New e- and p-selectin antagonists and their application to modulate hyperinflammation

Abstract

There is provided a compound of formula (I), and pharmaceutically acceptable salts thereof. This compound can be used as a medicament for example for the prevention or treatment of hyperinflammation, for example lung or respiratory hyperinflammation, or for the prevention or treatment of SIRS, for example SIRS caused by sepsis. (I)

Description

NEW E- AND P-SELECTIN ANTAGONISTS AND THEIR APPLICATION TO MODULATE HYPERINFLAMMATIONCROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit, under 35 U.S.C. § 119(e), of U.S. provisional application Serial No. 63 / 676,706, filed on July 29, 2024. All documents above are incorporated herein in their entirety by reference.FIELD OF THE INVENTION

[0001] The present invention relates to the field of hyperinflammation, and more specifically to the treatment of diseases and conditions associated with an excessive immune response such as systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), septic shock and sepsis.BACKGROUND OF THE INVENTION

[0002] Uncontrolled immune reaction to microbial threats presents significant challenges, potentially resulting in complications such as tissue damage, autoimmune disorders, allergies, cytokine imbalances, immunodeficiency, chronic inflammation, drug sensitivities and sepsis. Sepsis stands out as a particularly dangerous and significant cause of mortality among patients in intensive care units. It is characterized by a complex systemic inflammatory response to pathogens and encompasses distinct and overlapping phases, contributing to its challenging nature.1The initial hyperinflammatory phase clears the host of the offending pathogen. However, when exacerbated, excessive tissue injury can occur in the infected organ. This is followed by a hypoinflammatory phase induced by anti-inflammatory cytokines, which aims to restore immune system homeostasis.2 3This phase also poses a significant danger, if aggravated, as it can favor re-infection and eventual death.

[0003] Acute lung injury and acute respiratory distress syndrome (ARDS), both severe life-threatening complications of COVID-19 caused by the SARS-CoV-2 virus strain, are linked to sepsis.4-6These conditions are associated with hyperinflammation induced by massive cytokine / chemokine production.7Excessive neutrophil infiltration in the lungs, which is E- and P-selectin dependent, and the resulting immune thrombotic response induced by SARS-CoV-2 are thought to be the driving force behind the severity of the disease.4Cytokines produced by infected neutrophils recruit other immune cells that release more cytokines. Disease severity is also characterized by the presence of immature neutrophils and the dysregulation of the myeloid cell compartment.8Furthermore, SARS- CoV-2 infection is linked to a prothrombotic platelet phenotype, which contributes to the development and progression of thrombo-inflammatory diseases.9

[0004] There is a need for the development of novel compounds, therapies and regimes for the treatment and management of diseases and conditions associated with an excessive immune response.10 22SUMMARY OF THE INVENTION

[0005] In accordance with the present invention, there is provided:1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein:Ri and R2 independently represent -O-R20, or -NR21R22, wherein R20 represents alkyl, and R21 and R22 independently represent H, alkyl or aryl, or R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, R3 represents H, -CH2-O-R23, or -CH2-NR24R25, wherein:R23 represents H, benzoyl (Bz), or aryl unsubstituted or substituted with one or more halogen or haloalkyl (preferably the halogen is -F; preferably the haloalkyl is CF3),R24 represents H, andR25 represents -C(=O)-R26, wherein R26 represents alkyl, or aryl, each of which being unsubstituted or substituted with one or more halogen atoms,R4 represents -O-R27, wherein R27 represents H, or benzoyl (Bz),R? represents H, with the proviso that when Re representsat least one of R1 and R2 (preferably both) represents -NR21R22, and / or R3 represents -CH2-NR24R25, and with the proviso that when Rs and Re together form cycle A and Rw represents -COOH, then: at least one of Ri and R2 (preferably both) represents -NR21R22, and / orRe represents -CH2-NR24R25, and / orR11 represents benzyl (Bn).2. The compound of embodiment 1, wherein R1 and R2 represent identical substituents.3. The compound of embodiment 1 or 2, wherein R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl.4. The compound of embodiment 1 or 2, wherein R1 and R2 represent -NR21R22.5. The compound of any one of embodiments 1 to 4, wherein R21 and R22 represent identical substituents.6. The compound of any one of embodiments 1 to 4, wherein R21 and R22 represent different substituents, preferably wherein one of R21 and R22 represents H, the other of R21 and R22 represents alkyl or aryl.7. The compound of any one of embodiments 1 to 6, wherein the alkyl in R21 and R22 is methyl or propyl (preferably isopropyl).8. The compound of any one of embodiments 1 to 7, wherein the aryl in R21 and R22 is phenyl.9. The compound of any one of embodiments 1 to 8, wherein R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably wherein said nitrogen atom is the only heteroatom in the heterocycloalkyl group.10. The compound of any one of embodiments 1 to 9, wherein R21 and R22 together with the nitrogen atom to which they are attached form, more preferably11. The compound of any one of embodiments 1 to 8, wherein R21 and R22 represent alkyl.12. The compound of any one of embodiments 1 to 8, wherein R21 and R22 represent aryl.13. The compound of any one of embodiments 1 to 12, wherein the one or more halogen atom substituting the aryl in R23 is fluorine.14. The compound any one of embodiments 1 to 13, wherein the one or more halogen atom substituting the one or more alkyl substituting the aryl in R23 is fluorine.15. The compound any one of embodiments 1 to 14, wherein the one or more alkyl substituted with one or more halogen atom in R23 is CF3.16. The compound of any one of embodiments 1 to 15, wherein R23 represents H.17. The compound of any one of embodiments 1 to 15, wherein R23 represents benzoyl (Bz).18. The compound of any one of embodiments 1 to 15, wherein R23 represents aryl unsubstituted or substituted with one or more: halogen atom and / or alkyl substituted with one or more halogen atoms.19. The compound of any one of embodiments 1 to 18, wherein the alkyl in R26 is methyl unsubstituted or substituted with one or more halogen atoms.20. The compound of any one of embodiments 1 to 19, wherein the aryl in R26 is phenyl unsubstituted or substituted with one or more halogen atoms.21 . The compound of any one of embodiments 1 to 20, wherein the halogen atoms substituting the alkyl and / or the aryl in R26 are fluorine atoms.22. The compound of any one of embodiments 1 to 21 , wherein R26 is methyl or trihalomethyl, preferably methyl or -CF3.23. The compound of any one of embodiments 1 to 21 , wherein R26 is phenyl or para-halophenyl, preferably phenyl or parafluorophenyl.24. The compound of any one of embodiments 1 to 23, wherein R3 represents H.25. The compound of any one of embodiments 1 to 23, wherein R3 represents -CH2-O-R23.26. The compound of any one of embodiments 1 to 23, wherein R3 represents -CH2-NR24R25.27. The compound of any one of embodiments 1 to 26, wherein R27 represents H.28. The compound of any one of embodiments 1 to 26, wherein R27 represents benzoyl (Bz).29. The compound of any one of embodiments 1 to 28, wherein R5 represents H, and Re represents30. The compound of any one of embodiments 1 to 29, wherein Re represents31 . The compound of any one of embodiments 1 to 29, wherein Re represents32. The compound of any one of embodiments 1 to 28, wherein R5 and Re together form cycle A.33. The compound of any one of embodiments 1 to 32, wherein Rw represents -COOH.34. The compound of any one of embodiments 1 to 33, wherein Rw representsN N35. The compound of any one of embodiments 1 to 34, wherein Rn represents H.36. The compound of any one of embodiments 1 to 34, wherein Rn represents benzyl (Bn).37. The compound of any one of embodiments 1 to 36, wherein when Re representsthen at least one of Ri and R2 (preferably both) represents -NR21R22.38. The compound of any one of embodiments 1 to 37, wherein when R5 and Re together form cycle A and Rw represents -COOH, then at least one of R1 and R2 (preferably both) represents -NR21R22.39. The compound of any one of embodiments 1 to 38, wherein when R5 and Re together form cycle A and Rw represents -COOH, then R3 represents -CH2-NR24R25.40. The compound of any one of embodiments 1 to 39, wherein when R5 and Re together form cycle A and Rw represents -COOH, then Rn represents benzyl (Bn).41 . The compound of any one of embodiments 1 to 40, wherein R5 and Re together form cycle A and Rw representsthe tetrazolyl: N N , preferably wherein Rn represents H, and / or R1 and R2 represent identical substituents, and / or R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl, and / or R3 represents -CH2-O-R23, preferably wherein R23 represents H, or benzoyl (Bz), and / or R27 represents H.42. The compound of embodiment 41 , wherein R23 represents H.43. The compound of embodiment 41 , wherein R23 represents benzoyl (Bz).44. The compound of any one of embodiments 1 and 41 to 43, being of formula (II):wherein Bz is benzoyl, iPr is isopropyl and Bz is benzoyl and R23 represents H, or benzoyl (Bz), or a pharmaceutically acceptable salt thereof.45. The compound of any one of embodiments 1 to 40, wherein R5 represents H, Re represents, and Ri and R2 represent -NR21 R22, preferably wherein R28 represents -COOH, and / or R1 and R2 represent identical substituents, and / or the alkyl in R21 and R22 is methyl, and / or the aryls in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R3 represents -CH2-O-R23.46. The compound of embodiment 45, wherein R21 and R22 represent identical substituents, 47. The compound of embodiment 45 or 46, wherein R21 and R22 represent alkyl.48. The compound of embodiment 45, R21 and R22 together with the nitrogen atom to which they are attached form49. The compound of any one of embodiments 45 to 48, wherein R23 represents H.50. The compound of any one of embodiments 45 to 48, wherein R23 represents benzoyl (Bz). 51 . The compound of any one of embodiments 45 to 50, wherein R27 represents H.52. The compound of any one of embodiments 45 to 50, wherein R27 represents benzoyl (Bz).53. The compound of any one of embodiments 1 and 45 to 52, being of formula (III):or a pharmaceutically acceptable salt thereof.54. The compound of any one of embodiments 1 to 40, wherein R5 and Re together form cycle A, R10 represents -represents H, and R1 and R2 represent -NR21 R22, preferably wherein R1 and R2 represent identical substituents, and / or the alkyl in R21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R3 represents -CH2-O-R23.55. The compound of embodiment 54, wherein R21 and R22 represent identical substituents.56. The compound of embodiment 54 or 55, wherein R21 and R22 represent alkyl.57. The compound of embodiment 54, wherein R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably I I — —NI, p yJ158. The compound of any one of embodiments 54 to 57, wherein R23 represents H.59. The compound of any one of embodiments 54 to 57, wherein R23 represents benzoyl (Bz).60. The compound of any one of embodiments 57 to 59, wherein R27 represents H.61. The compound any one of embodiments 1 and 57 to 60, being of formula (IV):, , , , or a pharmaceutically acceptable salt thereof. 62. The compound of any one of embodiments 1 to 40, wherein R5 and Re together form cycle A, R10 represents -represents H, and R3 represents -CH2-NR24R25, wherein R25 represents -C(=O)-R26, preferably wherein the alkyl in R26 is methyl unsubstituted or substituted with one or more halogen atoms, preferably methyl or trihalomethyl, and / or the aryl in R26 is phenyl unsubstituted or substituted with one or more halogen atoms, preferably phenyl or para-halophenyl, and / or the one or more halogen atoms in R26 is fluorine, the alkyl in R21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R27 represents H.63. The compound of embodiment 62, wherein R1 and R2 represent identical substituents.64. The compound of embodiment 62 or 63, wherein R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl. 65. The compound of embodiment 62 or 63, wherein R1 and R2 represent -NR21R22.66. The compound of any one of embodiments 62, 63, and 65, wherein R21 and R22 represent alkyl.67. The compound of any one of embodiments 62, 63, and 65, wherein R21 and R22 represent aryl.The compound of any one of embodiments 62, 63, and 65, wherein R21 e nitrogen atom to which they are attached form a heterocycloalkyl group, preferablymore preferablyThe compound of any one of embodiments 62 to 68, being of formula (V):(V), whereins benzoyl, Ri, R2, and R25 are as defined in any one of embodiments 62 to 68, or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1 to 40, wherein R5 represents H, and Re represents, preferably wherein R1 and R2 represent identical substituents, and / or the alkyl inR21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R2? represents H. The compound of embodiment 70, wherein R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl.72. The compound of embodiment 70, wherein Ri and R2 represent -NR21R22.73. The compound of any one of embodiments 70 to 72, wherein R21 and R22 represent identical substituents.74. The compound of any one of embodiments 70 to 73, wherein R21 and R22 represent alkyl.75. The compound of any one of embodiments 70 to 73, wherein R21 and R22 represent aryl. 76. The compound of any one of embodiments 70 to 72, wherein R21 and R22 together with the nitrogen atom tohich they are attached form a heterocycloalkyl group, preferably Iw I — —NI or - / , more preferably77. The compound of any one of embodiments 70 to 76, wherein R3 represents -CH2-O-R23, preferably wherein R23 represents H. 78. The compound of any one of embodiments 70 to 76, wherein R23 represents benzoyl (Bz).79. The compound of any one of embodiments 70 to 78, being of formula (VI):(VI), wherein Bz is benzyl, Bz is benzoyl, R1 and R2 are as defined in any one of embodiments 70 to 78, R23 represents H, or benzoyl (Bz), and R27 represents H, or benzoyl (Bz), or a pharmaceutically acceptable salt thereof.80. The compound of any one of embodiments 1 to 40, wherein R5 and Re together form cycle A, R10 represents -represents benzyl (Bn), preferably wherein R1 and R2 represent identical substituents, and / or the alkyl in R21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R27 represents H.81. The compound of embodiment 81, wherein R1 and R2represent -O-R20, preferably wherein R20 represents isopropyl.82. The compound of embodiment 81 , wherein R1 and R2represent -NR21R22.83. The compound of any one of embodiments 81 to 83, wherein R21 and R22 represent identical substituents.84. The compound of any one of embodiments 81 to 84, wherein R21 and R22 represent alkyl.85. The compound of any one of embodiments 81 to 84, wherein R21 and R22 represent aryl.86. The compound of any one of embodiments 81 to 83, wherein R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably, more preferably87. The compound of any one of embodiments 81 to 87, wherein R3 represents -CH2-O-R23, preferably wherein R23 represents H.88. The compound of any one of embodiments 81 to 87, wherein R23 represents benzoyl (Bz).89. The compound of any one of embodiments 81 to 89, being of formula (VII):wherein Bz is benzyl, Ph is phenyl, Ri and R2 are as defined in any one of embodiments 81 to 89, R23 representsH, or benzoyl (of a pharmaceutically acceptable salt thereof. 90. The compound of any one of embodiments 1 to 90, being: c -(CH2)4-preferably(LCB-2318) (LCB-2294), or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of any one of embodiments 1 to 91 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient. The compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for use as a medicament. The compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for use in the prevention or treatment of hyperinflammation, for example lung or respiratory hyperinflammation, in a subject. A method for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, comprising administering to a subject in need thereof an effective amount of compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92. Use of the compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, in a subject. Use of the compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for the manufacture of a medicament for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, in a subject. The compound or pharmaceutical composition of embodiment 94, the method of embodiment 95, or the use of embodiment 96 or 97, wherein the hyperinflammation is caused by a virus (e.g., a viral infection). The compound, pharmaceutical composition, method, or use of embodiment 98, wherein the virus is a rhinovirus, an influenza virus, a respiratory syncytial virus (RSV) or a coronavirus. The compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for use in the prevention or treatment of SIRS, for example SIRS caused by sepsis, in a subject.100. A method for preventing or treating systemic inflammatory response syndrome (SIRS) comprising administering to a subject in need thereof an effective amount of the compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92.101. Use of the compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for preventing or treating SIRS in a subject.102. Use of the compound of any one of embodiments 1 to 91 or the pharmaceutical composition of embodiment 92, for the manufacture of a medicament for preventing or treating SIRS in a subject.103. The compound or pharmaceutical composition of embodiment 100, the method of embodiment 101 , or the use of embodiment 102 or 103, wherein the SIRS is associated or caused by sepsis.104. The compound, pharmaceutical composition, method, or use of embodiment 104, wherein the SIRS is caused by a viral infection, for example an infection by an influenza virus or a severe acute respiratory syndrome (SARS) virus such as SARS-CoV-2.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] In the appended drawings:Figs 1A-1B. Results of an in vivo peritoneal inflammation cell migration assay 2 hours after the injection of thioglycolate (TGA) using the indicated compounds. Fig. 1A: total neutrophil populations. Fig. 1 B: PSGL-1 positive populations. Significance was determined in comparison to TGA stimulated mice using one-way ANOVA. *p<0.05, **p<0.001, ***p<0.0001 , ****p<0.00001Fig. 2A shows the chemical structures of Sialyl Lewisx(sLex) and of previously reported glycomimetic sLexanalogues.Fig. 2B shows the general chemical approach and completion of the synthesis of selectin antagonists 12 and 13 with a tetrazole carboxyl bioisostere (Scheme 1 )Figs. 3A-3F show the In vivo cell recruitment model Oh, 2h and 48h stimulations. Figs. 3A, 3C, 3E are the experimental timelines. Figs. 3B, 3D, 3F: C57BL / 6 wild type mice (n=6-8) were injected with 1 mL 3% thioglycolate (TG) and compounds (Compd) according to experimental timeline using 2.5 mmol / kg doses. Cells were collected from the cavity and identified using flow cytometry. Neutrophils were identified as CD11b+, CD11c-, Ly-6C+, Ly-6G+. PSLG-1 positive population was identified from total live cells. CD11b positive population was identified from total live PSGL-1 + cells. Macrophage / Monocyte population was identified as CD11 b+, CD11c-, Ly-6C+, Ly-6G- Significance was determined in comparison to thioglycolate stimulated mice using one-way ANOVA. *p<0.05, **p<0.001, ***p<0.0001, ****p<0.00001. Natural saline solution (NSS) served as the vehicle.Fig. 4 shows a human monomeric cellular adhesion assay. 2pig / mL of E- or P-Selectin was coated on 96 well plates.100 000 fluorescently tagged HL-60 with LeukoTracker™ were then incubated for 1 hr. Antagonists were added for 30 min at the indicated concentrations (mM) to dislodge adhered cells. Remaining cells were imaged using fluorescence microscopy. %lnhibition was calculated as 100% - %binding observed by fluorescence. Results are mean (±SEM) of three independent experiments normalized to respective external controls. Significance was determined in comparison with sLex. *p<0.05.Fig. 5 shows other selectin cell-based adhesion assays. 2 pig / mL of P-Selectin was coated on 96 well plates. Fluorescently tagged HL-60 with LeukoTracker were then incubated for 1 hr with P- selectins. Antagonists were added for 30 min at the indicated concentrations to dislodge bound cell. %inhibition was calculated as 100%- %bi nd ing observed by fluorescence. Results are mean (±SEM) of three independent experiments normalised to respective external controls. Significance was determined by Student’s t test. *p<0.05Fig. 6 shows the results of a surface plasmon resonance (SPR) direct binding assay of representative compounds according to the present disclosure (LCB-2259 and LCB-2322) to P- and E-selectin. Double referenced binding responses with P-selectin Fc (Pselfc, black) and E-selectin Fc (ESelfc, grey) are the mean of three independent injections (±SEM) normalized to the corrected response of the known selectin antagonist LCB-110.Fig. 7 shows the results of in vivo peritoneal inflammation cell migration assay 2 hours after the injection of thioglycolate (TGA). Significance was determined in comparison to TGA stimulated mice using one-way ANOVA. *p<0.05, **p<0.001, ***p<0.0001, ****p<0.00001. Natural saline solution (NSS) served as the vehicle.DETAILED DESCRIPTION OF THE INVENTION

[0007] Turning now to the invention in more details, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein:Ri and R2 independently represent -O-R20, or -NR21 R22, wherein R20 represents alkyl, and R21 and R22 independently represent H, alkyl, or aryl, or R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group,R3 represents H, -CH2-O-R23, or -CH2-NR24R25, wherein:R23 represents H, benzoyl (Bz), or aryl unsubstituted or substituted with one or more halogen atoms and / or alkyl substituted with one or more halogen atoms,R24 represents H, andR25 represents -C(=O)-R26, wherein R26 represents alkyl, or aryl, each of which being unsubstituted or substituted with one or more halogen atoms,R4 represents -O-R27, wherein R27 represents H, or benzoyl (Bz),Rs represents H, and Re representsthe tetrazolyl:N N, and Rn represents H, or benzyl (Bn), andR? represents H, with the proviso that when Re representsat least one of R1 and R2 (preferably both) represents -NR21R22, and / orRs represents -CH2-NR24R25, andwith the proviso that when R5 and Re together form cycle A and Rw represents -COOH, then: at least one of Ri and R2 (preferably both) represents -NR21R22, and / orR3 represents -CH2-NR24R25, and / orR11 represents benzyl (Bn).

