms having an extended conformation of at least 5 A, 6 A, 7 A, 8 A, 9 A, 10 A, 11 A, 12 A, 13 A, 14 A, or 15 A in length.88. The compound of any preceding clause, wherein L1includes or also includes (PEG)n or aza-(PEG)n, where n is in the range from about6 to about 36, from about 7 to about 36, from about 8 to about 36, from about 9 to about 36, from about 11 to about 36.89. The compound of any preceding clause, wherein L1includes or also includes an hydrophobic region attached to T, and having an extended conformation of at least 1 A, 2 A, 3 A, 4 A, 5 A, 6 A, 7 A, 8 A, 9 A, 10 A, 11 A, 12 A, or 13 A in length.90. A compound of the formulaand pharmaceutically acceptable salts and solvates thereof, wherein:Q comprises an optionally substituted trivalent nitrogen atom, an optionally substituted trivalent group, or an optionally substituted CH;Docket No. 1165.071132WO01Q1comprises a divalent atom selected from the group consisting of O, S, optionally substituted CH2, and optionally substituted NH;L1, L2, and L3are each an independently selected bivalent linker; andA1and A2are each a radical of an independently selected hapten.90A. A compound of the formula: / N\ HOH N^N / =< TNH L2-A’and pharmaceutically acceptable salts and solvates thereof, wherein:Q comprises an optionally substituted trivalent nitrogen atom, an optionally substituted trivalent group, or an optionally substituted CH;Q1comprises a divalent atom selected from the group consisting of O, S, optionally substituted CH2, and optionally substituted NH;L1, L2, and L3are each an independently selected bivalent linker; andA1and A2are each a radical of an independently selected hapten.91. The compound of clause 90, wherein L1, L2and L3are as defined according to any one of clauses 1-89.92. The compound of clause 90 or 91, wherein A1and A2are as defined according to any one of clauses 1-89.93. The compound of clause, any one of clauses 90 to 92, wherein Q is N.94. The compound of clause, any one of clauses 90 to 92, wherein Q1is optionally substituted NH.95. A compound of the formulaHUY u OH / \NH OH N^,N.-L / =< Y H T VN0r O' o H 11 I o H O. HI J or a pharmaceutically acceptable salt or solvate thereof.Docket No. 1165.071132WO0196. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.97. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.98. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.99. A compound of the formulaDocket No. 1165.071132WO01or a pharmaceutically acceptable salt or solvate thereof.99A. A compound of the formula100. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.101. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.102. A compound of the formulaDocket No. 1165.071132WO01or a pharmaceutically acceptable salt or solvate thereof.103. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.104. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.105. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.106. A compound of the formulaDocket No. 1165.071132WO01or a pharmaceutically acceptable salt or solvate thereof.106 A. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.107. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.108. A compound of the formulaa pharmaceutically acceptable salt or solvate thereof.109. A compound of the formulaDocket No. 1165.071132WO01pharmaceutically acceptable salt or solvate thereof.110. A compound of the formulaos , or a pharmaceutically acceptable salt or solvate thereof., or a pharmaceutically acceptable salt or solvate thereof.112. A compound of the formulaDocket No. 1165.071132WO01pharmaceutically acceptable salt or solvate thereof.113. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.114. A compound of the formulaC O XCfCyCor a pharmaceutically acceptable salt or solvate thereof.115. A compound of the formula-n tV'O rVvior a pharmaceutically acceptable salt or solvate thereof.116. A compound of the formula('''A'"'''! <VU'N^N'^NUyU UyU v ,or a pharmaceutically acceptable salt or solvate thereof.117. A compound of the formulaDocket No. 1165.071132WO01T'"I Ao AA Ao k / M AJ o <NxJA <zNyU MyU oOOAO or a pharmaceutically acceptable salt or solvate thereof.118. A compound of the formulaA A A AA Aor a pharmaceutically acceptable salt or solvate thereof.119. A compound of the formulaA AA AAA-J A0^ A- J \ i ix° WoxiXo" or a pharmaceutically acceptable salt or solvate thereof.120. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.121. A compound of the formula> A V A AN'\ AA O AC^A^OY^< ; : :or a pharmaceutically acceptable salt or solvate thereof.122. A compound of the formulaor a pharmaceutically acceptable salt or solvate thereof.123. A compound of the formulaDocket No. 1165.071132WO01a pharmaceutically acceptable salt or solvate thereof.124. A compound of the formulaa pharmaceutically acceptable salt or solvate thereof.

[0035] The foregoing illustrative compounds, as defined by clauses 1-124 may be included in any of the compositions, unit doses, uses, or methods described herein.CONJUGATES

[0036] The conjugate compounds described herein may be formed from a ligand that is capable of targeting a protein of an RSV-infected cell. In many embodiments, the protein is on the surface of an RSV-infected cell, or is otherwise accessible from the surface of an RSV-infected cell. The conjugates described herein may also be formed from two or more haptens, each comprising an immune system responsive epitope or antigen. Described herein are numerous selections for each of the ligand and haptens. Each of the ligands and haptens described herein may be proteinaceous or small molecules. It is to be understood that any ligand and any haptens described herein may be combined to form the conjugates.

[0037] In some embodiments, the conjugates have a dual mechanism of action, where the conjugate inhibits the virus, and also labels or decorates virus-infected cells for intervention by the immune system of the host animal, including humans. The conjugates elicit host animal immune response against the virus or virus-infected cell by recruiting antibodies in the host animal. Illustratively, the antibodies are endogenous.

[0038] Without being bound by theory, it is believed that once recruited, the anti-hapten antibodies bind to the hapten and activate the innate immune system against the target virus and virus-infected cells. The haptens may be the same or different. In the conjugates where the haptens are the same, the immune system of the host animal may be multiplied. In the conjugates where the haptens are different, the immune system of the host animal may respond in multiple ways. The conjugates described herein provide a therapeutic delivery system for selectively orDocket No. 1165.071132WO01specifically delivering haptens to target virus and virus-infected cells. In certain embodiments, the haptens are selected to activate the innate immune system of the subject to recruit immune cells and / or otherwise leverage the subject’s own immune system against the virus. The targeting ligand can selectively or specifically recognize a target protein or receptor, such as an envelope protein of a virus, which can be highly or exclusively expressed on the virus, the surface of an infected cell, or accessible from the surface of an infected cell.

[0039] The compounds, compositions, unit doses, and methods described herein are useful in treating RSV infections, including all strains of RSV, including resistant strains of RSV including, for example, RSV-A and RSV-B.

[0040] Without being bound by theory, it is believed that the method described herein can elicit an immune response leading to clearance of an antibody (Ab)-coated virus or an Ab-coated-virally infected cell via Ab-dependent cellular phagocytosis (ADCP), Ab-dependent cellular cytotoxicity (ADCC), and / or complement-dependent cytotoxicity (CDC) which works in conjunction with the inhibition of viral budding by neuraminidase inhibition leading to viral eradication. The method for activating an immune response can further comprise administering to the subject autologous antibodies, allogeneic IgG antibodies, or human IVIG. In these and other embodiments, the subject may be further treated with anti-hapten antibodies.

[0041] The present disclosure includes conjugates comprising small-molecule inhibitors of F glycoprotein (F protein) of respiratory syncytial virus (RSV) and their use in the treatment of RSV. The small-molecule inhibitors of F protein are used as ligands to target a conjugated agent to F protein present on the surface of RSV and RSV-infected cells. When the conjugate binds to F protein on the virus, it prevents the virus from binding to nucl eolin on the surface of a cell and entering the cell.

[0042] In one example, the RSV targeting ligand is an RSV fusion (F) glycoprotein ligand, or a compound capable of binding to a fusion (F) glycoprotein.

[0043] In one example, the RSV targeting ligand is an RSV attachment glycoprotein (G) ligand, or a compound capable of binding to an RSV attachment glycoprotein (G).

[0044] In many embodiments, illustrative ligands include compounds that target RSV fusion (F) glycoprotein. Illustrative ligands also include compounds that target RSV attachment glycoprotein (G).

[0045] In many embodiments, illustrative ligands include compounds that are inhibitors of RSV fusion (F) glycoprotein, including RSV fusion inhibitors and compounds that inhibit the six-helix bundle formation. Illustrative ligands include compounds that are inhibitors of RSV attachment glycoprotein (G).Docket No. 1165.071132WO01

[0046] In many embodiments, the ligand is of the formulawhere X is CH2, O, S, or SO2; n is 1 or 2 with the proviso that if X is not CH2, n is 2; and Y is alkyl, halo, CN, alkoxy, alkyl-OH, or H.

[0047] In many embodiments, the ligand is TMC353121or an analog or derivative thereof, such as compounds disclosed in WO 2005 / 058869, WO 2005 / 058871, WO 20025 / 058874, and the like.

[0048] In many embodiments, the ligand is of the formulaNH2 or or analogs or derivatives thereof, such as compounds disclosed in Roymans et al. PNAS 107(l):208- 13 (2010), such as compounds disclosed in WO 2005 / 058869 (US 2007 / 0099924), WO 2005 / 058871 (US 2007 / 0043022), WO 2005 / 058874 (US 2007 / 0093502), and the like, the contents of which are incorporated herein by reference.

[0049] In many embodiments, T is a radical of the formulaDocket No. 1165.071132WO01HO OHor or an analog or derivative thereof,.

[0050] In many embodiments, the ligand is of the formulaor an analog or derivative thereof.

[0051] In many embodiments, the ligand is of the formulawhere Ri is NH2, NHRn, where Rn is alky, amino, hydroxyalkyl, OR, or OH; R2 is alkyl (C-l to C-4), halo, CN, N3, OR; R3 is alkyl (C-l to C-4); and R4is alkyl (C-l to C-4), halo, CN, N3, OR.

[0052] In many embodiments, the ligand is presatovirClDocket No. 1165.071132WO01or an analog or derivative thereof, such as compounds disclosed in Mackman et al. J Med Chem 58:1630-43 (2015), WO 2011 / 163518 (US 2012 / 0003215), and the like, the contents of which are incorporated herein by reference.

[0053] In many embodiments, T is a radical of the formula

[0054] In many embodiments, the ligand is of the formula( | )nNH2wherein Ra and Rb are independently selected from alkyl (C1-C4), alkoxyl (C1-C4), halo, cyano, and azido; and n is 1, 2, or 3.

[0055] In many embodiments, the ligand is of the formulaor an analog or derivative thereof, such as compounds disclosed in Bonfanti et al. J Med Chem 51:875-96 (2008), Andries at al. J Antiviral Res 60:209-19 (2003), WO 2001 / 000611, and the like, the contents of which are incorporated herein by reference.

[0056] In many embodiments, T is a radical of the formulaDocket No. 1165.071132WO01

[0057] In many embodiments, the ligand is susinatovirFor an analog or derivative thereof, such as compounds disclosed in Cockerill et al. J Med Chem 64:3658-76 (2021), and the like.

[0058] In many embodiments, T is a radical of the formula

[0059] In many embodiments, the ligand is JNJ-49153390or an analog or derivative thereof.Docket No. 1165.071132WO01

[0060] In many embodiments, T is a radical of the formula

[0061] In many embodiments, the ligand is of the formulaor an analog or derivative thereof.

[0062] In many embodiments, T is a radical of the formula

[0063] In many embodiments, the ligand is BMS-433771or an analog or derivative thereof.

[0064] In many embodiments, T is a radical of the formulaDocket No. 1165.071132WO01

[0065] In many embodiments, the ligand is of the formulaor an analog or derivative thereof, such as compounds disclosed in Yamaguchi-Sasaki et al. ACS Med Chem Lett 11:1145-51 (2020), and the like.

[0066] In many embodiments, the ligand is Ziresoviror an analog or derivative thereof.

[0067] In many embodiments, T is a radical of the formula

[0068] In many embodiments, the ligand is VP-14637or an analog or derivative thereof.

[0069] In many embodiments, T is a radical of the formulaDocket No. 1165.071132WO01

[0070] In many embodiments, the ligand is RFI-641x'-x. ,NH -nNT ?Q0~S~OOor an analog or derivative thereof.

[0071] In many embodiments, the ligand is risetoviror an analog or derivative thereof.

[0072] In many embodiments, T is a radical of the formulaDocket No. 1165.071132WO01

[0073] In many embodiments, the ligand is selected from risetovir, BMS-433771, rilematovir, ziresovir, or an analog or derivative of the foregoing, such as compounds disclosed in Zheng et al. J Med Chem 62:6003-14 (2019), and the like, RSV-IN-1, RSV-IN-5, or an analog or derivative of the foregoing, such as compounds disclosed in Lundin et al. Antiviral Res 88:317-24 (2010), and the like, YM 53403, or BTA-9981, and analogs and derivatives thereof.

[0074] It is to be understood that a radical may be formed on any atom of any of the foregoing ligands to form the radical T.

[0075] In many embodiments, the ligand is a peptide, such as a peptide having SEQ ID NO: 1, or a fragment thereof, including compounds described in Lambert et al. PNAS 93:2186-91 (1996); or a peptide having SEQ ID NO: 18, or a fragment thereof, including compounds described in Outlaw et al. JACS 142:2140-44 (2020).

[0076] In many embodiments, the ligand is SEQ ID NO: 16 (T118); SEQ ID NO: 34 (T205), SEQ ID NO: 40 (VIQKI), or a substitution isomer selected from VIQKLI456F (SEQ ID NO: 41) and VIQKI-I454F / I456F SEQ ID NO: 42).

[0077] In many embodiments, the ligand is VALDPIDISIVLNKIKSQLEESKEWIRRSNKILDSI (VIQKI) (SEQ ID NO: 40), VALDPIDFSIVLNKIKSQLEESKEWIRRSNKILDSI (VIQKI-I456F) (SEQ ID NO: 41), or VALDPIDFSFVLNKIKSQLEESKEWIRRSNKILDSI (VIQKLI454F / I456F) (SEQ ID NO: 42), and analogs and derivatives thereof.

[0078] Illustrative peptide ligands also include GEPIINFYOPLVFPSDEFDASISQVNEKINQSLAFIRKSDELLHNVNAGKSTT (SEQ ID NO: 1), and fragments thereof, including but not limit to IINFYDPLVFPSDEFDASISQVNEKINQSLAFIRK (SEQ ID NO: 2) INFYDPLVFPSDEFDA8ISQVNEKINQSLAFIRKS (SEQ ID NO: 3) NFYDPLVFPSDEFDASISQVNEKINQSLAFIRKSD (SEQ ID NO: 4) FYDPLVFPSDEFDASISQVNEKINQSLAFIRKSDE (SEQ ID NO: 5)Docket No. 1165.071132WO01YDPLVFPSDEFDASISQVNEKINQSLAFIRKSDEL (SEQ ID NO: 6) DPLVFPSDEFDASISQVNEKINQSLAFIRKSDELL (SEQ ID NO: 7) PLVFPSDEFDASISQVNEKINQSLAFIRKSDELLH (SEQ ID NO: 8) LVFPSDEFDASISQVNEKINQSLAFIRKSDELLHN (SEQ ID NO: 9) VFPSDEFDASISQVNEKINQSLAFIRKSDELLHNV (SEQ ID NO: 10) FPSDEFDASISQVNEKINQSLAFIRKSDELLHNVN (SEQ ID NO: 11) PSDEFDASISQVNEKINQSLAFIRKSDELLHNVNA (SEQ ID NO: 12) SDEFDASISQVNEKINQSLAFIRKSDELLHNVNAG (SEQ ID NO: 13) DEFDASISQVNEKINQSLAFIRKSDELLHNVNAGK (SEQ ID NO: 14) EFDASISQVNEKINQSLAFIRKSDELLHNVNAGKS (SEQ ID NO: 15) FDASISQVNEKINQSLAFIRKSDELLHNVNAOKST (SEQ ID NO: 16) DASISQVNEKINQSLAFIRKSDELLHNVNAGKSTT (SEQ ID NO: 17)

[0079] Illustrative peptide ligands also include YTPNDOITLNNSVALDPIDISIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSSTT (SEQ ID NO: 18)and fragments thereof, including but not limit to YTPNDITLNNSVALDPIDISIELNKAKSDLEESKE (SEQ ID NO: 19) TPNDITLNNSVALDPIDISIELNKAKSDLEESKEW (SEQ ID NO: 20) PNDITLNNSVALDPIDISIELNKAKSDLEESKEWI (SEQ ID NO: 21) NDITLNNSVALDPIDISIELNKAKSDLEESKEWIR (SEQ ID NO: 22) DITLNNSVALDPIDISIELNKAKSDLEESKEWIRR (SEQ ID NO: 23) ITLNNSVALDPIDISIELNKAKSDLEESKEWIRRS (SEQ ID NO: 24) TLNNSVALDPIDISIELNKAKSDLEESKEWIRRSN (SEQ ID NO: 25) LNNSVALDPIDISIELNKAKSDLEESKEWIRRSNQ (SEQ ID NO: 26) NSVALDPIDISIELNKAKSDLEESKEWIRRSNQKL (SEQ ID NO: 27) SVALDPIDISIELNKAKSDLEESKEWIRRSNQKLD (SEQ ID NO: 28) VALDPIDISIELNKAKSDLEESKEWIRRSNQKLDS (SEQ ID NO: 29) ALDPIDISIELNKAKSDLEESKEWIRRSNQKLDSI (SEQ ID NO: 30) LDPIDISIELNKAKSDLEESKEWIRRSNQKLDSIG (SEQ ID NO: 31) DPIDISIELNKAKSDLEESKEWIRRSNQKLDSIGN (SEQ ID NO: 32) PIDISIELNKAKSDLEESKEWIRRSNQKLDSIGNW (SEQ ID NO: 33) IDISIELNKAKSDLEESKEWIRRSNQKLDSIGNWH (SEQ ID NO: 34) DISIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQ (SEQ ID NO: 35) ISIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQS (SEQ ID NO: 36)Docket No. 1165.071132WO01SIELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSS (SEQ ID NO: 37) IELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSST (SEQ ID NO: 38) ELNKAKSDLEESKEWIRRSNQKLDSIGNWHQSSTT (SEQ ID NO: 39)

[0080] It is to be understood that radicals may be formed at the N-terminus, the C-terminus, or on an interior atom on the peptide chain to form the radical T. It is also to be understood that other radicals may be formed on a side chain of an amino acid to form the radical T.

[0081] In many embodiments, T is selected from the group consisting of radicals of the formulae

[0082] The haptens described herein can each be bound by an antibody. After administration to a subject, each hapten (A1and A2) can be bound by an antibody. In certain embodiments, the two haptens, A1and A2can each be bound by a different antibody after administration to a subject. It is to be understood that any hapten, including peptide sequences, that elicit an immunological response in the host animal may be used to form the conjugates described herein. It is to be further understood an immunological response in the host animal may be elicited or supplemented via vaccination as a co-therapy to the methods and uses described herein.

[0083] In another embodiment, A1and A2are each an independently selected radical of an antigen where for each antigen there is an endogenous antibody present in the host animal.Illustrative haptens include, but are not limited to, a rhamnose, including L-rhamnose, a nitrophenyl, a nitrophenol, a nitroaniline, a dinitrophenyl (DNP), a dinitrophenol, a dinitroaniline, a trinitrophenyl (TNP), a trinitrophenol, a trinitroaniline, chloronitrophenyl, a chloronitrophenol, a chloronitroaniline, an iodonitrophenyl, an iodonitrophenol, anDocket No. 1165.071132WO01iodonitroaniline, a nitrotyrosine, an hydroxynitrotyrosine, an aminonitrotyrosine, 4-hydroxy-3- nitrophenyl acetic acid, an a-galactosyl moiety, a sulfated Gal, compounds of the formulae ,GH ..at HQ "?A.--0 NHAc ^GlcNacat „ OH vx..,o „ L AcKH tiHAc HQ" GaWe Sc 1-4} GstNAa HO QQNAc ^r-4; GO.Ca phosphorylcholine, a bacterial antigen, a viral antigen, and the like, and any combination of two or more of the foregoing.

[0084] Illustrative haptens include, but are not limited to, rhamnose, a-galactosyl moiety, dinitrobenzene, dinitroaniline, trinitrobenzene, and dinitroaniline.

[0085] In many embodiments, the hapten is selected from a dinitrophenyl (DNP), a dinitrophenol, and a dinitroaniline. In many embodiments, A1and / or A2is a radical of a dinitrophenyl (DNP), a dinitrophenol, or a dinitroaniline, including radicals of the formulaeNO2 orNO2where L2or L3is attached at (*).

[0086] In many embodiments, the hapten is selected from a rhamnose, including L-rhamnose. In many embodiments, A1and / or A2is a radical of a rhamnose, including L-rhamnose, and including a radicals of the formulaeOH OHwhere L2or L3is attached at (*).

[0087] In many embodiments, A1is a DNP radical and A2is a rhamnose radical, or vice versa. In many embodiments, A1is a DNP radical and A2is an L-rhamnose radical, or vice versa.

[0088] In another embodiment, neither A1nor A2comprises a fluorescein, such as FITC, and theDocket No. 1165.071132WO01like.

[0089] In many embodiments, Q is a trivalent nitrogen atom. In some embodiments, Q is aN atom. In some embodiments, Q is N(CH2)3. In some embodiments, Q is N(CH2CH2)3. In some embodiments, Q is N(CH2CH2O)3. In some embodiments, Q is C(O)-N(CH2)2. In some embodiments, Q is C(O)-N(CH2CH2)2. In some embodiments, Q is C(O)-N(CH2CH2O)2. In some embodiments, Q is C(O)-N(CH2CH2O)2. Alternatively, in any of the compounds described herein, Q can be a trivalent group, such as a trivalent group of formula:such that the compound of Formula I can be of the formula:. Thus, for example, in a compound of the formulaN>0NNand pharmaceutically acceptable salts and solvates thereof,Q can be a trivalent group such as a trivalent group of formula:. Similarly, in a compound of the formula:\ HOH N^N / =< T_ / NNHand pharmaceutically acceptable salts and solvates thereof, wherein:Docket No. 1165.071132WO01Q can be a trivalent group such as a trivalent group of formula:

[0090] As used herein, the term “linker” generally refers to a chain of atoms that connects two or more functional parts of a molecule to form a conjugate. Illustratively, the chain of atoms is selected from C, N, O, S, Si, and P, or C, N, O, S, and P, or C, N, O, and S. The chain of atoms covalently connects different functional capabilities of the conjugate. The linker may have a wide variety of lengths, such as in the range from about 2 to about 100 atoms in the contiguous backbone. The atoms used in forming the linker may be combined in all chemically relevant ways, such as chains of carbon atoms forming alkylene, alkenylene, and alkynylene groups, and the like; chains of carbon and oxygen atoms forming ethers, polyoxyalkylene groups, or when combined with carbonyl groups forming esters and carbonates, and the like; chains of carbon and nitrogen atoms forming amines, imines, polyamines, hydrazines, hydrazones, or when combined with carbonyl groups forming amides, ureas, semicarbazides, carbazides, and the like; chains of carbon, nitrogen, and oxygen atoms forming alkoxyamines, alkoxylamines, or when combined with carbonyl groups forming urethanes, amino acids, acyloxylamines, hydroxamic acids, and the like; and many others. In addition, it is to be understood that the atoms forming the chain in each of the foregoing illustrative embodiments may be either saturated or unsaturated, thus forming single, double, or triple bonds, such that for example, alkanes, alkenes, alkynes, imines, and the like may be radicals that are included in the linker. In addition, it is to be understood that the atoms forming the linker may also be cyclized upon each other or be part of cyclic structure to form divalent cyclic structures that form the linker, including cycloalkanes, cyclic ethers, cyclic amines, and other heterocycles, arylenes, heteroarylenes, and the like in the linker. In this latter arrangement, it is to be understood that the linker length may be defined by any pathway through the one or more cyclic structures. Illustratively, the linker length is defined by the shortest pathway through the each one of the cyclic structures. It is to be understood that the linkers may be optionally substituted at any one or more of the open valences along the chain of atoms, such as optional substituents on any of the carbon, nitrogen, silicon, or phosphorus atoms. It is also to be understood that the linker may connect the two or more functional parts of a molecule to form a conjugate at any open valence, and it is not necessary that any of the two or more functional parts of a molecule forming the conjugate are attached at any apparent end of the linker.

[0091] In one illustrative embodiment, compounds are described herein that include linkersDocket No. 1165.071132WO01having predetermined length. In one aspect, linkers are described herein that satisfy one or more minimum length requirements, or a length requirement falling within a predetermined range. In another aspect, satisfaction of a minimum length requirement may be understood to be determined by computer modeling of the extended conformations of linkers. In another aspect, satisfaction of a minimum length requirement may be understood to be determined by having a certain number of atoms, whether or not substituted, forming a backbone chain of atoms connecting the target ligand and the hapten. In another aspect, linkers are described herein to provide and facilitate ligand binding with the target protein pocket and hapten display in the extracellular domain. In another aspect, linkers are described herein are described to provide certain pharmacokinetic properties. In another aspect, linkers are described herein based on their rigidity or flexibility requirements such as linkers that include one or more rigid functionalities or one or more flexible functionalities and combinations thereof, such as linkers as described herein.

[0092] It has been observed that ligands binding in the pocket in the pre-fusion trimer at the 6 helical bundle prevents conformational change to a post f. Described herein are illustrative embodiments of conjugates with linkers of various length, shape, and / or chemical compositions that help facilitate ligand binding. In many embodiments it has been found that a linker of about 24 A permit haptens of the conjugates to reach the surface of the targeted protein complex.

[0093] In one embodiment, the atom-length of the linker is defined by the number of atoms separating the targeting ligand, or analog or derivative thereof, and the hapten.

[0001] In many embodiments, L1, L2, and L3each, independently comprises a chain of atoms from 3 atoms to about 60 atoms in length. In many embodiments, L1, L2, and L3each, independently comprises a chain of atoms from about 4 A to about 72 A in length. The chain of atoms are part of the backbone of the conjugate of Formula I. As used herein, the term “backbone” of the linker L refers to the shortest chain of contiguous atoms forming a covalently bonded connection between T and L2, between T and L3, between A1and L1, or between A2and L1.

[0002] In another embodiment, the length of the linker (L) is defined by measuring the length of an extended conformation of the linker. Such extended conformations may be measured in art-recognized computer modeling programs. Accordingly, in another illustrative embodiment, linkers are described having a chain length of at least 15 A, at least 20 A, at least 21 A, at least 22 A, at least 23 A, at least 24 A, or at least 25 A.

[0003]

[0094] In many embodiments, L1, L2, or L3each, independently, comprise a chain of atoms at least 3 atoms in length, at least 7 atoms in length, at least 10 atoms in length, at least 14Docket No. 1165.071132WO01atoms in length, or at least 20 atoms in length. In many embodiments, L1, L2, or L3each, independently, have 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, between 50 and 60 atoms in length, between 60 and 70 atoms in length, between 70 and 80 atoms in length, between 80 and 90 atoms in length, or between 90 and 100 atoms in length. In many embodiments, L1, L2, or L3each, independently, comprise a chain of 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, 5960, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 atoms in length.As used herein, the term “between” is inclusive of the endpoints meaning that between 3 and 5 atoms in a chain length includes 3 atoms, 4 atoms, and 5 atoms.

[0095] It is to be understood that while both L2and L3are covalently attached to L1, both L2and L3may be attached to the same atom of L1, or L2and L3may each be attached to different atoms of L1. In another embodiment, L2and L3are attached to the same atom on L1where that atom is not a carbon atom.

[0096] In many embodiments, L1, L2, or L3can each, independently, comprise one or more amino acid or peptide residues.

[0097] As used herein, the term “amino acid” refers generally to beta, gamma, and longer amino acids, and including cyclic groups, that have both an amino group and an acid group from each of which a radical can be formed. Illustrative acyclic amino acids include the formula-N(R)-(CR'R")q-C(O)-where R is hydrogen, alkyl, acyl, or a suitable nitrogen protecting group, R' and R" are hydrogen or a substituent, each of which is independently selected in each occurrence, and q is an integer such as 1, 2, 3, 4, or 5. Illustratively, R' and / or R" independently correspond to, but are not limited to, hydrogen or the side chains present on naturally occurring amino acids, such as methyl, benzyl, hydroxymethyl, thiomethyl, carboxyl, carboxylmethyl, guanidinopropyl, and the like, and derivatives and protected derivatives thereof. The above described formula includes all stereoisomeric variations. For example, the amino acid may be selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, and the like.

[0098] In many embodiments, L1, L2, or L3can each, independently, comprise a polyethyleneDocket No. 1165.071132WO01glycok (PEGn) moiety, wherein n = 1-36. In many embodiments, a linker comprises one or more PEG moieties where all carbon and oxygen atoms of the one or more PEG moieties are part of the backbone of the linker.

[0099] In many embodiments, L1, L2, or L3can each, independently, comprise one or more alkyl groups.