[0008] Herein, benzoylHerein, benzyl (Bn) is

[0009] Herein, wavy lines used in illustrations of substituents represent the point of attachment to said substituents to the remainder of the compound of formula (I).

[0010] In preferred embodiments, R1 and R2 represent identical substituents.

[0011] In embodiments, R1 and R2 represent -O-R20, and preferably R20 represents isopropyl.

[0012] In alternative embodiments, R1 and R2 represent -NR21R22. Examples of preferred alkyls in R21 and R22 include methyl and propyl (preferably isopropyl). Examples of preferred aryls in R21 and R22 include phenyl. In preferred embodiments, R21 and R22 represent alkyl. In alternative embodiments, R21 and R22 represent aryl. In yet other embodiments, R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group. The skilled person will understand that the heterocycloalkyl group is a heterocycle by virtue of comprising at least said nitrogen atom to which R21 and R22 are both attached. In embodiments, the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group. In preferred embodiments, R21 and R22X N . I — together with the nitrogen atom to which they are attached form I —NI or \ ' —J1 , more preferably

[0013] In preferred embodiments, R21 and R22 represent identical substituents.

[0014] In alternative embodiments, R21 and R22 represent different substituents.

[0015] In embodiments, when one of R21 and R22 represents H, the other of R21 and R22 represents alkyl or aryl,

[0016] In embodiments, R3 represents H. In alternative embodiments, R3 represents -CH2-O-R23. In other alternative embodiments, R3 represents -CH2-NR24R25. In embodiments, R23 represents H. In alternative embodiments, R23 represents benzoyl (Bz). In other alternative embodiments, R23 represents aryl unsubstituted or substituted with one or more halogen atoms and / or alkyl substituted with one or more halogen atoms. In preferred embodiments, the one or more halogen atoms substituting the aryl are fluorine. In preferred embodiments, the one or more halogen atoms substituting the alkyl substituting the aryl are fluorine. In preferred embodiment the alkyl substituted with one or more halogen atoms is CF3.

[0017] Preferred alkyls in R26 include methyl unsubstituted or substituted with one or more halogen atoms,preferably methyl and trihalomethyl. Preferred aryl in R26 include phenyl unsubstituted or substituted with one or more halogen atoms, preferably phenyl and para-halophenyl. Preferred halogen atoms include fluoride.

[0018] In embodiments, R27 represents H. In alternative embodiments R27 represents benzoyl (Bz).

[0019] In embodiments, R5 represents H, and Re represents. In more preferred

[0020] In alternative embodiments, R5 and Re together form cycle A. In embodiments, Rw represents -COOH. In alternative embodiments, Rw represents the tetrazolyl:embodiments, Rn represents H. In alternative embodiments, Rn represents benzyl (Bn).

[0021] In embodiments, when Re represents, then at least one of R1 and R2(preferably both) represents -NR21R22.

[0022] In embodiments, when R5 and Re together form cycle A and Rw represents -COOH, then at least one of R1 and R2 (preferably both) represents -NR21R22.

[0023] In embodiments, when R5 and Re together form cycle A and Rw represents -COOH, then R3 represents - CH2-NR24R25.

[0024] In embodiments, when R5 and Re together form cycle A and Rw represents -COOH, then Rn represents benzyl (Bn).

[0025] In embodiments, R5 and Re together form cycle A and Rw represents the preferred such embodiments, Rn represents H. In preferred such embodiments, R1 substituents. In preferred such embodiments, R1 and R2 represent -O-R20, and moreisopropyl. In preferred such embodiments, Rs represents -CH2-O-R23, wherein R23 represents H, or benzoyl (Bz). Inpreferred such embodiments, R23 represents H. In alternative preferred such embodiments, R23 represents benzoyl (Bz). In preferred such embodiments, R27 represents H. Preferred compounds include compounds of formula (II):wherein Bz is benzoyl, iPr is isopropyl and Bz is benzoyl and R23 representsH, or benzoyl (Bz), as well as pharmaceutically acceptable salts thereof.

[0026] In embodiments, R5 represents H, Re represents , and R1 and R2 represent -NR21R22. In preferred such embodiments, R28 represents -COO H. In preferred such embodiments, R1 andR2 represent identical substituents. Examples of preferred alkyls in R21 and R22 include methyl. Examples of preferred aryls in R21 and R22 include phenyl. In preferred such embodiments, R21 and R22 represent alkyl. In preferred embodiments, R21 and R22 represent identical substituents. In other preferred such embodiments, R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group. In preferred such embodiments, the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group. In preferred such embodiments, R21 and R22 together with the nitrogen atom to which theyX are attached form I I — —NI or, more preferably. In preferred such embodiments R3 represents -CH2-O-R23. In preferred such embodiments, R23 represents H. In alternative preferred such embodiments, R23 represents benzoyl (Bz). In embodiments, R27 represents H. In alternative embodiments R27 represents benzoyl (Bz). Preferred compounds include compounds of formula (III)R22 g , 23 p , y , 27 p , y ,pharmaceutically acceptable salts thereof.identical substituents. In preferred such embodiments, Ri and R2 represent -O-R20, and preferably R20 represents isopropyl. In alternative preferred such embodiments, R1 and R2 represent -NR21R22. Examples of preferred alkyls in R21 and R22 include methyl. Examples of preferred aryls in R21 and R22 include phenyl. In preferred such embodiments, R21 and R22 represent alkyl. In alternative preferred such embodiments, R21 and R22 represent aryl. In yet other preferred such embodiments, R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group. The skilled person will understand that the heterocycloalkyl group is a heterocycle by virtue of comprising at least said nitrogen atom to which R21 and R22 are both attached. In preferred such embodiments, the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group. In preferred such embodiments, R21 and R22 together with the nitrogen atom to which they are attached formor, more preferably. In embodiments, R27 represents H. Preferred compounds include compounds of formula (V):(V), wherein R10 is -COOH or the tetrazolyl:benzoyl, R1 and R2 are as defined above, and R25 represents -C(=O)-R26, wherein R26 is as defined above, as well as pharmaceutically acceptable salts thereof.

[0029] In embodiments, R5 represents H, and Re representspreferred such embodiments, R1 and R2 represent identical substituents. In preferred such embodiments, R1 and R2 represent -0- R20, and preferably R20 represents isopropyl. In alternative preferred such embodiments, R1 and R2 represent - NR21R22. Examples of preferred alkyls in R21 and R22 include methyl. Examples of preferred aryls in R21 and R22 include phenyl. In preferred such embodiments, R21 and R22 represent alkyl. In alternative preferred such embodiments, R21 and R22 represent aryl. In yet other preferred such embodiments, R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group. In preferred such embodiments, the nitrogenatom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group. In preferred such embodiments, R21 and R22 together with the nitrogen atom to which they are attached form,X more preferably. In preferred such embodiments, R21 and R22 represent identical substituents. In preferred such embodiments, R3 represents -CH2-O-R23. In preferred such embodiments, R23 represents H. In alternative preferred such embodiments, R23 represents benzoyl (Bz). In preferred such embodiments, R27 represents H.Preferred compounds include compounds of formula (VI):(VI), wherein Bz is benzyl, Bz is benzoyl, R1 and R2 are as defined above, R23 represents H, or benzoyl (Bz), and R27 represents H, or benzoyl (Bz), as well as pharmaceutically acceptable salts thereof._

[0030] In embodiments, R5 and Re together form cycle A, Rw represents -COOH, or the tetrazolyl: N N R11 represents benzyl (Bn). In preferred such embodiments, Rw represents -COOH. In alternative preferred such embodiments, Rw represents the tetrazolyl:preferred such embodiments, R1 and R2 represent identical substituents. In preferred such embodiments, R1 and R2 represent -O-R20, and preferably R20 represents isopropyl. In alternative preferred such embodiments, R1 and R2 represent -NR21R22. Examples of preferred alkyls in R21 and R22 include methyl. Examples of preferred aryls in R21 and R22 include phenyl. In preferred such embodiments, R21 and R22 represent alkyl. In alternative preferred such embodiments, R21 and R22 represent aryl. In yet other preferred such embodiments, R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group. In preferred such embodiments, the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group. In preferred such embodiments, R21 and R22 together with thenitrogen atom to which they are attached form, more preferably. In preferred such embodiments, R21 and R22 represent identical substituents. In preferred such embodiments, R3 represents - CH2-O-R23. In preferred such embodiments, R23 represents H. In alternative preferred such embodiments, R23 represents benzoyl (Bz). In embodiments, R27 represents H. Preferred compounds include compounds of formula (VII):Rio(VII), wherein Bz is benzyl, Ph is phenyl, Ri and R2 are as defined above, R23 represents H, or benzoyl (Bz), and R10 is -COOH or the tetrazolyl:s well as pharmaceutically acceptable salts thereof.

[0031] Preferred compounds include:as well as pharmaceutically acceptable salts thereof.

[0032] The present invention relates to the compounds of the invention as hereinbefore defined as well as to salts thereof. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of the invention.

[0033] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention that are pharmacologically acceptable and substantially non-toxic to the subject to which they are administered. More specifically, these salts retain the biological effectiveness and properties of compounds of the invention and are formed from suitable non-toxic organic or inorganic acids or bases.

[0034] For example, these salts include acid addition salts of the compounds of the invention which are sufficiently basic to form such salts. Such acid addition salts include 2-hydroxyethanesulfonate, 2- naphthalenesulfonate, 3-phenylpropionate, aceglutamate, acephyllinate, acetamidobenzoate, acetate, acetylasparaginate, acetylaspartate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, arylsulfonates such as a benzenesulfonates, ascorbate, aspartate, benzoate, benzylate, besylate, bicarbonate, bisulphate, bitartrate, borate, bromide, butylbromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, chlorophemoxyacetate, cinnamate, citrate, closylate, cromesilate, cyclamate, cyclopentanepropionate, dehydrochloate, digluconate, dihydrochloride, dimalonate, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethylbromide, ethylsulfate, fendizoate, fluoride, formate, fosfatex, fumarate, gluceptate, glucoheptanoates, gluconate, glucoronate, glutamate, glycerophosphate, glycinate, glycollylarsinilate, glycyrrhizate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrobromide, hydrochloride, hydrogen sulphates, hydroiodide, hydroxybenzenesulfonate, hydroxybenzoate, iodide, isethionate, itaconates,lactate, lactobionate, lower alkanesulfonates such as a methanesulfonates, lysine, malate, maleate, mandalate, mandelate, mesylate, methylbromide, methyliodide, methylnitrate, methylsulphate, monophosadenine, mucate, napadisylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, oxoglurate, pamoate, pantothenate, pectinate, perchlorates, persulfates, phenylethylbarbiturate, phosphate, picrate, pivalate, policrilix, polistirex, polygalacturonate, propionate, pyridoxylphosphate, saccharinate, salicylate, stearate, stearylsulphate, subacetate, succinate, sulfate, sulfonate, sulfosalicylate, tannate, tartrate, teoclate, teprosilate, terephthalate, thiocyanate, timonaciate, toluenesulfonates (also known as tosylates), such as p-toluenesulfonate, triethiodide, trifluoromethanesulfonats, undecanoate, xinafoate salts and the like. Preferred acid addition salts include acetate, besylate, bisulphate, bromide, carbonate, chloride, citrate, fluoride, formate, iodide, maleate, mesylate, methylsulphate, nitrate, nitrite, pamoate, phosphate, stearate, sulfate, tartrate, and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0035] Also, where the compounds of the invention are sufficiently acidic, the salts of the invention include base salts formed with an inorganic or organic base. Such salts include alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; metal salts such as aluminium salts, manganese salts, iron (ferric, ferrous) salts, zinc salts, copper salts, nickel salts and a cobalt salts; and inorganic amine salts such as ammonium or substituted ammonium salts, such as e.g. trimethylammonium salts. These salts also include salts with pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of such salts include 2-diethylaminoethanol, 2-dimethylaminoethanol, arginine, betaine, caffeine, chloroprocaine, choline, dibenzylamine, dicyclohexylamine, diethanolamine, ethanolamine, ethylamine (including diethylamine and triethylamine), ethylenediamine, glucamine, glucosamine, guanidine, histidine, hydrabamine, isopropylamine, lysine, methylamine (including dimethylamine and trimethylamine), methylglucamine, morpholine, N,N'-dibenzylethylenediamine, N-benzyl-phenethylamine salts, N- ethyl-morpholine, N-ethylpiperidine, N-methylglucamine salts, phenylglycine alkyl ester salts, piperazine, piperidine, polyamine resins, procaine, purine, t-butyl amine, tetramethylammonium, theobromine, t-octylamine, triethylamine, trimethylamine, tripropylamine, tris-(2-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane, tromethamine, and the like.

[0036] Such salts can be formed quite readily by those skilled in the art using standard techniques. Indeed, the chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists, (See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457). Salts of the compounds of the invention may be formed, for example, byreacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0037] Salts in the solid form may exist in more than one crystal structure (polymorph), and may also be in the form of hydrates. All of those are envisioned herein.Use of the Compounds of the Invention

[0038] In another aspect, the present disclosure relates to the compound or pharmaceutical composition described herein, for use as a medicament.

[0039] In another aspect, present disclosure relates to the compound or pharmaceutical composition described herein, for use in the prevention or treatment of hyperinflammation, for example lung or respiratory hyperinflammation, in a subject. The present disclosure also relates to a method for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutical composition described herein. The present disclosure also relates to the use of the compound or pharmaceutical composition described herein, for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, in a subject. The present disclosure also relates to the use of the compound or pharmaceutical composition described herein for the manufacture of a medicament for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, in a subject.

[0040] The term “hyperinflammation” is used in the context of the present disclosure referring to severe and ongoing inflammatory processes in the body. For example, hyperinflammation can refer to severe and ongoing inflammatory processes in airway and / or lungs, kidney or liver. In this way, hyperinflammation can affect multiple organs in the body and their vasculature. In an example, the hyperinflammation is triggered by viral infection. In an example, hyperinflammation is associated with a cytokine storm or cytokine release syndrome (CRS). In an example, the cytokine storm or CRS involves significant release of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1) and / or interleukin-6 (IL-6).

[0041] In an embodiment, the hyperinflammation is caused by a virus. In a further embodiment, the virus is a rhinovirus, an influenza virus, a respiratory syncytial virus (RSV) or a coronavirus.

[0042] In another aspect, present disclosure relates to the compound or pharmaceutical composition described herein, for use in the prevention or treatment of SIRS, for example SIRS caused by sepsis, in a subject. The present disclosure also relates to a method for preventing or treating systemic inflammatory response syndrome (SIRS) comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutical composition described herein. The present disclosure also relates to the use of the compound or pharmaceutical composition described herein, for preventing or treating SIRS in a subject. The present disclosure also relates to the use of the compound or pharmaceutical composition described herein for the manufacture of a medicament for preventing or treating SIRS in a subject.

[0043] As used herein the terms "preventing", "prevent" or "prevention" include reducing the occurrence and / or severity of a disease or condition or one or more symptoms thereof in a subject (e.g., a subject at risk of suffering from SI RS / sepsis) relative to an untreated control subject, or delaying the onset of one or more symptoms of the disease or condition in a subject (e.g., a subject at risk of suffering from SIRS / sepsis) relative to the untreated control subject.

[0044] The term “systemic inflammatory response syndrome” or “SIRS” refers to a condition related to systemic inflammation in response to an insult such as an infection, a trauma, burns, pancreatitis, or a variety of other injuries, and that results in multiple organ dysfunctions; acute lung injury (ALI) represents the most common and earliest organ failure. SIRS may occur as a consequence of various pathogenic events, with sepsis syndrome being the most prevalent and lethal cause. SIRS is identified by two or more symptoms including fever or hypothermia, tachycardia, tachypnoea and change in blood leucocyte count.

[0045] In an embodiment, the SIRS is associated or caused by sepsis. The term "sepsis" is applied to a number of diseases, conditions and / or syndromes which may have an infectious (for example viral, bacterial and / or fungal) etiology. It encompasses sepsis (which is often defined as "SIRS in response to an infectious process"), severe sepsis (that is sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (which itself might manifest as hypotension, elevated lactate or decreased urine output) and septic shock (severe sepsis plus persistently low blood pressure despite, for example, the administration of intravenous fluids).

[0046] The term "sepsis" is most often applied to diseases, conditions and / or syndromes which result from "bacterial sepsis". Bacterial sepsis may stem from the presence of bacteria in blood and may sometimes be referred to as "bacteremia" or "septicemia". The term "sepsis" may also embrace diseases and / or conditions which are caused or contributed to by the presence of bacterial components such as LPS, toxins and / or membrane fragments in the blood. Components of this type may originate from primary infections present in other tissues and / or organs, for example, infections present in the lungs, brain, skin, urinary tract, pelvis and / or abdomen. Sepsis can be a very severe condition which occasionally leads to multiple organ failure and death. There may be a number of pathologies and / or symptoms associated with each type of sepsis and these will be collectively referred to hereinafter as "sepsis associated pathologies". For example, sepsis associated pathologies may include, for example, fever, increased heart rate, increased rate of respiration and / or low blood pressure. The primary mechanism which underpins the pathology of sepsis and many of the symptoms and outcomes associated therewith is an exacerbated, exaggerated and / or inappropriate host immune response. This exacerbated immune response (which is the body's response to infection) leads to host tissue damage and / or organ damage / failure. The exacerbated or inappropriate immune response may include the dysregulation of innate immune responses as well as the production and / or over production of certain pro-coagulation cytokines (including, for example, TNF, IL-1 and / or IL-6).

[0047] In an embodiment, the SIRS is caused by a viral infection, for example an infection by an influenza virus or a severe acute respiratory syndrome (SARS) virus such as SARS-CoV-2.Definitions

[0048] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0049] The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. In contrast, the phrase “consisting of” excludes any unspecified element, step, ingredient, or the like. The phrase “consisting essentially of” limits the scope to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the invention.

[0050] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein.

[0051] Similarly, herein a general chemical structure, such as Formula I to VII, with various substituents (Ri, R2, etc.) and various radicals (alkyl, halogen atom, etc.) enumerated for these substituents is intended to serve as a shorthand method of referring individually to each and every molecule obtained by the combination of any of the radicals for any of the substituents. Each individual molecule is incorporated into the specification as if it were individually recited herein. Further, all subsets of molecules within the general chemical structures are also incorporated into the specification as if they were individually recited herein.

[0052] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0053] The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0054] No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0055] Herein, the term "about' has its ordinary meaning. In embodiments, it may mean plus or minus 10% or plus or minus 5% of the numerical value qualified.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0057] Herein, the terms " alkyl', “alkylene", "alkenyl', " alkenylene'' , "alkynyf, "alkynylene" and their derivatives (such as alkoxy, alkyleneoxy, etc.) have their ordinary meaning in the art. For more certainty, herein:

[0058] It is to be noted that, unless otherwise specified, the hydrocarbon chains of the above groups can be linear or branched. Further, unless otherwise specified, these groups can contain between 1 and 18 carbon atoms, more specifically between 1 and 12 carbon atoms, between 1 and 6 carbon atoms, between 1 and 3 carbon atoms, or contain 1 or 2, preferably 1 , or preferably 2 carbon atoms.

[0059] Herein, the terms "cycloalkyl ", "aryl", "heterocycloalkyl" , "heteroaryl", and "methylene" have their ordinary meaning in the art. For more certainty, herein:

[0060] It is to be noted that, unless otherwise specified, each ring of the above groups can comprise between 4 and 8, preferably 5 or 6 ring atoms.

[0061] Also, each of the above compound may comprise more than one ring.

[0062] Herein, at “heteroatom” is an atom other than a carbon atom or a hydrogen atom. Preferably, the heteroatom is oxygen or nitrogen.

[0063] Herein, a “ring atom”, such as a ring carbon atom or a ring heteroatom, refers to an atom that forms (with other ring atoms) a ring of a cyclic compound, such as a cycloalkyl, an aryl, etc.

[0064] Herein, halogen atoms are the atoms of group 17, preferably F, Cl, Br, and I.

[0065] Herein, a "group substituted with one or more A, B, and / or C" means that one or more hydrogen atoms of the group are replaced with substituents selected from A, B, and C. Of note, these substituents do not need to be identical: for example, one hydrogen atom may be replaced by A, while another may be replaced by B.

[0066] Herein, a "group interrupted with one or more A, B, and / or C" means that one or more A, B, and / or C groups are inserted between pairs adjacent carbon atoms of the group (for example, a butylene group (-CH2-CH2- CH2-CH2-) interrupted by -O- may be -CH2-CH2-O-CH2-CH2- . Preferably, only one of A, B or C is inserted between any given pair of adjacent carbon atoms. However, when more than one pair of adjacent carbon atoms are thus interrupted, the A, B, and C groups do not need to be identical: for example, one hydrogen atom may be replaced by A, while another may be replaced by B (for example a butylene group (-CH2-CH2-CH2-CH2-) interrupted by -O- and - NR- may be -CH2-NR-CH2-O-CH2-CH2-.

[0067] Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0068] The present invention is illustrated in further details by the following non-limiting examples.Comparative Example 1

[0069] Tetrasaccharide sLexattached to ESL-1 and PSGL-1 proteins, which are constitutively present on the surface of leukocytes, binds in a calcium-dependent manner to the carbohydrate recognition domain (CRD) of selectins (a, Figure 2a).23 24

[0070] In the majority of the investigated sLexmimetics, the GIcNAc moiety is replaced by a substituted cyclohexyl ring, as in Rivipansel (b Figure 2a). Most of the selectin antagonists reported thus far target E-selectin or are coupled to other pharmaceutical effectors (e.g. GMI-1359, a CXR4 antagonist) for the treatment of certain cancers.9’25'30

[0071] sLexglycomimetics that have both P- and E-selectin antagonist activity (c Figure 2a), in which the GIcNAcwas replaced with an acyclic tether, were also reported.31 32

[0072] Further, the C9-axial and C9-equatorial compounds LCB-2248 and LCB-2267 were prepared.33The axial isomer LCB-2248 was active in interfering with neutrophil interactions and adhesion to umbilical endothelial cells activated by histamine (P-selectin dependent).33Comparative Example 2

[0073] In previously reported studies using the peritonitis model,3435mice received a first intraperitoneal (IP) injection of a 3% thioglycolate (TG) solution to trigger the acute inflammatory response. After ten minutes, sLex, analogues of sLex, or vehicle were administered by intravenous (IV) injection. Two hours later, the mice were sacrificed, and the peritoneal cavity was lavaged. A block of one million cells was then stained with antibodies for subsequent flow cytometric analysis. The number of neutrophils, macrophages / monocytes, CD11 b+ and total PSGL- 1 positive cells were measured.

[0074] Using this assay, the activity of selected compounds was tested, and the results are reported in Figs. 1 A- 1B. These results shows that compound 2294 is particularly potent at inhibiting the recruitment of PSGL-1 positive cells.

[0075] The following comparative compounds were tested in a cell-based assay and by surface plasmon resonance.Entry Cpd R3R2R4R6E-SelxbP-SelxbP-SelxbStatic Static dynamic1 1 slex 1.0 1.0 1.0 1.0 1.0 1.0(comparative)2 15 H Bz H H 0.58 5.6 0.47 7.2 0.72 9.0(comparative)3 16 El Bz Bz El ND ND ND ND ND ND(comparative)4 17 H Bz Bz Bz 0.253 14.0 0.174 17.8 0.033 25.4(comparative)5 18 Bn Bz H H 0.22 16.1 0.19 17.6 0.53 19.0(comparative)6 19 Bn Bz Bz H 0.076 45.8 0.067 52.5 0.018 54.5(comparative)7 20 Bn Bz Bz Bz 0.072 46.8 0.065 53.9 0.013 74.5(comparative)aICso relative = IC50 sLex / ICso compound,bX =1 / IC50 relative = IC50 compound / IC50 sLex; means X time more active than the sLexStatic in cell based assay, dynamic using SPR assay (Biacore).Example 1 : Synthesis of E- and P-selectin antagonists

[0076] Compounds of the invention LCB-2242, 2294, 2318, 2322, and 2259 have been synthesized:

[0077] Comparative compounds considered include the ones discussed above as well as the following:Class A: First Generation analogues Class B: Sidechain modificationsClass D: Bicyclic pyranosides5.12 (LCB-2251 ) R-, = H5.63 (LCB-2298) R., = CH2OBzSynthesis of 14 (LCB-2242)Compound LCB-2242:Scheme S1. Synthetic procedures for compounds with bicyclic galactoside from tri-O-acetyl Glucal as for example the preparation of 14 (LCB-2242).

[0078] A solution of 1 (1 .37 g, 5.73 mmol, 1 .00 equiv), which is obtained from tri-O-acetyl Glucal using reported conditions36, in ethanol (190 mL, 0.030 M) was placed under a nitrogen atmosphere. Palladium on carbon (305 mg, 0.286 mmol, 0.05 equiv, 10 wt. %) was added, the reaction mixture was degassed and flushed with a hydrogen filled balloon. After stirring at room temperature under a hydrogen atmosphere for 2 h, the reaction mixture was degassedand flushed with nitrogen gas. The reaction mixture was filtered through a pad of silica gel using methanol as the eluent and concentrated in vacuo to provide 2 (0.84 g, 61 %) as a white solid: [O]D25+58 (C 1.0, DCM); CnH^NCe;MW = 241.2430 gmol1; IR (neat, cm1) vmax2961 , 2878, 1742, 1242;1H NMR (500 MHz, CDCI3) 5 4.85 (d, J = 5.1 Hz, 1 H), 4.70 (apptd, J = 10.5, 4.7 Hz, 1 H), 4.28 (dd, J = 12.4, 5.0 Hz, 1 H), 4.15 (dd, J = 12.3, 1.9 Hz, 1 H), 3.98 - 3.88 (m, 1 H), 2.32 - 2.22 (m, 1 H), 2.13 - 2.05 (m, 1 H), 2.08 (s, 3H), 2.06 (d, J = 1.0 Hz, 3H), 1.99 (appdt, J = 14.4, 3.5 Hz, 1 H), 1.90 - 1.78 (m, 1 H) ppm;13C NMR (126 MHz, CDCI3) 5 170.7, 169.8, 116.7, 74.4, 66.4, 64.2, 62.3, 27.7, 25.5, 21.0, 20.8 ppm; HRMS (ESI) calcd for CnHi5NO6Na [M+Na+]: 264.0848, found 264.0837 (-2.0 ppm).

[0079] A solution of 2 (1.28 g, 5.34 mmol, 1.00 equiv) in MeOH (35 mL, 0.10 M) at 0 °C was treated with a solution of sodium methoxide (0.079 mL, 0.35 mmol, 0.1 equiv, 4.4 M solution in MeOH). The mixture was stirred at 0 °C for 1 hour and then neutralized (pH = 7.0) using amberlite (IR-120) resin. The reaction mixture was then evaporated under reduced pressure and co-evaporated twice with toluene (20 mL x 2). The crude diol obtained was dissolved in pyridine (10.7 mL). DIEA (1.12 mL, 6.41 mmol, 1.2 equiv), TrCI (1.65 g, 5.88 mmol, 1.10 equiv) and DMAP (0.0326 g, 0,279 mmol, 0.0500 equiv) were then sequentially added. The reaction mixture was heated to 40 °C for 16 hours, then cooled to 25 °C before being passed over a pad of silica gel using EtOAc:Hex as the eluant. Purification by flash chromatography (Hexanes / EtOAc) provided 3 (1 .65 g, 77% over two steps) as a yellowish thick gum: [a]D25+3.4 (c 1.0, DCM); C26H25NO3; MW = 399.4900 gmoH;1H NMR (500 MHz, CDCI3) 5 7.48 - 7.38 (m, 5H), 7.37 - 7.29 (m, 5H), 7.27 (d, J = 6.8 Hz, 5H), 4.80 - 4.76 (m, 1 H), 3.67 (ddd, J = 9.4, 5.3, 4.3 Hz, 1 H), 3.64 - 3.58 (m, 1 H), 3.45 (dd, J = 10.0, 4.0 Hz, 1 H), 3.32 (dd, J = 9.9, 5.5 Hz, 1 H), 2.61 (d, J = 3.0 Hz, 1 H), 2.15 - 2.07 (m, 1 H), 2.01 - 1.92 (m, 2H), 1.84 - 1.72 (m, 1 H) ppm;13C NMR (126 MHz, CDCI3) 5 143.4, 128.7, 128.2, 127.5, 117.2, 87.6, 76.8, 68.0, 64.8, 64.1 , 28.01 , 28.00 ppm; HRMS (ESI) calcd for C26H25NO3Na [M+Na+]: 422.1732, found 422.1725 (- 0.29 ppm).

[0080] To a solution of alcohol 3 (19.4 g, 48.6 mmol, 1.00 equiv) in DCM (490 mL, 0.10 M) at O °C, acetic anhydride (13.8 mL, 146 mmol, 3.00 equiv) and pyridinum dichromate (22.0 g, 58.4 mmol, 1.20 equiv) were added. The solution was stirred at 0 °C for 16 hours. The reaction mixture was then poured on a pad of silica gel (elution with DCM 100%) to provide 4 (18 g, 93%) as a colorless thick gum: [O]D25+37 (c 1 .0, DCM); C26H23NO3; MW = 397.4740 gmol-1; IR (neat, cm1) vmax3059, 2938, 1732, 1490, 1449;1H NMR (500 MHz, CDCI3) 5 7.44 - 7.38 (m, 6H), 7.34 - 7.29 (m, 6H), 7.28 - 7.23 (m, 3H), 5.09 (appt, J = 5.3 Hz, 1 H), 4.34 (dd, J = 4.9, 2.8 Hz, 1 H), 3.57 - 3.46 (m, 2H), 2.72 (appt, J = 6.9 Hz, 2H), 2.62 - 2.52 (m, 1 H), 2.38 - 2.28 (m, 1 H) ppm;13C NMR (126 MHz, CDCI3) 5204.1 , 143.6, 128.8, 128.0, 127.3, 117.1, 87.2, 80.2, 63.3, 62.4, 35.2, 28.0 ppm; HRMS (ESI) calcd for C26H23O3NNa [M+Na-]: 420.1576, found 420.1570 (-0.04 ppm).

[0081] To a solution of ketone 4 (188 mg, 0.473 mmol, 1.00 equiv) placed under an N2atmosphere in THF (4.7 mL, 0.10 M) at - 78 °C, vinylmagnesium chloride (1.2 mL, 1.2 mmol, 2.5 equiv, 1.0 M solution in THF) was added dropwise. After stirring for 4 hours at - 78 °C, a saturated solution of NaHCO3(5 mL) was added to the reaction mixture, which was then warmed to room temperature. The aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo.1H NMR spectroscopic analysis of the unpurified product indicated the formation of a 15:1 ratio of C4 diastereomers 5a:5b. Purification by flash chromatography (Hexanes / EtOAc) provided 5a (130 mg, 64%) as a white foam with trace amounts of 5b: [O]D25+ 30 (c 0.8, DCM); C23H27NO3; MW = 425.5280 gmoh1; IR (neat, cm-1) vmax 3489, 3087, 3060, 2943, 2885, 1491 , 1449, 1095;1H NMR (500 MHz, CDCI3) 5 7.49 - 7.43 (m, 6H), 7.36 - 7.30 (m, 6H), 7.29 - 7.25 (m, 3H), 5.62 (dd, J = 16.9, 10.8 Hz, 1 H), 5.36 (d, J = 17.0 Hz, 1 H), 5.11 (d, J = 5.5 Hz, 1 H), 5.01 (d, J = 10.5 Hz, 1 H), 4.35 (bs, 1 H), 3.70 (bs, 1 H), 3.62 - 3.55 (m, 1 H), 3.25 - 3.18 (m, 1 H), 2.70 - 2.58 (m, 1 H), 1.93 - 1.84 (m, 1 H), 1.80 - 1.68 (m, 2H) ppm;13C NMR (126 MHz, CDCI3) 5 143.2, 140.7, 128.6, 128.1 , 127.4, 117.7, 115.1 , 87.9, 76.5, 72.2, 65.3, 64.4, 32.0, 24.1 ppm; HRMS (ESI) calcd for C28H27O3NNa [M+Na-]: 448.1889, found 448.1882 (- 0.3 PPm).

[0082] A flow of O3was bubbled through a DCM (62 mL, 0.15 M) solution of 5a (1.8 g, 4.1 mmol, 1.0 equiv) at - 78 °C until TLC monitoring indicated complete consumption (30 minutes). N2gas was then bubbled through the solution to remove excess ozone. Methanol (12 mL) was added to the mixture, followed by NaBH4(98 pL, 0.25 mmol, 2.5 equiv). The mixture was warmed to 0 °C and stirred for 2 hours, after which a saturated solution of NH4CI solution (60 mL) was added. The aqueous layer was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc) provided 6 (0.90 g, 51 %) as a colorless gum: [O]D25+ 31 (c 1.3, DCM); C27H27NO4; MW = 429.5160 gmoH; IR (neat, cm1) Vmax 3472, 3060, 2942, 2250, 1491 , 1449;1H NMR (500 MHz, CDCI3) 5 7.46 - 7.40 (m, 6H), 7.37 - 7.32 (m, J = 7.7 Hz, 6H), 7.30 - 7.25 (m, 3H), 4.99 (d, J = 5.4 Hz, 1 H), 4.00 (d, J = 1.2 Hz, 1 H), 3.77 (dd, J = 4.3, 2.7 Hz, 1 H), 3.57 (dd, J = 10.7, 4.5 Hz, 1 H), 3.42 (dd, J = 11.5, 4.8 Hz, 1 H), 3.33 (dd, J = 10.7, 2.6 Hz, 1 H), 3.21 (dd, J = 11.5, 8.3 Hz, 1 H), 2.56 - 2.44 (m, 1 H), 2.34 (dd, J = 8.3, 4.9 Hz, 1 H), 1.83 - 1.69 (m, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 142.9, 128.4, 128.2, 127.5, 117.4, 88.2, 75.8, 70.4, 67.5, 64.9, 64.0, 28.4, 24.0 ppm; HRMS (ESI) calcd forC27H27NO4Na [M+Na-]: 452.1838, found 452.1832 (-0.09 ppm).

[0083] To a solution of diol 6 (1.89 g, 4.40 mmol, 1.00 equiv) in DCM (44 mL, 0.10 M) at 0 °C, trifluoroacetic acid (1.8 mL, 24.2 mmol, 5.5 equiv), and water (0.79 mL, 44 mmol, 10 equiv.) were added. After warming the mixture to room temperature and stirring for 2 hours, NH4OH was added dropwise to neutralize the solution (pH=7.0). The mixture was concentrated in vacuo and fractionated coarsely through a pad of silica gel using MeOH:DCM (15:85) as the eluent. The volatiles were evaporated under reduce pressure and two coevaporations of the residue obtained were performed with toluene. The residue was then partly dissolved in DCM (37 mL) under an N2 atmosphere at -78 °C before the addition of 2,6-lutidine (1.95 mL, 16.8 mmol, 3.75 equiv) and TESOTf (3.17 mL, 14.0 mmol, 3.75 equiv). The mixture was allowed to warm slowly to -20 °C and stirred for 4 hours. At which point, the mixture was diluted with Et20 (40 mL) and a saturated solution of N H4CI (40 mL). The organic layer was washed with a saturated aqueous NaHCOs (50 mL), dried over MgSCU, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc) provided 7 (1.9 g g, 94%) as a yellowish oil: [O]D25+ 8.5 (C 1.7, DCM);C26H55NO4Si3; MW = 529.3439 gmoH; IR (neat, cm-1) vmax2957, 2077, 1459, 1239;1H NMR (500 MHz, CDCI3) 5 4.84 (d, J = 5.2 Hz, 1 H), 3.86 (dd, J = 11.1 , 4.2 Hz, 1 H), 3.79 (dd, J = 6.3, 4.3 Hz, 1 H), 3.61 (dd, J = 11.1, 6.5 Hz, 1 H), 3.58 (d, J = 10.2 Hz, 1 H), 3.53 (d, J = 10.2 Hz, 1 H), 2.23 (apptdd, J = 13.6, 5.3, 4.1 Hz, 1 H), 1.95 (apptd, J = 14.0, 4.1 Hz, 1 H), 1.84 - 1.79 (m, 1 H), 1.72 - 1.65 (m, 1 H), 1.02 - 0.91 (m, 27H), 0.67 - 0.54 (m, 18H) ppm;13C NMR (126 MHz, CDCI3) 5 117.8, 79.1 , 73.7, 67.8, 64.2, 62.2, 28.7, 24.5, 7.2, 6.92, 6.89, 6.8, 4.6, 4.5 ppm; HRMS (ESI) calcd for C2oH4i04NNaSi2 [M+Na+]: 438.2472, found 438.2479 (+ 1 .6 ppm) (loss of one TES- group under the chemical ionization conditions employed formass analysis).

[0084] To a cooled (-78 °C) solution of oxalyl chloride (1.05 mL, 12.2 mmol, 4.00 equiv) in DCM (15 mL) under a nitrogen atmosphere was added DMSO (1 .74 mL, 24.5 mmol, 8.00 equiv). After stirring for 10 minutes, a solution of 7 (1.63 g, 3.06 mmol, 1.00 equiv) in DCM (15.3 mL) was added dropwise. The mixture was warmed to -50 °C and stirred for 3 hours before the addition of Et3N (4.26 mL, 30.6 mmol, 10.0 equiv). The reaction mixture was then stirred for an additional 45 minutes, followed by the addition of saturated aqueous NH4CI (30 mL) and Et20 (50 mL). The organic layer was washed with a saturated aqueous NaHCOs (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford an aldehyde. The unpurified aldehyde was diluted in 30.5 mL of THF and the resulting solution was cooled to -78 °C under a nitrogen atmosphere. At which point, vinyl magnesium bromide (6.09 mL, 6.09 mmol, 2.00 equiv) was added to the mixture dropwise. After stirring for 5 minutes, saturated aqueous NaHCOs (30 mL) and Et20 (50 mL) were added. The organic layer was dried over MgSO4, filtered, and concentratedin vacuo. Purification by flash chromatography (Hexanes / EtOAc) provided 8 (1.12 g, 87%) as a colorless oil: [O]D25- 4.9 (c 0.57, DCM); C22H43NO4Si2; MW = 441.7590 gmoH; IR (neat, cm-1) vmax3504, 2966, 2877, 1458, 1380;1H NMR (500 MHz, CDCI3) 5 5.90 (ddd, J = 17.1 , 10.5, 5.5 Hz, 1 H), 5.38 - 5.31 (m, 1 H), 5.21 (appdt, J = 10.5, 1.5 Hz, 1 H), 4.94 (d, J = 5.3 Hz, 1 H), 4.55 (dd, J = 5.5, 1.4 Hz, 1 H), 3.98 (s, 1 H), 3.84 (d, J = 1 .2 Hz, 1 H), 3.77 (appt, J = 7.7 Hz, 1 H), 3.59 (d, J = 9.8 Hz, 1 H), 2.36 - 2.25 (m, 1 H), 2.22 - 2.12 (m, 1 H), 1 .80 - 1 .69 (m, 2H), 0.99 (appt, J = 7.9 Hz, 12H), 0.70 - 0.60 (m, 18H) ppm;13C NMR (126 MHz, CDCI3) 5 137.6, 117.2, 116.1, 77.1 , 76.6, 71.1 , 67.8, 64.8, 28.9, 24.3, 7.1 , 6.8, 6.7, 4.37 ppm; HRMS (ESI) calcd for C22H43NO4Si2Na [M+Na+]: 464.2628, found 464.2622 (- 0.18 PPm).