[0100] In other embodiments, L1, L2, or L3can includeh9h9 O \v'x 7 \ 'y / o PI X PIA, orxwhere x is an integer from 0 to 50 (e.g., 1 to 20, 1 to 3, 2 to 5, 1 to 10, 1 to 6, 3 to 8; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13) and y is an integer from 0 to 50 (e.g., 1 to 20, 1 to 3, 2 to 5, 1 to 10, 1 to 6, 3 to 8; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13), wherein RAis alkyl, such as Ci-Ce alkyl.

[0101] In many embodiments, L1, L2, or L3can each, independently, comprise one or more aryl groups, such as styryl groups, such as aryl and styryl groups comprising hydrophilic groups, such as sulfonic acid groups:from 0 to 50 (e.g., 1 to 20, 1 to 3, 2 to 5, 1 to 10, 1 to 6, 3 to 8; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13).

[0102] In many embodiments, L1, L2, or L3can each, independently, comprise one or more or sugar moieties, glycan residues, or peptidoglycan residues.Docket No. 1165.071132WO01

[0103] 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 each linker. In each of the foregoing, the atoms of each linker in the chain can be substituted or unsubstituted.

[0104] In addition, it is to be understood that the atoms forming the linker may also be cyclized to form saturated, unsaturated, or aromatic divalent cyclic radicals in the linker.

[0105] In some embodiments, L1, L2, or L3comprises suitable substituents that change the hydrophobicity or hydrophilicity of the linker. Illustrative hydrophobic groups include alkyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted.

[0106] In other embodiments, L1, L2, or L3can include an amide, ester, urea, carbonate, carbamate, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl cycloalkyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof. In some embodiments, L1, L2, or L3can include a glycosylated amino acid. In some embodiments, L1, L2, or L3can include one or more monosaccharide, disaccharide, polysaccharide, glycan, or peptidoglycan. In some embodiments, L1, L2, and L3do not comprise a glycan. In some embodiments, L1, L2, and L3do not comprise a sugar.

[0107] In some embodiments, L1, L2, or L3can include a rigid functionality such as an oligoproline or oligopiperidine.

[0108] 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).

[0109] In some embodiments, a carboxy piperidine linker 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.

[0110] In some embodiments, L1, L2, or L3can 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 group (e.g., C(O)N(H)C2-Cis alkyl- or C2-C18 alkyl-C(O)N(H)-), an alkylamidoalkyl group (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)- group), or a combination of two or more of the foregoing.

[0111] In some embodiments, L1, L2, or L3can compriseDocket No. 1165.071132WO01wherein m is an integer from 0 to 20, such as from 1 to 20, 0 to 15, 1 to 10, 2 to 10, 2 to 8 or 3 to 9. For example, m can be 0 or 1. Or m can be 5 or 6. Or m can be 7 or 8. In some embodiments, L1, L2, or L3can comprisewherein p and q are each, independently, an integer from 0 to 20, such as from 1 to 20, 0 to 15, 1 to 10, 2 to 10, 2 to 8 or 3 to 9. For example, p can be 2 or 3. For example, q can be 2 or 3. In some embodiments, L1, L2, or L3can comprisewherein d is an integer from 0 to 20, such as from 1 to 20, 0 to 15, 1 to 10, 2 to 10, 2 to 8 or 3 to 9. For example, d can be 1, 2 or 3.

[0112] In some embodiments, L1, L2, and L3taken together do not comprisesuch as wherein m, p, d, and q are each, independently, an integer from 0 to 30, such as from 1 to 30, 0 to 15, 1 to 10, 2 to 10, 2 to 8 or 3 to 9. For example, m can be 0 or 1. Or m can be 5 or 6. Or m can be 7 or 8. For example, p can be 2 or 3. For example, q can be 2 or 3. For example, d can be 1, 2 or 3.

[0113] In some embodiments, L1, L2, and L3taken together do not comprise

[0114] L1, L2, and / or L3can increase the water-solubility of the conjugate or plasma protein binding. In many embodiments, L1, L2, and L3can each, independently, comprise one or more of an amino acid residue, a polyethylene glycol (PEG) monomer group, a PEG oligomer group, aDocket No. 1165.071132WO01PEG polymer group, or a combination of any of the foregoing. In many embodiments, L1, L2, and L3can each, independently, comprise an oligomer of peptidoglycan groups, glycan groups, or a combination of any of the foregoing. In many embodiments, L1, L2, and L3can each, independently, comprise at least one 2,3 -diaminopropionic acid group, at least one glutamic acid group, at least one cysteine group, or a combination of two or more of the foregoing. In some embodiments, the linker includes from 3 to 24 PEG units, In some embodiments, the linker includes a PEG 8 or is of a similar length as PEG 8.

[0115] In many embodiments, one or more of L1, L2, and L3independently comprise one or more rigid or conformationally restricting linkers. As used herein a “rigid linker,” “conformationally restricting linkers,” or a “rigid functionality” is a linker or a portion of a linker that includes any chemical moiety that contains non-rotatable bonds. Examples of rigid linkers and conformationally restricting linkers include alkenes, alkynes, aromatic groups, spirocycles, polysarcosines, carboxy piperidine, heterocycles, oligoproline, oligoalkyne, oligophenyl and oligopiperidine groups. In many embodiments, one or more of L1, L2, and L3independently comprise one or more flexible or conformationally less restricted or unrestricted linkers. As used herein a “flexible linker,” “conformationally unrestricting linkers,” or a “flexible functionality” is a linker or a portion of a liner that includes any chemical moiety that contains rotatable bonds. Nonlimiting examples of flexible linkers include alkanes, oligoethylene groups, peptides, and the like. In many embodiments, one or more of L1, L2, and L3independently comprise one or more of an oligoethylene group, a PEG group, an alkyl, oligopeptide group, polypeptide group, a peptidoglycan group, an oligoproline group, an oligopiperidine group or any combination thereof. In these and other embodiments, one or more of L1, L2, and L3independently comprise an oligoethylene glycol group or a PEG group. In some embodiments, one or more of L1, L2, and L3independently comprise an oligoethylene glycol group. In some embodiments, one or more of L1, L2, and L3independently comprise a PEG group.

[0116] In some embodiments, when any of L1, L2, and L3comprises a rigid functionality, that rigid portion of the linker has between (and including the end points of the ranges) 2 and 50, 2 to 40, or 2 to 30, or 2 to 20, or 2 to 15, to 2 to 10, or 2 to 6 repeating units.

[0117] In some embodiments, when any of L1, L2, and L3is an oligoproline or oligopiperidine group, then such oligoproline or oligopiperidine group has between (and including the end points of the ranges) 2 and 50 , 2 to 40, or 2 to 30, or 2 to 20, or 2 to 15, to 2 to 10, or 2 to 6 repeating units. In many embodiments such repeating units are prolines (for oligoprolines) and piperidines (for oligopiperidine).Docket No. 1165.071132WO01

[0118] In some embodiments, when any of L1, L2, and L3comprises a flexible functionality, that flexible (e.g. allowing free rotation) portion of the linker has between (and including the end points of the ranges) 2 and 50, 2 to 40, or 2 to 30, or 2 to 20, or 2 to 15, to 2 to 10, or 2 to 6 repeating units.

[0119] In some embodiments, when any of L1, L2, and L3is an oligoethylene group, a PEG group, an alkyl, or an oligopeptide group, then such group has between (and including the end points of the ranges) 2 and 50, 2 to 40, or 2 to 30, or 2 to 20, or 2 to 15, to 2 to 10, or 2 to 6 repeating units. In many embodiments, such repeating units are PEG units.

[0120] In some embodiments, L1, L2, and L3comprise a flexible functionality and a rigid functionality, that flexible portion of the linker has between (and including the end points of the ranges) 2 and 50 , 2 to 40, or 2 to 30, or 2 to 20, or 2 to 15, to 2 to 10, or 2 to 6 repeating units

[0121] In many embodiments, one or more of L1, L2, and L3may independently comprise a moiety comprising an ester, a phosphate, an oxime, an acetal, a pyrophosphate, a polyphosphate, a sulfate, a hydrazide, an imine, a carbonate, a carbamate which may, in turn, be used to bind A1or A2to L3and L2, respectively.

[0122] In many embodiments, one or more of L1, L2, and L3may independently comprise a moiety comprising an ester, a phosphate, an oxime, an acetal, a pyrophosphate, a polyphosphate, a sulfate, a hydrazide, an imine, a carbonate, a carbamate which may, in turn, be used to bind A1or A2to L3and L2, respectively. Thus, for example, A1can be bound to L3by a moiety comprising an ester, a phosphate, an oxime, an acetal, a pyrophosphate, a polyphosphate, a sulfate, a hydrazide, an imine, a carbonate, a carbamate; and A2can be bound to L2by a moiety comprising an ester, a phosphate, an oxime, an acetal, a pyrophosphate, a polyphosphate, a sulfate, a hydrazide, an imine, a carbonate, a carbamate.

[0123] In many embodiments, L1, L2, and / or L3may be substituted so as to alter the affect the hydrophobicity or hydrophilicity of L1, L2, and / or L3. Thus, for example L1, L2, and / or L3may have a hydrophobic side chain group, such as an alkyl, cycloalkyl, aryl, arylalkyl, or like group, each of which is optionally substituted. In these and other embodiments, L1, L2, and / or L3comprise or further comprise one or more amino acids with side chains, such as phenylalanine (Phe) and tyrosine (Tyr), including substituted variants thereof, and analogs and derivatives of such side chains. Examples of amino acid side chains include:Docket No. 1165.071132WO01

[0124] In some embodiments, L1, L2, and / or L3comprise portions that are neutral under physiological conditions. In some embodiments, L1, L2, and / or L3comprise portions that can be protonated or deprotonated to carry one or more positive or one or more negative charges, respectively. In some embodiments, L1, L2, and / or L3comprises neutral portions and portions that may be protonated to carry one or more positive charges. Examples of neutral portions include polyhydroxyl groups, such as sugars, carbohydrates, saccharides, inositols, and the like, and / or polyether groups, such as polyoxyalkylene groups, including polyoxyethylene, polyoxypropylene, and the like. Examples of portions that can be protonated to carry one or more positive charges include amino groups, such as polyaminoalkylenes, including ethylene diamines, propylene diamines, butylene diamines and the like, and / or heterocycles, including pyrrolidines, piperidines, piperazines, and other amino groups, each of which can be optionally substituted. Examples of portions that can be deprotonated to carry one or more negative charges include carboxylic acids, such as aspartic acid, glutamic acid, and longer chain carboxylic acid groups, and sulfuric acid esters, such as alkyl esters of sulfuric acid.

[0125] The conjugate can be water-soluble. L1, L2, and / or L3can increase the water-solubility of the conjugate. In one example, the total combined length of L1+ L2+ L3is between about 17 and 100 A or between about 17 to about 75 A. In many embodiments, L1, L2, and L3can each, independently, comprise one or more of an amino acid residue, a polyethylene glycol (PEG) monomer group, a PEG oligomer group, a PEG polymer group, or a combination of any of the foregoing. In many embodiments, L1, L2, and L3can each, independently, comprise an oligomer of peptidoglycan groups, glycan groups, or a combination of any of the foregoing. In many embodiments, L1, L2, and L3can each, independently, comprise at least one 2,3-diaminopropionic acid group, at least one glutamic acid group, at least one cysteine group, or a combination of two or more of the foregoing.

[0126] In many embodiments, one or more of L1, L2, and L3independently comprise carbonyl, thionocarbonyl, alkylene, cycloalkylene, alkylenecycloalkyl, alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl, l-alkylenesuccinimid-3-yl, 1-(carbonylalkyl)succinimid-3-yl, alkylenesulfoxyl, sulfonylalkyl, alkylenesulfoxylalkyl, alkylenesulfonylalkyl, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydrofuranyl, 1-(carbonyltetrahydro-2H-pyranyl)succinimid-3-yl or l-(carbonyltetrahydrofuranyl)succinimid-3-yl, each of which is optionally substituted.

[0127] In these and other embodiments, one or more of L1, L2, and L3independently comprise or further comprise a nitrogen such that one or more of L, L1, and L2comprise alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl or l-(carbonylalkyl)succinimid-3-yl groups, eachDocket No. 1165.071132WO01of which is optionally substituted, bonded to said nitrogen to form an amide. In these and other embodiments, one or more of L1, L2, and L3independently comprise or further comprise a sulfur atom and alkylene or cycloalkylene groups, each of which is optionally substituted with carboxy, and is bonded to the sulfur to form a thiol. In some embodiments, L1, L2, and L3independently comprise or further comprise a sulfur atom and l-alkylenesuccinimid-3-yl and 1-(carbonylalkyl)succinimid-3-yl groups bonded to the sulfur to form a succinimid-3-ylthiol.

[0128] In many embodiments, one or more of L1, L2, and / or L3can each, independently, comprise an amino acid such as an amino acid selected from Lys, Asn, Thr, Ser, He, Met, Pro, His, Gin, Arg, Gly, Asp, Glu, Ala, Vai, Phe, Leu, Tyr, Cys, and Trp.

[0129] The compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the invention described herein is not limited to any particular stereochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

[0130] Similarly, the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds, or spatial arrangements, such as cis, trans, syn, and anti, relative configurations on a ring. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.

[0131] The conjugates hereof can be “deuterated,” meaning one or more hydrogen atoms can be replaced with deuterium. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made. Deuteration is well known to those of ordinary skill in the art. As used herein, the term “solvates” refers to compounds described herein 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 that where the compounds are to be used as pharmaceuticals, such solvents are pharmaceutically acceptableDocket No. 1165.071132WO01solvents. 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.

[0132] As used herein, the term “composition” generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and / or coordination compounds with water and / or various solvents, in the various physical forms of the compounds. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other solid forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various hydrates and / or solvates of the compounds described herein. In addition, it is to be understood that the compositions may be prepared from various co-crystals of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various solid forms and / or solvate or hydrate forms of the compounds described herein.

[0133] Pharmaceutical compositions can be prepared by combining one or more conjugates with one or more pharmaceutically acceptable excipients, carriers, or diluents, or any combination thereof, and, optionally, one or more additional pharmaceutically active agents DEFINITIONS

[0134] 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.

[0135] 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, andDocket No. 1165.071132WO01every possible subrange for that variable. For example, the recitation that n is an integer from 3 to 36, describes that range, the individual and selectable values of 3, 4, 5, 6, 7, 8 and so on up to 36, such as n is 3, or n is 4, or n is 5, etc. In addition, the recitation that n is an integer from 3 to 36 also describes each and every subrange, each of which may for the basis of a further embodiment, such as n is an integer from 3 to 8, from 3 to 7, from 3 to 6, from 2 to 8, from 2 to 7, from 3 to 20, from 10 to 30, etc.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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 allDocket No. 1165.071132WO01the 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 sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.

[0140] As used herein the term “radical” with reference to, for example, a 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. T, A1, A2, X1, X2, X3, L1, L2, L3, Q, PEG1, PEG2and PEG3are examples of groups that include an atom or group with at least one radical for covalent linking or conjugation to another group, for example, to A1and A2in the case of the ligand and PEG2or PEG3, respectively, in the case of the hapten.

[0141] An “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 (C1-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 the linker, 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.

[0142] 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 quarternized. 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— CH3, — CH2— CH2— S(O)— CH3, — CH2— CH2— S(O)2— CH3, — CH2=CH— O— CH3, — Si(CH3)3, — CH2— CH=N— OCH3, — CH=CH— N(CH3)— CH3, — O— CH3, — O— CH2—Docket No. 1165.071132WO01CH3, and — CN. Up to two heteroatoms may be consecutive, such as, for example, — CH2 — NH— OCH3.

[0143] An “alkylene group” is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms (C1-C10 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 (C1-C3 alkyl), or 2 to 6 (C2-C6 alkyl) carbon atoms.

[0144] 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.

[0145] Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group. Furthermore, when the cyclic groups such as heteroaryl, heterocyclyl are substituted, they include all the positional isomers.

[0146] 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, heteroaryl alkyl, 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.

[0147] The term “trivalent nitrogen atom” or “substituted trivalent nitrogen atom” or “optionally substituted trivalent nitrogen atom” as used herein has its traditional chemical meaning of a nitrogen atom with three atoms bonded thereto. Thus, for example, “Q” may be an optionally substituted trivalent nitrogen atom (to differentiate from a tetravalent nitrogen atom, where the nitrogen atom has four atoms bonded thereto and has a positive charge), includes embodiments wherein Q is:Docket No. 1165.071132WO01uwv1wherein the wavy line “* / VW ” represents a bonding to an additional atom. For clarity, when Q is defined as N(alkyl)s or C(O)-N(alkyl)3, the bond from Q to L1, L2, and L3may be made by replacing one of the alkyl groups or the C(O) group with a bond to L1, L2or L3, or the bond from Q to L1, L2and L3may be made by replacing one of the hydrogen atoms on the alkyl groups or by filing the open vacancy of the C(O) group with a bond to L1, L2or L3.

[0148] The term “trivalent group” includes groups that can serve as a “hub” for connecting L1, L2, and L3to, e.g., Q. The trivalent group can be cyclic or acyclic. Examples of trivalent groups include, but are not limited to, trimesic acid group that can serve as a hub for L1, L2, and L3:a trivalent group of formula:

[0149] Illustrative substituents include, but are not limited to, a radical -(CH2)xZx, where x is an 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 Cs-Cs 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.

[0150] 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 canDocket No. 1165.071132WO01be 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.

[0151] 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 in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.

[0152] 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.

[0153] 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, andDocket No. 1165.071132WO01the like, and combinations thereof, and / or include co-administration 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.

[0154] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, optically enriched, optically pure, or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0155] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt thereof may exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this disclosure.

[0156] Pharmaceutically acceptable salts of the compounds described herein are within the scope of this disclosure. In addition, the compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof.

[0157] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0158] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by aDocket No. 1165.071132WO01deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0159] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0160] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0161] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0162] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.EXAMPLES

[0163] The following examples serve to further illustrate the invention described herein. The examples are illustrative of the many embodiments of the invention and are not to be construed as limiting the scope of the invention in any way.List of AbbreviationsAbbreviation MeaningTLC Thin layer chromatographyRM Reaction mixtureSM Starting materialDocket No. 1165.071132WO01RT Room temperaturemin Minute(s)h or hr Hour(s)L Literg Grammg milligrammmol millimolemL milliliter°C CelsiusMS Mass spectroscopyeq- EquivalentRBF Round Bottom Flask1HNMR Proton Nuclear Magnetic ResonanceLCMS or LC-MS Liquid Chromatography Mass Spectrometry HPLC High performance liquid chromatography LC-HRMS Liquid Chromatography -High Resolution Mass Spectrometry Prep-HPLC Preparative scale HPLCMeOH MethanolDCM dichloromethanetosyl toluenesulfonyl groupEtOAc Ethyl acetateTFA Trifluoracetic acidCOMPOUND EXAMPLES

[0164] General. Unless otherwise indicated, all starting compounds and reagents are commercially available and used as received without further purification unless otherwise noted. Unless otherwise indicated, reactions are performed under an ambient atmosphere, and at ambient temperature and pressure, and reaction progress is monitored by TLC, LCMS, or both.Docket No. 1165.071132WO01Unless otherwise indicated, solutions are concentrated and compounds are isolated by rotary evaporation under reduced pressure, under high vacuum, or both.

[0165] Reference to compound numbers is intended to be limited to the specific example disclosed in the following exemplary syntheses. For example, reference to 1 in Example 1 is distinct from reference to 1 in Example 7. Similarly, in examples having multiple parts, such as Example 7, reference to a compound number in one part may be limited to that specific part. For example, reference to 1 in Part 1 of Example 7 is distinct from reference to 1 in Part 2 of Example 7. In addition, within a specific example there may be a distinction between reference to a compound designated by a given number and reference to a compound designated by the same number preceded by “Compound.” For example, reference to “5” in Example 1 (or Part 5 of Example 7) is distinct from reference to “Compound 5” within the same Example. The synthetic schemes disclosed herein provide a full overview of the chemical reactions described in the following examples.

[0166] Example 1 Synthesis of N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)-l-( 1 -( 1 -( 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hy droxypropyl)-5 -methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 5)Docket No. 1165.071132WO0120% TFA in DCM, rt Cp8OAcCp 11 4A°MS (w / w), BF, Etherate, DCM, O°C-rt 13Cp-9, DIPEA, DMF Cp-13TEMPO, Phl(OAc)2, DCM, RT - ~ ODocket No. 1165.071132WO01

[0167] Synthesis of 1 -(!-(!-( !-(!-( 1 -(((9H-fhioren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (5)

[0168] Solid support peptide synthesis of l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (5) on a 2CTC (2-Chlorotrityl chloride) resin and utilizing Fmoc / O / -Bu strategy.

[0169] General procedure:

[0170] Resin loading to prepare (3): In a peptide vessel 2CTC resin (1, 2.0 g, 2.8 mmol / g) was swollen in DCM for 30 min. A solution of l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carboxylic acid (2, 2.0 eq.; BLD Pharma) in N,N Diisopropylethyl amine (DIPEA, 3.0 eq.) wasDocket No. 1165.071132WO01added and the vessel was shaken for 12 h. After the reaction, the free sites of the resin were capped with methanol and the resin (3) was washed with dichloromethane (DCM) (2 X 20 mL).

[0171] Fmoc De-protection: Peptide reaction vessel containing swollen peptidyl resin in N,N dimethylformamide (DMF) was added 20% piperidine in DMF. The reaction vessel was shaken at room temperature for 0.5 h. The resin was filtered and was washed with DMF (3x30 mL) and DCM (3X20 mL).

[0172] Amide coupling to prepare (4): The activated amino acid was prepared by weighing out an appropriate amount of amino acid (2.0 eq.) and coupling agent (HATU; 2.5 eq.) and dissolving them in A, N dimethylformamide (20 mL). The activated amino acid solution and DIPEA (3.0 eq.) was added to the reaction vessel containing swollen resin. The reaction vessel was shaken for 2 h. (Repeated cycle five times).

[0173] Resin Cleavage: 2CTC resin loaded with protected peptide (1) was suspended in 2% trifluoroacetic acid (TFA) in dichloromethane (20 mL) in the peptide reaction vessel. Thereafter, reaction vessel was shaken for 30 min. The resin was filtered and washed three times with portions of 2% trifluoroacetic acid (TFA) in dichloromethane. To the combined filtrates were added chilled diethyl ether to afford l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (5) (0.80 g.). LC-MS (ESI) m / z 907.20 [M+l]+.

[0174] Synthesis of tert-butyl (14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (8)

[0175] To the stirred solution of l-fluoro-2,4-dinitrobenzene (GLR, 6, 0.55 g, 2.96 mmol) & tertbutyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (Chemscene, 7, 0.99 g, 2.96 mmol) in N,N dimethyl formamide (6 mL), A, A Diisopropylethyl amine (1.54 mL, 8.87 mmol) was added and the reaction mixture was heated at 50°C for 16 h. After the completion of the reaction, the reaction mixture was acidified (up to pH=5) with Citric acid solution. Then, it was extracted with ethyl acetate (2x100 mL), combined organic layers was dried over sodium sulfate, concentrated under reduced pressure to afford the crude compound, which was purified using silica gel column chromatography using 50% Ethyl acetate in Heptane as eluent to afford tert-butyl (14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (8) as an orange yellow gummy liquid. Yield: 1.37 g, 92.25%. LC-MS (ESI) m / z 520.15 [M +NH4]+.

[0176] Synthesis ofNI-(2,4-dinitrophenyl)-3,6,9,12-tetraoxatetradecane-l,14-diamine (9)

[0177] To the stirred solution of tert-butyl (14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (8, 1.37 g, 2.73 mmol) in dichloromethane (10 mL), trifluoroaceticDocketNo. 1165.071132WO01acid (2.0 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 concentrated to afford N1-(2,4-dinitrophenyl)-3,6,9,12-tetraoxatetradecane-l,14-diamine (9) as orange yellow gummy liquid. Yield: 1.0 g, crude; LC-MS (ESI) m / z 403.15 [M +H]+.

[0178] Synthesis of 14-hydroxy-3, 6, 9, 12-tetraoxatetradecyl 4-methylbenzene sulfonate (11)

[0179] To the stirred solution of 3,6,9, 12-tetraoxatetradecane-l,14-diol (Combi-blocks; 10, 6.0 g, 24.12 mmol) in dichloromethane (60 mL) was added triethylamine (10.52 mL, 74.16 mmol) and 4-Toluenesulfonyl chloride (3.84 g, 20.2 mmol) at 0° C and the reaction mixture was allowed to stir at ambient temperature for 2 h. After the completion of the reaction, reaction mixture was diluted with water (100 mL) and extracted with di chloromethane (2X100 mL), dried over sodium sulfate, concentrated under reduced pressure to afford the crude. The crude was purified over silica gel column chromatography using 0-10% methanol in di chloromethane as eluent to afford 14-hydroxy-3, 6, 9, 12-tetraoxatetradecyl 4-methylbenzenesulfonate as colorless gummy liquid. Yield: 3.5 g, 30.36%; LC-MS (ESI) m / z 410.05 [M +NH4]+.

[0180] Synthesis of (2S,4R,5R,6R)-2-methyl-6-((14-(tosyloxy)-3,6,9,12-tetraoxatetradecyl)oxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate (13)

[0181] To the solution of (2S,3R,4R,6S)-6-methyltetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (12, 2.69 g, 8.09 mmol), 14-hydroxy-3, 6, 9, 12-tetraoxatetradecyl 4-methylbenzenesulfonate (11, 3.49 g, 8.90 mmol) and MS 4A (10 g) in anhydrous dichloromethane (50 mL) was added Et2O-BF3 (6.15 ml, 48.60 mmol) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h at same temperature. Progress of the reaction was monitored by TLC and LCMS. Upon the completion of reaction, the reaction mixture was diluted with dichloromethane (100 mL) and filtered through a pad of Celite. The solution was washed with water (2X100 mL) and saturated sodium bicarbonate solution (2x100 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated. The product was purified over silica gel chromatography using 40% ethyl acetate in heptane as eluent to give (2S,4R,5R,6R)-2-methyl-6-((14-(tosyloxy)-3,6,9,12-tetraoxatetradecyl)oxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate (13) as off white solid. Yield: 2.83 g, 52.59 %; LCMS (ESI) m / z 682.15 [M+NH4]+.

[0182] Synthesis of (2R,3R,4R,6S)-2-((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 (14)

[0183] To the stirred solution of N1-(2,4-dinitrophenyl)-3,6,9,12-tetraoxatetradecane-l,14-diamine (9, 0.50 g, 1.35 mmol) in A, N dimethylformamide (5.0 mL,) was added N-Docket No. 1165.071132WO01ethyldiisopropylamine (0.5 mL, 2.65 mmol) and the reaction mixture was allowed to stir at ambient temperature for 10 min and then solution of (2S,4R,5R,6R)-2-methyl-6-((14-(tosyloxy)-3,6,9, 12-tetraoxatetradecyl)oxy)tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (13, 0.90 g, 1.35 mmol) in YA -di methyl form am ide (5.0 mL) was added to it. The reaction mixture was allowed to stir at 60°C for 12 hours. After the completion of the reaction, reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (2x20mL), Organic layer was then washed with ice cold water several times and then combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the crude. This crude was purified by silica gel column chromatography (silica gel) using 0-10% methanol in dichloromethane to afford (2R,3R,4R,6S)-2-((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 (14) as yellowish liquid. Yield: 0.30 g, 25.81 %; LCMS (ESI) m / z 895.20 [M+H]+.

[0184] Synthesis of (2R,3R,4R,6S)-2-((15-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)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 (15)

[0185] To the stirred solution of l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (5, 0.30 g, 0.33 mmol) and (2R,3R,4R,6S)-2-((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 (14, 0.29 g, 0.33 mmol) in YA'-dimethylformamide (5 mL), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (0.25 g, 0.49 mmol) and A-ethyldiisopropylamine (0.17 mL, 0.99 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 the reaction, solvent was concentrated under high vacuum to get the crude that was purified in silica gel column chromatography using 0-10% methanol in dichloromethane gradient to afford (2R,3R,4R,6S)-2-((15-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)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 (15) as pale yellow liquid. Yield: 0.21 g, 35.59%. LC-MS (ESI) m / z 1782.10 [M+H]+.Docket No. 1165.071132WO01

[0186] 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 (16)

[0187] To the stirred solution of (2R,3R,4R,6S)-2-((15-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)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 (15, 0.19 g, 0.11 mmol) in anhydrous N, Y-di methyl form am ide (5.0 mL), piperidine (1.0 mL) was added at ambient temperature and the reaction mixture was allowed to stir for 30 min. Progress of the reaction was monitored by TLC. After completion, solvent was concentrated and dried under reduced pressure. The crude was triturated with diethyl ether to afford (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 (16) as a light yellow liquid which was used for the next reaction. Yield: 0.14 g, 84.17%; LCMS (ESI) m / z 1559.05 [M-H]'.