[0085] To a solution of 8 (100 mg, 0.226 mmol, 1.00 equiv) placed under an N2 atmosphere in DCM (1.1 mL, 0.20 M) at room temperature, DMAP (5.5 mg, 0.045 mmol, 0.20 equiv), benzoyl chloride (0.0460 ml, 0.396 mmol, 1.75 equiv) and triethylamine (0.316 mL, 2.26 mmol, 10.0 equiv) were added. After stirring 16 hours at 25 °C, one drop of water was added to the reaction mixture, which was then stirred for an additional 10 minutes. The mixture was concentrated in vacuo and purification by flash chromatography (Hexanes / EtOAc) provided 9 (104 mg, 84%) as a colorless gum: [O]D25-26 (C 1.8, DCM); C29H47NO5Si2; MW = 545.8670 gmoH; IR (neat, cm-1) vmax 2955, 2876, 1721, 1271 ;1H NMR (500 MHz, CDCI3) 5 8.11 - 8.06 (m, 2H), 7.58 - 7.53 (m, 1 H), 7.46 - 7.41 (m, 2H), 6.03 (ddd, J =17.1 , 10.5, 6.5 Hz, 1 H), 5.92 - 5.88 (m, 1 H), 5.40 (appdt, J = 17.2, 1 .2 Hz, 1 H), 5.26 (appdt, J = 10.4, 1 .1 Hz, 1 H), 4.96 - 4.88 (m, 1 H), 4.11 (d, J = 4.2 Hz, 1 H), 3.83 (d, J = 9.8 Hz, 1 H), 3.49 (d, J = 9.8 Hz, 1 H), 2.37 - 2.26 (m, 1 H), 2.22 - 2.13 (m, 1 H), 1.78 - 1.68 (m, 2H), 1.00 (t, J = 8.0 Hz, 9H), 0.86 (t, J = 7.9 Hz, 9H), 0.64 (q, J = 7.8 Hz, 6H), 0.50 - 0.40 (m, 6H) ppm;13C NMR (126 MHz, CDCI3) 5 165.5, 134.5, 133.1, 130.6, 130.0, 128.4, 118.4, 117.6, 77.8,74.1 , 72.7, 68.1, 64.7, 29.7, 24.7, 7.2, 6.9, 6.8, 4.5 ppm; HRMS (ESI) calcd for C29H47NO5Si2Na [M+Na+]: 568.2890, found 568.2869 (-2.8 ppm).

[0086] A flow of O3 was bubbled through a DCM (62 mL, 0.15 M) solution of 9 (0.104 g, 0.191 mmol, 1.00 equiv) at - 78 °C until TLC monitoring indicated complete consumption (30 minutes). N2gas was then bubbled through the solution to remove excess ozone and Et3N (0.0791 mL, 0.572 mmol, 3.00 equiv) was added. The reaction mixture was warmed slowly to room temperature and concentrated in vacuo. The residue was then passed through a pad of silica gel with EtOAc:Hex (20:80) as the eluant. After in vacuo evaporation of the volatiles, the residue was dissolved in 1.04 mL of DCM:MeOH (4:1) and the resulting solution was cooled to 0 °C, before the addition of pTsOH (1.8 mg, 0.095 mmol, 0.050 equiv). The mixture was maintained at O °C for 16 hours and then neutralized (pH 7) with EtsN.The mixture was concentrated in vacuo and purification by flash chromatography (Hexanes / EtOAc) provided 10a:1 Ob (71 mg, 86%) as a 4:1 mixture of anomers: C22H3iNOeSi; MW = 433.5760 gmoH;1H NMR (500 MHz, CDCI3) 5 8.11 - 8.02 (m, 4H, 10a and 10b), 7.60 - 7.53 (m, 2H, 10a and 10b), 7.48 - 7.39 (m, 4H, 10a and 10b), 5.58 (d, J = 3.7 Hz, 1 H, 10a), 5.36 (dd, J = 10.2, 3.7 Hz, 1 H, 10a), 5.25 (dd, J = 9.5, 7.5 Hz, 1 H, 10b), 4.95 - 4.89 (m, 2H, 10a and 10b), 4.75 (d, J = 6.9 Hz, 1 H, 10b), 4.24 (d, J = 10.2 Hz, 1 H, 10a), 3.93 (d, J = 12.4 Hz, 1 H, 10a), 3.80 (d, J = 6.8 Hz, 1 H, 10b), 3.78 (d, J = 3.9 Hz, 1 H, 10b), 3.47 (d, J = 12.4 Hz, 1 H, 10a), 3.42 (d, J = 12.8 Hz, 1 H, 10b), 2.73 (bs, 2H, 10a and 10b), 2.52 - 2.42 (m, 2H, 10a and 10b), 1 .85 - 1.63 (m, 6H, 10a and 10b), 1.07 - 0.96 (m, 18H, 10a and 10b), 0.78 - 0.63 (m, 12H, 10a and 10b) ppm;13C NMR (126 MHz, CDCI3) 5 167.5 (10b), 166.29 (10a), 133.6 (10b), 133.4 (10a), 130.1 (10b), 130.0 (10a), 129.8 (10a), 129.5 (10b), 128.59 (10b), 128.57 (10a), 117.6 (10a), 117.4 (10b), 97.3 (10b) , 91.7 (10a), 77.5 (10b), 74.0 (10a), 72.8 (10b), 71.4 (10a), 70.5 (10b), 70.0 (10b), 69.9 (10a), 65.7 (10a), 64.58 (10a), 64.55 (10b), 28.0 (10a), 27.9 (10b), 24.0 (10a), 23.8 (10b), 7.24 (10b), 7.22 (10a), 6.63 (10b), 6.59 (10a) ppm; HRMS (ESI) calcd for C22H3iNO6SiNa [M+Na+]: 456.1818, found 456.1820 (+1.6 ppm).

[0087] To a solution of 10a, b (0.681 g, 1.57 mmol, 1.00 equiv) in DCM (9.4 mL, 0.17 M) under an N2atmosphere at O °C was added trichloroacetonitrile (0.945 mL, 9.42 mmol, 6.00 equiv) and DBU (0.094 ml, 0.63 mmol, 0.40 equiv). After stirring 1 hour at 0 °C, the reaction mixture was concentrated in vacuo and passed over a pad of silica gel using EtOAc:Hex (30:70) as eluant. The resulting trichoroacetimidate intermediates was then dissolved in DCM (9.1 mL, 0.10M) under an N2atmosphere at -40 °C. Ethanethiol (0.226 mL, 3.14, mmol, 2.00 equiv) and TMSOTf (0.029 mL, 0.16 mmol, 0.1 equiv) were then added to the mixture. After maintaining the reaction mixture for 2 hours at -40 °C, pyridine (0.17 mL, 1.9 mmol, 1.2 equiv) and silica gel (1 g) were sequentially added. The mixture was concentrated in vacuo, poured over a pad silica gel and eluted with EtOAc:Hex (30:70). The thioether mixture obtained was then dissolved in THF (2.81 mL, 0.50 M) and the resulting solution was cooled to 0 °C, before the addition of TBAF (1.68 mL, 1.69 mmol, 1.0M solution, 1.2 equiv). After stirring 10 minutes, silica (1g) was added, and the mixture was evaporated under reduced pressure. Purification by flash chromatography (Hexanes / EtOAc) provided 11 a:11 b (0.49 g, 86% over three steps) as an 8:1 mixture of anomers: C18H21NO5S; MW = 363.4280 grnol1;1H NMR (500 MHz, CDCI3) 5 8.08 - 8.02 (m, 4H, 11a and 11 b), 7.62 - 7.54 (m, 2H, 11a and 11b), 7.50 - 7.39 (m, 4H, 11a and 11 b), 5.80 (d, J = 5.9 Hz, 1 H, 11 b), 5.47 (dd, J = 10.2, 5.9 Hz, 1 H, 11 b), 5.40 (t, J = 9.7 Hz, 1 H, 11a), 4.95 (d, J = 6.0 Hz, 1 H, 11b), 4.93 (d, J = 5.6 Hz, 1 H, 11a), 4.61 (d, J = 9.9 Hz, 1 H, 11a), 4.16 (d, J = 10.2 Hz, 1 H, 11 b), 3.94 (d, J = 9.5 Hz, 1 H, 11a), 3.81 (d, J = 12.2 Hz, 1 H, 11a), 3.53 (d, J = 12.2 Hz, 1 H, 11a), 3.44 (d, J = 12.1 Hz, 1 H, 11b), 2.82 - 2.65 (m, 6H, 11a and 11b), 2.60 - 2.44 (m, 2H, 11a and 11 b), 1.88 - 1.70 (m, 6H, 11a and 11 b), 1.28 - 1.21 (m, 6H, 11a and 11b) ppm, One labile proton missing due to exchange,'13C NMR (126 MHz, CDCI3) 5 165.9 (11 b), 165.6 (11a), 133.5 (11b), 133.4 (11a), 130.2 (11 b), 130.0 (11a), 129.7(11 b), 128.60 (11 b), 128.56 (11b), 117.07 (11 b), 117.03 (11a), 85.1 (11a), 83.4 (11b), 78.4 (11a), 74.5 (11 b), 73.90 (11a), 69.0 (11b), 68.5 (11a),67.9 (11a), 65.7 (11b), 64.8 (11a), 64.7(11b), 27.1 (11b), 27.0 (11a), 24.5 (11a), 24.4 (11b), 23.8 (11b), 23.7 (11a), 15.0 (11a), 14.7 (11b) ppm; HRMS (ESI) calcd for Ci8H2iNO5SNa [M+Na-]: 386.1038, found 386.1043 (+2.8ppm).(Acceptor)

[0088] A solution of 11a, b (0.209 g, 0.575 mmol, 1.00 equiv), fucoside tartrate acceptor (0.561 g, 0.863 mmol, 1 .50 equiv) and 3 A oven dried molecular sieves (209 mg) in DCM (5.7 mL, 0.10 M) was stirred at 25 °C for one hour under an N2 atmosphere31. The mixture was then cooled to -30 °C, before the sequential addition of N- iodosuccinimide (0.388 g, 1.73 mmol, 3.00 equiv) and TMSOTf (0.021 ml, 0.12 mmol, 0.20 equiv). After 3 hours, Et3N (2 drops) was added, followed by saturated aqueous NaHCO3(10 mL) and saturated aqueous Na2S2C>3 (5 mL). The aqueous layer was extracted EtOAc (3 X 20 mL), the combined organic layers were dried over MgSCU, filtered, and concentrated in vacuo.1H NMR analysis of the crude mixture indicated the diastereoselective formation of the 0- anomer. Purification by flash chromatography (Hexanes / EtOAc) provided 12 as a white foam (0.38 g, 70%): [O]D25-26 (c 1 .9, DCM); C53H61NO15; MW = 952.0630 gmot1; IR (neat, cm-1) vmax 3477, 2981, 1732, 1268, 1103;1H NMR (500 MHz, CDCI3) 5 8.02 (d, J = 8.1 Hz, 2H), 7.53 - 7.43 (m, 1 H), 7.43 - 7.35 (m, 4H), 7.35 - 7.19 (m, 13H), 5.38 (dd, J = 9.3, 6.4 Hz, 1 H), 4.99 - 4.81 (m, 6H), 4.78 (d, J = 12.1 Hz, 1 H), 4.74 (d, J = 11.8 Hz, 1 H), 4.68 (d, J = 12.0 Hz, 1 H), 4.67 (d, J = 11.6 Hz, 1 H), 4.61 - 4.56 (m, 2H), 4.42 (d, J = 4.8 Hz, 1 H), 4.10 (d, J = 6.4 Hz, 1 H), 3.95 (s, 2H), 3.75 (d, J = 9.5 Hz, 1 H), 3.68 (d, J = 12.1 Hz, 1 H), 3.57 (s, 1 H), 3.31 (d, J = 12.2 Hz, 1 H), 3.26 (bs, 1 H), 2.55 - 2.42 (m, 1 H), 1.83 - 1.71 (m, 2H), 1.60 (t, J = 13.0 Hz, 1 H), 1.17 (appd, J = 5.5 Hz, 9H), 1.13 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 168.2, 168.1 , 165.4, 139.0, 138.9, 138.8, 133.2, 130.0, 129.9, 128.5, 128.4, 128.4, 128.3, 127.8, 127.64, 127.59, 127.55, 127.5, 117.3, 101.7, 99.9, 79.4, 77.8, 77.74, 77.72, 77.16, 77.0, 75.7, 74.8, 73.03, 72.98, 70.9, 70.8, 69.6, 69.2, 67.6, 67.0, 64.6, 29.7, 27.3, 23.7, 21.79, 21.75, 21.73, 21.70, 16.6 ppm; HRMS (ESI) calcd for C53H6iNOi5Na [M+Na-]: 974.3939, found 974.3934 (-0.51 ppm).

[0089] In a thick wall high-pressure glass flask, 12 (0.0640 g, 0.672 mmol, 1 .00 equiv) was dissolved in DMF (0.67 mL, 0.1 M). Sodium azide (0.0166 mg, 0.255 mmol, 3.80 equiv) and triethylamine hydrochloride (0.0352 mg, 0.255 mmol, 3.80 equiv) were then added. The mixture was warmed to 130 °C for 90 minutes. At which point the mixture was cooled to room temperature and additional portions of sodium azide (0.0166 mg, 0.255 mmol, 3.80equiv) and triethylamine hydrochloride (0.0352 mg, 0.255 mmol, 3.80 equiv) were added. The mixture was warmed to 130 °C for an hour, before being cooled to room temperature and evaporated under reduced pressure. Purification by flash chromatography (MeOH / DCM) provided 13 (0.059 g, 88%) as a white foam: [O]D25-57 (C 1.0, MeOH); C53H62N4O15; MW = 1017.078 gmoH; IR (neat, cm-1) vmax 2968, 1727, 1270, 1100;1H NMR (500 MHz, CD3OD) 5 7.94 - 7.89 (m, 2H), 7.53 - 7.48 (m, 1 H), 7.42 - 7.36 (m, 4H), 7.35 - 7.23 (m, 13H), 5.38 (dd, J = 10.1 , 7.8 Hz, 1 H), 5.32 (d, J = 6.4 Hz, 1 H), 4.96 - 4.88 (m, 1 H), 4.87 - 4.85 (m, 1 H), 4.83 (d, J = 3.7 Hz, 1 H), 4.76 - 4.68 (m, 3H), 4.70 - 4.64 (m, 1H), 4.59 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 11.2 Hz, 1 H), 4.46 (d, J = 7.8 Hz, 1 H), 4.46 (d, J = 4.1 Hz, 1 H), 4.33 (d, J = 4.1 Hz, 1 H), 4.02 (q, J = 6.5 Hz, 1 H), 3.92 (dd, J = 10.3, 2.8 Hz, 1 H), 3.78 (dd, J = 10.3, 3.7 Hz, 1 H), 3.68 (d, J = 1.8 Hz, 1 H), 3.59 (d, J = 12.3 Hz, 1 H), 3.57 (d, J = 10.1 Hz, 1 H), 3.27 (d, J = 12.3 Hz, 1 H), 2.63 - 2.51 (m, 1 H), 2.13 - 1.97 (m, 2H), 1.66 - 1.56 (m, 1 H), 1.20 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H) ppm Labile protons missing due to exchange,'13C NMR (126 MHz, CD3OD) 5 170.2, 169.2, 167.4, 159.5 (broad and weak signal attributed to presence of protonated and deprotonated tetrazole species), 140.10, 140.07, 140.05, 134.1 , 131.7, 130.9, 129.38, 129.37, 129.31 , 129.29, 129.2, 128.79, 128.76, 128.62, 128.57, 128.5, 103.6, 101.1, 80.3, 79.6, 79.0, 78.9, 76.7, 76.1 , 75.8, 74.0, 73.6, 72.0, 70.9, 70.4, 69.1, 68.9, 67.9, 27.9, 22.4, 22.0, 21.94, 21.85, 21.8, 16.8 ppm; HRMS (ESI) calcd for C53H62N4Oi5Na [M+Na-]: 1017.4109, found 1017.4121 (+ 1.2 ppm).

[0090] A solution of 13 (39.0 mg, 0.0382 mmol, 1.00 equiv) in methanol (3.2 mL, 0.010 M) was prepared in a round bottom flask equipped with a reflux condenser and under a nitrogen atmosphere. Palladium on carbon (49.0 mg, 0.046 mmol, 1.20 equiv, 10 wt. %) was added, and the resulting reaction mixture was degassed and flushed with a hydrogen filled balloon. After stirring at 50 °C under a standard hydrogen atmosphere for 16 h, the reaction mixture was degassed and flushed with nitrogen gas. The reaction mixture was filtered through a pad of silica gel using methanol as the eluent and concentrated in vacuo. Purification by reverse phase C18 chromatography (H2O / MeOH, 60:40) provided 14 (LCB-2242) (23 mg, 79%) as a white foam: [O]D25-76 (C 0.82, MeOH); C32H44N4O15; MW = 746.703 gmoH;1H NMR (300 MHz, CD3OD) 5 7.98 - 7.89 (m, 2H), 7.67 - 7.57 (m, 1 H), 7.52 - 7.41 (m, 2H), 5.36 (d, J = 6.4 Hz, 1 H), 5.31 (dd, J = 10.0, 7.9 Hz, 1 H), 5.15 - 5.01 (m, 1 H), 4.66 - 4.59 (m, 2H), 4.58 - 4.49 (m, 2H), 4.38 (d, J = 2.8 Hz, 1 H), 4.01 (q, J = 6.4 Hz, 1 H), 3.71 - 3.62 (m, 3H), 3.58 (d, J = 10.0 Hz, 1 H), 3.55 (d, J = 0.9 Hz, 1 H), 3.46 (d, J = 12.4 Hz, 1 H), 2.68 - 2.50 (m, 1 H), 2.17 - 1 .97 (m, 2H), 1 .74 - 1.58 (m, 1 H), 1 .29 (d, J = 6.2 Hz, 3H), 1.28 (d, J = 6.2 Hz, 3H), 1.10 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H) ppm Labile protons missing due to exchange,'13C NMR (151 MHz, CD3OD) 5 170.2, 168.7, 167.9, 160.0 (broad and weak signal attributed to equilibration between protonated and deprotonated tetrazole species), 134.3, 131.5, 131.1 , 129.2,104.5, 103.1 , 79.6, 78.8, 75.4, 73.5, 72.0, 71.8, 71.6, 71.4, 70.6, 69.7, 69.2, 68.7, 68.1 , 27.9, 22.6, 22.02, 22.01 , 21.9, 21.8, 16.4 ppm; HRMS (ESI) calcd for C32H44N4Oi5Na [M+Na-]: 747.2701 , found 747.2704 (41.40 ppm).Synthesis of example 17 (LCB-2294) and 19 (LCB-2318).Scheme S1b. Synthesis of previously reported bicyclic galactoside for the preparation of for example 17 (LCB-2294) and 19 (LCB-2318).Scheme S1 b. Synthesis of for example compound 17 (LCB-2294).

[0091] To a reaction vessel containing previously reported nitrile 1534(43 mg, 40 pmol, 1 .0 equiv) in anhydrous DMF (0.79 mL, 50 mM), triethylamine hydrochloride (22 mg, 0.16 mmol, 4.0 equiv) and sodium azide (10 mg, 0.16 mmol, 4.0 equiv) were added. The reaction vessel was sealed, and the mixture was warmed to 130 °C and stirred for 2 h. After cooling to room temperature, triethylamine hydrochloride (22 mg, 0.16 mmol, 4.0 equiv) and sodium azide (10 mg, 0.16 mmol, 4.0 equiv) were added. The reaction mixture was warmed to 130 °C and stirred for another 2 h. The reaction mixture was cooled to room temperature, filtered over silica, and subsequently concentrated in vacuo. Purification by reverse-phase C18 (H2O / MeOH, 10:90) provided tetrazole 16 (31 mg, 70%) as a clear oil. Rf= 0.30 (MeOH / CH2CI2, 10:90); [a]D25-25 (c 1 .4, MeOH^CeiHeslWv; MW = 1129.2260 gmoH; IR (neat) vmax 3377, 2931 , 2511 , 2233, 2071 , 1721 , 1453, 1270 cm’1;1H NMR (500 MHz, CD3OD) 5 8.07 (dq, J = 8.0, 1.4 Hz, 2H), 7.91 (dt, J = 7.1, 1.4 Hz, 2H), 7.65 - 7.58 (m, 1 H), 7.54 - 7.42 (m, 3H), 7.41 - 7.15 (m, 17H), 5.41 (dd, J = 10.2, 7.8 Hz, 1 H), 5.30 (d, J = 6.3 Hz, 1 H), 4.84 - 4.78 (m, 2H), 4.74 - 4.65 (m, 5H), 4.62 - 4.49 (m, 4H), 4.47 (d, J = 5.0 Hz, 1 H), 4.34 (dd, J = 11.8, 7.7 Hz, 1 H), 4.28 (d, J = 5.1 Hz, 1 H), 3.97 (appq, J = 6.7, 6.2 Hz, 1H), 3.89 (dd, J = 10.2, 2.8 Hz, 1 H), 3.69 (dd, J = 10.2, 3.8 Hz, 1 H), 3.63 - 3.56 (m, 2H), 3.46 (dd, J = 7.7, 3.3 Hz, 1 H), 2.53 (dq, J = 13.2, 6.7, 5.7 Hz, 1 H), 2.23 - 2.08 (m, 2H), 1.86 - 1.79 (m, 1 H), 1.10 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H) ppm Labile protons were not observed due to exchange ;13C NMR (126 MHz, CD3OD) 5 170.1, 169.1 , 167.8, 167.7, 162.3, 140.2, 140.1 , 140.0, 134.4, 134.0, 131.8, 131.3, 131.0, 130.8, 129.7, 129.5, 129.4, 129.3, 129.2, 128.8, 128.7, 128.6, 128.5, 128.4, 102.7, 101.1 , 80.3, 79.8, 79.2, 79.0, 78.1 , 76.5, 76.1 , 75.6, 73.8, 73.6, 72.0, 70.9, 70.5, 70.4, 69.1 , 68.8, 63.6, 28.3, 23.2, 22.0, 21.9, 21.8, 21.7, 16.8 ppm (Due to overlapping carbon signals in the aromatic region, 1 peak is hidden) HRMS (ESI) m / z: Calcd for C6iH68N40i7Na [M+Na+], 1151.4477; Found 1151.4495 (+2.0 ppm).

[0092] To a solution of tetrazole 16 (20 mg, 17 pmol, 1.0 equiv) in MeOH (0.87 mL, 20 mM), palladium (10 wt. %) on activated carbon (28 mg, 26 pmol, 1 .5 equiv) was added. The reaction mixture was degassed under reducedpressure and backfilled with hydrogen (3x). After stirring at room temperature under a standard hydrogen atmosphere for 16 h, the reaction mixture was filtered through Celite® (pre-washed with MeOH to prevent benzoate migration) and concentrated in vacuo. Purification by reverse-phase C18 (H2O / MeOH, 40:60) provided compound 17 (LCB-2294) (12 mg, 78%) as a clear film. [a]D25-18 (c 0.6, MeOH); C4OH5ON4OI7; MW = 858.8510 gmoH; IR (neat) vmax 3388, 2936, 2743, 1757, 1720, 1274 cnr1;1H NMR (500 MHz, CD3OD) 5 8.06 ( (dd, J = 8.2, 1 .4 Hz, 2H), 7.66 - 7.59 (m, 1 H), 7.59 - 7.52 (m, 1 H), 7.54 - 7.47 (m, 2 (dd, J = 10.1 , 7.8 Hz, 1 H), 5.32 (d, J = 6.4 Hz, 1 H), 4.94 (hept, J = 6.3 Hz, 1 H), 4.72 4.1 Hz, 1 H), 4.64 - 4.51 (m, 3H), 4.45 (dd, J = 11.9, 7.6 Hz, 1 H), 4.35 (d, J = 3.4 Hz, 1 H), 3.88 (dd, J = 7.6, 3.3 Hz, 1 H), 3.83 (d, J = 10.1 Hz, 1 H), 3.67 (dd, J = 10.2, 3.2Hz, 1 H), 3.53 (dd, J = 3.4, 1.2 Hz, 1 H), 2.61 - 2.49 (m, 1 H), 2.33 (td, J = 13.5, 4.7 Hz, 1 H), 2.04 - 1.98 (m, 1 H), 1.89 - 1 .82 (m, 1 H), 1.18 (d, J = 6.3 Hz, 3H), 1 .09 (d, J = 7.8 Hz, 3H), 1 .07 (d, J = 7.8 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.3 Hz, 3H) ppm Labile protons were not observed due to exchange ;13C NMR (126 MHz, CD3OD) 5 170.4, 168.9, 167.8, 167.5, 161.8, 134.4, 134.0, 131.7, 131.3, 131.0, 130.8, 129.6, 129.3, 103.5, 103.2, 79.5, 79.2, 78.2, 75.6, 73.5, 71.8, 71.6, 71.4, 70.50, 70.49, 70.0, 68.7, 68.6, 63.8, 28.2, 23.3, 22.0, 21.90, 21.85, 21.80, 16.5 ppm; HRMS (ESI) m / z: Calcd for C40H5oN4Oi7Na [M+Na+], 881.3069; Found 881.3078 (+1.7 ppm).

[0093] To a solution of previously reported tetrazole 1834(42 mg, 41 pmol, 1.0 equiv) in MeOH (1.6 mL, 26 mM), palladium (10 wt. %) on activated carbon (65 mg, 61 pmol, 1 .5 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at room temperature under a standard hydrogen atmosphere for 20 h, the reaction mixture was filtered through Celite® (pre-washed with MeOH ) and concentrated in vacuo. Purification by reverse-phase C18 (fW / MeOH, 40:60) provided compound 19 (LCB- 2318)(23 mg, 75%) as a clear film. [O]D25-23 (c 1.2, MeOH); C33H46N4O16; MW = 754.7430 gmoH; IR (neat) vmax 3372, 2929, 1724, 1603, 1274 cm’1;1H NMR (500 MHz, CD3OD) 5 7.94 (d, J = 6.9 Hz, 2H), 7.64 - 7.57 (m, 1 H), 7.47 (t, J = 7.8 Hz, 2H), 5.42 (dd, J = 10.0, 7.8 Hz, 1 H), 5.34 (d, J = 6.3 Hz, 1 H), 5.08 - 5.01 (m, 1 H), 4.73 - 4.62 (m, 4H), 4.38 (d, J = 3.5 Hz, 1 H), 4.08 - 4.00 (m, 1 H), 3.84 (dd, J = 11 .7, 3.3 Hz, 1 H), 3.72 (dd, J = 11.8, 6.7 Hz, 1 H), 3.64 (dd, J = 10.2, 3.2 Hz, 1 H), 3.55 (dd, J = 10.3, 3.9 Hz, 1 H), 3.50 (d, J = 3.6 Hz, 1 H), 3.48 (d, J = 10.0 Hz, 1 H), 3.41 (dd, J = 6.8, 3.3 Hz, 1 H), 2.63 - 2.53 (m, 1 H), 2.15 - 2.02 (m, 2H), 1.88 - 1.81 (m, 1 H), 1.29 - 1.26 (m, 6H), 1.14 (d, J = 6.2 Hz, 3H), 1.04 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H) ppm Labile protons were not observed due to exchange13C NMR (126 MHz, CD3OD) 5 170.5, 169.1 , 167.2, 158.1 , 134.2, 131.6, 131.0, 129.4, 103.2, 102.9, 80.3,79.2, 79.1 , 76.5, 73.5, 71.9, 71.6, 71.4, 70.6, 70.5, 70.1, 68.6, 67.2, 60.8, 27.9, 22.4, 22.02, 22.00, 21.9, 21.8, 16.5 ppm; HRMS (ESI) m / z: Calcd for C33H46N4Oi6Na [M+Na+], 777.2807; Found 777.2811 (+1.3 ppm).

[0094] To a solution of previously reported galactopyranoside 2034(0.20 g, 0.28 mmol, 1.0 equiv) in anhydrous THF (5.7 mL, 50 mM) at -10 °C, TBAF (0.60 mL, 1.0 M in THF, 2.1 equiv) was added dropwise. The reaction mixture was stirred for 30 min before being diluted with EtOAc (10 mL), and a saturated solution of NH4CI (15 mL) was added. The aqueous layer was extracted with EtOAc (2 x 10 mL), and the organic layers were combined, washed with brine (35 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc, 20:80) provided diol 21 (87 mg, 78%) as a clear oil. Rf = 0.28 (Hexanes / EtOAc, 20:80); [O]D25-3.5 (c 1.0, CHCI3); C19H23NO6S; MW = 393.4540 gmoH; IR (neat) vmax 3460, 2934, 2252, 1719, 1451 , 1264 cm-1;1H NMR (500 MHz, CDCI3) 5 8.04 (d, J = 7.0 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2H), 5.52 (t, J = 9.7Hz, 1 H), 4.92 (d, J = 5.9 Hz, 1 H), 4.71 (d, J = 9.9 Hz, 1 H), 4.02 - 3.95 (m, 2H), 3.89 (d, J = 9.5 Hz, 1 H), 3.62 (s, 1 H), 3.47 (dd, J = 4.5, 3.1 Hz, 1 H), 2.80 - 2.72 (m, 2H), 2.69 - 2.52 (m, 2H), 1.93 - 1.89 (m, 1 H), 1.83 - 1.76 (m, 2H), 1.26 (t, J = 7.4 Hz, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 165.6, 133.4, 130.0, 129.8, 128.6, 117.1, 84.4, 80.4, 78.9, 69.6, 68.4, 64.7, 61.1 , 27.5, 24.5, 23.8, 15.0 ppm; HRMS (ESI) m / z: Calcd for Ci9H23NO6SNa [M+Na+], 416.1144; Found 416.1131 (-1.6 ppm).

[0095] Following a previously reported protocol37, to a solution of diol 21 (95 mg, 0.21 mmol, 1 .0 equiv) in CH2CI2 (1.7 mL, 30 mM), NEt3(0.27 mL, 1.9 mmol, 8.0 equiv) and 2,4,6-triisopropylbenzenesulfonylchloride (0.23 g, 0.72 mmol, 3.0 equiv) were added. The reaction mixture was stirred for 16 h at room temperature before water (10 mL) and CH2CI2 (10 mL) were added. The aqueous layer was extracted with CH2CI2 (2 x 10 mL), and the organic layers were combined, washed with brine (30 mL), dried over MgSCL, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / Et2O, 30:70) provided trisylate 22 (0.14 g, 88%) as a clear oil. Rf= 0.16 (Hexanes / EtOAc, 75:25); [a]D25+10 (c 0.5, CHCI3); C34H45NO8S2; MW = 656.8530 gmoF1; IR (neat) vmax3503, 2960, 1728, 1600, 1452, 1268 cm’1;1H NMR (500 MHz, CDCI3) 5 8.03 (d, J = 7.1 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 2H), 7.20 (s, 2H), 5.34 (t, J = 9.8 Hz, 1 H), 4.89 (d, J = 5.6 Hz, 1 H), 4.67 (d 11.3, 4.0 Hz, 1 H), 4.15 - 4.10 (m, 3H), 3.95 (d, J = 9.5 Hz, 1 H), 3.82 (dd, J = 6.3, 4.0 1 H), 2.75 - 2.64 (m, 3H), 2.46 - 2.37 (m, 1 H), 1.94 - 1.81 (m, 3H), 1.29 - 1.26 (m, 18 ppm;13C NMR (126 MHz, CDCI3) 5 165.6, 154.3, 151.0, 133.5, 130.1 , 129.5, 129.0, 178.6, 69.1 , 68.0, 66.4, 64.7, 34.4, 29.8, 26.9, 24.90, 24.89, 24.80, 24.6, 23.7, 23.6, 14.9 ppm; HRMS (ESI) m / z: Calcd for C34H45NO8S2Na [M+Na+], 682.2484; Found 682.2468 (-2.3 ppm).

[0096] Following a previously reported protocol37, to a solution of trisylate 22 (60 mg, 0.19 mmol, 1.0 equiv) in anhydrous DMF (3.8 mL, 50 mM), sodium azide (0.12 g, 1.9 mmol, 10 equiv) was added. The reaction mixture was warmed to 80 °C and vigorously stirred for 2 h. The solution was cooled to room temperature and water (10 mL) and Et2O (10 mL) were added. The aqueous layer was extracted with Et2O (2 x 10 mL), and the organic layers were combined, washed with brine (30 mL), dried over MgSCU, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc, 60:40) provided azide 23 (60 mg, 76%) as a white foam. Rf= 0.36(Hexanes / EtOAc, 50:50); [a]D25-45 (c 1.0, CHCI3); CI9H22N4O5S; MW = 418.4680 gmoH; IR (neat) vmax3469, 2932, 2872, 2102, 1721 , 1451 , 1264 cm’1;1H NMR (500 MHz, CDCI3) 5 8.07 - 8.01 (m, 2H), 7.62 - 7.55 (m, 1 H), 7.49 - 7.42 (m, 2H), 5.40 (t, J = 9.8 Hz, 1 H), 4.91 (d, J = 5.4 Hz, 1 H), 4.75 (d, J = 10.0 Hz, 1 H), 3.94 (d, J = 9.6 Hz, 1 H), 3.69 - 3.59 (m, 2H), 3.40 - 3.33 (m, 1 H), 2.91 (s, 1 H), 2.86 - 2.69 (m, 2H), 2.53 - 2.42 (m, 1 H), 1.83 - 1 .78 (m, 3H), 1.27 (t, J = 7.5 Hz, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 165.6, 133.5, 130.1 , 129.6, 128.6, 116.8, 84.2, 80.8, 78.8, 69.1 , 68.3, 64.6, 49.2, 26.9, 24.6, 23.8, 14.8 ppm; HRMS (ESI) m / z: Calcd for Ci9H22N4O5SNa [M+Na+], 441.1209; Found 441.1200 (-2.0 ppm).

[0097] To a solution of azide 23 (54 mg, 0.13 mmol, 1.0 equiv) in THF (3.0 mL, 43 mM), palladium hydroxide (20 wt. %) on carbon (36 mg, 51 pmol, 0.40 equiv) was added. The reaction mixture was stirred under standard hydrogen atmosphere for 1 h before MeOH was added and the solution was filtered through a pad of silica, concentrated in vacuo, and co-evaporated with toluene (2 x 10 mL) to ensure dryness. The crude amine was dissolved in CH2CI2(1.3 mL, 0.1 M) and BzCI (30 pL, 0.26 mmol, 2.0 equiv), NEt3(71 pL, 0.51 mmol, 4.0 equiv) and DMAP (4.7 mg, 38 pmol, 0.30 equiv) were added. The reaction mixture was stirred at room temperature for 2 h and a saturated solution of NaHCOs (10 mL) was added. The aqueous layer was extracted with EtOAc (2 x 10 mL), and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc, 20:80) provided benzamide 24 (61 mg, 95% over two steps) as a white foam. Rf= 0.26 (Hexanes / EtOAc, 20:80); [a]D25+29 (c 0.8, CHCI3); C^H^NAS; MW = 496.5780 gmoF1; IR (neat) vmax3329, 2966, 1717, 1647, 1539, 1451 , 1267 cm’1;1H NMR (500 MHz, CDCI3) 5 8.01 (d, J = 7.2 Hz, 2H), 7.82 (d, J = 7.3 Hz, 2H), 7.60 - 7.53 (m, 1 H), 7.53 - 7.47 (m, 1 H), 7.43 (td, J = 7.9, 1 .4 Hz, 4H), 7.00 (dd, J = 7.4, 4.3 Hz, 1 H), 5.46 (t, J = 9.7 Hz, 1 H), 4.90 (d, J = 5.7 Hz, 1 H), 4.71 (d, J = 9.9 Hz, 1 H), 4.16 - 4.07 (m, 1 H), 3.97 (d, J = 9.5 Hz, 1 H), 3.79 (dd, J = 8.7, 3.0 Hz, 1 H), 3.52 (s, 1 H), 3.47 - 3.39 (m, 1 H), 2.75 - 2.62 (m, 2H), 2.57 - 2.46 (m, 1 H), 2.07 - 1 .99 (m, 1 H), 2.00 - 1 .90 (m, 1 H), 1.88 - 1 .80 (m, 1 H), 1.18 (t, J = 7.4 Hz, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 168.0, 165.9, 134.2, 133.5, 131.8, 130.0, 129.6, 128.7, 128.6, 127.1, 116.9, 84.4, 79.9, 78.9, 69.3, 68.6, 64.7, 38.3, 26.6, 25.1 , 23.7, 15.2 ppm; HRMS (ESI) m / z: Calcd for C26H28N2O6SNa [M+Na+], 519.1566; Found 519.1563 (+0.5 ppm).

[0098] To a solution of glycosyl donor 24 (57 mg, 0.12 mmol, 1.0 equiv) and glycosyl acceptor31(0.22 g, 0.34 mmol, 3.0 equiv) in anhydrous CH2CI2 (2.3 mL, 0.050 M), activated 4A molecular sieves (1 .0 equiv) were added. The solution was stirred at room temperature for 30 min before being cooled to -35 °C, and W-iodosuccinimide (78 mg, 0.34 mmol, 3.0 equiv) and TMSOTf (4.0 pL, 23 pmol, 0.20 equiv) were added sequentially. The reaction mixture was stirred for 1-2 h at -35 °C or until starting material was completely consumed, as verified by TLC. Upon completion, the reaction mixture was filtered using Et20, and a saturated solution of Na2S2O3 was added dropwise to the dark brown solution until it became clear. After warming to room temperature, a saturated solution of NaHCO3 was added. The aqueous layer was extracted with Et20 (3x) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc, 20:80) provided glycoside 25 (0.10 g, 83%) as a colorless oil. Rf = 0.44 (Hexanes / EtOAc, 20:80); [O]D25-12 (c 0.9, CHCI3); C6IH68N20I6; MW = 1085.2130 gmoH; IR (neat) vmax3394, 2982, 1734, 1654, 1532, 1271 cm’1;1H NMR (500 MHz, CDCI3) 5 8.05 (d, J = 7.7 Hz, 2H), 8.00 (d, J = 7.5 Hz, 2H), 7.58 (dd, J = 8.7, 2.9 Hz, 1 H), 7.47 - 7.25 (m, 21H), 5.32 (dd, J = 9.9, 7.6 Hz, 1 H), 5.19 (d, J = 7.5 Hz, 1 H), 5.01 (hept, J = 6.3 Hz, 1 H), 4.89 (d, J = 5.7 Hz, 1 H), 4.87 - 4.80 (m, 3H), 4.78 (d, J = 12.0 Hz, 1 H), 4.67 (d, J = 12.1 Hz, 2H), 4.64 - 4.59 (m, 2H), 4.57 (d, J = 4.8 Hz, 1 H), 4.50 (d, J = 11 .6 Hz, 1 H), 4.21 (ddd, J = 14.1 , 8.6, 2.3 Hz, 1 H), 3.91 - 3.80 (m, 3H), 3.72 (d, J = 9.9 Hz, 1 H), 3.32 (dd, J = 8.8, 2.3 Hz, 1 H), 3.29 - 3.21 (m, 1 H), 3.20 - 3.16 (m, 1 H), 2.73 (s, 1 H), 2.49 - 2.38 (m, 1 H), 2.00 - 1.93 (m, 1 H), 1.83 - 1.76 (m, 1 H), 1.67 - 1.63 (m, 1 H), 1.23 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 168.6, 168.2, 167.8, 166.0, 138.80, 138.74, 138.71 , 134.3, 133.2, 131.6, 130.1 , 129.9, 128.60, 128.59, 128.54, 128.50, 128.4, 128.3, 128.1 , 127.9, 127.8, 127.7, 127.6, 127.5, 116.9, 99.9, 98.9, 79.7, 78.2, 77.6, 77.2, 77.1 , 76.0, 75.2, 74.7, 73.2, 73.0, 70.4, 69.9, 69.7, 68.9, 67.5, 64.6, 37.7, 26.9, 23.8, 21.8, 21.73, 21.70, 21.6, 16.5 ppm; HRMS (ESI) m / z: Calcd for C6iH68N20i6Na [M+Na+], 1107.4467; Found 1107.4457 (-0.3 ppm).