[0188] Synthesis of tert-butyl l-oxo-3,6,9, 12, 15, 18,21 ,24-octaoxaheptacosan-27-oate (18)

[0189] To the stirred solution of tert-butyl l-hydroxy-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate (BLD Pharm; 17, 0.30 g, 0.60 mmol) in dichloromethane (5 mL), 2,2,6,6-tetramethyl-l-oxypiperidine (0.047 g, 0.30 mmol) was added and the reaction mixture was stirred for 5 min. Acetoxyphenyliodo acetate (0.62 g, 1.93 mmol) was added to the reaction mixture and stirring was continued for another 45 min. Progress of the reaction was monitored by TLC. After completion, crude was purified by column chromatography using 2-5% methanol in dichloromethane as eluent to afford tert-butyl l-oxo-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oate (18) as viscous colourless liquid. Yield: 0.22 g, 73.63 %.JH NMR (CDCh) 89.74 (s, 0.5 H), 4.16 (s, 1H), 3.75-3.50 (m, 32H), 2.51-2.54 (m, 2H), 2.07 (s, 1H), 1.44 (s, 9H).

[0190] Synthesis of tert-butyl l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6, 9, 12, 15, 18, 21,24, 27-octaoxa-3-azatriacontan-30-oate (20)

[0191] To the stirred ice cold solution of 2-((2-((l-(2-aminoethyl)piperidin-4-yl)amino)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyri din-3 -ol (19, 0.60 g, 1.08 mmol) in Methanol (40 mL), tert-butyl l-oxo-3,6,9, 12, 15, 18,21, 24-octaoxaheptacosan-27-oate (18, 0.43 g, 0.86 mmol), Molecular sieves (4 ,DocketNo. 1165.071132WO01w / w) and acetic acid (cat.) was added at same temperature and the reaction mixture was stirred at room temperature for next 30 mins. Sodium cyanoborohydride (0.33 mg, 5.40 mmol) was added to the reaction mixture and was stirred at ambient temperature for another 1 h. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was filtered, filtrate was concentrated and dried to get crude. The crude was purified by silica gel column chromatography using 5-7% methanol in 0.1% triethyl amine in dichloromethane as eluent. The desired fractions were concentrated to afford tert-butyl l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin- 1 -yl)-6,9, 12,15,18,21 ,24,27-octaoxa-3 -azatriacontan-30-oate (20) as colorless liquid. Yield: 0.55 g, 49.24 %; LC-MS (ESI) m / z 1038.25 [M+H]+.

[0192] Synthesis of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)~ 5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21, 24, 27-octaoxa-3-azatriacontan-30-oic acid (21)

[0193] To the stirred solution of tert-butyl l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oate (20, 0.55 g, 0.53 mmol) in dichloromethane (10 mL), 4 M HC1 in 1,4 dioxane (2.0 mL) was added at 0° C and the reaction mixture was stirred at ambient temperature for 6 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated to afford l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oic acid (21) as colorless liquid. Yield: 0.50 g, crude; LC-MS (ESI) m / z 982.17 [M+H]+.

[0194] Synthesis of ( 2R, 3R, 4R, 6S)-2-( (29 -( (2, 4-dinitrophenyl)amino)~ 15-( l-(l-(l-(l-(l-(l-(l-(4-((l-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27-octaoxa-3-azatriacontan-30-oyl)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 (22)

[0195] To the stirred ice cold solution of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oic acid (21, 0.07 g, 0.071 mmol) and (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(l-(l-(l-DocketNo. 1165.071132WO01(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 (16, 0.156 g, 0.099 mmol) in Acetonitrile (4.0 ml), N,N, N T -tetramethylchloroformamidinium hexafluorophosphate (TCFH; 0.028 g, 0.099 mmol) and 1 -Methylimidazole (0.05 ml, 0.57 mmol) was added at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solvent was concentrated under high vacuum to get the crude which was purified by Prep-HPLC purification using acetonitrile in H2O with 0.1% ammonium acetate. Desired fractions were concentrated to afford (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)- 15 -( 1 -( 1 -( 1 -( 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)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 (22) as yellow sticky solid. Yield: 0.013 g, 7.22 %; LC-HRMS (ESI) m / z 2526.38 [M+H]+.

[0196] Synthesis ofN-(l 4-( ( 2, 4-dinitrophenyl)amino)-3, 6, 9, 12-tetraoxatetradecyl)-l-( 1 -(!-(!-( 1-(1-(1 -(4-( (l-(( 3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-( ((2R, 3R, 4R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9, 12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 5).

[0197] To the stirred solution of (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(l-( 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hy droxypropyl)-5 -methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azanonacosan-29-oyl)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 (22, 0.013 g, 0.005 mmol) in methanol (0.3 mL) and water (0.4 mL), N-ethyldiisopropylamine (0.3 mL, 0.005 mmol) was added and the reaction mixture was stirred at ambient temperature for 4 h. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was evaporated to dryness and lyophilised to afford N-(14-((2,4-dinitrophenyl)amino)-3 ,6, 9, 12-tetraoxatetradecyl)- 1 -( 1 -( 1 -( 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-DocketNo. 1165.071132WO01methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 5).) as yellow solid. Yield: 11.5 mg, 93.7 %; LC-MS (ESI) m / z 2399.98 [M+H]+.

[0198] An illustrative synthesis for Example 1 is also shown in FIG. 2. The following additional compounds can be synthesized in a similar fashion with the appropriate selection of starting materials:

[0199] l-(l-(l-(l-(l-(l-(26-((2-((l-cyclopropyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)-l-(3-(methylsulfonyl)propyl)-lH-benzo[d]imidazol-5-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosanoyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 8);

[0200] N-( 14-((2,4-dinitrophenyl)amino)-3 ,6,9,12-tetraoxatetradecyl)- l-(l-(l-(l-(l-(l-(26-((l-(3-(methylsulfonyl)propyl)-2-((2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)-lH-indol-5-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosanoyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 9);

[0201] N-( 14-((2,4-dinitrophenyl)amino)-3 ,6,9,12-tetraoxatetradecyl)- 1 -( 1 -( 1 -( 1 -( 1 -( 1 -(26-((3 -(((2-( 1 , 1 -dioxido-2,3 -dihydrobenzo[f] [ 1 ,4]thiazepin-4(5H)-yl)-6-methylquinazolin-4-yl)amino)methyl)oxetan-3-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosanoyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9, 12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 10); and

[0202] l-(l-(l-(l-(l-(l-(26-((2-((l-cyclopropyl-2-oxo-l,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)-l-(4-hydroxybutyl)-lH-benzo[d]imidazol-5-yl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosanoyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-((2,4-dinitrophenyl)amino)-Docket No. 1165.071132WO013,6,9,12-tetraoxatetradecyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 11).

[0203] Additional compounds can be synthesized in a similar fashion with the appropriate selection of starting materials: for example, the rigid linker component of Compound 29 and Compound 30 in Fig. 13. Compound 30, for example, uses (E)-4-(4-amino-2-sulfostyryl)-3-sulfobenzoic acid in place of carboxy piperidine.

[0204] Example 2. Synthesis of l-(3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanamido)-12-(l"'-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35-yl)-[l,4':r,4":l",4"'-quaterpiperidin]-4-yl)-N-(2-(2-(2-(2-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3,6,9,15,18,21-hexaoxa-12-azatetracosan-24-amide (Compound 4)TsCI , Et3N, DCM, rt9Docket No. 1165.071132WO01Cp-9, DIPEA, DMF, 40 °C 114A°MS (w / w),MeOH:Et3N (7:3), Na[BH3(CN)J (2.0 eq), rtDocketNo. 1165.071132WO01Compound 4

[0205] Synthesis of (2R,3R,4R,5S,6S)-2-((l-azido-12-(tert-butoxycarbonyl)-24-oxo- 3,6,9, 15, 18,21 ,28,31 ,34-nonaoxa-12,25-diazahexatriacontan-36-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (3)

[0206] To a stirred solution of l-azido-12-(tert-butoxycarbonyl)-3,6,9,15,18,21-hexaoxa-12- azatetracosan-24-oic acid (1, 1.0 g, 1.91 mmol; Angene) and (2R,3R,4R,5S,6S)-2-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethoxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (2, 1.07 g, 2.03 mmol) in A,A-dimethylformamide (15.0 mL)hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU, 0.034 g, 0.09 mmol) was added at 0 °C. After 10 minutes N,N, Diisopropylethylamine (1.77 mL, 9.57 mmol) was added dropwise to the reaction mixture at the same temperature and was stirred at ambient temperature for 12 h. Progress of the reaction was monitored by LCMS and after completion, the reaction mixture was concentrated under reduced pressure to get crude which was purified by silica gel column chromatography eluting in 5% MeOH / DCM to afford (2R,3R,4R,5S,6S)-2-((l-azido-12- (tert-butoxycarbonyl)-24-oxo-3,6,9,15,18,21,28,31,34-nonaoxa-12,25-diazahexatriacontan-36- yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (3) as a yellowish liquid. Yield: 1.20 g, 64.65 %; LCMS (ELSD) m / z 970.60 [M+H]+.

[0207] Synthesis of tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)(l 3-oxo-l- ( ((2R, 3R, 4R, 5R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9,16, 19, 22- hexaoxa-12-azatetracosan-24-yl)carbamate (4)

[0208] To a solution of (2R,3R,4R,5S,6S)-2-((l-azido-12-(tert-butoxycarbonyl)-24-oxo- 3,6,9,15,18,21,28,31,34-nonaoxa-12,25-diazahexatriacontan-36-yl)oxy)-6-methyltetrahydro-2H- pyran-3,4,5-triyl triacetate (3, 1.0 g, 1.03 mmol) in methanol ( 50.0 mL), 10 % Palladium on carbon (1.00 g) was added and stirred at ambient temperature under hydrogen atmosphere for 6 h. After completion, the reaction mixture was filtered through celite bed, washed with methanol and filtrate was concentrated and dried to get crude. The crude was triturated with diethyl ether to afford tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)(13-oxo-l-(((2R,3R,4R,5R,6S)-Docket No. 1165.071132WO013,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,16,19,22-hexaoxa-12- azatetracosan-24-yl)carbamate (4) as a pale yellow viscous liquid. Yield: (0.80 g, 82.2 %);LCMS (ELSD) m / z 944.65 [M+H]+.

[0209] Synthesis of (2R,3R,4R,5S,6S)-2-((25-(tert-butoxycarbonyl)-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 ( 6)

[0210] To a stirred solution of 3-(2-((2,4-dinitrophenyl)amino)ethoxy)propanoic acid (5, 0.11 g, 0.37 mmol) and tert-butyl (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)(13-oxo-l- (((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,16,19,22-hexaoxa-12-azatetracosan-24-yl)carbamate (4, 0.35 g, 0.37 mmol) in A, A-dimethylformamide (10.0 mL), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU, 0.15 g, 0.40 mmol) was added at 0 °C. After 10 minutes ethylbi s(propan-2-yl)amine (0.34 mL, 1.85 mmol) was added dropwise to the reaction mixture at the same temperature and was stirred at ambient temperature for 12 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was concentrated under reduced pressure to get crude which was purified by silica gel column chromatography eluting in 10% MeOH / DCM to afford (2R,3R,4R,5S,6S)-2- ((25-(tert-butoxycarbonyl)-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 (6) as a yellowish liquid. Yield: 0.20 g, 44.03 %; LCMS (ESI) m / z 1225.30 [M+H]+.

[0211] Synthesis of (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 (7)

[0212] To a stirred solution of (2R,3R,4R,5S,6S)-2-((25-(tert-butoxycarbonyl)-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 (6, 0.31 g, 0.25 mmol), in anhydrous dichloromethane (5.0 mL), trifluoroacetic acid (3.0 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 LCMS. After completion solvent was concentrated and dried under reduced pressure to get crude material (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 (7) as a light yellow liquid which was used for the next reaction. Yield: 0.22 g, Crude; LCMS (ESI) m / z 1125.10 [M+H]+.Docket No. 1165.071132WO01

[0213] Synthesis of 32-hydroxy-3,6,9, 12,15, 18,21 ,24,27,30-decaoxadotriacontyl 4-methylbenzenesulfonate (9)

[0214] To a stirred solution of 3,6,9,12,15,18,21,24,27,30,33-undecaoxa-l,35-pentatriacontanediol (8, 2.0 g, 3.66 mmol; BLD Pharma) in DCM (25 ml). Triethylamine (2.64 mL, 18.3 mmol) and p-(chlorosulfonyl)toluene (0.558 g, 2.93 mmol) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (2x100 mL), the organic layer was washed with saturated brine solution(100 mL), the organic layer was dried over Na2SO4and concentrated under reduced pressure to get crude. Crude was purified by column chromatography using 2-5% methanol / dichloromethane as eluent to afford 32-hydroxy-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl 4-methylbenzenesulfonate (9) as viscous liquid. Yield: 0.80 g, 24.5 %. LC-MS (ESI) m / z 674 [M+NH4]+.

[0215] Synthesis of [1,4' -bipiper idin] -4-one (11)

[0216] A solution of 8-(piperidin-4-yl)-l,4-dioxa-8-azaspiro[4.5]decane (Vyas bio, 10, 0.4 g, 1.77 mmol) in Cone, HC1 (20.0 mL) was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC. After completion, solvent was concentrated and dried under reduced pressure. Reaction crude was diluted with IN NaOH solution (pH=12) and extracted with dichloromethane (2x100 mL), the organic layer was washed with saturated brine solution (100 mL), the organic layer was dried over Na2SO4and concentrated under reduced pressure to afford [l,4'-bipiperidin]-4-one (11) as viscous liquid. Yield: 0.280 g, 86 %. ELSD-MS (ESI) m / z 183.18 [M+H]+.

[0217] Synthesis of l'-(32-hydroxy-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-[l,4'-bipiperidin] -4-one (12)

[0218] To a solution of [l,4'-bipiperidin]-4-one (11; 0.850 g, 4.66 mmol) and 32-hydroxy-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl 4-methylbenzenesulfonate (9; 3.0 g, 4.66 mmol) in dry N,N-Dimethylformamide (10 mL), N,N-Diisopropylethylamine (2.44 mL, 14.0 mmol) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 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 purified by neutral alumina column chromatography eluting in 15% methanol in di chloromethane to afford l'-(32-hydroxy-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-[l,4'-bipiperidin]-4-one (12) as a light yellowish liquid. Yield: 1.20 g, 38.5 %; ELSD-MS (ESI) m / z 667.31 [M+H]+.Docket No. 1165.071132WO01

[0219] Synthesis of 32-(4-(l, 4-dioxa-8-azaspiro[ 4.5 ]decan-8-yl)-[ 1, 4 1 ', 4"-terpiperidin ]-l "~yl)~ 3, 6, 9, 12, 15, 18, 21,24, 27 ,30-decaoxadotriacontan-l-ol (13)

[0220] To a stirred solution of l'-(32-hydroxy-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)- [l,4'-bipiperidin]-4-one (12; 0.70 g, 1.05 mmol) and 8-(piperidin-4-yl)-l,4-dioxa-8-azaspiro[4.5]decane (9; 0.238 g, 1.05 mmol) in Methanol (7 mL), triethylamine (3.0 mL) was added and the reaction mixture was stirred for 30 min at ambient temperature. Sodium cyanoborohydride (0.198 g, 3.15 mmol) was added and the reaction mixture was stirred at 70 °C for 12 h. Progress of the reaction was monitored by ELSD-MS. After completion, the reaction mixture was filtered, filtrate was concentrated and dried to get crude, the crude was purified by Sephadex LH20 column chromatography using methanol, desired fraction was concentrated and dried to afford 32-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[l,4': l',4"-terpiperidin]-l"-yl)- 3.6.9.12.15.18.21.24.27.30-decaoxadotriacontan-l-ol (13) as colorless sticky solid. Yield: 0.300 g, 32.5 %; ELSD-MS (ESI) m / z 877.39 [M+H]+.

[0221] Synthesis of 32-(4-(l, 4-dioxa-8-azaspiro[ 4.5 ]decan-8-yl)-[ 1, 4 1 ', 4"-terpiperidin ]-l "~yl)~ 3.6.9.12.15.18.21.24.27.30-decaoxadotriacontanal (14)

[0222] To a stirred solution of 32-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[l,4':l',4"-terpiperidin]-l"-yl)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-l-ol (1.0 eq.) in acetonitrile (10 Vol.), 2-azaadamantane N-oxyl (AZADO) (3 mol %), Copper(I) chloride (10 mol %) and 1-Methylimidazole (10 mol %) will be added at ambient temperature, the reaction mixture will be stirred under open air atmosphere. After completion, the reaction mixture will be filtered, concentrated and dried to get crude, the crude was purified by Sephadex LH20 column chromatography using methanol to afford 32-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[l,4':l',4"-terpiperidin]-l"-yl)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontanal (14).

[0223] Synthesis of 2-((2-((l-(35-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[l,4':l',4"-terpiperidin ]-l "-yl)-6, 9, 12, 15, 18, 21, 24, 27,30, 33-decaoxa-3-azapentatriacontyl)piperidin-4-yl)amino)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyridin-3-ol (16)

[0224] To a stirred solution of 32-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[l,4':l',4"-terpiperidin]-l"-yl)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontanal (14, 1.0 eq.) and 2-((2-((l-(2-aminoethyl)piperidin-4-yl)amino)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)- lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyridin-3-ol (15, 1.0 eq.) in methanol (15 Vol.), MS 4A (W / W) and Acetic acid (cat.) will be added to the reaction mixture and was stirred at ambient temperature for 30 mins. Sodium cyanoborohydride (2.0 eq.) will be added at 0°C and the reaction mixture will be stirred at ambient temperature. After completion, the reaction mixtureDocket No. 1165.071132WO01will be filtered, filtrate will be concentrated and dried to get crude, the crude was purified by Sephadex LH20 column chromatography using methanol to afford 2-((2-((l-(35-(4-(l,4-dioxa-8- azaspiro[4.5]decan-8-yl)-[l,4':l',4"-terpiperidin]-l"-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3- azapentatriacontyl)piperidin-4-yl)amino)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyridin-3-ol (16).

[0225] Synthesis of "-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33-decaoxa-3-azapentatriacontan-35-yl)-[ 1, 4 r,4":l", 4"’-quaterpiperidin] -4-one (17)

[0226] Cone. HC1 (20 Vol.) will be added to 2-((2-((l-(35-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-[l,4':l',4"-terpiperidin]-l"-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3- azapentatriacontyl)piperidin-4-yl)amino)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyridin-3-ol (16, 1.0 eq.), at 0 °C and the reaction mixture will be stirred at ambient temperature for 2 h. After completion solvent will be concentrated and dried under reduced pressure to afford 1 "'-( 1 -(4-((l - ((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33-decaoxa-3-azapentatriacontan-35-yl)-[l,4':r,4":l",4"'- quaterpiperidin]-4-one (17) which will be used for next reaction without further purification.

[0227] Synthesis of (2R,3R,4R,6S)-2-((43-((2,4-dinitrophenyl)amino)-25-( "-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)- lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35-yl)-[ 1, 4 l',4":l", 4"'-quaterpiperidin ]-4-yl)-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 (19)

[0228] To a stirred solution of l"'-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35-yl)-[l,4':r,4":l",4"'- quaterpiperidin]-4-one (17; 1.0 eq.) and (2R,3R,4R,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 (18, 1.0 eq.) in Methanol: triethylamine (7:3), Sodium cyanoborohydride (2.0 eq.) will be added and stirred at ambient temperature. After 10 mins, reaction mixture will be heated at 70° C for 12 h. Upon completion, the reaction mixture will be filtered, filtrate will be concentrated and dried to get crude. The crude will be purified byDocketNo. 1165.071132WO01Sephadex LH20 column chromatography using methanol to afford (2R,3R,4R,6S)-2-((43-((2,4- dinitrophenyl)amino)-25-(l"'-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35-yl)-[l,4':r,4":l",4"'- quaterpiperidin]-4-yl)-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 (19).

[0229] Synthesis of l-( 3-(2-( (2, 4-dinitrophenyl)amino)ethoxy)propanamido)-12-( 1 "'-( 1 -( 4-( (1- ((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ( (2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33-decaoxa-3-azapentatriacontan-35-yl)-[ 1, 4 r,4":l", 4"’-quaterpiperidin]-4-yl)-N-(2-(2-(2-(2-( ( (2R, 3R, 4R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3, 6, 9, 15, 18,21 -hexaoxa- 12-azatetracosan-24-amide (Compound 4).

[0230] To a stirred solution of (2R,3R,4R,6S)-2-((43-((2,4-dinitrophenyl)amino)-25-(l'"-(l-(4- ((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33-decaoxa-3-azapentatriacontan-35-yl)-[l,4':r,4":l",4"'- quaterpiperidin]-4-yl)-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 (19, 1.0 eq.) in water (10 Vol.), 5% NaOH solution will be added dropwise till pH=12.The reaction mixture will be stirred at ambient temperature for 1 h. After completion, the reaction mixture will be concentrated and purified by Prep-HPLC. Desired fraction will be Lyophilized to afford l-(3-(2- ((2,4-dinitrophenyl)amino)ethoxy)propanamido)-12-(r"-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33-decaoxa-3-azapentatriacontan-35-yl)- [ 1 ,4' : l',4" : 1 ",4"'-quaterpiperidin]-4-yl)-N-(2-(2-(2-(2-(((2R,3R,4R,6S)-3 ,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3,6,9,15,18,21-hexaoxa-12- azatetracosan-24-amide (Compound 4).

[0231] An illustrative synthesis for Example 2 is shown in FIG. 1. The following additional compounds can be synthesized in a similar fashion with the appropriate selection of starting materials:

[0232] (2R, 3R,4R, 6 S)-2-(( 1 -((2,4-dinitrophenyl)amino)- 18-( 1 -( 1 -(4-(( 1 -((3 -hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azanonacosan-29-Docket No. 1165.071132WO01yl)-[l,4':r,4":l",4"':r",4"":l"",4 -sexipiperidin]-4-yl)-3,6,9,12,15,21,24,27,30,33,36,39-dodecaoxa-18-azahentetracontan-41-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol (Compound 17), and for example, the hapten core component of Compound 29 and Compound 30 in Fig. 13.

[0233] Example 3. Synthesis of N-(18-((2,4-dinitrophenyl)amino)-13-oxo-3,6,9,16-tetraoxa-12-azaoctadecyl)-l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)m ethyl)- lH-benzo[d]imidazol-2-yl)amino)piperidin- 1 -yl)-N-(l 3 -oxo- 1 -(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,16,19,22-hexaoxa- 12-azatetracosan-24-y 1) - 6 , 9 , 12, 15, 18, 21, 24, 27, 30, 33, 36-undecaoxa-3 -azanonatriacontan-39-amide (Compound 1)HODocketNo. 1165.071132WO01

[0234] Synthesis of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)~ 5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27,30, 33,36-undecaoxa-3-azanonatriacontan-39-oic acid (1)

[0235] Common intermediate (13) prepared in Example 5 synthesis of Compound 6.

[0236] Synthesis of (2R,3R,4R,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 (2)

[0237] Common intermediate (18) prepared in Example 2 synthesis of Compound 4.

[0238] Synthesis of (2R,3R,4R,6S)-2-((40-(18-((2,4-dinitrophenyl)amino)-13-oxo-3,6,9,16- tetraoxa-12-azaoctadecyl)-l-( 4-( (l-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ( 2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 39, 52-dioxo-6, 9, 12, 15, 18,21, 24, 27,30,33,36, 43, 46, 49, 56, 59, 62-heptadecaoxa-3, 40, 53- triazatetrahexacontan-64-yl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (3)

[0239] To a stirred solution of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oic acid (1; 1.0 eq.) and (2R,3R,4R,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 (1.0 eq.) in N,N-dimethylformamide (10 Vol.) at 0° C , Benzotriazole- 1-yl-oxy -tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 1.2 eq.) and N,N-Diisopropylethylamine (DIPEA; 2.5 eq.) will be added and the reaction mixture will be stirred at ambient temperature for 16 h. Progress of the reaction will be monitored by LCMS. After completion, the reaction mixture will be concentrated under reduced pressure to get crude which will be purified by Sephadex LH20 column chromatography using methanol to afford (2R,3R,4R,6S)-2-((40-(18-((2,4- dinitrophenyl)amino)- 13 -oxo-3 ,6, 9, 16-tetraoxa- 12-azaoctadecyl)- 1 -(4-(( 1 -((3 -hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-Docket No. 1165.071132WO01benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-39,52-dioxo- 6,9,12,15,18,21,24,27,30,33,36,43,46,49,56,59,62-heptadecaoxa-3,40,53-triazatetrahexacontan- 64-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (3).

[0240] Synthesis of N-( 18-((2, 4-dinitrophenyl)amino)-13-oxo-3, 6, 9,16-tetraoxa- 12- azaoctadecyl)-l-( 4-( (l-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ( ( 2-( 3-hydroxypropyl)-5- methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-N-( 13-oxo-l- ( ((2R, 3R, 4R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9,16, 19, 22- hexaoxa-12-azatetracosan-24-yl)-6, 9, 12, 15, 18, 21,24, 27,30, 33,36-undecaoxa-3- azanonatriacontan-39-amide (Compound 1).

[0241] To a stirred solution of (2R,3R,4R,6S)-2-((40-(18-((2,4-dinitrophenyl)amino)-13-oxo- 3 , 6,9, 16-tetraoxa- 12-azaoctadecyl)- 1 -(4-(( 1 -((3 -hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3 - hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l- yl)-39,52-dioxo-6,9,12,15,18,21,24,27,30,33,36,43,46,49,56,59,62-heptadecaoxa-3,40,53- triazatetrahexacontan-64-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (3, 1.0 eq.) in water (5 Vol.), 5% NaOH solution will be added (up to pH=12). The reaction mixture will be stirred for 1 h. After completion, crude reaction mixture will be purified by Prep-HPLC purification. The desired fraction will be collected and lyophilized to afford N-(18-((2,4- dinitrophenyl)amino)- 13 -oxo-3 ,6, 9, 16-tetraoxa- 12-azaoctadecyl)- 1 -(4-(( 1 -((3 -hydroxy-6- methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH- benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-N-(13-oxo-l-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6- methyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,6, 9, 16,19,22-hexaoxa- 12-azatetracosan-24-yl)- 6,9,12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-amide (Compound 1).

[0242] Example 4: Synthesis of (2R,3R,4R,6S)-2-((42-(17-((2,4-dinitrophenyl)amino)- 3,6,9, 12, 15-pentaoxaheptadecyl)-l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3- hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l- yl)-6,9,12,15,18,21,24,27,30,33,36,39,45,48,51,54,57,60,63-nonadecaoxa-3,42- diazapentahexacontan-65-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol. (Compound 2)20% TFA in DCM, it iDocket No. 1165.071132WO01TsCl, EtjN, ...PCM, rt _ ^ ^ ^ ^ ^ ^ ^HO^O^O^O^°^O^ - - ° - ^OTsCp-9, DIPEA, DMF Cp-12Docket No. 1165.071132WO01Cp-13 Cp-15 4A’MS (w / w), NaCNBHj, MeOH, AcOH, rtCompound 2

[0243] Synthesis of tert-butyl (17-((2,4-dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl) carbamate (3)

[0244] To a stirred solution of l-fluoro-2,4-dinitrobenzene (1, 1.0 eq.) & tert-butyl (17-amino- 3,6,9, 12, 15-pentaoxaheptadecyl)carbamate (2, 1.0 eq) in A, A-di methyl formamide (10 vol.), N,N Diisopropylethyl amine (3.0 eq.) will be added and the reaction mixture will be heated at 50°C for 16 h. After the completion of the reaction, Reaction mixture will be acidified (up to pH=5) with Citric acid solution. Then, it will be extracted with ethyl acetate (2x100 mL) , combined organic layers will be dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude compound, which will be purified using flash chromatography on silica gel to afford tert-butyl (17-((2,4-dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl)carbamate (3).

[0245] Synthesis ofNI-(2,4-dinitrophenyl)-3,6,9,12,15-pentaoxaheptadecane-l,17-diamine (4)

[0246] To a stirred solution of tert-butyl (17-((2,4-dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl)carbamate (3) in di chloromethane (5 vol.), trifluoroacetic acid (5 vol.) will be added at 0° C and the reaction mixture will be stirred at room temperature for 2 h. Progress ofDocket No. 1165.071132WO01the reaction will be monitored by TLC and LCMS. After completion, the reaction mixture will be concentrated to afford N1-(2,4-dinitrophenyl)-3,6,9,12,15-pentaoxaheptadecane-l,17-diamine (4).

[0247] Synthesis of 20-hydroxy-3, 6, 9, 12,15, 18-hexaoxaicosyl 4-methylbenzenesulfonate (6)

[0248] To a stirred solution of 3,6,9,12,15,18-hexaoxaicosane-l,20-diol (5, 1.0 eq) in dichloromethane (10 vol.) will be added triethylamine (3.0 eq) and 4-Toluenesulfonyl chloride (0.8 eq.) at 0° C and the reaction mixture will be allowed to stir at ambient temperature for 2 h. After the completion of the reaction, reaction mixture will be diluted with water and extracted with dichloromethane, dried over sodium sulfate, concentrated under reduced pressure to afford the crude. The crude will be purified over silica gel column chromatography to afford 20-hydroxy-3,6,9, 12, 15,18-hexaoxaicosyl 4-methylbenzenesulfonate (6).

[0249] Synthesis of (2S,4R,5R,6R)-2-methyl-6-((20-(tosyloxy)-3,6,9, 12, 15, 18-hexaoxaicosyl) oxy) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate ( 8)

[0250] To a solution of 20-hydroxy-3,6,9, 12, 15, 18-hexaoxaicosyl 4-methylbenzenesulfonate (6, 1.0 eq.), 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (7, 1.2 eq.) and MS 4A in anhydrous dichloromethane will be added Et2O-BF3 (6.0 eq.) at 0 °C. The reaction mixture will be allowed to warm to ambient temperature and stirred for 16 h at the same temperature. Progress of the reaction will be monitored by TLC and LCMS. Upon the completion of reaction, the reaction mixture will be diluted with di chloromethane and filtered through a pad of Celite. The solution will be washed with water and saturated sodium bicarbonate solution (2x100 mL). The combined organic layers will be dried over anhydrous sodium sulphate and concentrated. The product will be purified over silica gel chromatography as eluent to give (2S,4R,5R,6R)-2-methyl-6-((20-(tosyloxy)-3,6,9, 12, 15,18-hexaoxaicosyl)oxy)tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (8).

[0251] Synthesis of (2R,3R,4R,6S)-2-((l-((2,4-dinitrophenyl)amino)- 3, 6, 9, 12, 15,21, 24, 27,30,33,36, 39-dodecaoxa-18-azahentetracontan-41-yl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (9)

[0252] To a stirred solution of N1-(2,4-dinitrophenyl)-3,6,9,12,15-pentaoxaheptadecane-l,17-diamine (4, 1.0 eq.) in A A-di methyl form am ide (5 vol) will be added N,N-Diisopropylethylamine (2.5 eq.) and the reaction mixture will be allowed to stir at ambient temperature for 10 min and then solution of (2S,4R,5R,6R)-2-methyl-6-((20-(tosyloxy)-3,6,9, 12,15, 18-hexaoxaicosyl)oxy)tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (8, 1.0 eq.) in N,N-dimethylformamide (5 vol.) will be added to it. The reaction mixture will be allowed to stir at 60°C for 24 hours. After the completion of the reaction, reaction mixture will be diluted with iceDocket No. 1165.071132WO01cold water and extracted with ethyl acetate, Organic layer will be washed with ice cold water several times and then combined organic layers will be dried over sodium sulfate and concentrated under reduced pressure to afford the crude. This crude will be then purified by combi flash column chromatography (silica gel) to afford (2R,3R,4R,6S)-2-((l-((2,4- dinitrophenyl)amino)-3,6,9,12,15,21,24,27,30,33,36,39-dodecaoxa-18-azahentetracontan-41-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (9).

[0253] Synthesis of 38-hydroxy-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontyl 4-methylbenzenesulfonate (11)

[0254] To a stirred solution of 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontane-l,38- diol (10, 1.0 eq) in di chloromethane (10 vol.) will be added triethylamine (3.0 eq) and 4- Toluenesulfonyl chloride (0.8 eq.) at 0° C and the reaction mixture will be allowed to stir at ambient temperature for 2 h. After the completion of the reaction, reaction mixture will be diluted with water and extracted with dichloromethane, dried over sodium sulfate, concentrated under reduced pressure to afford the crude. The crude will be purified over silica gel column chromatography to afford 38-hydroxy-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontyl 4-methylbenzenesulfonate (11).

[0255] Synthesis of (2R, 3R, 4R, 6S)-2-( (24-( 17 -((2, 4-dinitrophenyl)amino)-3, 6, 9, 12, 15-pentaoxaheptadecyl)-62-hydroxy-3, 6, 9, 12, 15, 18, 21,27,30,33,36, 39, 42, 45, 48, 51, 54, 57, 60-nonadecaoxa-24-azadohexacontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (12)

[0256] To a stirred solution of (2R,3R,4R,6S)-2-((l-((2,4-dinitrophenyl)amino)- 3,6,9,12,15,21,24,27 ,30,33,36,39-dodecaoxa-18-azahentetracontan-41-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (9, 1.0 eq.) in A A -di methyl form am ide (5 vol) will be added MA-Di isopropyl ethyl amine (2.5 eq.) and the reaction mixture will be allowed to stir at ambient temperature for 10 min and then solution of 38-hydroxy- 3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxaoctatriacontyl 4-methylbenzenesulfonate (11, 1.0 eq.) in A A -di methyl form am ide (5 vol.) will be added to it. The reaction mixture will be allowed to stir at 60°C for 24 hours. After the completion of the reaction, reaction mixture will be diluted with ice cold water and extracted with ethyl acetate, Organic layer will be then will be washed with ice cold water several times and then combined organic layers will be dried over sodium sulfate and concentrated under reduced pressure to afford the crude. This crude will be then purified by combi flash column chromatography (silica gel) to afford (2R,3R,4R,6S)-2-((24-(17- ((2,4-dinitrophenyl)amino)-3,6,9, 12, 15-pentaoxaheptadecyl)-62-hydroxy- 3,6,9,12,15,18,21,27,30,33,36,39,42,45,48,51,54,57,60-nonadecaoxa-24-azadohexacontyl)oxy)- 6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (12).DocketNo. 1165.071132WO01

[0257] Synthesis of (2R,3R,4R,6S)-2-((24-(17-((2,4-dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-62-oxo-3, 6, 9, 12, 15, 18, 21,27,30,33,36, 39, 42, 45, 48, 51, 54, 57, 60-nonadecaoxa-24-azadohexacontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (13)

[0258] To a stirred solution of (2R,3R,4R,6S)-2-((24-(17-((2,4-dinitrophenyl)amino)- 3,6,9,12,15-pentaoxaheptadecyl)-62-hydroxy- 3,6,9,12,15,18,21,27,30,33,36,39,42,45,48,51,54,57,60-nonadecaoxa-24-azadohexacontyl)oxy)- 6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (12, 1.0 eq.) in dichloromethane (5 vol.), 2,2,6,6-tetramethyl-l -oxypiperidine (TEMPO; 0.5 eq.) will be added and the reaction mixture will be stirred for 5 min. (Di acetoxy iodo)benzene (PIDA; 2.5 eq.) will be added. The reaction mixture will be stirred at room temperature for 30 min. Progress of the reaction will be monitored by TLC. After completion, crude will be purified by column chromatography to afford (2R,3R,4R,6S)-2-((24-(17-((2,4-dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-62-oxo- 3,6,9,12,15,18,21,27,30,33,36,39,42,45,48,51,54,57,60-nonadecaoxa-24-azadohexacontyl)oxy)- 6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (13).

[0259] Synthesis of (2R, 3R, 4R, 6S)-2-((42-( 17 -((2, 4-dinitrophenyl)amino)-3, 6, 9, 12, 15-pentaoxaheptadecyl)-l-( 4-( (l-(( 3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18,21, 24, 27,30, 33, 36, 39, 45, 48, 51, 54, 57, 60, 63-nonadecaoxa-3, 42-diazapentahexacontan-65-yl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (15)

[0260] To a stirred solution of 2-((2-((l-(2-aminoethyl)piperidin-4-yl)amino)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyri din-3 -ol (14, 1.0 eq.) and MS 4A(w / w) in methanol (3 vol), (2R,3R,4R,6S)-2-((24- (17 -((2,4-dinitrophenyl)amino)-3 ,6,9,12,15 -pentaoxaheptadecyl)-62-oxo- 3,6,9,12,15,18,21,27,30,33,36,39,42,45,48,51,54,57,60-nonadecaoxa-24-azadohexacontyl)oxy)- 6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (13, 1.0 eq.) and acetic acid (cat.) will be added and the reaction mixture will be stirred at room temperature for 30 mins. Progress of the reaction will be monitored by TLC. Sodium cyanoborohydride (4.5 eq.) will be added at 0° C and the reaction mixture will be stirred at ambient temperature for another 1 h. Progress of the reaction will be monitored by LCMS. After completion, the reaction mixture will be filtered, filtrate will be concentrated and dried to get crude. The crude will be purified by Sephadex LH20 column chromatography using methanol as eluent. The desired fractions will be concentrated to (2R,3R,4R,6S)-2-((42-(17-((2,4-dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-l-(4-((l- ((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-Docket No. 1165.071132WO016,9,12,15,18,21,24,27,30,33,36,39,45,48,51,54,57,60,63-nonadecaoxa-3,42- diazapentahexacontan-65-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (15).

[0261] Synthesis of (2R, 3R, 4R, 6S)-2-((42-( 17 -((2, 4-dinitrophenyl)amino)-3, 6, 9, 12, 15-pentaoxaheptadecyl)-l-( 4-( (l-(( 3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18,21, 24, 27,30, 33, 36, 39, 45, 48, 51, 54, 57, 60, 63-nonadecaoxa-3, 42-diazapentahexacontan-65-yl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triol (Compound 2)

[0262] To a stirred solution of (2R,3R,4R,6S)-2-((42-(17-((2,4-dinitrophenyl)amino)- 3,6,9, 12, 15-pentaoxaheptadecyl)-l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36,39,45,48,51,54,57,60,63-nonadecaoxa-3,42- diazapentahexacontan-65-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (15, 1.0 eq.) in water (10 vol.), 5% NaOH aqueous solution will be added dropwise till pH=12. The reaction mixture will be stirred at room temperature for 1 h. Progress of the reaction will be monitored by TLC and LCMS. After completion, the reaction mixture will be purified by Prep-HPLC. Desired fractions upon lyophilisation will be afforded (2R,3R,4R,6S)-2-((42-(17-((2,4- dinitrophenyl)amino)-3,6,9,12,15-pentaoxaheptadecyl)-l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36,39,45,48,51,54,57,60,63-nonadecaoxa- 3, 42-diazapentahexacontan-65-yl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triol (Compound 2).

[0263] Example 5. Synthesis of (2S)-N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)- 1 -(( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9, 12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-oyl)-L-prolyl-L-prolyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)pyrrolidine-2-carboxamide. (Compound 6)Docket No. 1165.071132WO01OAcDocket No. 1165.071132WO01H

[0264] Synthesis of (((9H-jluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-proline (5)

[0265] Solid support peptide synthesis of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-proline (5) on a 2CTC resin and utilizing Fmoc / O / -Bu strategy.

[0266] General procedure:

[0267] Resin loading to prepare (3): In a peptide vessel 2CTC resin (Chem Impex, 2.0 g, 2.8 mmol / g) was swollen in DCM for 30 min. A solution of Fmoc-Pro-OH (2, BLD Pharm, 2.0 eq.) in N,N Diisopropylethylamine (DIPEA; 3.0 eq.) was added and the vessel was shaken for 12 h. After the reaction, the free sites of the resin were capped with methanol and the resin was washed with dichloromethane (DCM) (2 X 20 mL).

[0268] Fmoc De-protection: Peptide reaction vessel containing swollen peptidyl resin in DMF was added 20% piperidine in A, A dimethyl formamide (DMF). The reaction vessel was shaken at room temperature for 0.5 h. The resin was filtered and was washed with DMF (3x30 mL) and DCM (3X20 mL).

[0269] Amide coupling to prepare (4): The activated amino acid was prepared by weighing out an appropriate amount of amino acid (2.0 eq.), coupling agent (HATU; 2.5 eq.) and dissolving them in N, N dimethylformamide (20 mL). The activated amino acid solution and DIPEA (3.0 eq.) was added to the reaction vessel containing swollen resin. The reaction vessel was shaken for 2 h. (Repeated cycle two times).

[0270] Resin Cleavage: 2CTC resin loaded with protected peptide (1) was suspended in 2% Trifluoroacetic acid (TFA) in DCM (20 mL) in the peptide reaction vessel. Thereafter, reaction vessel was shaken for 30 min. The resin was filtered and washed three times with portions of 2% TFA in DCM. To the combined filtrates were added chilled diethyl ether to give crude peptide solids (5). Crude peptide was purified by Prep-HPLC purification; yield, 0.30 g. LC-MS (ESI) m / z 532.07 [M+H]+.Docket No. 1165.071132WO01

[0271] Synthesis of (2R,3R,4R,6S)-2-((15-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl)-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 (7)

[0272] To a stirred ice cold solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-proline (5; 0.15 g, 0.28 mmol), and (2R,3R,4R,6S)-2-((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 (6; 0.20 g, 0.23 mmol) in dry A, A-dimethylformamide (5 mL), Benzotri azole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 0.18 g, 0.34 mmol) and AA-Diisopropylethylamine (0.15 mL, 0.69 mmol) was added at same temperature. The reaction mixture was stirred at ambient temperature for 6 h. Progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure to get crude which was purified by silica gel column chromatography eluting in 5-10 % MeOH / DCM to afford (2R,3R,4R,6S)-2-((15-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl)-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 (7) as yellowish sticky solid. Yield: 0.13 g, 33.93%; LCMS m / z 1424.75. [M+NH4]+.

[0273] Synthesis of (2R,3R,4R,6S)-2-((15-(L-prolyl-L-prolyl-L-prolyl)-29-((2,4-dinitrophenyl)amino)-3, 6, 9, 12, 18, 21, 24, 27-octaoxa-l 5-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (8)

[0274] To a stirred solution of (2R,3R,4R,6S)-2-((15-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl)-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 (7; 0.13 g, 0.092 mmol) in -di methyl form am ide (4 mL), Piperidine (0.8 mL) was added at ambient temperature for Ih. Progress of the reaction was monitored by LCMS. After completion the reaction mixture was concentrated under reduced pressure to get crude. The crude was triturated with 20% diethyl ether in pentane to afford (2R,3R,4R,6S)-2-((15-(L-prolyl-L-prolyl-L-prolyl)-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 (8) as yellowish sticky solid. Yield: 0.09 g, 84.03%; LCMS m / z 1186.50. [M+H]+.

[0275] Synthesis of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oic acid (9)

[0276] Common intermediate (5) synthesized in the Example 13 synthesis of Compound 28DocketNo. 1165.071132WO01

[0277] Synthesis of ( 2R, 3R, 4R, 6S)-2-( (29-( (2, 4-dinitrophenyl) amino)- 15-( (l-(4-((l-(( 3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6, 9, 12, 15, 18,21, 24, 27,30, 33,36-undecaoxa-3-azanonatriacontan-39-oyl)-L-prolyl-L-prolyl-L-prolyl)-3, 6, 9, 12, 18,21, 24, 27 -octaoxa- 15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (10)

[0278] To a stirred ice cold solution of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oic acid (9; 50 mg, 0.044 mmol) and (2R,3R,4R,6S)-2-((15-(L-prolyl-L-prolyl-L-prolyl)-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 (8; 52 mg, 0.048 mmol) in A( A -di methyl form am ide (2 mL), Benzotri azole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 35 mg, 0.067 mmol) and A( A-Diisopropylethylamine (0.04 mL, 0.12 mmol) was added at same temperature. The reaction mixture was stirred at ambient temperature for 6h. 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 size exclusion (Sephadex LH20) column chromatography using methanol as eluent to afford (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-((l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oyl)-L-prolyl-L-prolyl-L-prolyl)-3,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (10) as yellowish sticky liquid. Yield: 25 mg, 84.03%; LCMS m / z 1142.60 [M / 2+H]+.

[0279] Synthesis of (2S)-N-( 14-((2, 4-dinitrophenyl)amino)-3, 6, 9, 12-tetraoxatetradecyl)-l-((l -(4-((l-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33.36-undecaoxa-3-azanonatriacontan-39-oyl)-L-prolyl-L-prolyl)-N-( 14-( ( (2R, 3R, 4R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9, 12-tetraoxatetradecyl)pyrrolidine-2-carboxamide (Compound 6).

[0280] To a stirred ice cold solution of (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-((l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33.36-undecaoxa-3-azanonatriacontan-39-oyl)-L-prolyl-L-prolyl-L-prolyl)-3,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-Docket No. 1165.071132WO01triyl triacetate (10; 25 mg, 0.01 mmol) in water (1 mL), 5% NaOH (0.005 mL) solution was added (up to pH=12). The reaction mixture was stirred for Ih. Progress of the reaction was monitored by LCMS. After completion, crude reaction mixture was purified by Prep-HPLC purification using 0-50% acetonitrile in H2O with 0.1% ammonium acetate. Desired fractions were collected and lyophilized to afford (2S)-N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)- 1 -(( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9, 12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-oyl)-L-prolyl-L-prolyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)pyrrolidine-2-carboxamide (Compound 6). Yield: 2.5 mg, 10.50%; LC-HRMS m / z 2156.1773 [M+H]+.

[0281] Example 6. Synthesis of (2S)-N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)- 1 -(( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9, 12-tetraoxatetradecyl)pyrrolidine-2-carboxamide. (Compound 7)Docket No. 1165.071132WO01

[0282] Synthesis of (((9H-jluoren-9-yl)methoxy)carbonyl)-L-^ro\y\-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-proline (5)

[0283] Solid support peptide synthesis of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-proline (5) on a 2CTC (2-Chlorotrityl chloride) resin and utilizing Fmoc / O / -Bu strategy.

[0284] General procedure:DocketNo. 1165.071132WO01

[0285] Resin loading to prepare (3): In a peptide vessel 2CTC resin (2.0 g, 2.8 mmol / g) was swollen in dichloromethane for 30 min. A solution of Fmoc-Pro-OH (2, 2.0 eq.) in N,N diisopropylethyl amine (DIPEA; 3.0 eq.) was added and the vessel was shaken for 12 h. After the reaction, the free sites of the resin were capped with methanol and the resin was washed with dichloromethane (2 X 20 mL).

[0286] Fmoc De-protection: Peptide reaction vessel containing swollen peptidyl resin in DMF was added 20% piperidine in N,N dimethylformamide (DMF). The reaction vessel was shaken at room temperature for 0.5 h. The resin was filtered and was washed with DMF (3x30 mL) and DCM (3X20 mL).

[0287] Amide coupling to prepare (4): The activated amino acid was prepared by weighing out an appropriate amount of amino acid (2.0 eq.), coupling agent (HATU; 2.5 eq.) and dissolving them in N, N dimethylformamide (20 mL). The activated amino acid solution and DIPEA (3.0 eq.) was added to the reaction vessel containing swollen resin. The reaction vessel was shaken for 2 h. (Repeated cycle five times).

[0288] Resin Cleavage: 2CTC resin loaded with protected peptide (1) was suspended in 2% Trifluoroacetic acid (TFA) in DCM (20 mL) in the peptide reaction vessel. Thereafter, reaction vessel was shaken for 30 min. The resin was filtered and washed three times with portions of 2% TFA in DCM. To the combined filtrates were added chilled diethyl ether to give crude peptide solids (5). Crude peptide was purified by Prep-HPLC purification; yield, 0.30 g. LC-MS (ESI) m / z 532.07 [M+H]+.

[0289] Synthesis of (2R,3R,4R,6S)-2-((15-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-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 (7)

[0290] To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-proline (1.0 eq.), and (2R,3R,4R,6S)-2-((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 (1.0 eq.) in dry N,N-dimethylformamide (10 Vol.), Benzotriazole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 1.2 eq.) andN,N-Diisopropylethylamine (2.5 eq.) will be added at 0° C. The reaction mixture will be stirred at ambient temperature for 16 h. Progress of the reaction will be monitored by LCMS. After completion, the reaction mixture will be concentrated under reduced pressure to get crude which will be purified by silica gel column chromatography eluting in 5-10 % methanol in dichloromethane to afford (2R,3R,4R,6S)-2-((15-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-29-((2,4-dinitrophenyl)amino)-DocketNo. 1165.071132WO013,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (7).

[0291] Synthesis of (2R,3R,4R,6S)-2-((15-(L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-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 (8)

[0292] To a stirred solution of (2R,3R,4R,6S)-2-((15-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-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 (7; 1.0 eq.) in N,N-dimethylformamide (5 Vol), 20% Piperidine in N,N- dimethylformamide (10 Vol) will be added at ambient temperature for 1 h. Progress of the reaction will be monitored by LCMS. After completion, the reaction mixture will be concentrated under reduced pressure to get crude. The crude was triturated with diethyl ether to afford (2R,3R,4R,6S)-2-((15-(L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-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 (8).

[0293] Synthesis of (2R, 3R, 4R, 6S)-2-( (29-( (2, 4-dinitrophenyl)amino)-l 5-( 1 -(4-( (l-(( 3-hydroxy- 6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH- benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6, 9, 12, 15, 18, 21, 24, 27-octaoxa-3-azatriacontan-30-oyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-3, 6, 9, 12, 18,21, 24, 27 -octaoxa- 15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (10)

[0294] To a stirred solution of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oic acid (9; 1.0 eq.) and (2R,3R,4R,6S)-2- ((15-(L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-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 (8; 1.0 eq.) in N,N-dimethylformamide (10 Vol.) , Benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 1.2 eq.) andN,N-Diisopropylethylamine (DIPEA; 2.5 eq.) will be added at 0° C. The reaction mixture will be stirred at ambient temperature for 16 h. Progress of the reaction will be monitored by LCMS. After completion the reaction mixture will be concentrated under reduced pressure to get crude which will be purified by Sephadex LH20 column chromatography using methanol as eluent to afford (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-((l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-Docket No. 1165.071132WO01oyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-3,6,9,12,18,21,24,27-octaoxa-15- azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (10).

[0295] Synthesis of ( 2R)-N-( l4-((2, 4-dinitrophenyl)amino)-3, 6, 9, 12-tetraoxatetradecyl)-l-( (l-(4- ((!-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21, 24, 27-octaoxa-3-azatriacontan-30-oyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-N-( 14-( ( (2R, 3R, 4R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9, 12- tetraoxatetradecyl)pyrrolidine-2-carboxamide (Compound 7).

[0296] To a stirred solution of (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-((l-(4-((l- ((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-3,6,9,12,18,21,24,27-octaoxa-15-azanonacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (10; 1.0 eq.), water (5 Vol.), 5% NaOH solution will be added (up to pH=12). The reaction mixture will be stirred for 1 h. After completion, crude reaction mixture will be purified by Prep-HPLC purification. The desired fraction will be collected and lyophilized to afford (2R)-N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)-l-((l- (4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27-octaoxa-3-azatriacontan-30-oyl)-L-prolyl-L-prolyl-L-prolyl-L-prolyl-L-prolyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)- 3,6,9, 12-tetraoxatetradecyl)pyrrolidine-2-carboxamide (Compound 7).

[0297] Example 7. Synthesis of N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)- 1 - ( 1 - ( 1 - ( 1 - ( 1 - ( 1 -( 1 - (4- (( 1 - ((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)- 5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14- (((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 5)Part 1.Docket No. 1165.071132WO01Scheme 1.ZnCI2(1 eq), Na[BHj(CN)] (4 eq), MeOH, 10% Pd / C(w / w), H2(atm), 0°C »RT, 16h CbzHN MeOH, 18h, rt Step-5 '- / xNHBoc Step-6MnO2(15eq), ACN (50 V), MeOH (2V), DCM (2V), 45°C, 36h Step-1113BTPP (0.1 eq), Pd(PPh3)2CI2(0.1 eq) Cui (0.1 eq), Et3N (8 V), 10% Pd / C(w / w), H2(atm), DMF (4 V), RT MeOH, 18h, 50 °C Step-13 Step-1416 14

[0298] Step 1. Synthesis of 2-((dibenzylamino)methyl)-6-methylpyridin-3-ol (3).

[0299] In a 20 liter RBF, 6-m ethylpyri din-3 -ol (1, 500 g, 4.5817 mol) and dibenzylamine (2, 903.88 g, 1 eq., 4.5817 mol) were suspended in water (5 L) and warmed up to 50°C. To this stirred solution, 37% aq. solution of formaldehyde (1487.44 g, 4.0 eq., 18.327 mol) was added atDocket No. 1165.071132WO01the same temperature and the resulting mixture was stirred at 100°C until the complete consumption of starting material. The reaction progress was monitored by LCMS and TLC. Complete consumption of starting materials was observed in 6h. After completion of the reaction, the reaction mixture was cooled to RT and diluted with DCM (10 L) and the layers were separated. The organic layer was further washed with water (10 L) followed by sat. NH4Q solution (10 L). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was further purified by combi-flash column chromatography over 100-200 mesh size silica gel using gradient eluent system of 60-70% EtOAc in heptane which afforded the desired product 2-((dibenzylamino)methyl)-6-methylpyridin-3-ol (3) as a white solid (920 g, 63%). LCMS andJH NMR data were consistent with the compound structure.

[0300] Step 2: Synthesis of 2-(aminomethyl)-6-methylpyridin-3-ol TFA salt (4).

[0301] In an autoclave, to a stirred solution of 2-((dibenzylamino)methyl)-6-m ethylpyri din-3 -ol (3; 500 g, 1.5702 mol) in methanol (4 L), trifluoroacetic acid (120.2 mL, 1.5702 mol) was added at ambient temperature. Then, 10% Pd / C (357 g) was added under an inert atmosphere.Subsequently, the flask was evacuated, backfilled with hydrogen gas (120 psi) and left to stir at ambient temperature until the complete consumption of starting material. The progress of the reaction was monitored by LCMS and TLC. Complete consumption of starting materials was observed in 6h. After complete consumption of the starting material, the reaction mixture was filtered over a pad of celite and the celite bed was thoroughly washed with methanol (3 x 1.5 L). The combined filtrate was then concentrated under vacuum to obtain a colorless crystalline solid. The solid was further triturated with diethyl ether (2 x 2.5 L) to obtain 2-(aminomethyl)-6-methylpyri din-3 -ol (4, TFA salt) as an off-white crystalline solid (320 g, 79.19%). LCMS andJH NMR data were consistent with the compound structure.

[0302] Step 3: Synthesis of methyl 3-(((3-hydroxy-6-methylpyridin-2-yl)methyl)amino)-4-nitrobenzoate (6).

[0303] To a stirred solution of methyl 3-fluoro-4-nitrobenzoate (5, 160 g, 0.803 mol) and 2-(aminomethyl)-6-ethylpyridin-3-ol TFA salt (4, 320 g, 1.24mol) in DMF (1.6 L) was added triethylamine (224 mL, 1.6069 mol) at room temperature until the complete consumption of starting material. The progress of the reaction was monitored by LCMS and TLC. Complete consumption of starting materials was observed in 12h. After complete consumption of starting materials, the reaction mass was quenched with water (2 L) and extracted with ethyl acetate (3 x 2 L). The organic layer was further washed with brine solution (6 x 2 L), dried over anhydrous sodium sulphate, filtered and concentrated under vacuum at 45°C to get the crude material. TheDocket No. 1165.071132WO01crude material was stirred in diethyl ether (3 L), filtered and thus obtained solid product was further dried under reduced pressure at 50°C which afforded the desired product methyl 3-{[(3-hydroxy-6-methyl-2-pyridyl)methyl]amino}-4-nitrobenzoate (6, 190 g, 74%) as yellow solid. LCMS and1H NMR data were consistent with the compound structure.

[0304] Step 4: Synthesis of Methyl 4-amino-3-(((3-hydroxy-6-methylpyridin-2-yl)methyl)amino)benzoate (7).

[0305] To a stirred solution of methyl 3-{[(3-hydroxy-6-methyl-2-pyridyl)methyl]amino}-4-nitrobenzoate (6, 54 g, 0.1702 mol.) in methanol (2.16 L) was added a solution of ammonium chloride (91.03 g, 1.7019 mol.) in water (540 mL) at room temperature. The reaction mixture was stirred for 10 min and then Zn (55.64 g, 0.8509 mol.) was added at the same temperature. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 16h. After complete consumption of the starting materials, the reaction was diluted with water (5 L) and extracted with DCM (3 x 2 L). The organic layer was washed with brine (10 L), dried over anhydrous sodium sulphate, filtered and concentrated under vacuum at 45°C to give the crude material. The crude material was stirred in diethyl ether (4 L), filtered and the solid product was dried under reduced pressure at 50°C to afford the desired product methyl 4-amino-3-{[(3-hydroxy-6-methyl-2-pyridyl)methyl]amino}benzoate (7, 39 g, 79%) as a yellow solid. LCMS andJH NMR data were consistent with the compound structure.

[0306] Step 5: Synthesis of benzyl (l-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-4-y I) carbamate (10).