[0099] To a reaction vessel containing nitrile 25 (95 mg, 88 pmol, 1.0 equiv) in anhydrous DMF (1.8 mL, 50 mM), triethylamine hydrochloride (48 mg, 0.35 mmol, 4.0 equiv) and sodium azide (23 mg, 0.35 mmol, 4.0 equiv) were added. The reaction vessel was sealed, and the solution was warmed to 130 °C and stirred for 2 h. After cooling to room temperature, triethylamine hydrochloride (48 mg, 0.35 mmol, 4.0 equiv) and sodium azide (23 mg, 0.35 mmol, 4.0 equiv) were added. The reaction mixture was warmed to 130 °C and stirred for another 2 h. The reaction mixture was cooled to room temperature, filtered over silica and subsequently concentrated in vacuo. Purification by reversephase C18 (FhO / MeOH, 20:80) provided tetrazole 26 (69 mg, 70%) as a clear oil. Rf= 0.10 (Cf Ck / MeOH, 90:10); [a]D25-15 (c 1.5, MeOH); CeiHegNsO ; MW = 1128.2420 gmoH; IR (neat) vmax3370, 2935, 1731 , 1651 , 1538, 1453, 1272 cm’1;1H NMR (500 MHz, CD3OD) 5 7.96 - 7.87 (m, 4H), 7.56 - 7.49 (m, 1 H), 7.49 - 7.41 (m, 3H), 7.39 - 7.25 (m, 12H), 7.24 - 7.13 (m, 5H), 5.39 (dd, J = 10.2, 7.8 Hz, 1 H), 5.30 (d, J = 6.4 Hz, 1 H), 4.82 - 4.71 (m, 3H), 4.71 - 4.61 (m, 4H), 4.60 (d, J = 7.9 Hz, 1 H), 4.54 - 4.46 (m, 3H), 4.32 (d, J = 4.9 Hz, 1 H), 3.97 - 3.91 (m, 1 H), 3.92 - 3.85 (m, 1 H), 3.83 (dd, J = 10.3, 2.9 Hz, 1 H), 3.64 (dd, J = 10.2, 3.8 Hz, 1 H), 3.58 (d, J = 10.2 Hz, 1 H), 3.51 (dd, J = 2.9, 1.2 Hz, 1 H), 3.43 (dd, 0 = 14.1, 8.7 Hz, 1 H), 3.35 - 3.31 (m, 1 H), 2.60 - 2.48 (m, 1 H), 2.21 - 2.05 (m, 2H), 1.84 - 1.78 (m, 1 H), 1.12 (d, 0 = 6.3 Hz, 3H), 1.09 (d, 0 = 6.3 Hz, 3H), 1.08 (d, 0 = 6.2 Hz, 3H), 1.05 (d, 0 = 6.3 Hz, 3H), 0.92 (d, 0 = 6.4 Hz, 3H) ppm Labile protons were not observed due to exchange,'13C NMR (126 MHz, CD3OD) 5 169.94, 169.90, 169.6, 167.4, 165.6, 140.1 , 140.04, 140.00, 135.4, 134.1 , 132.9, 131.7, 131.0, 129.7, 129.40, 129.38, 129.33, 129.2, 129.1 , 128.9, 128.8, 128.7, 128.60, 128.57, 128.52, 101.9, 100.7, 80.4, 79.0, 78.9, 78.8, 78.4, 76.6, 76.2, 76.0, 73.9, 73.8, 71.9, 70.9, 70.7, 70.4, 68.7, 67.6, 39.3, 28.1 , 22.5, 22.0, 21.9, 21.84, 21.80, 16.7 ppm; HRMS (ESI) m / z: Calcd for C6iH69N5Oi6Na [M+Na+], 1150.4637; Found 1150.4663 (+2.7 ppm).

[0100] To a solution of tetrazole 26 (60 mg, 53 pmol, 1.0 equiv) in MeOH (2.7 mL, 20 mM), palladium (10 wt. %)on activated carbon (85 mg, 80 pmol, 1 .5 equiv) was added. The reaction mixture was degassed and flushed using a hydrogen-filled balloon. After stirring at 50 °C under a standard hydrogen atmosphere for 16 h, the reaction mixture was cooled to room temperature, filtered through Celite® (pre-washed with MeOH to prevent benzoate migration) with MeOH, and concentrated in vacuo. Purification by reverse-phase C18 (H2O / MeOH, 40:60) provided compound 27 (LCB-2322) (33 mg, 72%) as a clear film. [a]D25-18 (c 0.4, MeOH); C40H5iN5Oi6; MW = 857.8670 gmoH; IR (neat) Vmax3411 , 2935, 2498, 1725, 1636, 1454 cm’1;1H NMR (500 MHz, CD3OD) 5 7.91 - 7.84 (m, 4H), 7.60 - 7.51 (m, 2H), 7.50 - 7.40 (m, 4H), 5.37 (dd, J = 10.2, 7.8 Hz, 1 H), 5.32 (d, J = 6.3 Hz, 1 H), 4.86 - 4.80 (m, 1 H), 4.69 (d, J = 7.8 Hz, 1 H), 4.66 (d, J = 3.0 Hz, 1 H), 4.62 (d, J = 4.0 Hz, 1 H), 4.55 (hept, J = 6.4 Hz, 1 H), 4.34 (d, J = 3.0 Hz, 1 H), 4.10 - 4.03 (m, 1 H), 3.77 (d, J = 10.2 Hz, 1 H), 3.76 - 3.68 (m, 1 H), 3.70 - 3.64 (m, 3H), 3.60 (dd, J = 10.2, 4.0 Hz, 1 H), 3.53 (dd, J = 3.2, 1 .2 Hz, 1 H), 2.60 - 2.50 (m, 1 H), 2.27 (td, J = 13.5, 4.9 Hz, 1 H), 2.07 - 2.01 (m, 1 H), 1.88 - 1.81 (m, 1 H), 1.18 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H) ppm Labile protons were not observed due to exchange;13C NMR (126 MHz, CD3OD) 5 170.5, 170.3, 168.8, 167.9, 162.4, 135.6, 134.1, 132.7, 131.6, 131.1, 129.6, 129.3, 128.5, 103.5, 103.0, 79.6, 78.8, 78.4, 75.5, 73.4, 72.1, 71.7, 71.5, 70.7, 70.6, 69.7, 69.0, 68.7, 39.5, 28.2, 23.4, 22.0, 21.9, 21.8, 21.7, 16.5 ppm; HRMS (ESI) m / z: Calcd for C40H5iN5Oi6Na [M+Na+], 880.3229; Found 880.3235 (+1.3 ppm).Synthesis for example 32 (LCB-2259):

[0101] To a solution of previously reported tartaric acid 2831(1 .0 g, 1 .8 mmol, 1 .0 equiv) in DMF (8.8 mL, 0.20 M) cooled to 0°C, DIPEA (1.2 mL, 7.1 mmol, 4.0 equiv) was added. After stirring 5 min, pyrrolidine (0.32 mL, 3.9 mmol, 2.2 equiv) was added. After another 5 min, HATU (1 .5 g, 3.9 mmol, 2.2 equiv) was added. The reaction mixture was stirred for 30 minutes at 0 °C, subsequently warmed to room temperature and stirred for 3 h before being concentrated in vacuo. The crude residue was dissolved in CH2CI2 (10 mL) and HC1 1 .0 M (10 mL) was added. The aqueous phase was extracted with CH2CI2 (2x 10 mL) and the combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (EtOAc / MeOH, 95:5) provided tartramide 29 (1.0 g, 84 %) as a white foam. Rf= 0.10 (EtOAc / MeOH, 95:5); [O]D25-78 (c 2.3, MeOH); C39H48N2O8; MW = 672.8190 gmoH;1H NMR (500 MHz, CDCI3) 5 7.39 - 7.26 (m, 15H), 5.02 (d, J = 3.1 Hz, 1 H), 4.96 (d, J = 11 .5 Hz, 1 H), 4.84 (d, J = 11 .6 Hz, 1 H), 4.80 (d, J = 11.7 Hz, 1 H), 4.75 - 4.70 (m, 3H), 4.60 (d, J = 11.5 Hz, 1 H), 4.41 (d, J = 8.3 Hz, 1 H), 4.08 - 4.02 (m, 2H), 3.98 - 3.92 (m, 1 H), 3.84 (d, J = 2.4 Hz, 1 H), 3.82 - 3.70 (m, 3H), 3.67 - 3.65 (m, 1 H), 3.60 - 3.54 (m, 1 H), 3.45 - 3.37 (m, 4H), 1.95 - 1 .78 (m, 8H), 1 .02 (d, J = 6.5 Hz, 3H) ppm;13C NMR (126 MHz, CDCI3) 5 168.0, 167.8, 138.8, 138.6, 138.1 , 128.6, 128.5, 128.4, 128.34, 128.30, 128.0, 127.8, 127.7, 127.5, 101.4, 79.9, 79.8, 77.6, 76.1 , 75.1, 74.1 , 73.0, 72.4, 67.3, 46.6, 46.3, 46.04, 46.00, 26.1 , 26.0, 24.4,24.2, 16.7 ppm; HRMS (ESI) m / z: Calcd for C39H48N2O8Na [M+Na+], 695.3308; Found 695.3302 (-0.1 ppm).48%

[0102] To a solution of previously reported galactopyranoside 3031(30 mg, 39 pmol, 1.0 equiv) and glycosyl acceptor 29 (80 mg, 0.12 mmol, 3.0 equiv) in anhydrous MeCN (0.4 mL, 0.1 M), activated 4A molecular sieves (50 mg) were added. The reaction mixture was stirred at room temperature for 30 min before being cooled to 0 °C, and DMTSF (23 mg, 0.12 mmol, 3.0 equiv) and 2,6-lutidine (10 pL, 83 pmol, 2.1 equiv) were added. The reaction mixture was warmed to room temperature and stirred for 4 h before being filtered using EtOAc. A saturated solution of NaHCO3(5 mL) was added. The aqueous layer was extracted with EtOAc (2 x 5 mL) and the combined organic layers were washed with HC1 1.0 M (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (EtOAc / MeOH, 90:10) provided glycoside 31 (26 mg, 48%) as a colorless oil. Rf= 0.20 (EtOAc / MeOH, 90:10); [a]D25-22 (c 0.9, MeOH); C82H86N2Oi7; MW = 1371.5870 gmoH;1H NMR (500 MHz, CD3OD) 5 8.08 - 8.02 (m, 2H), 7.92 - 7.86 (m, 2H), 7.61 - 7.54 (m, 1 H), 7.53 - 7.46 (m, 3H), 7.47 - 7.40 (m, 2H), 7.36 - 7.18 (m, 23H), 7.04 - 6.98 (m, 2H), 6.89 - 6.81 (m, 5H), 5.65 - 5.60 (m, 1 H), 5.52 (dd, J = 9.9, 8.0 Hz, 1 H), 5.41 (d, J = 8.1 Hz, 1 H), 5.21 (s, 1 H), 5.05 (d, J = 8.0 Hz, 1 H), 4.92 (d, J = 11.5 Hz, 1 H), 4.87 (d, J = 0.9 Hz, 1 H), 4.81 - 4.74 (m, 2H), 4.74 - 4.65 (m, 4H), 4.54 (dd, J = 11 .4, 7.1 Hz, 2H), 4.49 - 4.42 (m, 2H), 3.97 - 3.87 (m, 4H), 3.82 - 3.74 (m, 1 H), 3.69 - 3.62 (m, 2H), 3.63 - 3.57 (m, 1 H), 3.58 - 3.49 (m, 4H), 3.31 - 3.23 (m, 4H), 2.77 (dd, J = 13.7, 5.6 Hz, 1 H), 2.66 (dd, J = 13.7, 6.6 Hz, 1 H), 1.84 - 1.66 (m, 6H), 1.63 - 1.52 (m, 1 H), 1.46 - 1.37 (m, 1 H), 1.01 (d, J = 6.4 Hz, 3H) ppm;13C NMR (126 MHz, CD3OD) 5 172.1, 170.3, 168.2, 167.3, 167.1 , 140.3, 140.14, 140.10, 139.2, 136.9, 136.8, 134.5, 134.3, 131.5, 131.1, 130.8, 130.6, 130.5, 129.8, 129.64, 129.60, 129.55, 129.51 , 129.47, 129.43, 129.34, 129.32, 129.30, 129.23, 129.20, 129.0, 128.8, 128.7, 128.63, 128.60, 128.5, 127.4, 100.3, 99.7, 80.2, 79.2, 79.0, 78.58, 78.50, 78.2, 76.8, 76.3, 74.7, 74.4, 73.7, 73.6, 72.7, 70.4, 68.9, 68.5, 67.5, 48.0, 47.8, 47.1 , 46.9, 40.2, 26.6, 26.4, 25.1 , 24.9, 17.1 ppm; HRMS (ESI) m / z: Calcd for C82H86N2Oi7Na [M+Na+], 1393.5824; Found 1393.5839 (+1.0 ppm).

[0103] To a solution of tartramide 31 (20 mg, 15 pmol, 1.0 equiv) in THF (1.2 mL, 0.013 M), palladium hydroxide (20 wt. %) on carbon (15 mg, 22 pmol, 1 .5 equiv) was added. The reaction mixture was degassed and flushed using a hydrogen filled balloon. After stirring at room temperature under a standard hydrogen atmosphere for 16 h, the reaction mixture was filtered through Celite® (pre-washed with MeOH to prevent benzoate migration) with MeOH and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH + 1 % formic acid, 50:50) provided compound 32 (LCB-2259) (2 mg, 15%) as a white powder. [O]D25-3.0 (c 0.2, MeOH); C47H56N2O17; MW = 920.9620 gmoH;1H NMR (500 MHz, CD3OD) 5 8.15 - 8.05 (m, 4H), 7.69 - 7.62 (m, 1 H), 7.63 - 7.56 (m, 1 H), 7.54 (t, J = 7.7 Hz, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.05 - 6.99 (m, 2H), 6.92 - 6.85 (m, 2H), 6.86 - 6.79 (m, 1 H), 5.78 (d, J = 3.1 Hz, 1 H), 5.51 - 5.41 (m, 2H), 4.95 (d, J = 3.8 Hz, 1 H), 4.92 (d, J = 8.1 Hz, 1 H), 4.58 (d, J = 8.1 Hz, 1 H), 4.46 (t, J = 6.1 Hz, 1 H), 4.15 (dd, J = 9.4, 3.2 Hz, 1 H), 3.96 (t, J = 6.2 Hz, 1 H), 3.81 - 3.74 (m, 2H), 3.75 - 3.53 (m, 8H), 3.35 (dd, J = 7.2, 5.5 Hz, 1 H), 3.32 - 3.23 (m, 3H), 2.82 - 2.71 (m, 2H), 1 .95 - 1 .64 (m, 8H), 1.05 (d, J = 6.6 Hz, 3H) ppm Labile protons were not observed due to exchange13C NMR (126 MHz, CD3OD) 5 174.5, 170.0, 168.0, 167.4, 167.3, 137.5, 134.5, 134.1 , 131.6, 131.2, 131.1, 130.9, 130.6, 129.7, 129.4, 128.8, 127.2, 102.6, 100.8, 79.7, 78.5, 78.4, 77.9, 75.8, 73.5, 72.5, 71.7, 70.0, 68.5, 68.3, 61.8, 47.94, 47.90, 47.2, 47.1 , 40.2, 26.7, 26.6, 25.1 , 25.0, 16.7 ppm; HRMS (ESI) m / z Calcd for C47H56N2Oi7Na [M+Na+], 943.3477; Found 943.3431 (-0.7 ppm).Synthesis for example 41 (LCB-2321 ), 32 (LCB-2259), 42 (LCB-2381 ), 45 (LCB-2376), and 46 (LCB-2380)28, (R,R)-diacid 75 %, 34, (R,R)-fucosylated allyl tartrate33, (S,S)-diacid 73 %, 35, (S, S)-fucosylated allyl tartrateScheme S1c. Synthesis of for example 41 (LCB-2321), 32 (LCB-2259), 42 (LCB-2381), 45 (LCB-2376), and 46 (LCB-2380)

[0104] To a solution of the diacid 2831 44b(0.50 g, 0.88 mmol, 1 .0 equiv) and Na2CO3 (400 mg, 3.79 mmol, 4.30 equiv) in water (4.1 mL, 55 mM), a solution of allyl bromide (0.34 mL, 3.9 mmol, 4.5 equiv) and Bu4NI (650 mg, 1.76 mmol, 2.00 equiv) in CH2CI2 (4.9 mL, 0.18 M) was added. The biphasic mixture was stirred vigorously for 16 h, then diluted with H2O and extracted with ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (Hexanes / EtOAc, 60:40) provided the desired product 34 (0.50 g, 88 %) as a colorless oil. Rf = 0.38 (Hexanes / EtOAc, 70:30); [a]D25-37 (c 1 .0, CDCI3); Formula C37H42O10, MW 646.7330 g / mol; IR (neat) vmax3457, 2935, 2880, 1753 cm’1;1H NMR (500 MHz, CDCI3) 5 7.38 - 7.33 (m, 5H), 7.33 - 7.25 (m, 10H), 5.94 - 5.80 (m, 2H), 5.36 - 5.21 (m, 4H), 4.95 (d, J = 11 .5 Hz, 1 H), 4.92 (d, J = 3.1 Hz, 1 H), 4.79 (d, J = 11 .7 Hz, 1 H), 4.78 (d, J = 11 .6 Hz, 1 H), 4.74 (d, J = 11 .7 Hz, 1 H), 4.71 (d, J = 11 .4 Hz, 1 H), 4.65 (ddd, J = 9.7, 5.8, 2.1 Hz, 2H), 4.605 (d, J = 11.2 Hz, 1 H), 4.595 (d, J = 4.2 Hz, 1 H), 4.57 - 4.54 (m, 1 H), 4.53 - 4.48 (m, 2H), 4.25 (q, J = 6.5 Hz, 1 H), 4.06 - 4.03 (m, 2H), 3.70 (apps, 1 H), 1 .07 (d, J = 6.5 Hz, 3H) ppm, Labile proton was not observed due to exchange13C{1H} NMR (126 MHz, CDCI3) 5 170.3, 168.9, 138.74, 138.66, 138.3, 131.5, 131.4, 128.53, 128.49, 128.43, 128.35, 128.2, 127.84, 127.75, 127.68, 127.56, 119.4, 119.1 , 100.7, 79.6, 78.9, 77.7, 75.9, 75.0, 74.0, 73.0, 72.5, 67.9, 66.5, 66.2, 16.7 ppm; HRMS (ESI) m / z: calcd for C37H42OioNa [M+Na+] 669.2670, found 669.2671 (+0.1 ppm).