[0307] To a stirred solution of benzyl piperidin-4-ylcarbamate (8, 100 g, 0.4268 mol) and tertbutyl (2-oxoethyl)carbamate (9, 101.91 g, 0.6402 mol) in methanol (1.0 L) was added ZnCh (58.17 g, 4268 mol) at 0°C. The reaction mixture was stirred for 2 h at room temperature, then sodium cyanoborohydride (107.28 g, 1.7072 mol.) was added at 0°C. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 16h. After complete consumption of starting materials, the reaction was quenched with ice water (2 L) and extracted with 10% MeOH / DCM (3 x 2 L). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under vacuum at 45°C to give the crude material. The crude material was purified by column chromatography over 100-200 mesh silica gel using gradient eluent system of 5-8% MeOH in DCM which afforded benzyl (l-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-4-yl)carbamate (10, 122 g, 75.72%) as a white solid. LCMS andJH NMR data were consistent with the compound structure.Docket No. 1165.071132WO01

[0308] Step 6: Synthesis of tert-butyl (2-(4-aminopiperidin-l-yl) ethyl) carbamate (11).

[0309] A stirred solution of benzyl (l-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-4-yl) carbamate (10, 120 g, 0.3179 mol.) in MeOH (1.2 L) was purged with N2 gas for 15 min. Then 10% Pd / C (50% wet) (60 g, 50% w / w) was added at room temperature. The resultant reaction mixture was stirred for stipulated period at 50 °C under H2 pressure (200 psi). The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 18 h. After completion of the reaction, the suspension was filtered over a celite pad and washed with methanol (5 L). The filtrate was then concentrated to afford the desired product tert-butyl [2-(4-amino-l-piperidyl)ethyl]carbamate (11, 70 g, 90%) as a yellow liquid. LCMS data was consistent with the compound structure.

[0310] Steps 7, 8, and 9: Synthesis of methyl 2-((l-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-4-yl)amino)-l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (12). Step 7.

[0311] To a stirred solution of Zc / V-butyl (2-(4-aminopiperidin-l-yl)ethyl)carbamate (11, 29 g, 0.1192 mol) in DMF (290 mL) was added l,l'-thiocarbonyldiimidazole (25.49 g, 0.1430 mol.) at 0 °C. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 18 h. Step 8. After consumption of the starting materials, methyl 4-amino-3-(((3-hydroxy-6-methylpyridin-2-yl)methyl) amino)benzoate (7, 27.39 g, 0.0953 mol) was added to the reaction mixture and it was further stirred for the stipulated period. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 36 h. Step 9. To the reaction mixture of Step 8, DIPEA (41.63 mL, 0.2383 mol) and CuCl (29.49 g, 0.2979 mol) were added at room temperature for 15 min, then the reaction mixture was further stirred at 80°C for the stipulated period. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 18 h. Upon completion of the reaction, the reaction mixture was filtered, and the solid material was washed with ethyl acetate (200 mL). The filtrate was further diluted with water (500 mL) and extracted with ethyl acetate (4 x 400 mL). The combined organic layer was concentrated under reduced pressure at 50°C to give the crude material. The crude material was purified by column chromatography over 100-200 mesh silica gel using gradient eluent system of 12% MeOH in DCM, which afforded methyl 2-((l-(2-((tert-butoxycarbonyl)amino)ethyl)piperidin-4-yl)amino)-l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (12, 12.0 g,Docket No. 1165.071132WO0118.7% over three steps) as an off-white solid. LCMS and 'H NMR data were consistent with the compound structure.

[0312] Step 10: Synthesis of2-{4-[6-(hydroxymethyl)-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]~ lH-l,3-benzimidazol-2-ylamino]-l-piperidyl}ethyl 2-methyl-2-propanecarbamate (13 A).

[0313] To a stirred solution of methyl 2-(l-{2-[tert-butyl(oxycarbonylamino)]ethyl}-4-piperidylamino)-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazole-6-carboxylate (12, 27 g, 0.0476 mol) in THF (270 mL) was added LiAlH4(2M in THF) (119 mL, 0.238 mol) at 0°C. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 3 h. After completion of the reaction, the reaction mass was quenched with Na2SO4- IOH2O (270 g) and stirred for 30 min. This material was further diluted with 10% MeOH / DCM (400 mL), filtered and washed with water (2 L). The organic fractions were collected together and concentrated under reduced pressure at 50°C, which afforded the desired product 2-{4-[6-(hydroxymethyl)-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazol-2-ylamino]-l-piperidyl} ethyl 2-methyl-2-propanecarbamate (13A, 18 g, 70%) as yellow solid. LCMS andJH NMR data were consistent with the compound structure.

[0314] Step 11: Synthesis of 2-(4-{6-formyl-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazol-2-ylamino}-l-piperidyl)ethyl 2-methyl-2-propanecarbamate (13B).

[0315] 2-{4-[6-(Hydroxymethyl)-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazol-2-ylamino]-l -piperidyl (ethyl 2-methyl-2-propanecarbamate (13A, 18 g, 0.0333 mol) was added in the pre-mixed solution of acetonitrile (900 mL), MeOH (36 mL) and DCM (36 mL) at RT. Then MnCh (43.4 g, 0.50 mol) was added at room temperature, followed by heating at 45°C for the stipulated period. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of the starting materials. Complete consumption of the starting materials was observed in 18 h. After consumption of the starting material, the reaction was filtered through a Celite pad and washed with 10% MeOH / DCM (2 L). The filtrate was concentrated under reduced pressure at 50°C to give the crude material. The crude material was purified through silica gel (60-120 mesh) using gradient eluent system of 0-4% MeOH / DCM, which afforded the desired product 2-(4-{6-formyl-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazol-2-ylamino}-l-piperidyl)ethyl 2-methyl-2-propanecarbamate (13B, 11 g, 62%) as a yellow solid. LCMS and1H NMR data were consistent with the compound structure.Docket No. 1165.071132WO01

[0316] Step 12: Synthesis of 2-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l, 3-benzimidazol-2-ylamino}-l-piperidyl)ethyl 2-methyl-2-propanecarbamate (15).

[0317] To a stirred solution of 2-(4-{6-formyl-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazol-2-ylamino}-l-piperidyl)ethyl 2-methyl-2-propanecarbamate (13B, 9.5 g, 0.0179 mol) and 3 -(2-amino-4-tolyl)-l -propanol (14, 3.36 g, 0.0179 mol) in MeOH (19 mL) was added acetic acid (4.75 mL) at room temperature and stirred at the same temperature for 5 hours. Then the reaction mixture was brought at 0°C and sodium cyanoborohydride (2.25 g, 0.0358 mol) was added and allowed to stir at RT for the stipulated period. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials.Complete consumption of starting materials was observed in 3 h. After consumption of the starting material, the reaction was filtered, and a solid material was washed with MeOH (20 mL). This solid material was further dried under high vacuum at 50°C, which afforded the desired product 2-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl } - 1H- 1 ,3 -benzimidazol-2-ylamino} - 1 -piperidyl)ethyl 2-methyl-2-propanecarbamate (15, 7.3 g, 56%) as an off-white solid. LCMS and1H NMR data were consistent with the compound structure.

[0318] Step 13: Synthesis of 3-(2-nitro-4-tolyl)-2-propyn-l-ol (18).

[0319] To a stirred solution of 4-iodo-3 -nitrotoluene (16, 100 g, 0.380 mol) in triethylamine (800 mL) and DMF (400 mL), PPhs (9.97 g, 0.038 mol) and Cui (7.24 g, 0.038 mol) were added at room temperature. The reaction mixture was further degassed with N2 gas for 30 min, followed by addition of Pd(PPh3)2C12 (26.7 g, 0.038 mol) at the same temperature. After complete purging, 2-propyn-l-ol (17, 32.9 mL, 0.570 mol) was added and the reaction mixture was allowed to stir at RT for the stipulated period. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 4 h. After consumption of starting material, the reaction was diluted with ethyl acetate (2 L). The diluted reaction mixture was filtered through a Celite pad and washed with ethyl acetate (1 L). The organic layer was further washed with saturated brine solution (8 x 1 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 50°C to give the crude material. The crude material was further purified by flash column chromatography over 60-120 mesh silica gel using gradient eluent system of 40% ethyl acetate in heptane which afforded the desired product 3-(2-nitro-4-tolyl)-2-propyn-l-ol (18, 50 g, 70%) as a yellow solid. LCMS and1H NMR data were consistent with the compound structure.

[0320] Step 14: Synthesis of 3-(2-amino-4-tolyl)-l-propanol (14).Docket No. 1165.071132WO01

[0321] To a stirred andN2 purged solution of 3-(2-nitro-4-tolyl)-2-propyn-l-ol (18, 45 g, 0.209 mol) in MeOH (450 mL) was added 10% Pd / C (50% wet) (20 g) at room temperature. The reaction mixture was further stirred under H2 atmosphere (200 psi) at 50°C for the stipulated period. The progress of the reaction was monitored with TLC and LCMS until the complete consumption of starting materials. Complete consumption of starting materials was observed in 30 h. After consumption of starting material, the reaction was filtered through a Celite pad and washed with MeOH (3 L). The filtrate was concentrated under vacuum at 50°C, which afforded the desired product 2-{4-[6-(hydroxymethyl)-l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-lH-l,3-benzimidazol-2-ylamino]-l -piperidyl} ethyl 2-methyl-2-propanecarbamate (14, 30 g, 77%) as a brown solid. LCMS and1H NMR data were consistent with the compound structure.Part 2,Scheme 2.Step-3 5Docket No. 1165.071132WO01Step- 6T3P (50 % in EtOAc), Cp7Et3N, EtOAc, RT,16h

[0322] Step 1: Synthesis of (9H-jluoren-9-yl)methyl 4-(4-(tert-butoxycarbonyl) piperidine-1- carbonyl)piperidine- 1-carboxylate (3).

[0323] To a stirred solution of l-[(9H-fluoren-9-yl) methoxy carbonyl]-4-piperidinecarboxylic acid (1, 250 g, 0.7114 mol) in tetrahydrofuran (2.5 L) at 0-5 °C was added diisopropylethylamine (372.78 mL, 2.1343 mol, 3.0 eq.) dropwise over 10 min. The reaction mixture was stirred for an additional 10 min before the slow addition of T3P (724 g, 2.28 mol, 3.2 eq., 50% solution in EtOAc) over 15-20 min at the same temperature. After stirring for 30 min, a solution of tert-butyl 4-piperidinecarboxylate (2, 171 g, 925 mmol, 1.3 eq.) in THF (2.5 V) was added dropwise over 20 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC. Upon completion of the reaction, the reaction was quenched with saturated aqueous NaHCOs (10 V) and extracted with ethyl acetate (3 / | 5 V). The combined organic layers were washed sequentially with saturated NaHCOs (l x 5 V), water (1 x 5 V), brine (1 x 5 V) and dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford the crude product as a sticky residue. The crude residue was suspended in methyl tert-butyl ether (MTBE, 10 V) and stirred at 5-10 °C for 1 h. The resultingDocket No. 1165.071132WO01solid was collected by filtration, washed with cold MTBE (2 * 2.5 V), and dried under reduced pressure to afford (9H-fluoren-9-yl) methyl 4-[(4-tert-butoxycarbonyl-l-piperidyl) carbonyl]-l-piperidinecarboxylate (3) (300 g, 81.3%) as an off-white solid. LCMS andJH NMR data were consistent with the compound structure.

[0324] Step 2: Synthesis of l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (4).

[0325] To a stirred solution of (9H-fluoren-9-yl) methyl 4-[(4-tert-butoxycarbonyl-l -piperidyl) carbonyl]-l-piperidinecarboxylate (3, 300 g, 578 mmol) in dichloromethane (600 mL, 2 V) at 0-5 °C was added trifluoroacetic acid (20% v / v in DCM, 3000 mL, 10 V) dropwise over 10 min. The reaction mixture was maintained at 0-5 °C for an additional 30 min, then allowed to warm to ambient temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC. The reaction mixture was concentrated under reduced pressure to remove volatiles. The residue was subjected to azeotropic distillation with DCM (2 x 5 V), followed by methyl tert-butyl ether (2 x 5 V) to remove residual TFA, affording the crude product. The crude residue was triturated with cold MTBE (5 V) at 5-10 °C for 1 h, filtered, and washed with additional MTBE (2 x 2.5 V). The solid was dried under reduced pressure to yield l-({l-[(9H-fluoren-9-yl)methoxycarbonyl]-4-piperidyl}carbonyl)-4-piperidinecarboxylic acid (4, 242 g, 90.45%) as an off-white solid. LCMS andJH NMR data were consistent with the compound structure.

[0326] Step 3: Synthesis of (9H-fluoren-9-yl)methyl 4-(4-(4-(tert-butoxycarbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l -carboxylate (5).

[0327] To a stirred solution of l-({l-[(9H-fluoren-9-yl) methoxy carbonyl]-4-piperidyl} carbonyl)-4-piperidinecarboxylic acid (4, 240 g, 0.5189 mol.) in tetrahydrofuran (2.4 L) at 0-5 °C was added diisopropylethylamine (277 mL, 1.5566 mol, 3.0 eq.) dropwise over 10 min. The reaction mixture was stirred for an additional 10 min, followed by the slow addition of T3P (1056.59 g, 1.6604 mol, 3.2 eq., 50% solution in EtOAc) over 15-20 min at the same temperature. After stirring for 30 min, a solution of tert-butyl 4-piperidinecarboxylate (124.97 g, 0.6745 mol. 1.3 eq.) in THF (2.5 V) was added dropwise over 20 min. The reaction mixture was then allowed to warm at ambient temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated aqueous NaHCCh (10 V) and extracted with ethyl acetate (3 x 15 V). The combined organic layers were washed sequentially with saturated NaHCCh (1 x 5 V), water (1 x 5 V) and brine solution (1 x 5 V), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford the crude product as a sticky residue (352 g). The crude residue was purified by column chromatography on silica gel (60-120 mesh), eluting with 70-80% ethyl acetate in n-heptane. The desired fractions wereDocket No. 1165.071132WO01combined and concentrated under reduced pressure to afford (9H-fluoren-9-yl)methyl4-({4-[(4-tert-butoxy carbonyl- 1 -piperidyl)carbonyl]- 1 -piperidyl } carbonyl)- 1 -piperidinecarboxylate (5, 225 g, 68.85% yield) as an off-white solid. LCMS andJH NMR data were consistent with the compound structure.

[0328] Step 4: Synthesis of l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid ( 6).

[0329] To a stirred solution of (9H-fluoren-9-yl)methyl 4-({4-[(4-tert-butoxycarbonyl-l-piperidyl)carbonyl]-l -piperidyl] carbonyl)- 1 -piperidinecarboxylate (5, 100 g, 0.1588 mol.) in di chloromethane (0.2 L) at 0-5 °C was added trifluoroacetic acid (20% v / v in DCM, 1000 mL, 10 V) dropwise over 10 min. The reaction mixture was maintained at 0-5 °C for an additional 30 min, then allowed to warm to ambient temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC. The mixture was concentrated under reduced pressure to remove volatiles. The residue was subjected to azeotropic distillation with DCM (2 x 5 V) followed by methyl tert-butyl ether (2 x 5 V) to remove residual TFA, affording the crude product. The crude residue was triturated with cold MTBE (5 V) at 5-10 °C, filtered, and washed with additional MTBE (2 x 2.5 V). The resulting solid was dried under reduced pressure to yield l-l-{ [l-({ 1-[(9H-fluoren-9-yl)methoxycarbonyl]-4-piperidyl] carbonyl)-4-piperidyl] carbonyl]-4-piperidinecarboxylic acid (6, 73 g, 80.14%) as an off-white solid. LCMS andJH NMR data were consistent with the compound structure.

[0330] Step 5: Synthesis of tert-butyl 1-(1 -(piper idine-4-carbonyl)piper idine-4-carbonyl)piperidine-4-carboxylate ( 7) .

[0331] To a dry, nitrogen-flushed 10 L round-bottom flask equipped with a mechanical stirrer were added (9H-fluoren-9-yl)methyl 4-({4-[(4-tert-butoxycarbonyl-l-piperidyl)carbonyl]-l-piperidyl] carbonyl)- 1 -piperidinecarboxylate (5, 100 g, 159 mmol) and anhydrous N,N-dimethylformamide (2 V). The resulting solution was cooled to 0-5 °C in an ice bath, and a solution of piperidine (20% v / v in DMF, 10 V) was added dropwise over 10 min. The reaction mixture was allowed to warm at ambient temperature and stirred for 6 h under a nitrogen atmosphere. The reaction progress was monitored by thin-layer chromatography (TLC) and LCMS. The mixture was concentrated under reduced pressure to remove volatiles. The residue was suspended in methyl tert-butyl ether (MTBE, 10 V) and stirred for 1 h at room temperature. The resulting solid was collected by filtration, washed with MTBE (5 V), and dried under vacuum to afford tert-butyl 1 -({ 1 -[(4-piperidyl) carbonyl]-4-piperidyl] carbonyl)-4-piperidinecarboxylate (7) as an off-white solid (47 g, 72% yield). LCMS andJH NMR data were consistent with the compound structure.DocketNo. 1165.071132WO01

[0332] Step 6: Synthesis of (9H-jluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-(tert-butoxycarbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l -carbonyl) piperidine- 1 -carboxylate ( 8).

[0333] To a solution of l-{[l-({l-[(9H-fluoren-9-yl)methoxycarbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidinecarboxylic acid (6, 50 g, 0.0871 mol) in ethyl acetate (500 mL) was added triethylamine (100.81 mL, 0.7173 mol.) at room temperature. The reaction mixture was stirred for 30 min and tert-butyl l-({l-[(4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidinecarboxylate (7, 49.73 g, 1.4 eq., 0.1220 mol) was added to the reaction mixture, followed by addition of T3P (128.4 mL, 0.2179 mol, 50% solution in EtOAc) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction progress was monitored by thin-layer chromatography (TLC) and LCMS. After consumption of starting material, the reaction was filtered, and the solid compound was washed with n-pentane (1 L). The solid compound was slurred with water (2 x 500 mL), filtered and dried under vacuum at 50 °C. The solid compound was azeotroped with DCM and dried under vacuum to give (9H-fluoren-9-yl)methyl 4-({4-[(4-{[4-({4-[(4-tert-butoxycarbonyl-l-piperidyl)carbonyl]-l-piperidyl}carbonyl)-l-piperidyl]carbonyl}-l-piperidyl)carbonyl]-l-piperidyl}carbonyl)-l-piperidinecarboxylate (8, 50 g, 55%) as a white solid. LCMS andJH NMR data were consistent with the compound structure.

[0334] Step 7: Synthesis of l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (9).

[0335] To a stirred solution of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-(tert-butoxycarbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperi dine- l-carbonyl)piperi dine- 1 -carboxylate (8, 25.0 g, 25.9 mmol) in dichloromethane (DCM, 250 mL, 2 V) at 0-5 °C was added trifluoroacetic acid (TFA, 50 ml) dropwise over 10 min. The reaction mixture was maintained at 0-5 °C for an additional 30 min, then allowed to warm to ambient temperature and stirred for 16 h. The reaction was monitored by LCMS and TLC until the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove volatiles. The residue was subjected to azeotropic distillation with DCM (2 x 5 V) followed by methyl tert-butyl ether (MTBE, 2 / 5 V) to remove residual TFA, affording the crude product. The crude residue was triturated with cold MTBE (5 V) at 5-10 °C for 1 h, filtered, and washed with additional MTBE (2 x 2.5 V). The solid was dried under reduced pressure to yield l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-Docket No. 1165.071132WO01carbonyl)piperidine-4-carboxylic acid (9) (20.0 g, 87.1%) as an off-white solid. LCMS andJH NMR data were consistent with the compound structure.Part 3,Scheme 3.20% TFA in DCM, 0C » RT, xh Step-2OAc AcOz, ,OAc AcO' O TsCI, Ag2O, 4A MS (W / W), Et3N, DCM, BF3.OEt2, DCM, RT, xh 0°C » RT, xh 6 Step-4DIPEA (2.0 eq), DMF (20V), 60°C, 16h Step-5OH Acetic anhydride (8 eq), OAc Pyridine (10V), HO,, A >OH 0°C » RT, 16h HO* rr ''OH Step-67

[0336] Step J: Synthesis of tert-butyl (14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (3).

[0337] To a stirred solution of l-fluoro-2,4-dinitrobenzene (1, 50.0 g, 269 mmol) and 14-amino-3,6,9, 12-tetraoxatetradecyl 2-methyl-2-propanecarbamate (2, 90.4 g, 269 mmol) in dry DMF (750 mL, 9.69 mol) was added DIPEA (104.0 g, 143 mL, 806 mmol, 3.00 equiv) at ambient temperature under N2 atmosphere. The reaction mixture was further heated at 50°C for the stipulated period. The progress of the reaction was monitored through TLC and LCMS.Docket No. 1165.071132WO01Complete consumption of starting materials was observed within 16 h. Upon completion, the reaction mixture was cooled to room temperature and the pH was adjusted to 5 using 15% aqueous solution of citric acid (10 V). The product was extracted with ethyl acetate (3 ^ 15 V), and the combined organic layers were subsequently washed with water (3 x 10 V) and brine (1 x 10 V), followed by drying over anhydrous Na2SC>4. The mixture was then filtered and concentrated under reduced pressure. To remove any residual DMF impurity, the crude material was re-dissolved in ethyl acetate (40 V) and washed with cold water (3 x 15 V) and brine (1 x 5 V). Concentration under reduced pressure afforded the desired product tert-butyl (14-((2,4-dinitrophenyl)amino) -3,6,9, 12-tetraoxatetradecyl)carbamate (3, 120 g, 88%) as a yellow semisolid. LCMS and 'H NMR data were consistent with the compound structure.

[0338] Step 2: Synthesis of 2-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)-l-(2,4-dinitrophenylamino ) e thane (4).

[0339] To a stirred and ice-cold solution of tert-butyl (14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (3, 120.0 g, 238 mmol) in dry DCM (950 mL) was added trifluoroacetic acid (180 mL, 1.5 V) dropwise over a period of 10 min under an inert atmosphere of N2. The reaction mixture was allowed to warm to ambient temperature and further stirred for the stipulated period. The progress of the reaction was monitored through TLC and LCMS.Complete consumption of starting materials was observed within 6 h. Upon completion, the mixture was concentrated under reduced pressure to afford 2-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)-l-(2,4-dinitrophenylamino)ethane as a TFA salt. The crude residue was dissolved in DCM (20 V) and washed successively with saturated aqueous NaHCCh solution (2 x 10 V), water (1 x 10 V), and brine (1 x 5 V). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product 4 (89.0 g, 92%) as a free base as a yellow semi-solid. LCMS and 'H NMR data were consistent with the compound structure.

[0340] Step 3: Synthesis of 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzene sulfonate (6).

[0341] To a stirred solution of 3,6,9, 12-tetraoxa-l,14-tetradecanediol (5, 65 g, 273 mmol) in DCM (975 ml) was added Nal (45 g, 1.1 eq., 0.3 mol) followed by Ag2O (94.8 g, 1.5 eq., 0.409 mol) and p-TsCl (41.6 g, 0.8 eq., 0.218 mmol) sequentially under an inert atmosphere of N2. The resultant reaction mixture was further stirred at 0°C for the stipulated period. The progress of the reaction was monitored through TLC and LCMS. Complete consumption of starting material was observed within 30 min. Upon completion, the reaction mixture was filtered through a Celite pad and washed with DCM (2 V). The combined organic layers were washed successively with saturated NaHCCh (2 x 10 mL), H2O (1 x 10 mL), and brine (1 x 10 mL), then dried overDocket No. 1165.071132WO01Na2SC>4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel (60-120 mesh) column chromatography (eluent: 0-5% MeOH in CH2CI2) to provide the desired compound 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate as a colorless gummy liquid (6, 60g, 56%). LCMS andJH NMR data were consistent with the compound structure.

[0342] Step 4: Synthesis of (2S,3S, 4R,5R,6R)-2-methyl-6-((14-(tosyloxy)-3, 6, 9,12-tetraoxatetradecyl)oxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate (8).

[0343] To a stirred solution of 2-[2-(2-{2-[2-(tosyloxy)ethoxy]ethoxy}ethoxy)ethoxy]ethanol (6, 60.0 g, 153 mmol), (2S,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl acetate (7, 78.2 g, 1.2 eq., 183 mmol) and activated 4 A molecular sieves (60.0 g, w / w) in anhydrous DCM (0.9 L) was added BF3 OEt2 (104 mL, 5.5 eq., 841 mmol) in dropwise fashion at 0-5°C under an inert atmosphere of nitrogen. The reaction mixture was allowed to warm to an ambient temperature and stirred for the stipulated period. The progress of the reaction was monitored through TLC and LCMS. Complete consumption of starting materials was observed within 16 h. Upon completion, the reaction mixture was diluted with DCM (2 x reaction volume) and filtered through a pad of Celite. The filtrate was washed sequentially with saturated aqueous NaHCCh (2 x 2 x reaction volume), water (2 x 2 x reaction volume) and brine (1 x 1 x reaction volume). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient eluent system of 40 to 80% ethyl acetate in heptane which afforded the desired compound (8, 45.0 g, 44%) as a colorless liquid. LCMS andJH NMR data were consistent with the compound structure.

[0344] Step 5: Synthesis of (2R,3R,4R,5S,6S)-2-((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 (9).

[0345] To a stirred solution of (2S,3S,4R,5R,6R)-2-methyl-6-((14-(tosyloxy)-3,6,9,12-tetraoxatetradecyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8, 85 g, 119 mmol) and 2-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethoxy)-l-(2,4-dinitrophenylamino)ethane (4, 69.6 g, 1.25 eq., 149 mmol) in anhydrous DMSO (850 ml) was added DIPEA (63.5 mL, 3 eq., 357 mmol) dropwise at ambient temperature under an inert atmosphere of N2. The reaction mixture was further stirred at 60°C for the stipulated period. Progress of the reaction was monitored by thin-layer chromatography (TLC) using 5% MeOH in DCM as eluent and LCMS. Complete consumption of starting materials was observed in 16 h. Upon completion, the reaction mixture was cooled to room temperature and diluted with deionized water (5 x reaction volume). TheDocket No. 1165.071132WO01aqueous phase was extracted with DCM (3 x reaction volume). The combined organic extracts were washed sequentially with water (1 x 10 V) and brine (1 x 10 V), then dried over anhydrous Na2SC>4. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude product. Purification of the crude material was performed by column chromatography on silica gel (60-120 mesh). Elution was carried out using a gradient eluent system of 4-5% methanol in DCM which afforded the desired product (2R,3R,4R,5S,6S)-2-((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 (9, 26.5 g, 25%) as a yellow semi-solid. LCMS andJH NMR data were consistent with the compound structure.

[0346] Step 6: Synthesis of (2S,3R,4R, 6S)-6-methyltetrahydro-2H-pyran-2, 3,4, 5-tetrayl tetraacetate (7).

[0347] To a stirred solution of (2R,3R,4R,6R)-tetrahydro-2H-pyran-2,3,4,5,6-pentol (10, 100 g, 602 mmol) in pyridine (1 L), acetic anhydride (455 mL, 8 eq., 4.82 mol) was added dropwise at 0-10°C under an inert atmosphere of N2. The reaction mixture was further stirred at ambient temperature for the stipulated period. The progress of the reaction was monitored through TLC and LCMS. Complete consumption of starting materials was observed within 16 h. Upon completion, the reaction mixture was diluted with ethyl acetate (20 V) and quenched by the slow addition of 1 M aq. HC1 (10 V). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 V). The combined organic layers were washed sequentially with 1 N HC1 (3 x 10 V), water (10 V), and brine (10 V), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired compound (2S,3R,4R,6S)-6-methyltetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (7, 180 g, 90%) as a colorless viscous liquid. LCMS and H NMR data were consistent with the compound structure.Docket No. 1165.071132WO01Part 4,Scheme 4.

[0348] Step 1: Synthesis of (2R,3R,4R, 6S)-2-((15-(l-(l-(l-(l-(l-(l-(((9H-jluoren-9-yl)methoxy)carbonyl)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 (3).