[0105] To a solution of the glycosyl donor 3031(300 mg, 394 pmol, 1 .00 equiv) and glycosyl acceptor 34 (0.51 g, 0.79 mmol, 2.0 equiv) in CH2CI2 (5.0 mL, 79 mM), 3A molecular sieves (0.3 g) were added with stirring for 1 h followed by cooling to -30 °C. W-iodosuccinimide (270 mg, 1.18 mmol, 3.00 equiv) and TfOH (7.0 pL, 0.79 mmol, 0.20 equiv) were added followed by stirring at -30 °C for 3h. The reaction mixture was diluted with EtOAc and quenched with a saturated solution of NaHCOs. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with a saturated solution of Na2S2O3 and brine, and then dried over MgSO4, filtered andconcentrated in vacuo. Purification by reverse-phase C18 (HgO / MeCN, 15:85) provided 36 (0.44 g, 83 %) as a lightyellow oil. Rf = 0.40 (Hexanes / EtOAc, 70:30); [a]D25- 11 (c 0.8, CH2CI2); Formula CsoHsoOig, MW 1345.5010 g / mol; IR (neat) vmax3063, 2976, 2934, 2872, 1725 cnr1;1H NMR (500 MHz, CDCI3) 5 8.07 (appdd, J = 7.1 , 4.6 Hz, 4H), 7.59 (t, J = 7.4 Hz, 1 H), 7.50 - 7.43 (m, 4H), 7.41 - 7.20 (m, 26H), 7.00 - 6.97 (m, 1 H), 6.92 (ddd, J = 19.6, 9.6, 4.2 Hz, 4H), 5.83 - 5.73 (m, 2H), 5.72 (appd, J = 3.0 Hz, 1 H), 5.55 (dd, J = 9.8, 8.1 Hz, 1 H), 5.28 - 5.22 (d, J = 9.9, 3.3 Hz, 1 H), 5.16 (d, J = 10.5 Hz, 1 H), 5.06 (dd, J = 10.6, 1.1 Hz, 1 H), 4.96 (d, J = 8.0 Hz, 1 H), 4.92 - 4.84 (m, 3H), 4.79 - 4.64 (m, 6H), 4.64 - 4.55 (m, 3H), 4.53 - 4.33 (m, 7H), 4.07 (appdd, J = 12.8, 6.2 Hz, 1 H), 3.93 (apps, 2H), 3.85 (dd, J = 9.9, 3.3 Hz, 1 H), 3.73 (t, J = 6.5 Hz, 1 H), 3.57 (dd, J = 9.4, 5.7 Hz, 1 H), 3.51 - 3.45 (m, 2H), 2.84 (dd, J = 13.6, 5.6 Hz, 1 H), 2.74 (dd, J = 13.7, 7.0 Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3H) ppm;13C{1H} NMR (126 MHz, CDCI3) 5 170.7, 168.5, 168.3, 165.9, 165.5, 139.1 , 138.98, 138.87, 137.7, 135.8, 135.4, 133.4, 132.7, 131.74, 131.69, 130.7, 130.22, 130.16, 129.7, 129.5, 128.6, 128.5, 128.4, 128.30, 128.27, 128.20, 128.0, 127.93, 127.87, 127.64, 127.58,127.49, 127.46, 126.4, 118.9, 118.0, 100.5, 100.3, 79.5, 78.6, 77.59, 77.58, 77.2, 76.8, 75.8, 74.8, 73.9, 73.1 , 73.0,72.7, 71.1 , 67.9, 67.6, 66.38, 66.36, 65.9, 65.8, 39.2, 16.6 (Due to overlapping carbon signals in the aromatic region,

[0106] To a solution of the diallyl tartrate 36 (0.88 g, 0.66 mmol, 1 .0 equiv) and triphenylphosphine (800 mg, 3.08 mmol, 4.70 equiv) in 1,4-dioxane (30.7 mL, 21.3 mM), a previously prepared solution of formic acid (520 pL, 13.8 mmol, 21.0 equiv) and triethylamine (21.8 mL, 13 mmol, 20 equiv 0 equiv) in 1 ,4-dioxane (17.6 mL, 37.2 mM) was slowly added. After stirring for 5 minutes at room temperature, a solution of Pd(OAc)2 (59 mg, 0.26 mmol, 0.40 equiv) in 1,4-dioxane (17.6 mL, 37.2 mM) was added. The reaction mixture was stirred for 3h and then concentrated under reduced pressure. The mixture was filtered through Celite®, washed with MeOH and concentrated in vacuo. Purification by reverse-phase C18 (HgO / MeOH, 25:85) provided the diacid intermediate 38 as a white solid (0.47 g, 56 %). [ajo25-8 (c 1.0, CDCI3); Formula C74H72O19, MW 1265.3710 g / mol; IR (neat) vmax3065, 3032, 2935, 2879, 1751 , 1722 cm’1;1H NMR (500 MHz, CDCI3) 5 8.14 (t, J = 8.8 Hz, 4H), 7.64 (t, J = 7.3 Hz, 1 H), 7.57 - 7.49 (m, 3H), 7.41 - 7.33 (m, 12H), 7.33 - 7.24 (m, 11 H), 7.12 (apps, 2H), 7.04 - 7.01 (m, 2H), 6.96 (app Hz, 1 H), 5.59 - 5.55 (m, 1 H), 5.34 (d, J = 3.7 Hz, 1 H), 5.09 (d, J = 2.8 Hz, 1 H), 4.98 - 4.93 Hz, 1 H), 4.71 (appt, J = 5.4 Hz, 3H), 4.64 (dd, J = 11 .7, 5.8 Hz, 2H), 4.56 - 4.46 (m, 3H), 4. 4.06 (dd, J = 10.1, 3.7 Hz, 1 H), 3.96 (dd, J = 10.5, 4.5 Hz, 2H), 3.92 (dd, J = 10.2, 2.6 Hz, 1 1 H), 3.61 (qd, J = 9.5, 6.6 Hz, 3H), 2.83 (dd, J = 13.6, 5.8 Hz, 1 H), 2.77 (dd, J = 13.7, 7.0 H Hz, 3H) ppm, Labile protons were not observed due to exchange,'13C {1H} NMR (126 MHz,168.5, 165.84, 165.78, 138.5, 138.4, 137.1 , 136.7, 135.6, 135.3, 133.6, 133.1 , 132.25, 132.17, 130.34, 130.25,129.9, 129.6, 129.0, 128.9, 128.8, 128.61 , 128.55, 128.53, 128.50, 128.46, 128.44, 128.41, 128.35, 128.32, 128.2, 128.1 , 127.84, 127.79, 127.6, 126.5, 103.8, 97.1 , 80.3, 78.9, 77.8, 77.3, 77.2, 76.4, 75.8, 75.2, 74.8, 74.0, 73.5, 72.6, 70.6, 68.3, 68.0, 66.5, 66.1, 39.1 , 16.4 ppm; HRMS (ESI) m / z: calcd for Cy^O NalM+Na*] 1287.4565, found 1287.4567 (+0.56 ppm).

[0107] To a solution of the L-tartrate diacid 38 (230 mg, 183 pmol, 1.00 equiv) in DMF (11 mL, 17 mM) at 0 °C, DIPEA (192 pL, 1.10 mmol, 6.00 equiv) was added. After stirring for 5 minutes, dimethylamine hydrochloride (45 mg, 0.55 mmol, 3.0 equiv) was added followed by stirring for an additional 5 minutes before the addition of HATU (0.15 g, 0.40 mmol, 2.2 equiv). The reaction mixture was stirred for 30 minutes at 0 °C, then warmed to room temperature for 16h followed by addition of water and CH2CI2. The aqueous phase was extracted with CH2CI2 (3x), and the combined organic layers were washed with HCI (1 N) and brine. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. Co-evaporation with toluene (3x) was necessary to remove excess of DMF. Purification by flash chromatography (100 % EtOAc) provided 39 (0.14 g, 60 %) as a white foam. Rf = 0.30 (100 % EtOAc); [a]o25- 28 (c 0.8, CDCI3); Formula C78H82N2O17, MW 1319.5110 g / mol; IR (neat) vmax3062, 3031 , 2919, 2851 , 1726, 1650 cm1;1H NMR (500 MHz, CDCI3) 5 8.11 - 8.06 (m, 2H), 7.92 - 7.89 (m, 2H), 7.57 - 7.46 (m, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.35 - 7.20 (m, 27H), 6.99 - 6.95 (m, 1 H), 6.94 - 6.91 (m, 2H), 6.89 - 6.84 (m, 2H), 5.66 (appd, J = 3.0 Hz, 1 H), 5.60 (dd, J = 9.6, 8.3 Hz, 1 H), 5.47 (d, J = 8.1 Hz, 1 H), 5.30 (d, J = 8.1 Hz, 1 H), 5.16 (d, J = 3.6 Hz, 1 H), 4.94 (dd, J =14.8, 9.3 Hz, 3H), 4.82 (d, J = 12.2 Hz, 1 H), 4.77 (d, J = 11.9 Hz, 1 H), 4.70 (d, J = 11 .7 Hz, 1 H), 4.68 - 4.64 (m, 2H), 4.62 - 4.56 (m, 2H), 4.45 (dt, J = 23.5, 8.6 Hz, 2H), 4.03 (dd, J = 10.2, 3.6 Hz, 1 H), 3.98 - 3.89 (m, 3H), 3.84 (q, J = 6.4 Hz, 1 H), 3.63 (dd, J = 9.9, 6.7 Hz, 1 H), 3.56 (dd, J = 9.8, 5.4 Hz, 1 H), 3.50 (appd, J = 1 .4 Hz, 1 H), 3.07 (s, 3H), 2.91 (s, 3H), 2.84 (s, 3H), 2.82 - 2.79 (m, 1 H), 2.78 (appd, J = 4.8 Hz, 3H), 2.72 (dd, J = 13.9, 7.2 Hz, 1 H), 0.99 (d, J = 6.4 Hz, 3H) ppm;13C{1H} NMR (126 MHz, CDCI3) 5 170.6, 170.5, 168.2, 165.9, 165.3, 139.3, 138.9, 138.7, 137.8, 135.7, 135.3, 133.4, 133.0, 130.6, 130.1, 130.0, 129.6, 129.3, 128.71, 128.62, 128.55, 128.53, 128.50, 128.393, 128.385, 128.34, 128.31 , 128.28, 128.0, 127.83, 127.78, 127.65, 127.4, 127.3, 126.4, 98.8, 98.2, 79.5, 77.7, 77.1,76.9, 75.8, 75.6, 75.0, 73.9, 73.2, 73.0, 72.7, 71.3, 69.1, 67.1, 66.9, 66.4, 39.2, 37.6, 37.2, 35.8, 35.5, 16.5 (Due to overlapping carbon signals in the aromatic region 2 peaks are hidden. Due to insufficient signal-to-noise ratio in the13C NMR spectrum, one aliphatic carbon could not be confidently assigned) ppm; HRMS (ESI) m / z: calcd for C78H82N2Oi7Na [M+Na+] 1341.5511, found 1341.5496 (-0.69 ppm).

[0108] To a solution of the L-tartramide 39 (144 mg, 109 pmol, 1.00 equiv) in MeOH (5.5 mL, 20 mM), palladium on activated carbon (10 wt. %) (232 mg, 218 pmol, 2.00 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH + 1% formic acid, 50:50) provided the final compound 41 (LCB-2321) (68.8 mg, 73 %) as a white foam. [a]D25-9.2 (c 2.8, CH3OH); Formula C43H52N2O17, MW 868.8860 g / mol; IR (neat) vmax3411 , 2978, 1718, 1635 cm-1;1H NMR (500 MHz, CD3OD) 5 8.16 - 8.09 (m, 4H), 7.70 - 7.64 (m, 1 H), 7.60 (dd, J = 13.1 , 5.7 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 7.1 Hz, 2H), 6.90 (t,

[0109] To a solution of the L-tartramide 40 (17.1 mg, 12.7 pmol, 1.00 equiv) in MeOH (0.63 mL, 20 mM), palladium on activated carbon (10 wt. %) (27.0 mg, 25.4 pmol, 2.00 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH + 1% formic acid, 30:70) provided the final compound 42(LCB-2381) (5.5 mg, 48 %) as a white foam. [a]o25+18 (c 0.6, CH3OH); Formula C45H56N2O17, MW 896.9400 g / mol; IR (neat) vmax3399, 2975, 2932, 2877, 1723, 1655 cm1;1H NMR (500 MHz, CD3OD) 5 8.16 (d, J = 7.9 Hz, 2H), 8.11 - 8.07 (m, 2H), 7.71 - 7.60 (m, 3H), 7.54 (t, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 2H), 6.86 (t, J = 7.5 Hz, 2H), 6.79 (t, J = 7.4 Hz, 1 H), 5.82 (apps, 1 H), 5.47 (dd, J = 9.8, 8.1 Hz, 1 H), 4.93 (d, J = 7.9 Hz, 1 H), 4.79 (d, J = 3.7 Hz, 1 H), 4.63 (d, J = 3.4 Hz, 1 H), 4.53 - 4.48 (m, 1 H), 4.41 (d, J = 3.4 Hz, 1 H), 4.25 (dd, J = 9.9, 1.8 Hz, 1 H), 4.02 (m, 1 H), 3.89 (t, J = 6.3 Hz, 1 H), 3.82 (dd, J = 13.1 , 6.6 Hz, 1 H), 3.75 - 3.67 (m, 2H), 3.66 - 3.55 (m, 4H), 2.80 (appd, J = 5.5 Hz, 2H), 1.27 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1 .08 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H) ppm, Labile protons were not observed due to exchange13C{1H} NMR (126 MHz, CD3OD) 5 169.3, 168.8, 168.7, 166.9, 165.5, 133.2, 133.0, 130.1 , 130.0, 129.54, 129.46, 129.1 , 128.2, 128.1 , 127.3, 125.7, 101.1 , 100.8, 78.8, 78.4, 75.6, 74.4, 72.0, 71.9, 70.1, 68.6, 67.8, 66.4, 60.0, 41.52, 41 .46, 38.8, 21 .3, 21.1 , 20.90, 20.88, 15.3 (Due to overlapping carbon signals in the aromatic region 1 peak is hidden. Due to insufficient signal-to-noise ratio in the13C NMR spectrum, one aliphatic carbon could not be confidently assigned) ppm; HRMS (ESI) m / z: calcd for C45H56N20i?Na [M+Na+] 919.3471, found 919.3471 (-0.04 PPm).

[0110] To a solution of the D-tartramide 43, that was prepared in a similar manner as the corresponding L- tartramide 39, (27.4 mg, 20.8 pmol, 1.00 equiv) in 1 ,4-dioxane (1.0 mL, 21 mM), palladium on activated carbon (10 wt. %) (33.1 mg, 31.1 pmol, 1.50 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH + 1 % formic acid, 50:50) provided the final compound 45 (LCB-2376) (6.8 mg, 38 %) as a white foam. [a]o25+43 (c 0.7, CH3OH); Formula C43H52N2O17, MW 868.8860 g / mol; IR (neat) vmax 3384, 2932, 1718, 1639 cm1;1H NMR (500 MHz, CD3OD) 5 8.16 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 7.2 Hz, 2H), 7.70 - 7.58 (m, 2H), 7.53 (t, J = 7.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 6.86 (t, J = 7.3 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1 H), 5.91 (apps, 1 H), 5.64 (d, J = 3.9 Hz, 1 H), 5.47 (dd, J = 10.4, 3.8 Hz, 1 H), 5.04 (d, J = 7.2 Hz, 1 H), 4.96 (d, J = 7.2 Hz, 1 H), 4.60 (d, J = 3.9 Hz, 1 H), 4.58 (s, 1 H), 4.50 (d, J = 7.5 Hz, 1 H), 4.07 (t, J = 6.4 Hz, 1 H), 3.66 (dd, J = 13.0, 6.5 Hz, 1 H), 3.59 - 3.49 (m, 3H), 3.39 - 3.34 (m, 1 H), 3.18 (s, 3H), 3.12 (s, 3H), 2.93 (s, 3H), 2.85 (s, 3H), 2.84 - 2.76 (m, 2H), 2.73 (apps, 1 H), 0.93 (d, J = 6.5 Hz, 3H) ppm, Labile protons were not observed due to exchange13C{1H} NMR (126 MHz, CD3OD) 5 170.8, 170.1 , 168.4, 167.2, 137.5, 134.5, 134.4, 131.7, 131.1 , 131.0, 130.9, 130.5, 129.68, 129.65, 128.7, 127.2, 99.9, 97.9, 77.2, 76.4, 74.6, 73.5, 72.7, 71.84, 71.79, 71.3, 69.6, 68.9, 68.4, 61.4, 40.3, 38.5, 38.2, 36.3, 36.2, 16.4 (Due to insufficient signal-to-noise ratio in the13C NMR spectrum, onecarbonyl carbon could not be confidently assigned) ppm; HRMS (ESI) m / z: calcd for C43H52N2Oi7Na [M+Na+] 891.3164, found 891.3159 (+0.12 ppm).