[0349] To a stirred solution of l-{[l-({l-[(l-{[l-({l-[(9H-fluoren-9-yl)methoxycarbonyl]-4- piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4- piperidyl]carbonyl}-4-piperidinecarboxylic acid (1, 10 g, 10.5 mmol) and (2R,3R,4R,6S)-4,5- diacetoxy-2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2,4- dinitrophenylamino)ethoxy]ethoxy } ethoxy)ethoxy]ethylamino] ethoxy)ethoxy]ethoxy } ethoxy)et hoxy]-6-methyltetrahydro-2H-pyran-3-yl acetate (2, 10.3 g, 10.5 mmol) inDMF (0.2 L, 2.58 mol) was added T3P (8.81 mL, 1.2 eq., 12.6 mmol) and DIPEA (9.32 mL, 5 eq., 52.4 mmol) at 0°C. The resultant reaction mixture was further allowed to stir at RT for the stipulated period. The progress of the reaction was monitored through TLC and LCMS. Complete consumption of starting materials was observed within 12 h. After completion, the solvent was removed underDocket No. 1165.071132WO01reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 0-10% MeOH in CH2CI2) to afford the desired product (9H-fluoren-9-yl)methyl 4-[(4-{[4-({4-[(4-{[4-({2-[2-(2-{2-[2-(2,4-dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}(2-{2-[2-(2-{2-[(2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yloxy]ethoxy } ethoxy)ethoxy]ethoxy } ethyl)carbamoyl)- 1 -piperidyl] carbonyl } - 1 -piperidyl)carbonyl]- 1 -piperidyl } carbonyl)- 1 -piperidyl] carbonyl } - 1 -piperidyl)carbonyl]- 1 -piperidinecarboxylate (3, 10 g, 53%) as a pale yellow liquid. LCMS and 'H NMR data were consistent with the compound structure.

[0350] Step 2: 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 (4).

[0351] To a stirred solution of (9H-fluoren-9-yl)methyl 4-[(4-{[4-({4-[(4-{[4-({2-[2-(2-{2-[2-(2,4-dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}(2-{2-[2-(2-{2-[(2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yloxy]ethoxy } ethoxy)ethoxy]ethoxy } ethyl)carbamoyl)- 1 -piperidyl] carbonyl } - 1 -piperidyl)carbonyl]- 1 -piperidyl } carbonyl)- 1 -piperidyl] carbonyl } - 1 -piperidyl)carbonyl]- 1 -piperidinecarboxylate (3, 5 g, 2.8 mmol) in anhydrous THF (50 mL) was added piperidine (10 mL, 2 V) dropwise over 10 min at 0-5 °C under an inert atmosphere of N2. The reaction mixture was allowed to warm to ambient temperature and further stirred for 2 h. Reaction progress was monitored by thin-layer chromatography (TLC) using 100% ethyl acetate in heptane as the eluent. After completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 0-10% MeOH in CH2CI2) which afforded (2R,3R,4R,6S)-4,5-diacetoxy-2-{2-[2-(2-{2-[2-({2-[2-(2-{2-[2-(2,4-dini trophenylamino)ethoxy] ethoxy }ethoxy)ethoxy]ethyl }[1-({1-[(1-{[1-({1 -[(4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-6-methyltetrahydro-2H-pyran-3-yl acetate (4, 2.5 g, 57.12%) as a pale yellow solid. LCMS and 'H NMR data were consistent with the compound structure.Docket No. 1165.071132WO01Part 5,Scheme 5.37% aq. HCI, 1,4-Dioxane (10 v), 50°C, 6h Step 4TCFH, NMI, MeCN, 0C » RT, 3hStep 6 DIPEA:water:MeOH (3:3:4 vol), RT, 3hCompound 5Docket No. 1165.071132WO01TEMPO, KBr, NaOCI, DCM, 0°C 5°C, 30 min Step-1Compound 5

[0352] Step J: Synthesis of tert-butyl 26-formyl- 4,7,10,13,16,19,22,25-octaoxahexacosanoate (3).

[0353] To a stirred solution of tert-butyl 27-hydroxy-4,7, 10, 13, 16, 19,22,25-octaoxaheptacosanoate (7, 50 g, 0.1 mol) in DCM (0.5 L) was added KBr (1.19 g, 0.010 mol) followed by TEMPO (0.788 g, 0.005 mol) at 0°C. NaOCI solution (250 mL, 5% w / v) at a pH close to 8.5 was prepared separately (pH was adjusted to said value by addition of solid NaHCCh (25 g)). The NaOCI solution was added dropwise to the reaction mixture at 0°C in a dropwise manner. The resulting reaction mixture was stirred at 0°C for the stipulated period. The progress of the reaction was monitored by TLC and LCMS. Complete consumption of starting material was observed within 30 min. After completion of the reaction, the reaction mass was diluted with DCM (500 mL). The layers were separated and the aqueous layer was further extracted with DCM (2 x 500 mL). The combined organic layers were washed with saturated NaHCCh solution (500 mL), followed by water (500 mL) and brine (500 mL), then dried over anhydrous Na2SC>4, filtered and concentrated under vacuum at 50°C to afford the desired product tert-butyl 26-formyl- 4,7,10,13,16,19,22,25-octaoxahexacosanoate (3, 42 g, 84%) as a yellow liquid. LCMS and 'H NMR data were consistent with the compound structure.

[0354] Step 2: Synthesis of 2-({2-[l-(2-aminoethyl)-4-piperidylamino]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-l-yl}methyl)-6-methyl-3-pyridinol — hydrogen chloride (1 / 3) (2).

[0355] To a solution of2-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-2-ylamino}-l-piperidyl)ethyl 2-methyl-2-propanecarbamate (1, 20 g, 0.0286 mol) in dichloromethane (60 mL) was added 4M HC1 in dioxane (60 mL) at 0°C. The progress of the reaction was monitored through TLC andDocketNo. 1165.071132WO01LCMS. Complete consumption of the starting material was found in 3 h. After consumption of starting material, the crude reaction mass was concentrated under vacuum at 50°C water bath temperature. This crude material was slurred in n-pentane (50 mL) and filtered. The solid material was further dried under vacuum at 50°C, which afforded the desired product 2-({2-[ 1 -(2-aminoethyl)-4-piperidylamino]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-l-yl}methyl)-6-methyl-3-pyridinol — hydrogen chloride (1 / 3) (2, 20 g, 96%) as a yellow solid. LCMS andJH NMR data were consistent with the compound structure.

[0356] Step 3: Synthesis of tert-butyl 30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l, 3-benzimidazol-2-ylamino}-l-piperidyl)- 4.7.10.13.16.19.22.25-octaoxa-28-azatriacontanoate (4).

[0357] To a stirred solution of 2-({2-[l-(2-aminoethyl)-4-piperidylamino]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl } - 1H- 1 ,3 -benzimidazol- 1 -yl }methyl)-6-methyl-3 -pyridinol — hydrogen chloride (2, 20 g, 0.0273 mol) and tert-butyl 26-formyl-4,7, 10, 13, 16, 19,22,25-octaoxahexacosanoate (3, 13.6 g, 0.0273 mol) in methanol (2 L) was added 4A molecular sieves (20 g) and acetic acid (15.6 mL, 0.273 mol) at room temperature. The reaction mixture was stirred for 10 min at the same temperature. Next, the whole reaction mixture was brought to 0°C and then sodium cyanoborohydride (8.58 g, 0.137 mmol) was added. The progress of the reaction was monitored through TLC and LCMS. Complete consumption of starting material was found in 3 h. After consumption of starting material, the reaction mass was concentrated under reduced pressure at 50°C water bath temperature to provide the crude material in yellow liquid form. The crude material was diluted with acetonitrile (150 mL) and Celite (30 g) was added. The slurry was concentrated under reduced pressure, and purified through reverse phase column chromatography over Cl 8 column (WelFlash Cl 8-1, regular Cl 820-40pm, 120g) using gradient eluent system of 40-50% acetonitrile in H2O with 0.1% ammonium acetate. Desired fractions were concentrated at 50°C water bath temperature to afford the desired product tert-butyl 30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-1 ,3 -benzimidazol -2 -ylamino} - 1 -piperidyl)-4,7, 10,13,16,19,22,25-octaoxa-28-azatriacontanoate (4, 8.92 g, 28%) as a yellow liquid. LCMS andJH NMR data were consistent with the compound structure.

[0358] Step 4: Synthesis of 30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l, 3-benzimidazol-2-ylamino}-l-piperidyl)- 4.7.10.13.16.19.22.25-octaoxa-28-azatriacontanoic acid — hydrogen chloride (5).

[0359] To a solution of tert-butyl 30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl } - 1H- 1 ,3 -benzimidazol-2-ylamino}- 1 -piperidyl)-Docket No. 1165.071132WO014.7.10.13.16.19.22.25-octaoxa-28-azatriacontanoate (4, 8.92 g, 7.76 mmol) was added 4 N aq HC1 in dioxane (prepared from 37% aq. HC1 and 1,4-dioxane) (89.2 mL) at 0°C. The reaction mixture was further stirred at 50°C for the stipulated period. The reaction progress was monitored through TLC and LCMS. Complete consumption of starting material was observed in 6 h. After consumption of starting material, the reaction was concentrated under vacuum at 50°C to give crude material. The crude material was azeotroped with acetonitrile (50 mL), concentrated under reduced pressure at 50°C which afforded the desired product 30-(4- { 1 -[(3 -hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-2-ylamino} - 1 -piperidyl)-4,7, 10,13,16,19,22,25-octaoxa-28-azatriacontanoic acid (5, 8.8 g, 88%) as a yellow solid. LCMS andJH NMR data were consistent with the compound structure.

[0360] Step 5: Synthesis of (2S,3S,4R,5R,6R)-4,5-diacetoxy-6-{2-[2-(2-{2-[2-({2-[2-(2-{2-[2- (2, 4-dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}(l -{[ 1 -({!-[(!-{[ 1-({1-[3O~(4-{1-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3- benzimidazol-2-ylamino}-l-piperidyl)-4, 7,10, 13,16, 19,22,25-octaoxa-28-azatriacontanoyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-2-methyltetrahydro-2H-pyran-3-yl acetate (6).

[0361] To a solution of 30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl } - 1H- 1 ,3 -benzimidazol-2-ylamino}- 1 -piperidyl)- 4.7.10.13.16.19.22.25-octaoxa-28-azatriacontanoic acid (5, 8.8 g, 0.00686 mmol) and (2R,3R,4R,5S,6S)-4,5-diacetoxy-2-{2-[2-(2-{2-[2-({2-[2-(2-{2-[2-(2,4- dini trophenylamino)ethoxy] ethoxy }ethoxy)ethoxy]ethyl }[1-({1-[(1-{[1-({1 -[(4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-6-methyltetrahydro-2H-pyran-3-yl acetate (4 of Part 4, 10.5 g, 0.00672 mol) in acetonitrile (264 mL) was added 1 -methylimidazole (17.6 mL, 0.221 mol) at 0°C. The reaction mixture was stirred for 5 min at this temperature and then a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (3.1 g, 0.0112 mol) in acetonitrile (26.4 mL) was added at 0°C. The resultant reaction mixture was further allowed to stir at room temperature for the stipulated period. The progress of the reaction was monitored through LC-HRMS. The complete consumption of starting material was observed in 3 h. After consumption of starting material, the reaction was concentrated under reduced pressure at 50 °C to give a yellow liquid. The crude material was diluted with acetonitrile (250 mL) and Celite (50 g) wasDocket No. 1165.071132WO01added. The slurry was concentrated under reduced pressure, the crude material was purified through reverse phase column chromatography using C18 column (Wei Flash C18-1, regular C18 20-40pm, 120 g) using 40-65% using acetonitrile in H2O with 0.1% ammonium acetate. The desired fractions were concentrated at 50°C to afford the desired product (2S,3S,4R,5R,6R)-4,5- diacetoxy-6-{2-[2-(2-{2-[2-({2-[2-(2-{2-[2-(2,4- dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}(l-{[l-({l-[(l-{[l-({l-[30-(4-{l-[(3-hydroxy-6- methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-2-ylamino} - 1 -piperidyl)-4,7, 10,13,16,19,22,25-octaoxa-28-azatriacontanoyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-2-methyltetrahydro-2H-pyran-3-yl acetate (6, 5.2 g, 27%) as a yellow liquid. HRMS andJH NMR data were consistent with the compound structure.

[0362] Step 6: Synthesis ofN-{2-[2-(2-{2-[2-(2,4-dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}-N-(2-{2-[2-(2-{2-[(2R,3R,4R,5R,6S)- 3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yloxy]ethoxy}ethoxy)ethoxy]ethoxy}ethyl)-l- {[l-({l-[(l-{[l-({l-[30-(4-{l-[( 3-hydroxy-6-methyl-2-pyridyl)methyl -6-{[ 2-(3-hydroxypropyl)~ 5-toluidino]methyl}-lH-l,3-benzimidazol-2-ylamino}-l-piperidyl)-4, 7,10,13,16,19,22,25-octaoxa-28-azatriacontanoyl ]-4-piperidyl}carbonyl)-4-piperidyl ]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidinecarboxamide (Compound 5).

[0363] To a solution of (2S,3S,4R,5R,6R)-4,5-diacetoxy-6-{2-[2-(2-{2-[2-({2-[2-(2-{2-[2-(2,4- dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}(l-{[l-({l-[(l-{[l-({l-[30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-2-ylamino} - 1 -piperidyl)-4,7, 10,13,16,19,22,25-octaoxa-28-azatriacontanoyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}-2-methyltetrahydro-2H-pyran-3-yl acetate (6, 4.7 g, 0.00171 mol) in methanol (18.8 mL) and water (14.1 mL) was added DIPEA (14.1 mL, 0.0809 mol) at room temperature. The resultant reaction mixture was further allowed to stir at room temperature for the stipulated period. The progress of the reaction was monitored through LC-HRMS. The complete consumption of starting material was observed in 3 h. After consumption of starting material, the reaction was concentrated under vacuum at 50°C to give crude material. The crude material was diluted with water (150 mL) and extracted with 20% MeOH / DCM (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum at 50°C to give crudeDocket No. 1165.071132WO01material. The crude material was dissolved in DCM (25 mL) and precipitated with diethyl ether (200 mL) and filtered (this process was repeated three times). The solid compound was azeotroped with n-pentane (50 mL) and dried under reduced pressure at 50°C to afford the desired product N-{2-[2-(2-{2-[2-(2,4-dinitrophenylamino)ethoxy]ethoxy}ethoxy)ethoxy]ethyl}-N-(2-{2-[2-(2-{2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yloxy]ethoxy}ethoxy)ethoxy]ethoxy}ethyl)-l-{[l-({l-[(l-{[l-({l-[30-(4-{l-[(3-hydroxy-6-methyl-2-pyridyl)methyl]-6-{[2-(3-hydroxypropyl)-5-toluidino]methyl}-lH-l,3-benzimidazol-2-ylamino} - 1 -piperidyl)-4,7, 10,13,16,19,22,25-octaoxa-28-azatriacontanoyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidyl)carbonyl]-4-piperidyl}carbonyl)-4-piperidyl]carbonyl}-4-piperidinecarboxamide (Compound 5, 3.1 g, 70%) as a yellow solid. LCMS andJH NMR data were consistent with the compound structure.

[0364] Example 8: Synthesis of N-(14-((2,4-dinitrophenyl)amino)-3,6,9,12-tetraoxatetradecyl)-1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 12) o oOAcOAc4Docket No. 1165.071132WO01HOHO5% NaOH in H2O, NleOH, rtCompound 12

[0365] Synthesis of l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (1)

[0366] Common intermediate (6) synthesized in Example 7 synthesis of Compound 5 in Part 2, Step 4

[0367] Synthesis of (2R,3R,4R,6S)-2-((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 (2)

[0368] Common intermediate (14) synthesized in Compound 5 in Example 1 intermediate.

[0369] Synthesis of (2R,3R,4R,6S)-2-((15-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)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 (3)Docket No. 1165.071132WO01

[0370] To the stirred ice cold solution of l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (1; 150 mg, 0.26 mmol) and (2R,3R,4R,6S)-2-((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 (2; 280 mg, 0.31 mmol) in YA -di methyl form am ide (5 mL), N,N-Diisopropylethylamine (0.24 mL, 1.31 mmol) and l-[Bis(dimethylamino)methylene]-lA-l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 0.12 g, 0.31 mmol) were added to the reaction mixture at the same temperature. The resultant reaction mixture was stirred at room temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, reaction mass was diluted with water (10 mL) and extracted with ethyl acetate (EtOAc) (2 x 10 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography using eluents 5-10% MeOH in DCM to get (2R,3R,4R,6S)-2-((15-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)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 (3) as a yellow solid. Yield: 200 mg, 52.73%. LC-MS (ESI) m / z 1467.29 [M+NH4]+.

[0371] Synthesis of (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(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 (4)

[0372] To the stirred ice cold solution of (2R,3R,4R,6S)-2-((15-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)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 (3; 0.20 g, 0.14 mmol) in N,N-dimethylformamide (2.5 mL) was added piperidine (0.5 mL) at ambient temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS. After the completion, reaction mass was triturated with 20% diethyl ether in heptane (3 x 10 mL) and concentrated under reduced pressure to afford the crude (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(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 (4) as a yellow semi-solid. Yield: 0.12 g, 70.86%. LC-MS (ESI) m / z 1228.38 [M+H]+.Docket No. 1165.071132WO01

[0373] Synthesis of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)~ 5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33.36-undecaoxa-3-azanonatriacontan-39-oic acid (5)

[0374] Common intermediate (5) synthesized in the Example 13 synthesis of Compound 28

[0375] Synthesis of (2R, 3R, 4R, 6S)-2-( (29-( (2, 4-dinitrophenyl)amino)-15-(l-( 1-(1-(1 -(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6, 9, 12, 15, 18, 21,24, 27,30, 33,36-undecaoxa-3-azanonatriacontan-39-oyl)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 (6)

[0376] To the stirred ice cold solution of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oic acid (5; 80 mg, 0.071 mmol) and (2R,3R,4R,6S)-2-((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 (4; 0.11 g, 0.086 mmol) inA -di methyl form am ide (3 mL), N,N- Diisopropylethylamine (0.06 mL, 0.35 mmol) and Benzotri azole- 1-yl-oxy -tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 41 mg, 0.078 mmol) were added to the reaction mixture at the same temperature. The resultant reaction mixture was stirred at room temperature for 12h. The progress of the reaction was monitored by LCMS. After completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by size exclusion column chromatography (Sephadex LH20) using MeOH as eluent to afford (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(l-(l-(4-((l-((3-hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3-hy droxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin- 1 -yl)-6,9, 12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-oyl)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 (6) as a yellow solid. Yield: 52 mg, 29.96%. LC-MS (ESI) m / z 1162.65 [M / 2+H]+.

[0377] Synthesis ofN-(l 4-( ( 2, 4-dinitrophenyl)amino)-3, 6, 9, 12-tetraoxatetradecyl)-l-( l-(l-(l-(4-((l-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6.9.12.15.18.21.24.27.30.33.36-undecaoxa-3-azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-( 14-( f2R, 3R, 4R, 6S -3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9, 12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 12)Docket No. 1165.071132WO01

[0378] To a stirred solution of (2R,3R,4R,6S)-2-((29-((2,4-dinitrophenyl)amino)-15-(l-(l-(l-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oyl)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 (6; 52 mg, 0.105 mmol) in water (2.0 ml.), 5% NaOH aqueous solution (0.01 ml) was added dropwise till pH=12. The reaction mixture was stirred at room temperature for Ih. 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 N-( 14-((2,4-dinitrophenyl)amino)-3 ,6,9,12-tetraoxatetradecyl)- 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3-hy droxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin- 1 -yl)-6,9, 12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(14-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperidine-4-carboxamide (Compound 12) as a yellow solid. Yield: 7 mg, 14.23%. LC-HRMS (ESI) m / z 2198.23 [M+H]+.

[0379] Example 9: Synthesis of N-(26-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)- 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9, 12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(26-(((2R,3R,4R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)piperidine-4-carboxamide (Compound 13).Docket No. 1165.071132WO018Compound 13Docket No. 1165.071132WO01

[0380] Synthesis of tert-butyl (26-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)carbamate (3)

[0381] To an ice cold solution of tert-butyl (26-amino-3,6,9,12,15,18,21,24-octaoxahexacosyl)carbamate (BroadPharm; 1; 1 g, 1.95 mmol) in di chloromethane (10 mL) under nitrogen atmosphere, N-ethyldiisopropylamine (1.02 mL, 5.85 mmol) and l-fluoro-2,4-dinitrobenzene (Spectrochem; 2; 0.36 g, 1.95 mmol) were added to the reaction mixture subsequently. The resulting reaction mixture was allowed to stir at 50°C for Ih. The advancement of reaction progress was monitored by TLC and LCMS. Reaction mass was diluted with citric acid solution (20 mL) and extracted with DCM (2x50 mL) and washed with brine solution (2x50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude tert-butyl (26-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)carbamate (3) as a yellow semi-solid. Yield: 1.30 g, 98%. LC-MS (ESI) m / z 677.25 [M-H]+.

[0382] Synthesis of Nl-(2, 4-dinitrophenyl)-3, 6, 9, 12, 15, 18, 21 ,24-octaoxahexacosane-l , 26-diamine (4)

[0383] To an ice cold solution of tert-butyl (26-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24-octaoxahexacosyl)carbamate (3; 1.3 g, 1.92 mmol) in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added to the resulting reaction mixture and was allowed to stir at ambient temperature for Ih. The advancement of reaction progress was monitored by TLC and LCMS. Reaction mass was concentrated under reduced pressure to get the crude. The crude was triturated with diethyl ether (20 mL) and dried under reduced pressure to get N1 -(2,4-dinitrophenyl)-3,6,9,12,15,18,21,24-octaoxahexacosane-l,26-diamine (4) as a yellow semi-solid. Yield: 1.1 g, 96%. LC-MS (ESI) m / z 579.15 [M+H]+.

[0384] Synthesis of 26-hydroxy-3,6,9, 12, 15, 18,21 ,24-octaoxahexacosyl 4-methylbenzenesulfonate (6)

[0385] To a stirred solution of 3,6,9,12,15,18,21,24-octaoxahexacosane-l,26-diol (BLD Pharm; 5; 3 g, 7.24 mmol) in dichloromethane (30 mL), triethylamine (3.03 mL, 21.7 mmol) and tosylDocket No. 1165.071132WO01chloride (1.24 g, 0.9 eq., 6.51 mmol) was added at the same temperature and the reaction mixture was allowed to stir at ambient temperature for 12h. After the completion of the reaction, reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude, this crude was purified in by combi flash column chromatography eluting in 4% MeOH / DCM gradient to afford the pure compound 26-hydroxy-3,6,9,12,15,18,21,24-octaoxahexacosyl 4-methylbenzenesulfonate (6) as colorless gummy liquid. Yield: 1.4 g, 34%. LC-MS (ESI) m / z 586.15 [M+NH4]+.

[0386] Synthesis of (2S,4R,5R,6R)-2-methyl-6-((26-(tosyloxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)oxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate (8)

[0387] To a stirred solution of 26-hydroxy-3,6,9,12,15,18,21,24-octaoxahexacosyl 4-methylbenzenesulfonate (6; 1.4 g, 2.46 mmol) in dichloromethane (25 mL), (2S,3R,4R,6S)-6-methyltetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (7; 0.98 g, 2.95 mmol) and activated powder molecular sieves were added. The reaction mixture was allowed to stir at ambient temperature for 2h. The reaction mixture was cooled to 0°C and Boron trifluoride etherate (3.74 mL, 29.5 mmol) was added dropwise at the same temperature. After complete addition reaction mixture was allowed to stir at ambient temperature for 16h. After the completion of the reaction, reaction mixture was diluted with DCM (50 mL) and the resulting suspension was filtered off. Then, the filtrate was washed with water (3x50 mL). Organic layer was further washed with chilled aq. NaHCCh solution (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography over (40g snap, silica) by using eluents 5% MeOH in DCM to get (2S,4R,5R,6R)-2-methyl-6-((26-(tosyloxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)oxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate (8) as a semi-solid. Yield: 1.5 g, 72%. LC-MS (ESI) m / z 857.93 [M+NH4]+.

[0388] Synthesis of (2R,3R,4R,6S)-2-((53-((2,4-dinitrophenyl)amino)~3, 6, 9, 12, 15, 18, 21, 24,30, 33,36, 39, 42, 45, 48, 51-hexadecaoxa-27 -azatripentacontyl) oxy) -6-methyltetrahydro-2H-pyran-3, 4,5-triyl triacetate (9)

[0389] To the stirred ice-cold solution of Nl-(2,4-dinitrophenyl)-3,6,9,12,15,18,21,24-octaoxahexacosane-l,26-diamine (4; 0.5 g, 0.864 mmol) in YA -di methyl form am ide (10 mL), Y -Diisopropylethylamine (0.45 mL, 2.59 mmol) and (2S,4R,5R,6R)-2-methyl-6-((26-(tosyloxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8; 0.51 g, 0.605 mmol) were added and the resulting reaction mixture was allowed to stir at 60°C for 24h. The advancement of reaction progress was monitored by TLC and LCMS. AfterDocket No. 1165.071132WO01the completion of the reaction, reaction mass was concentrated under reduced pressure to get the crude. The crude was further purified by combi-flash column chromatography using eluents 8- 10% MeOH in DCM to afford (2R,3R,4R,6S)-2-((53-((2,4-dinitrophenyl)amino)- 3.6.9.12.15.18.21.24.30.33.36.39.42.45.48.51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (9) as a semi-solid. Yield: 0.15 g, 14%. LC-MS (ESI) m / z 1247.22 [M+H]+.

[0390] Synthesis of (2R,3R,4R,6S)-2-((27-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-53- ( (2, 4-dinitrophenyl)amino)-3, 6, 9, 12, 15, 18, 21,24,30, 33,36, 39, 42, 45, 48, 5 l-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (11)

[0391] To the stirred solution of l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (10; 0.18 g, 0.305 mmol) and (2R,3R,4R,6S)-2-((53-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (9; 0.38 g, 0.305 mmol) in Y, A -di methyl form am ide (5 mL), A,A-Diisopropylethylamine (0.10 mL, 0.915 mmol) and Benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP; 238 mg, 0.458 mmol) were added to the reaction mixture at 0°C. The resultant reaction mixture was stirred at room temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After reaction completion, reaction mass was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography using eluents 5-10% MeOH in DCM to get (2R,3R,4R,6S)-2-((27-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-53-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (11) as a yellow solid. Yield: 250 mg, 50%. LC-MS (ESI) m / z 1800.96 [M-H]+.

[0392] Synthesis of (2R,3R,4R,6S)-2-((53-((2 ,4-dinitrophenyl)amino)-27-(l-(l-(piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)- 3.6.9.12.15.18.21.24.30.33.36.39.42.45.48.51-hexadecaoxa-27 -azatripentacontyl) oxy) -6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (12)

[0393] To a stirred ice cold solution of (2R,3R,4R,6S)-2-((27-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-53-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (11; 0.25 g, 0.14DocketNo. 1165.071132WO01mmol) in Af, A -di methyl form am ide (2.5 mL), was added piperidine (0.5 mL) at room temperature under a nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC and LCMS. After reaction completion, reaction mass was concentrated under reduced pressure and triturated with heptane (3 x 10 mL) to afford the crude (2R,3R,4R,6S)-2-((53-((2,4-dinitrophenyl)amino)-27-(l-(l-(piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (12) as a yellow semi-solid. Yield: 0.20 g, 91%. LC-MS (ESI) m / z 1581.25 [M+H]+.

[0394] Synthesis of (2R,3R,4R,5S,6S)-2-((53-((2,4-dinitrophenyl)amino)-27-(l-(l-(l-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ( (2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27,30, 33,36-undecaoxa-3-azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)- 3, 6, 9, 12, 15, 18, 21, 24,30, 33,36, 39, 42, 45, 48, 5 l-hexadecaoxa-27 -azatripentacontyl) oxy) -6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (14)

[0395] To a stirred ice cold solution of l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oic acid (13; 0.1 g, 89.7 pmol) (prepared as shown in for intermediate (5) in Example 13) and (2R,3R,4R,5S,6S)-2-((53-((2,4-dinitrophenyl)amino)-27-(l-(l-(piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (12; 0.11 g, 71.8 pmol) in acetonitrile (6 mL), were added 1 -methylimidazole (0.5 mL, 89.7 pmol) and Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH; 25.2 mg, 89.7 pmol) in acetonitrile (0.5 mL) at the same temperature under a nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS. Reaction mass was concentrated under reduced pressure to get the crude. Crude was triturated with diethyl ether (2 x 5 mL) and dried under reduced pressure to get crude (2R,3R,4R,5S,6S)-2-((53-((2,4-dinitrophenyl)amino)-27-(l-(l-(l-(l-(4-((l-((3-hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3-hy droxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin- 1 -yl)-6,9, 12,15,18,21 ,24,27,30,33 ,36-undecaoxa-3 -azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-Docket No. 1165.071132WO01methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (14) as a yellow semi-solid. Yield: 0.28 g. LC-HRMS (ESI) m / z 2677.47 [M+H]+.

[0396] Synthesis of N-(26-((2, 4-dinitrophenyl)amino)-3, 6, 9, 12, 15, 18, 21,24-octaoxahexacosyl)-l-(1 -(!-(!-( 4-( (l-(( 3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ( 2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27,30, 33,36-undecaoxa-3-azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(26-(((2R, 3R, 4R, 5R, 6S -3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6,9, 12, 15, 18,21 ,24-octaoxahexacosyl)piperidine-4-carboxamide (Compound 13)

[0397] To a stirred ice cold solution of (2R,3R,4R,5S,6S)-2-((53-((2,4-dinitrophenyl)amino)-27-( 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-3,6,9,12,15,18,21,24,30,33,36,39,42,45,48,51-hexadecaoxa-27-azatripentacontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (14; 0.28 g, 0.105 mmol) in methanol (0.9 mL) and water (0.9 mL), A,A-Diisopropylethylamine (1.2 mL, 0.02 mmol) was added and the reaction mixture was stirred at ambient temperature for 4h. The progress of the reaction was monitored by LC-HRMS. The reaction mass was concentrated under reduced pressure to get crude. The Crude was purified by Prep-HPLC purification using Ammonium Acetate buffer to afford N-(26-((2,4-dinitrophenyl)amino)-3 ,6, 9, 12,15,18,21 ,24-octaoxahexacosyl)- 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6,9,12,15,18,21,24,27,30,33,36-undecaoxa-3-azanonatriacontan-39-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)-N-(26-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)piperidine-4-carboxamide (Compound 13) as a yellow solid. Yield: 45 mg, 15.52%. LC-HRMS (ESI) m / z 2551.44 [M+H]+.

[0398] Example 10: Synthesis ofN-(27-((2,4-dinitrophenyl)amino)-5-(3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-21-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9, 12, 15,18-hexaazahenicosanamido)-9, 12, 15,18,21,24-hexamethyl-4,7,10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21,24-octaazaheptacosyl)-l-(l-(l-(l-( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hy droxypropyl)-5 -methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-Docket No. 1165.071132WO016,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamide (Compound 14)Docket No. 1165.071132WO0120% TFA:DCM1621OK2CO3, Mel, DMF 20% PIP in DMF Fmoc' NHBoc NHBoc 22Cp-24 Cp-25HATU, DIPEA, DMFDocket No. 1165.071132WO01Aq. NaOH, MeOHCp-29 O O OH HATU, DIPEA, DMF 0 0 0 31NHBocDocket No. 1165.071132WO01Cp-32CP34Compound 14Docket No. 1165.071132WO01

[0399] Synthesis of tert-butyl N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate (3)

[0400] To the stirred ice cold solution of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycine (Chemscene; 1, 5.8 g, 18.6 mmol) and tert-butyl methylglycinate (Angene; 2, 5.41 g, 37.3 mmol) in A, A-di methyl formamide (50 mL), l-[Bis(dimethylamino)methylene]-UT-l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 7.7 g, 20.6 mmol) and N,N-Diisopropylethylamine (10.3 mL, 55.8 mmol) were added at the same temperature. The resulting reaction mixture was allowed to stir at ambient temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get crude. The crude was purified by combi-flash column chromatography by using eluents 30-35% EtOAc in Heptane to get tert-butyl N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate (3) as a transparent semi-solid. Yield: 7.9 g, 96%. LC-MS (ESI) m / z 439.15 [M+H]+.

[0401] Synthesis ofN-(N-(((9H-jluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycine (4)

[0402] To an ice-cold solution of tert-butyl N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate (3, 7.9 g, 18 mmol) in dichloromethane (0.1 L) was added trifluoroacetic acid (25 mL, 18 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS. After reaction completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was further triturated with 20% Diethyl ether in pentane (2 x 100 mL) and concentrated under reduced pressure to get N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycine (4) as a semi-solid. Yield: 6.8 g, 99%. LC-MS (ESI) m / z 383.20 [M+H]+.

[0403] Synthesis of perfluorophenyl N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate (5)Docket No. 1165.071132WO01

[0404] To a stirred ice-cold solution of N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycine (4, 16 g, 41.8 mmol) in ethyl acetate (150 mL), were added Diisopropylcarbodiimide (19.8 mL, 126.0 mmol) and 2,3,4,5,6-pentafluorophenol (8.47 g, 46.0 mmol). Then the resulting reaction mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. On completion, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a crude compound perfluorophenyl N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate (5) as a pale-yellow viscous liquid. Yield: 22 g, 96%. LC-MS (ESI) m / z 549.75 [M+H]+.

[0405] Synthesis of tert-butyl l-(9H-jluoren-9-yl)-4, 7,10-trimethyl-3,6,9-trioxo-2-oxa-4, 7,10-triazadodecan- 12-oate (6)

[0406] To a stirred ice-cold solution of perfluorophenyl N-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylglycyl)-N-methylglycinate (5, 22 g, 40.1 mmol) in tetrahydrofuran (0.2 L, 2.46 mol), N,N-Diisopropylethylamine (7.01 mL, 40.1 mmol) was added followed by the addition of tert-butyl methylglycinate (2, 5.82 g, 40.1 mmol). The resulting mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure to get crude. Crude was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude residue was purified by flash column chromatography over silica gel using 50-80% ethyl acetate in heptane as the eluent to afford tertbutyl l-(9H-fluoren-9-yl)-4,7,10-trimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate (6) as a brown solid. Yield: 11 g, 54%. LC-MS (ESI) m / z 510.45 [M+H]+.

[0407] Synthesis of l-(9H-fluoren-9-yl)-4, 7, 10-trimethyl-3, 6,9-trioxo-2-oxa-4, 7, 10-triazadodecan- 12-oic acid (7)

[0408] To an ice cold stirred solution of tert-butyl l-(9H-fluoren-9-yl)-4,7,10-trimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan- 12-oate (6, 5.5 g, 10.8 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (15 mL, 10.8 mmol) and the resultant mixture was stirred at ambient temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated under reduced pressure to get crude. Crude was triturated with Diethyl ether (2x 50 mL) and dried under reduced pressure to get l-(9H-fluoren-9-yl)-4,7,10-trimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oic acid (7) as an off-white semi-solid. The crude was used for the next step without doing further purification. Yield: 4.15 g, 84% LC-MS (ESI) m / z 454.35 [M+H]+.Docket No. 1165.071132WO01

[0409] Synthesis of tert-butyl N-methyl-N-(N-methyl-N-(methylglycyl)glycyl)glycinate (8)

[0410] To a stirred ice cold solution of tert-butyl l-(9H-fluoren-9-yl)-4,7,10-trimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan- 12-oate (6, 5.5 g, 10.8 mmol) in A( A -di methyl form am ide (20 mL) was added piperidine (4 mL, 8.8 mmol) and the resultant mixture was stirred at ambient temperature for next Ih under nitrogen atmosphere. The progress of the reaction was monitored by TLC. After reaction completion, the reaction mixture was evaporated to dryness and triturated with Diethyl ether (2x50mL) to afford crude of tert-butyl N-methyl-N-(N-methyl-N-(methylglycyl)glycyl)glycinate (8) as cream-colored sticky solid. Yield: 2.6 g, 41%. LC-MS (ESI) m / z 288.35 [M+H]+.

[0411] Synthesis of tert-butyl l-(9H-fluoren-9-yl)-4, 7,10,13,16,19-hexamethyl-3,6,9,12,15,18-hexaoxo-2-oxa-4, 7, 10, 13, 16, 19-hexaazahenicosan-21-oate (9)

[0412] To a stirred ice cold solution of l-(9H-fluoren-9-yl)-4,7,10-trimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oic acid (7, 3 g, 6.62 mmol) and tert-butyl N-methyl-N-(N-methyl-N-(methylglycyl)glycyl)glycinate (8, 1.9 g, 6.62 mmol) in A( A-dimethylformamide (15 mL), N,N-Diisopropylethylamine (3.47 mL, 19.8 mmol) and l-[Bis(dimethylamino)methylene]-U / -l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 3.77 g, 9.92 mmol) were added at the same temperature. The resultant mixture was stirred at ambient temperature for 3h under nitrogen atmosphere. The progress of the reaction was monitored by TLC and LCMS. Reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography by using eluents 5-7% MeOH in DCM to afford tert-butyl 1 -(9H-fluoren-9-yl)-4,7, 10,13,16,19-hexamethyl-3 ,6,9, 12,15,18-hexaoxo-2-oxa-4,7, 10,13,16,19-hexaazahenicosan-21-oate (9) as a semi-solid. Yield: 2.8 g, 56%. LC-MS (ESI) m / z 723.55 [M+H]+.

[0413] Synthesis of tert-butyl 5,8,11,14,17 -pentamethyl-4, 7,10,13,16-pentaoxo-2,5,8,l 1,14,17-hexaazanonadecan-19-oate (10)

[0414] To a stirred ice cold solution of tert-butyl l-(9H-fluoren-9-yl)-4,7,10,13,16,19-hexamethyl-3,6,9,12,15,18-hexaoxo-2-oxa-4,7,10,13,16,19-hexaazahenicosan-21-oate (9, 1 g, 1.38 mmol) in M / V-dimethylformamide (10 mL), was added piperidine (2 mL, 1.38 mmol) at the same temperature under a nitrogen atmosphere. The resultant reaction mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was evaporated to dryness. The Crude was further triturated with pentane and Diethyl ether (2 x 50 mL) and dried under reduced pressure to afford tert-butyl 5,8,ll,14,17-pentamethyl-4,7,10,13,16-pentaoxo-2,5,8,ll,14,17-hexaazanonadecan-19-oate (10) as a yellow solid. Yield: 600 mg, 86%. LC-MS (ESI) m / z 501.50 [M+H]+.DocketNo. 1165.071132WO01

[0415] Synthesis of tert-butyl 3-((2,4-dinitrophenyl)amino)propanoate (13)

[0416] To the stirred solution of l-fluoro-2,4-dinitrobenzene (Spectrochem; 11, 5 g, 26.9 mmol) and tert-butyl 3 -aminopropionate (BLD Pharm; 12, 4.29 g, 29.6 mmol) in N,N-dimethylformamide (50 mL) was added N,N-Diisopropylethylamine (14 mL, 80.6 mmol) at ambient temperature. The resulting reaction mixture was stirred at 50°C for 2h. The progress of the reaction was monitored by TLC and LCMS. On completion, the reaction mixture was concentrated under reduced pressure and diluted with water (60 mL). Then it was extracted with DCM (2x70 mL). The combined organic layers were washed with brine solution (80 mL) and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford a crude compound as a pale-yellow gum. The crude residue was purified by combi flash column chromatography eluting by 8-10% EtOAc in Heptane to afford tert-butyl 3 -((2,4-dinitrophenyl)amino)propanoate (13) as a pale-yellow gummy. Yield: 7 g, 84%. LC-MS (ESI) m / z 310.27 [M-H]+.

[0417] Synthesis of 3-((2,4-dinitrophenyl)amino)propanoic acid (14)

[0418] To a stirred ice cold solution of tert-butyl 3-((2,4-dinitrophenyl)amino)propanoate (13, 7 g, 22.5 mmol) in dichloromethane (70 mL), was added trifluoroacetic acid (25 mL, 8.29 pmol) at the same temperature and allowed to stir at ambient temperature for Ih. After the completion of the reaction (monitored by TLC), reaction volatiles were evaporated and co-distilled with DCM (3 times) to afford the crude 3-((2,4-dinitrophenyl)amino)propanoic acid (14) as yellowish solid. Yield: 5.5 g, 96%. LC-MS (ESI) m / z 256 [M+H]+

[0419] Synthesis of tert-butyl 2 l-((2,4-dinitrophenyl)amino)-3,6,9, 12, 15, 18-hexamethyl-4, 7, 10, 13, 16, 19-hexaoxo-3, 6,9, 12, 15, 18-hexaazahenicosanoate (15)

[0420] To a stirred ice cold solution of 3-(2,4-dinitrophenylamino)propionic acid (14, 0.25 g, 0.98 mmol) and tert-butyl 5,8,11,14, 17-pentamethyl-4, 7, 10,13, 16-pentaoxo-2, 5, 8,11,14, 17-hexaazanonadecan- 19-oate (10, 0.49 g, 0.98 mmol) in A Y-di methyl form am ide (5 mL), N,N-Diisopropylethylamine (0.51 mL, 2.94 mmol) and l-[Bis(dimethylamino)methylene]-lJ / -l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 0.56 g, 1.47 mmol) were added at the same temperature and stirred at ambient temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at ambient temperature for 5h. The progress of the reaction was monitored by TLC and LCMS. After reaction completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography eluting with 6-8% MeOH in DCM to afford tert-butyl 21-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-3,6,9,12,15,18-DocketNo. 1165.071132WO01hexaazahenicosanoate (15) as a yellow solid. Yield: 600 mg, 83%. LC-MS (ESI) m / z 738.55 [M+H]+

[0421] Synthesis of 21-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18-hexamethyl-4, 7,10,13,16,19-hexaoxo-3, 6,9, 12, 15, 18-hexaazahenicosanoic acid (16)

[0422] To an ice cold solution of tert-butyl 21-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-3,6,9,12,15,18-hexaazahenicosanoate (15, 0.6 g, 0.81 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) at the same temperature and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mass was concentrated under reduced pressure to get the crude. Crude was triturated with Diethyl ether (2x20 mL), and dried under reduced pressure to afford 21 -((2,4- dini trophenyl)amino)-3, 6, 9, 12, 15,18-hexamethyl-4, 7, 10, 13, 16, 19-hexaoxo-3, 6, 9, 12, 15, 18-hexaazahenicosanoic acid (16) as a yellow semi-solid. Yield: 650 mg, 98%. LC-MS (ESI) m / z 682.40 [M+H]+

[0423] Synthesis of 3-((( 2R, 3R, 4R, 5S, 6S)-3, 4, 5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanoic acid (19)

[0424] To a stirred ice cold solution of (2S,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl acetate (17, 8 g, 24.1 mmol) in dry dichloromethane (0.1 L), was added tert-butyl 3-hydroxypropionate (BLD Pharm;18, 5.28 g, 36.1 mmol) and activated powder molecular sieves (4 g) and then allowed to stir at ambient temperature. After 3h, the reaction mixture was cooled to 0°C and Boron trifluoride diethyl etherate (18.3 mL, 144 mmol) was added dropwise at the same temperature. After complete addition, the reaction mixture was allowed to stir at ambient temperature for next 12 hours. After completion, the reaction mixture was diluted with DCM (100 mL) and the resulting suspension was filtered off. The filtrate was washed with water (2x100 mL). The combined organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford the crude. The crude was further triturated with Diethyl ether (2x50 mL) and dried under reduced pressure to afford the crude 3-(((2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanoic acid (19) which was used for the next reaction without further purification. Yield: 8.7 g, 99%. LC-MS (ESI) m / z 361.15 [M-H]+.

[0425] Synthesis of (2S,3S,4R,5R,6R)-2-methyl-6-((2,2,6,9,12,15,18,21-octamethyl- 4, 7,10, 13,16, 19,22-heptaoxo-3-oxa-6, 9, 12, 15, 18, 21-hexaazatetracosan-24-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (20)

[0426] To a stirred ice cold solution of 3-[(2R,3R,4R,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yloxy]propionic acid (19, 0.4 g, 1.1 mmol) and tert-butyl 5,8,11,14, 17-pentamethyl-Docket No. 1165.071132WO014,7,10,13,16-pentaoxo-2,5,8,ll,14,17-hexaazanonadecan-19-oate (10, 553 mg, 1.1mmol) in A,A-dimethylformamide (0.5 mL, 6.46 mmol), N,N-Diisopropylethylamine (428 mg, 3.31 mmol) and l-[Bis(dimethylamino)methylene]-17 -l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 546 mg, 1.44 mmol) were added at the same temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at ambient temperature for 2h. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mass was concentrated under reduced pressure to get the crude. The crude was further purified by combi-flash column chromatography by using eluents 5-7% MeOH in DCM to (2S,3S,4R,5R,6R)-2-methyl-6-((2,2,6,9,12,15,18,21-octamethyl-4,7,10,13,16,19,22-heptaoxo-3-oxa-6,9,12,15,18,21-hexaazatetracosan-24-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (20) as a white solid. Yield: 380 mg, 40%. LC-MS (ESI) m / z 845.60 [M+H]+.

[0427] Synthesis of 3,6,9,12,15,18-hexamethyl-4, 7,10,13,16,19-hexaoxo-21-(((2R,3R,4R,5S,6S)~ 3, 4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6,9, 12, 15, 18-hexaazahenicosanoic acid (21 )

[0428] To an ice cold solution of (2S,3S,4R,5R,6R)-2-methyl-6-((2,2,6,9,12,15,18,21-octamethyl-4,7, 10,13,16,19,22-heptaoxo-3 -oxa-6,9, 12,15,18,21 -hexaazatetracosan-24-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (20, 330 mg, 0.39 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.5 mL). Th reaction mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mass was concentrated under reduced pressure to get the crude. Crude was further triturated with pentane (2x10 mL), diethyl ether (2x15 mL) and dried under reduced pressure to afford crude 3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-21-(((2R,3R,4R, 5S,6S)-3, 4, 5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9, 12, 15, 18-hexaazahenicosanoic acid (21) as an off-white semi-solid. Yield: 360 mg, 97%. LC-MS (ESI) m / z 787.55 [M-H]+.

[0429] Synthesis of methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)acetate (23)

[0430] To the stirred ice-cold solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)acetic acid (22, 4.5 g, 10.9 mmol) in A,A-dimethylformamide (15 mL), potassium carbonate (3.02 g, 21.8 mmol) was added and stirred for 10 mins. Then, iodomethane (2.04 mL, 32.7 mmol) was added to the reaction mixture and stirred for another 2h at ambient temperature. Progress of the reaction was monitored by TLC. After the completion of the reaction, reaction mixture was filtered, and filtrate was evaporated to get crude which was directly purified by column chromatography using 20% ethyl acetate in heptane to afford methylDocket No. 1165.071132WO012-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)acetate (23) as a white solid. Yield: 4.5 g, 95%. LC-MS (ESI) m / z 370.94 [M+NH4]+.

[0431] Synthesis of methyl 2-amino-2-((tert-butoxycarbonyl)amino)acetate (24)

[0432] To a stirred ice cold solution of methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)acetate (23, 2 g, 4.69 mmol) in YA -di methyl form am ide (10 mL), was added piperidine (4 mL, 4.69 mmol) at ambient temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for Ih. The progress of the reaction was monitored by TLC. After the completion of the reaction, reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified by combi-flash column chromatography by using eluents 30-35% EtOAc in Heptane to afford methyl 2-amino-2-((tert-butoxycarbonyl)amino)acetate (24) as a semi-solid. Yield: 630 mg, 66%.

[0433] Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-24-((2,4-dinitrophenyl)amino)- 6, 9, 12, 15, 18, 21-hexamethyl-4, 7, 10,13,16, 19, 22-heptaoxo-3, 6, 9, 12, 15, 18,21-heptaazatetracosanoate (25)

[0434] To a stirred ice cold solution of 21-((2,4-dinitrophenyl)amino)-3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-3,6,9,12,15,18-hexaazahenicosanoic acid (16, 650 mg, 954 pmol) and methyl 2-amino-2-((tert-butoxycarbonyl)amino)acetate (24, 234 mg, 1.14 mmol) in Y -di methyl form am ide (6 mL), N,N-Diisopropylethylamine (0.5 mL, 2.86 mmol) and l-[Bis(dimethylamino)methylene]-lA-l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 544 mg, 1.43 mmol) were added at room temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 4h. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mass was concentrated under reduced pressure to get the crude. The crude was further purified by combi-flash column chromatography by using eluents 6-8% MeOH in DCM to get methyl 2-((tert-butoxycarbonyl)amino)-24-((2,4-dinitrophenyl)amino)-6,9,12,15,18,21-hexamethyl-4,7,10,13,16,19,22-heptaoxo-3,6,9,12,15,18,21-heptaazatetracosanoate (25) as a yellow solid. Yield: 380 mg, 44%. LC-MS (ESI) m / z 866.6 [M-H]+.

[0435] Synthesis of 2-((tert-butoxycarbonyl)amino)-24-((2,4-dinitrophenyl)amino)- 6.9.12.15.18.21-hexamethyl-4, 7, 10,13,16, 19, 22-heptaoxo-3, 6, 9, 12, 15, 18,21-heptaazatetracosanoic acid (26)

[0436] To a stirred ice cold solution of methyl 2-((tert-butoxycarbonyl)amino)-24-((2,4-dinitrophenyl)amino)-6,9, 12,15,18,21 -hexamethyl-4,7, 10,13,16,19,22-heptaoxo- 3.6.9.12.15.18.21-heptaazatetracosanoate (25, 0.37 g, 0.42 mmol) in methanol (4 mL) was added 10% aq. Sodium hydroxide solution (1 mL) at ambient temperature under nitrogenDocket No. 1165.071132WO01atmosphere. The resultant reaction mixture was stirred at room temperature for Ih. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was neutralized using dowex H+resin and filtered. The filtrate was concentrated under reduced pressure to afford crude 2-((tert-butoxycarbonyl)amino)-24-((2,4-dinitrophenyl)amino)-6,9,12,15,18,21 -hexamethyl-4,7, 10,13,16,19,22-heptaoxo-3 ,6,9, 12,15,18,21-heptaazatetracosanoic acid (26) as a yellow solid. Yield: 350 mg, 93% LC-MS (ESI) m / z 852.25 [M-H]+.

[0437] Synthesis of (9H-fluoren-9-yl)methyl tert-butyl (27-((2,4-dinitrophenyl)amino)- 9, 12, 15, 18, 21, 24-hexamethyl-4, 7,10, 13,16, 19, 22, 25-octaoxo-3, 6, 9, 12, 15, 18, 21, 24-octaazaheptacosane-1 , 5-diyl)dicarbamate (28)

[0438] To the stirred ice cold solution 2-((tert-butoxycarbonyl)amino)-24-((2,4-dinitrophenyl)amino)-6,9, 12,15,18,21 -hexamethyl-4,7, 10,13,16,19,22-heptaoxo-3,6,9,12,15,18,21-heptaazatetracosanoic acid (26, 0.35 g, 0.41 mmol) and (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate (BLD Pharm, 27, 0.14 g, 0.45 mmol) in N,N-dimethylformamide (5 mL) , N,N-Diisopropylethylamine (0.21 mL, 1.23 mmol) and 1- [Bis(dimethylamino)methylene]-U / -l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 0.23 g, 0.61 mmol) were added into the resulting reaction mixture and was allowed to stir at ambient temperature for 2 h. The progress of reaction was monitored by TLC and LCMS. After the completion, reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography by using eluents 8-10% MeOH in DCM to afford (9H-fluoren-9-yl)methyl tert-butyl (27-((2,4-dinitrophenyl)amino)- 9.12.15.18.21.24-hexamethyl-4,7, 10, 13, 16, 19,22,25-octaoxo-3,6,9, 12, 15, 18,21 ,24-octaazaheptacosane-l,5-diyl)dicarbamate (28) as a yellow solid. Yield: 400 mg, 87%. LC-MS (ESI) m / z 1116.25 [M-H]+.

[0439] Synthesis of tert-butyl (l-amino-27-((2,4-dinitrophenyl)amino)-9, 12, 15, 18,21 ,24-hexamethyl-4, 7,10, 13,16, 19,22,25-octaoxo-3, 6,9, 12, 15, 18,21 ,24-octaazaheptacosan-5-yl)carbamate (29)

[0440] To the ice cold stirred solution of (9H-fluoren-9-yl)methyl tert-butyl (27-((2,4-dinitrophenyl)amino)-9, 12,15,18,21 ,24-hexamethyl-4,7, 10,13,16,19,22,25-octaoxo- 3.6.9.12.15.18.21.24-octaazaheptacosane-l,5-diyl)dicarbamate (28, 0.78 g, 0.69 mmol in N,N-dimethylformamide (10 mL), was added piperidine (1.5 mL) and the resulting reaction mixture was allowed to stir at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, reaction mass was concentrated under reduced pressure to get the crude. The crude was triturated with diethyl ether (3x40 mL) and dried under reducedDocket No. 1165.071132WO01pressure to afford tert-butyl (l-amino-27-((2,4-dinitrophenyl)amino)-9,12,15,18,21,24-hexamethyl-4,7,10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21,24-octaazaheptacosan-5-yl)carbamate (29) as a yellow solid. Yield: 580 mg, 92%. LC-MS (ESI) m / z 896.90 [M+H]+.

[0441] Synthesis of (9H-jluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-((tert-butoxycarbonyl)amino)~ 27-((2, 4-dinitrophenyl)amino)-9 , 12, 15, 18, 21, 24-hexamethyl-4, 7,10, 13,16, 19, 22, 25-octaoxo- 3.6.9.12.15.18.21.24-octaazaheptacosyl)carbamoyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carboxylate (32)

[0442] To the stirred ice cold solution of tert-butyl (l-amino-27-((2,4-dinitrophenyl)amino)- 9.12.15.18.21.24-hexamethyl-4,7, 10, 13, 16, 19,22,25-octaoxo-3,6,9, 12, 15, 18,21 ,24-octaazaheptacosan-5-yl)carbamate (29,0.58 g, 0.65 mmol) and l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (31, 0.65 g, 0.712 mmol) in A,A-dimethylformamide (10 mL), N,N-Diisopropylethylamine (0.34 mL, 1.94 mmol) and l-[Bis(dimethylamino)methylene]-17 / -l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU; 0.37 g, 0.97 mmol) were added and the resulting reaction mixture was allowed to stir at ambient temperature for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography by using eluents 10-15% MeOH in DCM to afford (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5 -((tertbutoxy carbonyl)amino)-27-((2,4-dinitrophenyl)amino)-9, 12, 15, 18,21, 24-hexamethyl-4,7,10,13,16,19,22,25-octaoxo-3 ,6,9, 12,15,18,21 ,24-octaazaheptacosyl)carbamoyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine-l -carboxylate (32) as a yellow solid. Yield 700 mg, 60%. LC-MS (ESI) m / z 1783.03 [M-H]+.

[0443] Synthesis of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-amino-27-((2,4-dinitrophenyl)amino)-9, 12, 15, 18,21 ,24-hexamethyl-4, 7, 10, 13, 16, 19,22,25 -octaoxo- 3.6.9.12.15.18.21.24-octaazaheptacosyl)carbamoyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carboxylate (33)

[0444] To a stirred ice cold solution of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-((tert-butoxycarbonyl)amino)-27-((2,4-dinitrophenyl)amino)-9,12,15,18,21,24-hexamethyl-4,7,10,13,16,19,22,25-octaoxo-3 ,6,9, 12,15,18,21 ,24-octaazaheptacosyl)carbamoyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -DocketNo. 1165.071132WO01carbonyl)piperidine-l -carboxylate (32, 0.4 g, 0.22 mmol) in dichloromethane (5 mL), was added trifluoroacetic acid (1.5 mL) and the resultant reaction mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After reaction completion, the reaction mass was concentrated under reduced pressure to get the crude. Crude was triturated with pentane (20 mL) and diethyl ether (20 mL) and dried under reduced pressure to afford (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-amino-27-((2,4-dinitrophenyl)amino)-9, 12,15,18,21 ,24-hexamethyl-4,7, 10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21 ,24-octaazaheptacosyl)carbamoyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate (33) as a yellow solid. Yield 300 mg, 79%. LC-MS (ESI) m / z 1685.43 [M+H]+.

[0445] Synthesis of (2R,3R,4R,5S,6S)-2-((23-((2-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido) ethyl) carbamoyl) -45 -( (2, 4-dinitrophenyl)amino)- 4, 7, 10,13,16, 19, 27,30, 33, 36, 39, 42-dodecamethyl-3, 6, 9, 12, 15, 18,21, 25, 28, 31, 34, 37, 40, 43-tetradecaoxo-4, 7, 10, 13, 16, 19, 22,24, 27,30, 33,36, 39, 42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (34)

[0446] To the stirred ice cold solution of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-amino-27-((2,4-dinitrophenyl)amino)-9, 12,15,18,21 ,24-hexamethyl-4,7, 10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21 ,24-octaazaheptacosyl)carbamoyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate (33, 0.1 g, 0.059 mmol) and 3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-21-(((2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9,12,15,18-hexaazahenicosanoic acid (21, 79.3 mg, 0.083 mmol) in Y -di methyl form am ide (3 mL), N,N-Diisopropylethylamine (0.05 mL, 0.29 mmol) and HATU (0.024 g, 0.061 mmol) were added at ambient temperature under a nitrogen atmosphere and the resultant reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mass was concentrated under reduced pressure to get the crude. Crude was diluted with water (10 mL) and extracted with DCM (2x10 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to get the crude. Crude was triturated with diethyl ether (2x5 mL) and dried under reduced pressure to get afford crude (2R,3R,4R,5S,6S)-2-((23-((2-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-DocketNo. 1165.071132WO01carboxamido)ethyl)carbamoyl)-45-((2,4-dinitrophenyl)amino)- 4,7,10,13,16,19,27,30,33,36,39,42-dodecamethyl-3,6,9,12,15,18,21,25,28,31,34,37,40,43-tetradecaoxo-4, 7, 10, 13, 16, 19, 22, 24, 27, 30, 33, 36, 39,42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (34) as a brownish solid. Yield 150 mg, 74% LC-MS (ESI) m / z 1226.61 [M / 2-H]+.

[0447] Synthesis of (2R,3R,4R,5S,6S)-2-((45-((2,4-dinitrophenyl)amino)~4, 7,10, 13,16, 19, 27,30, 33, 36, 39, 42-dodecamethyl-3, 6, 9, 12, 15, 18,21, 25, 28, 31, 34, 37, 40, 43-tetradecaoxo-23-( ( 2-( 1-(1-(1-(1-(1 -(piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-4, 7,10, 13,16, 19,22, 24,27,30, 33,36, 39, 42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (36)

[0448] To the stirred ice cold solution of (2R,3R,4R,5S,6S)-2-((23-((2-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-45-((2,4-dinitrophenyl)amino)- 4,7 ,10,13,16,19,: 27 ,30,: 33,36, 9,42-dodecamethyl-3, 6,9, 12,15,18,21,: 25,28,: 31,34,: 7 ,40,43-tetradecaoxo-4, 7, 10, 13, 16, 19, 22, 24, 27, 30, 33, 36, 39,42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (34, 0.3 g, 0.12 mmol) in N,N-dimethylformamide (4 mL) was added piperidine (0.8 mL, 122 pmol) at the same temperature under nitrogen atmosphere and the resultant reaction mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After the completion, reaction mass was concentrated under reduced pressure to get the crude. The crude was triturated with diethyl ether (2x5 mL) and DCM (2x5 mL). The crude was further dried under reduced pressure to afford (2R,3R,4R,5S,6S)-2-((45-((2,4-dinitrophenyl)amino)- 4,7,10,13,16,19,27,30,33,36,39,42-dodecamethyl-3,6,9,12,15,18,21,25,28,31,34,37,40,43-tetradecaoxo-23 -((2-( 1 -( 1 -(1 -( 1 -( 1 -(piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-4,7,10,13,16,19,22,24,27,30,33,36,39,42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H pyran-3, 4, 5-triyl triacetate (36) as a yellow solid. Yield 250 mg, 91%. LC-MS (ESI) m / z 1115.50 [M / 2-H]+.

[0449] Synthesis of ( 2R, 3R, 4R, 5S, 6S)-2-( ( 45-( 2, 4-dinitrophenyl)amino)-23-( ( 2-( 1-(1-(1-(1-(1-(1-(l-(4-((l-(( 3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ( 2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-DocketNo. 1165.071132WO01carbonyl)piperidine-4-carbonyl)piperidme-4-carbonyl)piperidme-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-4, 7,10, 13,16, 19,27,30, 33,36, 39, 42-dodecamethyl- 3, 6, 9, 12, 15, 18,21, 25, 28, 31, 34, 37, 40, 43-tetradecaoxo-4, 7, 10,13,16, 19, 22, 24, 27,30, 33, 36, 39, 42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (38)

[0450] To a stirred ice cold solution of (2R,3R,4R,5S,6S)-2-((45-((2,4-dinitrophenyl)amino)-4,7,10,13,16,19,27,30,33,36,39,42-dodecamethyl-3,6,9,12,15,18,21,25,28,31,34,37,40,43-tetradecaoxo-23 -((2-( 1 -( 1 -(1 -( 1 -( 1 -(piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-4,7,10,13,16,19,22,24,27,30,33,36,39,42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3, 4, 5-triyl triacetate (36, 91 mg, 40.7 pmol) and l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oic acid (37, 40 mg, 40.7pmol) in acetonitrile (2 mL, 38.3 mmol), NMI (0.1 mL, 0.407 mmol) and a solution of TCFH (11.4 mg, 40.7 pmol) in acetonitrile (0.5 mL) were added at the same temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, reaction mass was concentrated under reduced pressure to afford the crude (2R,3R,4R,5S,6S)-2-((45-((2,4-dinitrophenyl)amino)-23-((2-(l-(l-(l-(l-(l-(l-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-4,7,10,13,16,19,27,30,33,36,39,42-dodecamethyl-3,6,9, 12, 15,18,21 ,25,28,31 ,34,37,40,43-tetradecaoxo- 4, 7, 10, 13, 16, 19, 22, 24, 27, 30, 33, 36, 39,42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahy dro-2H-pyran-3, 4, 5-triyl triacetate (38) as a yellow solid. Yield 140 mg LC-MS (ESI) m / z 1599.12 [M / 2+H]+.

[0451] Synthesis of N-( 27 -((2, 4-dinitrophenyl)amino)-5-( 3, 6, 9, 12,15, 18-hexamethyl- 4, 7,10, 13,16, 19-hexaoxo-21-(((2R, 3R, 4R,5R, 6S)-3, 4, 5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 6, 9, 12, 15, 18-hexaazahenicosanamido)-9, 12, 15, 18,21, 24-hexamethyl- 4, 7,10, 13,16, 19,22,25-octaoxo-3, 6,9, 12, 15, 18,21,24-octaazaheptacosyl)-l-(l-(l-(l-(l-(l-(l-(4-((l-( (3-hydroxy-6-methylpyridin-2-yl)methyl)-6-( ((2-( 3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)- 6, 9, 12, 15, 18, 21,24, 27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-DocketNo. 1165.071132WO01carbonyl)piperidine-4-carbonyl)piperidme-4-carbonyl)piperidme-4-carbonyl)piperidine-4-carboxamide (Compound 14)

[0452] To a stirred ice cold solution of (2R,3R,4R,5S,6S)-2-((45-((2,4-dinitrophenyl)amino)-23-((2-( 1 -( 1 -( 1 -( 1 -( 1 -( 1 -( 1 -(4-(( 1 -((3 -hydroxy-6-methylpyri din-2 -yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido)ethyl)carbamoyl)-4,7 ,10,13,16,19,27 ,30,33,36,39,42-dodecamethyl-3,6,9,12,15,18,21,25,28,31,34,37,40,43-tetradecaoxo-4,7,10,13,16,19,22,24,27,30,33,36,39,42-tetradecaazapentatetracontyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (38, 130 mg, 40.7 pmol) in methanol (0.6 mL, 14.8 mmol) , N,N-Diisopropylethylamine (0.6 mL, 40.7 pmol) and water (0.8 mL, 44.4 mmol) were added at the same temperature under nitrogen atmosphere and the resultant reaction mixture was stirred at the same temperature for 3h. The progress of the reaction was monitored by LCMS. The reaction mass was concentrated under reduced pressure to get the crude. The Crude was further purified by Prep-HPLC using 0.1% TFA in water and acetonitrile to afford N-(27-((2,4-dinitrophenyl)amino)-5-(3,6,9,12,15,18-hexamethyl-4,7,10,13,16,19-hexaoxo-21-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,6,9, 12, 15,18-hexaazahenicosanamido)-9, 12, 15,18,21,24-hexamethyl-4,7,10,13,16,19,22,25-octaoxo-3,6,9,12,15,18,21,24-octaazaheptacosyl)-l-(l-(l-(l-( 1 -( 1 -( 1 -(4-(( 1 -((3 -hy droxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3 -hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamide (Compound 14) as a yellow solid. Yield: 4 mg; 3% over two steps. LC-MS (ESI) m / z 3070.6625 [M+H]+.

[0453] Additional compounds can be synthesized in a similar fashion with the appropriate selection of starting materials: for example, Compound 22 and Compound 26 in Fig. 13.

[0454] Example 11: Synthesis ofN-(18-((2,4-dinitrophenyl)amino)-9,12,15-trimethyl-5-(2-(N-methyl-2-(N-methyl-2-(N-methyl-3-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanamido)acetamido)acetamido)acetamido)-4,7, 10,13,16-pentaoxo-3,6,9, 12,15-pentaazaoctadecyl)-l-(l-(l-(l-(l-(l-(l-(4-((l-((3-hydroxy-6-methylpyridin-2-yl)methyl)-6-(((2-(3-hydroxypropyl)-5-methylphenyl)amino)methyl)-lH-benzo[d]imidazol-2-yl)amino)piperidin-l-yl)-6,9,12,15,18,21,24,27-octaoxa-3-azatriacontan-30-oyl)piperidine-4-Docket No. 1165.071132WO01carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamide (Compound 15)10PyBop, DIPEA, DMF, rtDocket No. 1165.071132WO01PyBop, DIPEA, DMFDocket No. 1165.071132WO01TCFH, NMI, ACN, rt OAcOH

[0455] Synthesis of 3-((2,4-dinitrophenyl)amino)propanoic acid (1)

[0456] Common intermediate (14) synthesized in Example 10 preparation of Compound 14.

[0457] Synthesis of tert-butyl N-methyl-N-(N-methyl-N-(methylglycyl)glycyl)glycinate (2)

[0458] Common intermediate (8) synthesized in Example 10 preparation of Compound 14.

[0459] Synthesis of tert-butyl N-(N-(N-(3-((2,4-dinitrophenyl)amino)propanoyl)-N-methylglycyl)- N-methylglycyl) -N -me thylglycinate (3)

[0460] To the stirred solution of 3-((2,4-dinitrophenyl)amino)propanoic acid (1; 1.8 g, 7.05 mmol) and tert-butyl N-methyl-N-(N-methyl-N-(methylglycyl)glycyl)glycinate (2; 2.03 g, 7.05Docket No. 1165.071132WO01mmol) in A, A-di methyl formamide (15 mL), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (3.67 g, 7.05 mmol) and A,7V-Diisopropylethylamine (6.5 mL, 55.8 mmol) were added at 0°C. The resulting reaction mixture was allowed to stir at ambient temperature for 4h. The progress of the reaction was monitored by TLC and LCMS. After completion the reaction mass was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude. The crude was purified by combi-flash column chromatography by using eluents 60-70% EtOAc in Heptane to obtain tert-butyl N-(N-(N-(3-((2,4-dinitrophenyl)amino)propanoyl)-N-methylglycyl)-N-methylglycyl)-N-methylglycinate (3) as yellowish solid. Yield: 1.5 g; 40.54% LC-MS (ESI) m / z 523.20 [M-H]'.

[0461] Synthesis of N-(N-(N-(3-( (2, 4-dinitrophenyl)amino)propanoyl)-N-methylglycyl)-N-methylglycyl) -N -me thy Igly cine (4)

[0462] To an ice-cold solution of tert-butyl N-(N-(N-(3-((2,4-dinitrophenyl)amino)propanoyl)-N-methylglycyl)-N-methylglycyl)-N-methylglycinate (3; 1.5 g, 2.86 mmol) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added dropwise. The resulting mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After the completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was triturated with 20% diethyl ether in pentane (2 x 50 mL), decanted and dried under reduced pressure to afford N-(N-(N-(3-((2,4-dinitrophenyl)amino)propanoyl)-N-methylglycyl)-N-methylglycyl)-N-methylglycine (4) as yellowish solid. Yield: 1.2 g; 89.58% LC-MS (ESI) m / z 485.90 [M+NH4]+.

[0463] Synthesis of 3-((( 2R, 3R, 4R, 5S, 6S)-3, 4, 5 -triacetoxy -6-methyltetr ahydro-2H-pyr an-2-yl)oxy)propanoic acid (5)

[0464] Common intermediated (19) synthesized in Example 10 preparation of Compound 14.

[0465] Synthesis of (2S,3S,4R,5R,6R)-2-methyl-6-((2,2,6,9,12-pentamethyl-4, 7,10,13-tetraoxo-3-oxa-6,9, 12-triazapentadecan-15-yl)oxy)tetrahydro-2H-pyran-3, 4,5-triyl triacetate (6)

[0466] To the stirred solution of 3-(((2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanoic acid (5; 2.0 g, 5.52 mmol) and tert-butyl N-methyl-N-(N-methyl-N-(methylglycyl)glycyl)glycinate (2; 1.59 g, 5.52 mmol) in AfA -di methyl formamide (15 mL), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP:2.87 g, 5.52 mmol) and A,A-Diisopropylethylamine (4.81 mL, 27.6 mmol) were added at 0°C. The resulting reaction mixture was allowed to stir at ambient temperature for 2h. The progress of the reaction was monitored by TLC and LCMS. After completion the reaction mass was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried overDocket No. 1165.071132WO01sodium sulphate, filtered and concentrated under reduced pressure to get crude. The crude was purified by combi-flash column chromatography by using eluents 2-5% MeOH in DCM to obtain (2S,3S,4R,5R,6R)-2-methyl-6-((2,2,6,9,12-pentamethyl-4,7,10,13-tetraoxo-3-oxa-6,9,12-triazapentadecan-15-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (6) as colorless liquid. Yield: 1.3 g; 37.28% LC-MS (ESI) m / z 632.55 [M+H]+.

[0467] Synthesis of N-methyl-N-(N-methyl-N-(N-methyl-N-(3-(((2R, 3R, 4R, 5S, 6S)-3, 4, 5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanoyl)glycyl)glycyl)glycine (7)

[0468] To an ice-cold solution of (2S,3S,4R,5R,6R)-2-methyl-6-((2,2,6,9,12-pentamethyl-4,7,10,13 -tetraoxo-3 -oxa-6, 9, 12 -tri azapentadecan- 15 -yl)oxy)tetrahy dro-2H-pyran-3 ,4,5 -triyl triacetate (6; 0.5 g, 0.79 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added dropwise. The resulting reaction mixture was stirred at ambient temperature for 2h. The progress of reaction was monitored by TLC and LCMS. After reaction completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was triturated with 20% diethyl ether in pentane (2 x 20 mL), decanted and dried under reduced pressure to afford N-methyl-N-(N-methyl-N-(N-methyl-N-(3-(((2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanoyl)glycyl)glycyl)glycine (7) as colorless liquid. Yield: 0.3 g; 65.85% LC-MS (ESI) m / z 593.40 [M+NH4]+.

[0469] Synthesis of methyl 2-amino-2-((tert-butoxycarbonyl)amino)acetate (8)

[0470] Common intermediate (24) synthesized in the Example 10 preparation of Compound 14.

[0471] Synthesis of methyl 2-((tert-butoxycarbonyl)amino)-15-((2,4-dinitrophenyl)amino)-6,9,12-trimethyl-4, 7,10, 13-tetraoxo-3, 6, 9, 12-tetraazapentadecanoate ( 9)

[0472] To the stirred solution of methyl 2-amino-2-((tert-butoxycarbonyl)amino)acetate (8; 0.37 g, 1.81 mmol) and N-(N-(N-(3-((2,4-dinitrophenyl)amino)propanoyl)-N-methylglycyl)-N-methylglycyl)-N-methylglycine (4; 0.85 g, 1.81 mmol) in N, A-dimethylformamide (15 mL), AA-Diisopropylethylamine (1.6 mL, 9.06 mmol) and l-[Bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU; 0.69 g, 1.81 mmol) were added subsequently at 0°C and the resultant mixture was stirred at ambient temperature for 3h under nitrogen atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography by using eluents 5-7% MeOH in DCM to afford methyl 2-((tert-butoxycarbonyl)amino)-15-((2,4-dinitrophenyl)amino)-6,9,12-trimethyl-4,7, 10, 13 -tetraoxo-3, 6, 9, 12-tetraazapentadecanoate (9) as yellowish solid. Yield: 0.7 g; 59.02% LC-MS (ESI) m / z 672.25 [M+NH4]+.Docket No. 1165.071132WO01

[0473] Synthesis of 2-((tert-butoxycarbonyl)amino)-15-((2,4-dinitrophenyl)amino)-6,9,12-trimethyl-4, 7, 10, 13-tetraoxo-3, 6, 9, 12-tetraazapentadecanoic acid (10)

[0474] To the stirred solution of 2-((tert-butoxycarbonyl)amino)-15-((2,4-dinitrophenyl)amino)- 6.9.12-trimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazapentadecanoate (9; 0.7 g, 1.08 mmol) in methanol (10 mL), 10% aq. sodium hydroxide solution (0.8 mL) was added at ambient temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mass was neutralized using dowex H+resin (upto pH=7). The reaction mass was filtered and the filtrate was concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-15-((2,4-dinitrophenyl)amino)-6,9,12-trimethyl-4,7,10,13-tetraoxo- 3.6.9.12-tetraazapentadecanoic acid (10) as a yellowish solid. Yield: 0.62 g; 87.79%; LC-MS (ESI) m / z 658.25 [M+NH4]+.

[0475] Synthesis of (9H-fluoren-9-yl)methyl tert-butyl (18-((2,4-dinitrophenyl)amino)-9, 12, 15-trimethyl-4, 7,10, 13,16-pentaoxo-3, 6, 9, 12, 15-pentaazaoctadecane-l ,5 -diyl) dicarbamate (12)

[0476] To the stirred solution of 2-((tert-butoxycarbonyl)amino)-15-((2,4-dinitrophenyl)amino)- 6.9.12-trimethyl-4,7, 10, 13-tetraoxo-3, 6, 9, 12-tetraazapentadecanoic acid (10; 0.62 g, 1.00 mmol) and (9H-fluoren-9-yl)methyl (2-aminoethyl)carbamate (BLD Pharm; 11; 0.30 g, 1.06 mmol) in A-dimethylformarnide (8 mL), YA'-Di isopropyl ethyl amine (0.95 mL, 5.46 mmol) and benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP; 0.57 g, 1.09 mmol) were added subsequently at 0°C. The resultant mixture was stirred at ambient temperature for 3h under nitrogen atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion, reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography by using eluents 5-7% MeOH in DCM to afford (9H-fluoren-9-yl)methyl tert-butyl (18-((2,4-dinitrophenyl)amino)-9,12,15 -trimethyl-4,7, 10,13,16-pentaoxo-3 ,6,9,12,15 -pentaazaoctadecane- 1 , 5 -diyl)dicarbamate (12) as yellowish solid. Yield: 0.5 g; 45.45% LC-MS (ESI) m / z 921.85 [M+NH4]+.

[0477] Synthesis of tert-butyl (l-amino-18-((2,4-dinitrophenyl)amino)-9,12,15-trimethyl-4, 7,10, 13,16-pentaoxo-3, 6, 9, 12, 15-pentaazaoctadecan-5-yl)carbamate (13)

[0478] To the stirred solution of (9H-fluoren-9-yl)methyl tert-butyl (18-((2,4-dinitrophenyl)amino)-9, 12, 15 -trimethyl-4,7, 10, 13, 16-pentaoxo-3,6,9, 12, 15-pentaazaoctadecane-l,5-diyl)dicarbamate (12; 0.5 g, 0.55 mmol) in A,A-dimethylformamide (4 mL), piperidine (0.8 mL) was added at ambient temperature under nitrogen atmosphere. The resultant reaction mixture was stirred at room temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, then reaction mixture was concentrated under reducedDocket No. 1165.071132WO01pressure to get crude. The crude was triturated using 20% diethyl ether in pentane (2 x 50 mL), decanted and dried under reduced pressure to afford tert-butyl (l-amino-18-((2,4- dinitrophenyl)amino)-9, 12, 15-trimethyl-4,7, 10, 13, 16-pentaoxo-3,6,9, 12, 15-pentaazaoctadecan-5-yl)carbamate (13) as yellowish solid. Yield: 0.3 g; 79.53% LC-MS (ESI) m / z 683.30 [M+H]+.

[0479] Synthesis of 1-(1 -(!-(!-( 1-(1 -(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid (14)

[0480] Common intermediate (5) synthesized in the Example 1 synthesis of Compound 5 or intermediate (9) in Example 7 Part 2, Step 7 synthesis of Compound 5.

[0481] Synthesis of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-((tert-butoxycarbonyl)amino)- 18-((2, 4-dinitrophenyl)amino)-9, 12, 15-trimethyl-4, 7,10, 13,16-pentaoxo-3, 6, 9, 12, 15-pentaazaoctadecyl)carbamoyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l -carboxy late (15)

[0482] To the stirred solution of tert-butyl (l-amino-18-((2,4-dinitrophenyl)amino)-9,12,15-trimethyl-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazaoctadecan-5-yl)carbamate (13; 0.25 g, 0.36 mmol) and 1 -( 1 -( 1 -( 1 -( 1 -( 1 -(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4- carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4- carbonyl)piperidine-4-carboxylic acid (14; 0.30 g, 0.32 mmol) in YA -di methyl form am ide (5 mL), / A-Diisopropylethylamine (0.28 mL, 1.66 mmol) and Benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP; 0.18 g, 0.32 mmol) were added at 0°C. The resulting reaction mixture was allowed to stir at ambient temperature for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion, the reaction mass was concentrated under reduced pressure to get the crude. The crude was purified by combi-flash column chromatography over by using eluents 10-15% MeOH in DCM to afford (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-((tert-butoxycarbonyl)amino)-18-((2,4-dinitrophenyl)amino)- 9, 12, 15-trimethyl-4,7, 10,13,16-pentaoxo-3 ,6,9, 12, 15-pentaazaoctadecyl)carbamoyl)piperidine- 1 - carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 - carbonyl)piperidine-l -carboxylate (15) as yellowish solid. Yield 0.28 g; 53.86% LC-MS (ESI) m / z 1589.20 [M+NH4]+.

[0483] Synthesis of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-amino-18-((2,4-dinitrophenyl)amino)-9, 12, 15-trimethyl-4, 7,10, 13,16-pentaoxo-3, 6, 9, 12, 15-pentaazaoctadecyl)carbamoyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l-carbonyl)piperidine-l -carboxy late (16)DocketNo. 1165.071132WO01

[0484] To an ice cold solution of (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5 -((tertbutoxy carbonyl)amino)- 18-((2,4-dinitrophenyl)amino)-9, 12, 15-trimethyl-4,7, 10,13,16-pentaoxo-3,6,9,12, 15-pentaazaoctadecyl)carbamoyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate (15; 0.28 g, 0.16 mmol) in dichloromethane (8 mL), trifluoroacetic acid (1.5 mL) was added dropwise and was stirred at ambient temperature for Ih. The progress of the reaction was monitored by TLC and LCMS. The reaction mass was concentrated under reduced pressure to get the crude. Crude was triturated with pentane (2x10 mL) and diethyl ether (2x15 mL) decanted and dried under reduced pressure to afford (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-amino-18-((2,4-dinitrophenyl)amino)-9,12,15-trimethyl-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazaoctadecyl)carbamoyl)piperi dine- l-carbonyl)piperi dine- l-carbonyl)piperi dine- 1-carbonyl)piperi dine- l-carbonyl)piperi dine- l-carbonyl)piperi dine- 1 -carboxylate (16) as an yellowish semi-solid. Yield: 0.22 g; 83.92% LC-MS (ESI) m / z 1471.60 [M+H]+.

[0485] Synthesis of (2R,3R,4R,5S,6S)-2-((14-((2-(l-(l-(l-(l-(l-(l-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidine-4-carboxamido) ethyl) carbamoyl) -27-( (2, 4-dinitrophenyl)amino)-4, 7, 10, 18, 21, 24-hexamethyl-3, 6,9, 12,16, 19,22,25-octaoxo-4, 7,10, 13, 15, 18,21 ,24-octaazaheptacosyl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (17)

[0486] To the stirred solution of N-methyl-N-(N-methyl-N-(N-methyl-N-(3-(((2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propanoyl)glycyl)glycyl)glycine (7; 0.12 g, 0.21 mmol) and (9H-fluoren-9-yl)methyl 4-(4-(4-(4-(4-(4-((5-amino-18-((2,4-dinitrophenyl)amino)-9, 12, 15-trimethyl-4,7, 10, 13, 16-pentaoxo-3,6,9, 12, 15-pentaazaoctadecyl)carbamoyl)piperi dine- l-carbonyl)piperi dine- l-carbonyl)piperi dine- 1-carbonyl)piperi dine- l-carbonyl)piperi dine- l-carbonyl)piperi dine- 1 -carboxylate (16; 0.34 g, 0.23 mmol) in A -di methyl form am ide (6 mL), N,N-Diisopropylethylamine (0.2 mL, 1.04 mmol) and benzotriazol- 1 -yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP; 0.12 g, 0.23 mmol) were added at 0°...

Claims

Docket No. 1165.071132WO01WHAT IS CLAIMED IS:

1. A compound of the formulaL2- A1T- L1— Q9 .9Formula Iand pharmaceutically acceptable salts and solvates thereof, whereinT is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;L1, L2, and L3are each an independently selected linker;Q comprises an optionally substituted trivalent nitrogen atom; andA1and A2are each a radical of an independently selected hapten;provided that L1, L2, and L3taken together do not compriseO VNN H Hwherein m, p, d, and q are each, independently, an integer from 0 to 20, such as from 1 to 20, 0 to 15, 1 to 10, 2 to 10, 2 to 8 or 3 to 9.

2. The compound of claim 1 of the formulaz(PEG2)n— A1T- x1- (PEG1)m-X2- x3-l'(PEG3)p— A2Formula IIand pharmaceutically acceptable salts and solvates thereof, wherein:T is a radical of a ligand for a target protein of an RSV or an RSV-infected cell;PEG1, PEG2, and PEG3are each, independently groups of the formula CH2CH2O;PEG2optionally comprises a C(O)NH group between two adjacent CH2CH2O groups;PEG3optionally comprises a NHC(O) group between two adjacent CH2CH2O groups;n, m, and p are each, independently 3 to 36;Docket No. 1165.071132WO01X1is alkylene, such as ethylene (-CH2CH2-);X2is absent or a group selected from:d , wherein d is 2 to 10;q, wherein q is 2 to 10; or, wherein r is 2 to 10;X3is absent or carbonyl (C(O)); andA1and A2are each, a radical of an independently selected hapten.

3. The compound of claim 1 or 2, wherein the target protein is an RSV fusion (F) glycoprotein.

4. The compound of claim 1 or 2, wherein the target protein is an RSV attachment glycoprotein (G).

5. The compound of claim 1 or 2, wherein the ligand is an inhibitor of RSV fusion (F) glycoprotein.

6. The compound of claim 1 or 2, wherein the ligand is an inhibitor of RSV attachment glycoprotein (G).

7. The compound of claim 1 or 2, wherein the ligand is of the formulaOH N N N >0N HNo=s=oDocket No. 1165.071132WO018. The compound of any preceding claim, wherein A1and A2are the same hapten.

9. The compound of preceding claim, wherein A1and A2are different haptens.

10. The compound of any preceding claim, wherein the hapten is selected from rhamnose, a- galactosyl moiety, dinitrobenzene, dinitroaniline, trinitrobenzene, and dinitroaniline.

11. The compound of any preceding claim, wherein A1and / or A2is a radical of a dinitrophenyl (DNP), a dinitrophenol, or a dinitroaniline.

12. The compound of any preceding claim, wherein A1and / or A2is a radical of a rhamnose, including L-rhamnose.

13. The compound of any preceding claim, wherein one of A1and A2is a radical of L- rhamnose; and the other of A1and A2is a radical of a dinitroaniline.

14. A compound selected fromDocket No. 1165.071132WO01Docket No. 1165.071132WO01or a pharmaceutically acceptable salt or solvate thereof.Docket No. 1165.071132WO0115. A compound selected fromHODocket No. 1165.071132WO01^II;° T; o 7^\2rAHN^ / ^0'2 s 2 nV oV''10Q .-N<TO OYC^OT.OAOVOJ'''O nA""] nA""] lYr / TiDocket No. 1165.071132WO01 -N<TO UyU Uy£J U / J M i % ' .° ° ° O^Y o A1"' M y yn < / y oJ^o OyN^J UyN njV <000oHOJV0H"°H0 / o ^ ^o or^NDocket No. 1165.071132WO01or a pharmaceutically acceptable salt or solvate thereof.

16. A composition comprising a compound of any preceding claim, or a pharmaceutically acceptable salt or solvate thereof, and optionally including one or more pharmaceutically acceptable diluents, carriers, or excipients, or combinations thereof.

17. A composition for use in treating RSV infection, the composition comprising a compound of any of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, and optionally including one or more pharmaceutically acceptable diluents, carriers, or excipients, or combinations thereof.

18. A unit dose for use in treating RSV infection, the unit dose comprising a compound of any of claims 1-15 or a pharmaceutically acceptable salt or solvate thereof, and optionally including one or more pharmaceutically acceptable diluents, carriers, or excipients, or combinations thereof.

19. A method for treating RSV infection in a host animal, the method comprising administering a therapeutically effective amount of a compound of any of claims 1-15 or a pharmaceutically acceptable salt or solvate thereof, or composition or unit dose comprising the compound.

20. Use of a compound of any of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, or composition or unit dose comprising the compound, in the manufacture of a medicament for use in treating RSV infection in a host animal.

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