[0111] To a solution of the D-tartramide 44 (23.4 mg, 17.1 pmol, 1.00 equiv) in 1 ,4-dioxane (0.82 mL, 21 mM), palladium on activated carbon (10 wt. %) (36.3 mg, 34.1 pmol, 2.00 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH + 1% formic acid, 30:70) provided the final compound 46 (LCB-2380) (2.5 mg, 16 %) as a white foam. [a]o25+48 (c 0.3, CH3OH); Formula C47H56N2O17, MW 920.9620 g / mol; IR (neat) vmax 3391, 2929, 2883, 1722, 1638 cm1;1H NMR (500 MHz, CD3OD) 5 8.16 (d, J = 7.2 Hz, 2H), 8.08 - 8.05 (m, 2H), 7.68 - 7.64 (m, 1 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 6.99 (d, J = 7.3 Hz, 2H), 6.84 (t, J = 7.3 Hz, 2H), 6.79 (d, J = 6.9 Hz, 1 H), 5.90 (apps, 1 H), 5.62 (d, J = 4.0 Hz, 1 H), 5.48 (dd, J = 10.5, 3.7 Hz, 1H), 4.83 (d, J = 7.5 Hz, 1 H), 4.79 (d, J = 7.6 Hz, 1 H), 4.60 (d, J = 4.0 Hz, 1 H), 4.58 (apps, 1 H), 4.52 (d, J = 8.7 Hz, 1 H), 4.07 - 4.04 (m, 1 H), 3.78 - 3.45 (m, 8H), 3.44 - 3.38 (m, 1 H), 3.36 (apps, 1 H), 3.30 - 3.17 (m, 4H), 2.85 (m, 2H), 2.00 - 1.78 (m, 8H), 0.92 (d, J = 6.5 Hz, 3H) ppm, Labile protons were not observed due to exchange,'13C{1H} NMR (126 MHz, CD3OD) 5 167.5, 167.1 , 166.7, 165.7, 133.1, 133.0, 130.4, 129.7, 129.6, 129.5, 129.1 , 128.3, 128.2, 127.3, 125.7, 98.7, 96.5, 71.9, 71.2, 70.6, 69.9, 68.2, 67.6, 67.0, 60.3, 39.4, 25.47, 25.46, 23.68, 23.64, 15.1 (Due to insufficient signai-to-noise ratio in the13C NMR spectrum, one aromatic, one carbonyl and 8 aliphatic carbons could not be confidently assigned} ppm; HRMS (ESI) m / z: calcd fo^yHselWvNa [M+Na+] 943.3471, found 943.3478 (+0.72 ppm).Synthesis for example 50 (LCB-2373)65 % 48% (2 steps)Scheme S1d. Synthesis of for example 50 (LCB-2373) followed procedures similar to the synthesis of 41 (LCB-2321) starting with previously reported bicyclic intermediate 47.34

[0112] To a solution of the L-tartramide 49 (61 mg, 52 pmol, 1.0 equiv) in MeOH (2.6 mL, 20 mM), palladium on activated carbon (10 wt. %) (167 mg, 78.5 pmol, 1.50 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH, 95:5) provided the final compound 50 (LCB-2373) (8.5 mg, 20 %) as a white foam. [a]o25-14 (c 1.0, H2O / MeOH, 50:50); Formula C38H48N2O17, MW 804.7990 g / mol; IR (neat) vmax 3405, 2924, 2853, 1721 , 1646 cm’1;1H NMR (500 MHz, D2O / MeOH) 5 8.15 (d, J = 7.9 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.70 (dd, J = 15.9, 7.9 Hz, 2H), 7.56 (dt, J = 15.4, 7.7 Hz, 4H), 5.24 (appd, J = 4.7 Hz, 2H), 4.92 (d, J = 7.4 Hz, 1 H), 4.65 (d, J = 7.4 Hz, 1 H), 4.60 (d, J = 7.4 Hz, 1 H), 4.57 (d, J = 1 .3 Hz, 1 H), 4.48 (dd, J = 12.1 , 7.8 Hz, 1 H), 4.28 (d, J = 6.1 Hz, 1 H), 4.13 - 4.07 (m, 2H), 3.66 (dd, J = 10.3, 3.2 Hz, 1 H), 3.58 (d, J = 3.2 Hz, 1 H), 3.53 (dd, J = 13.2, 6.6 Hz, 1 H), 3.43 (dd, J = 10.3, 4.0 Hz, 1 H), 2.87 (s, 3H), 2.79 (s, 3H), 2.75 (s, 3H), 2.64 (s, 3H), 2.23 - 2.08 (m, 2H), 1 .85 (appd, J = 13.4 Hz, 1 H), 1.70 - 1.61 (m, 1 H), 0.94 (d, J = 6.6 Hz, 3H) ppm, Labile protons were not observed due to exchange13C{1H} NMR (126 MHz, D2O / MeOH) 5 170.7, 169.8, 169.3, 168.6, 135.0, 134.7, 130.5, 130.2, 129.6, 129.54, 129.48, 101.1 , 100.5, 77.2, 76.7, 76.5, 75.9, 75.5, 72.1 , 71.8, 70.2, 70.1 , 68.4, 68.0, 63.8, 38.3, 38.1 , 36.4, 36.2, 27.7, 21 .8, 15.8 ppm (Due to overlapping carbon signals, 1 aromatic peak is hidden. Due to insufficient signal- to-noise ratio in the13C NMR spectrum, one carbonyl could not be confidently assigned) HRMS (ESI) m / z: calcd for C38H48N2Oi7Na [M+Na+] 827.2851 , found 827.2843 (-0.21 ppm).Synthesis of for example 55 (LCB-2374)Scheme S1e. Synthesis of for example 55 (LCB-2374) followed procedures similar to the synthesis of 41 (LCB-2321) with previously reported bicyclic intermediate 20.34

[0113] To a solution of the L-tartramide 54 (39.4 mg, 39.6 pmol, 1.00 equiv) in MeOH (2.0 mL, 20 mM), palladium on activated carbon (10 wt. %) (63.2 mg, 59.4 pmol, 1.50 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase C18 (H2O / MeOH, 95:5) provided the final compound 55 (LCB-2374) (6.9 mg, 24 %) as a white foam. [a]o25-36 (c 1.0, CH3OH); Formula C31H44N6O14, MW 724.7210 g / mol; IR (neat) vmax3356, 2937, 1717, 1641 cnr1;1H NMR (500 MHz, CD3OD) 5 7.99 - 7.95 (m, 2H), 7.63 - 7.59 (m, 1 H), 7.49 (t, J = 7.8 Hz, 2H), 5.37 (dd, J = 10.0, 7.9 Hz, 1 H), 5.32 (d, J = 6.3 Hz, 1 H), 5.14 (d, J = 7.9 Hz, 1 H), 5.05 (d, J = 8.0 Hz, 1 H), 5.02 (d, J = 3.6 Hz, 1 H), 4.85 (d, J = 8.1 Hz, 1 H), 3.90 (dd, J = 12.0, 2.9 Hz, 1 H), 3.81 (dd, J = 12.0, 6.8 Hz, 1 H), 3.76 - 3.67 (m, 3H), 3.63 (d, J = 10.0 Hz, 1 H), 3.60 - 3.58 (m, 1 H), 3.53 (dd, J = 6.8, 2.9 Hz, 1 H), 3.13 (s, 3H), 2.97 (s, 3H),2.85 (s, 3H), 2.70 (s, 3H), 2.61 - 2.53 (m, 1 H), 2.15 (dd, J = 13.1 , 4.5 Hz, 1 H), 2.12 - 2.06 (m, 1 H), 1.86 - 1.80 (m, 1 H), 1.07 (d, J = 6.6 Hz, 3H) ppm, Labile protons were not observed due to exchange,'13C{1H} NMR (126 MHz, CD3OD) 5 172.1, 169.9, 167.2, 159.8, 134.3, 131.5, 130.9, 129.6, 102.2, 100.5, 80.4, 77.1 , 76.9, 76.3, 73.5, 72.1 , 71.6, 70.7, 70.0, 68.4, 67.9, 60.9, 38.3, 37.8, 36.2, 35.7, 28.4, 22.9, 16.6 ppm; HRMS (ESI) m / z: calcd forC3iH44N60i4Na [M+Na+] 747.2813, found 747.2815 (- 3.9O ppm).Synthesis of for example 59 (LCB-2377)Scheme S1f. Synthesis of for example 59 (LCB-2377) followed procedures similar to the synthesis of 41 (LCB- 2321).

[0114] To a solution of the L-tartramide 58 (23.6 mg, 20.5 pmol, 1.00 equiv) in MeOH (1.0 mL, 20 mM), palladium on activated carbon (10 wt. %) (32.7 mg, 30.7 pmol, 1.50 equiv) was added. The reaction mixture was degassed under reduced pressure and backfilled with hydrogen (3x). After stirring at 50 °C for 16 hours, the reaction mixture was cooled to room temperature and was filtered through Celite® (prewashed with MeOH) and concentrated in vacuo. Purification by reverse phase 018 (H2O / MeOH, 20:80) provided the final compound 59 (LCB-2377) (5.0 mg, 28 %) as a white foam. [a]o25-39 (c 0.5, MeOH); Formula C42H52N6Oi5, MW 880.9050 g / mol; IR (neat) vmax 3378, 2973, 2935, 2882, 1720, 1641 cnr1;1H NMR (500 MHz, CD3OD) 5 8.14 - 8.10 (m, 2H), 8.00 (dd, J = 8.2, 1.1 Hz, 2H), 7.68 - 7.63 (m, 1 H), 7.61 - 7.52 (m, 3H), 7.46 (t, J = 7.8 Hz, 2H), 5.41 - 5.32 (m, 3H), 4.85 (d, J = 8.0 Hz, 1 H), 4.82 (d, J = 3.7 Hz, 1 H), 4.66 (dd, J = 12.0, 2.6 Hz, 1 H), 4.54 (dd, J = 12.1 , 7.7 Hz, 1 H), 4.43 (d, J = 7.9 Hz, 1 H), 4.00 (dd, J = 7.7, 2.6 Hz, 1 H), 3.85 (d, J = 9.5 Hz, 1 H), 3.73 (dd, J = 10.2, 3.1 Hz, 1 H), 3.71 - 3.67 (m, 2H), 3.67 - 3.63 (m, 1 H), 3.60 - 3.52 (m, 2H), 3.45 - 3.38 (m, 2H), 3.30 - 3.16 (m, 4H), 2.62 - 2.52 (m, 1 H), 2.31 (td, J = 13.5, 4.7 Hz, 1 H), 2.10 - 2.03 (m, 1 H), 1.91 (ddd, J = 13.2, 4.4, 2.1 Hz, 1 H), 1.80 - 1.69 (m, 4H), 1.69 - 1.60 (m, 2H), 1.56 (td, J = 12.7, 6.5 Hz, 1 H), 1 .51 - 1.42 (m, 1 H), 1 .01 (d, J = 6.5 Hz, 3H) ppm, Labile protons were not observed due to exchange13C{1H} NMR (126 MHz, CD3OD) 5 169.9, 168.2, 168.0, 167.4, 134.5, 134.2, 131.5, 131.2, 131.0, 130.8,129.8, 129.5, 102.7, 101.0, 79.9, 78.4, 78.2, 75.7, 73.4, 72.1, 71.6, 70.7, 69.8, 68.6, 68.3, 64.6, 47.8, 47.2, 47.0, 28.6, 26.6, 26.5, 25.1 , 24.9, 23.4, 16.7 ( The tetrazole carbon and one aliphatic carbon were not observed due to small amount of compound) ppm; HRMS (ESI) m / z: calcd for C42H52NeOi5Na [M+Na+] 903.3388, found 903.3386 (0.33 ppm).Example 2: Characterization of specific E- and P-selectin antagonistsBiology assays and protocolsSelectin preparation.

[0115] In-house selectin generation. Full-length selectins (P and E) were cloned in the pFUSE-hlgG1-Fc1 plasmid (using Agel, EcoRV and Agel, Bglll respectively). Plasmids were then transfected in AD293 cells using effectene with instructions provided by the manufacturer. Transfected cells were selected in 400pg / mL ZEOCIN. The proteins were secreted in the media. Media was collected, proteins were concentrated using Amicon Ultra centrifugal columns (Milipore, UFC903024). Selectins were purified on HiTrap® Protein G columns (GE Healthcare, 17-0404-01) using the manufacturer’s instructions. The elution was buffer exchanged to 1X PBS using Amicon columns. Commercial recombinant human PSGL-1-Fc (homodimer, 100-150 kDa) was purchased from R&D Systems (3345-PS). Commercial recombinant human P-selectin-Fc (homodimer, 260-300 kDa) was purchased from Sino Biological (13025-H02H). The commercial proteins were reconstituted to 0.25 mg / mL and stored at -78 °C following the manufacturer’s recommendations.SPR direct binding and competitive inhibition assay.

[0116] Molecular binding affinity analyses and competitive inhibition in solution assays by SPR were performed using a Biacore™ 3000 SPR system (GE Healthcare Life Sciences, Upsalaa, Sweden) equipped with research grade CM5 sensor chips (GE Healthcare, Freiburg, Germany, BR100012). Immobilization buffers (10 mM sodium acetate at pH 4.0, 4.5, and 5.0) and Amine Coupling Kit (BR100050) containing EDC, NHS, and ethanolamine were purchased from GE Healthcare. HBS-EP buffer 10x (0.1 M HEPES pH 7.4, 1.5 M NaCI, 0.03 M EDTA, 0.5% (v / v) Surfactant P-20) and HBS-N buffer 10x (0.1 M HEPES pH 7.4, 1.5 M NaCI) were purchased from GE Healthcare and diluted using HPLC grade water. All buffers were filtered using 0.22 pM Millex®-GP membrane filter units (Millipore Sigma, SLGP033R) and degassed prior to usage. HBS-EP buffer (10 mM HEPES pH 7.4, 150 mM NaCI, 3 mM EDTA, 0.005% (v / v) Surfactant P-20) was used for all immobilization procedures. HBS-Ca buffer (10 mM HEPES pH 7.4, 150 mM NaCI, 20 mM CaCfe, 0.010% (v / v) Surfactant P-20) was prepared from HBS-N buffer by supplementing with 20 mM CaCh and 0.01% (v / v) Surfactant P-20 (GE Healthcare, BR100054) as described. Commercial Bimosiamose was purchased from Cayman Chemical (Item No. 30878). Data were processed with Scrubber-2.0c (BioLogic Software Pty Ltd., Campbell, Australia). Visualization and fitting of equilibrium dissociation data was also carried out using the BIAevaluation software v.4.1 .1 (GE Healthcare). Double referencing (subtraction of reference surface and blank injection) was applied to each sample injection to correct bulk effects and other systematicartifacts. Nonlinear regression analysis of the dose-response inhibition data was carried out with GraphPad Prism version 8.00 (GraphPad Software, California, USA) to determine IC50 values.Direct binding assay for ranking of seiectin antagonists.

[0117] Using the Biacore™ 3000 Control Software Application Wizard’s “Aim for Immobilized Level” method, the surfaces of all flow cells (FC) were individually activated with NHS / EDC (1 :1) for seven minutes. The ligands, monomeric PSelFc or ESelFc in immobilization buffer (50 pg / mL in 10 mM sodium acetate buffer at pH 4.5) were injected at a flow rate of 5 pL / min over individual flow cells to achieve immobilized surface densities of 6200 RU (FC2) and 6300 RU (FC4) respectively. Finally, all sensor chip surfaces were deactivated with the injection of 1 M Ethanolamine hydrochloride at pH 8.5 for seven minutes. Two blank surfaces without ligands (FC1 and FC3) were prepared for in-line reference signal subtraction. Prior to SPR binding interaction analysis, the flow cells were equilibrated for 16 h in HBS-Ca buffer.

[0118] All assays were run at 25 °C, and five start-up cycles containing running buffer were included at the beginning of each assay to ensure baseline stability. Each cycle was injected serially using the “KINJECT” command over each prepared surface at a flow rate of 30 pL / min. For the evaluation of antagonists, serial dilutions of each analyte were prepared in running buffer (HBS-Ca). The injection cycles consisted of a 60 second association phase where the analytes were present at a concentration of 500 pM in running buffer, followed by an undisturbed 180 s dissociation period. A baseline stabilization period of 180 s, as well as two blank injection cycles containing running buffer were included after each analyte series to prevent carryover of trace residuals in the system.

[0119] For ranking of binding strength, SPR signals were recorded at a single analyte concentration (500 pM, in running buffer). The average of the signal recorded at 50 s to 55 s after injection (plateau) was calculated and divided by the molecular weight of the analyte. Triplicate injections of each analyte were tested on the same sensor chip surfaces to determine standard error (±SEM). The data were processed and normalized to the corrected binding response of LCB-110 on each surface.Competitive inhibition in solution assay.

[0120] Using the Biacore™ 3000 Control Software Application Wizard’s “Aim for Immobilized Level” method, the surfaces of all flow cells (FC) were individually activated with NHS / EDC (1 :1) for seven minutes. The ligand, homodimeric human PSGL-1-Fc (100-150 kDa) in immobilization buffer (50 pg / mL, in 10 mM sodium acetate buffer at pH 4.0) was injected at a flow rate of 5 pL / min over an individual flow cell to achieve an immobilized surface density of 2000 RU (FC2). Finally, all sensor chip surfaces were deactivated with the injection of 1 M Ethanolamine hydrochloride at pH 8.5 for seven minutes. A blank surface without PSGL-1-Fc (FC1) was prepared for in-line reference signal subtraction. Prior to SPR binding interaction analysis, the flow cells were equilibrated for 16 h in HBS-Ca buffer.

[0121] All assays were run at 25 °C, with cycles injected serially over each prepared surface at a flow rate of 10 pL / min. For the evaluation of antagonists, serial dilutions of each analyte were prepared in running buffer (HBS-Ca orHBS-Ca supplemented with 5% (v / v) DMSO for low solubility compounds). A preliminary inhibition screen of each antagonist at 500 pM in running buffer was carried out to determine the most potent candidates for the competition assay. Prior to injection, homodimeric recombinant human P-selectin-Fc was diluted to a final concentration of 2.8 pg / mL (~10 nM), with or without analytes and incubated for 30 minutes. The injection cycles consisted of a 180 s association phase where the analytes were present at a concentration of 0.97 pM to 500 pM in running buffer, followed by an undisturbed 180 s dissociation period. A 60 s regeneration injection of 1 M NaCI was performed, followed by a 120 s baseline stabilization period to prevent carryover of trace residuals in the system. A calibration block consisting of a series of five solutions of running buffer supplemented with 4% to 6% (v / v) DMSO was injected prior to analyte analysis blocks containing DMSO to investigate consistency of the calibration routine and to calibrate the solvent refractive index effects on the sensor chip surfaces. To determine the IC50 values of the selectin antagonists, a report point in the dissociation phase of the SPR binding response at 10 s after injection end of P- selectin-Fc in the presence of each analyte dilution was recorded (This method quantifies the amount of P-selectin- Fc bound to the PSGL-1-Fc surface after injection end and removes effects from systematic artifacts). The data for each assay was normalized with the binding response of P-selectin-Fc without antagonist (0% inhibition) and in the absence of calcium (100% inhibition), and the mean (±SEM) plotted as a function of analyte concentration.Cell-Selectin adhesion assay.

[0122] Cell-selectin assays were carried out in 96 well plates. Wells were coated with 2ug / mL of homemade P- Selectin Fc or E-Selectin Fc in 3%BSA-TrisCa (50mM tris-HCI pH7.4, 150mM NaCI, 50mM CaCI2). P-Selectin plates were coated overnight at 4°C while E-Selectin plates were coated 2h at 37°C. Plates were then blocked with a 1 :1 solution of 3%BSA-TrisCa and StabiliCoat® (Sigma, S0950) for 1 h at room temp with agitation. Simultaneously HL- 60 cells were tagged with LeukoTracker™ (Cell Biolabs, CBA-210) and incubated 1h at 37°C in serum-free IMDM (ATCC, 30-2005). 10 000 HL-60 were then added to each well of the plate and left to incubate for 1h at 37°C. The compounds at indicated concentrations or 50mM EDTA were then added and incubated for 30min at 37°C. Unbound cells were washed away, and the plate was imaged using the Zeiss AxioObserver Z1 microscope (Carl Zeiss). Cells bound were counted to determine binding and corrected over wells treated with EDTA using Fiji. Inhibition was determined as 100%-binding observed.In vivo cell migration assay.

[0123] Cell migration assay was carried out as described by Ray and Dittel38. Briefly, mice were injected according to experimental timeline. 1 mL 3% thioglycolate (Sigma-Aldrich, 70157) in the peritoneal cavity to stimulate leukocyte recruitment. Mice were sacrificed and the skin of the peritoneal cavity was removed, and the cavity was washed with 5mL of 2% heat-inactivated FBS 1X PBS (Gibco, 70013-032), PBS was collected, and red blood cells were lysed with Red Blood Cell Lysing Buffer Hybri-Max™ (Sigma-Aldrich, R7767). 1 million cells were used for identification by flow cytometry. Neutrophils were identified using a live / dead marker, and several surface proteins: PSGL1+, CD11 b+, CD11c-, Ly-6C+, Ly-6G+, were used to identify cell populations.

[0124] In the present work, installing a carboxylic acid bioisostere with either a benzoate or a free hydroxyl at C6of the fused galactopyranoside were instrumental to the discovery of the most potent E- and P-selectin antagonists - see Fig. 2A. Compound LCB-2318 was formed by Pd / C hydrogenation of the benzyl protecting groups following the [3+2] cycloaddition between sodium azide and nitrile 15. A C6-benzoyl group on the galactoside, previously shown to increase the potency of the first generation of antagonists, was introduced prior to tetrazole formation and final deprotection to yield LCB-2294.

[0125] The in vivo and in vitro activity of the novel selectin antagonists was assessed in a series of biological and biophysical assays. The in vivo activity of selectin antagonists LCB-2294 and LCB-2318 was tested in a mouse thioglycolate peritonitis model, which provided insight into the kinetics of leukocyte recruitment, particularly for neutrophils and monocytes / macrophages.35 39'42The activities of these lead molecules was compared with the results with other previously reported selectin antagonists (LCB-2248 and LCB-2267, Fig. 2A).34Additionally, to define the P- and E-selectin binding signature of these bioactive antagonists, direct binding and competition assays using surface plasmon resonance (SPR) were conducted.

[0126] In the preliminary study using the above-described protocol, compound LCB-2248 demonstrated activity at 2.5 mmol / kg (2 mg / kg) in lowering neutrophil levels, while compounds LCB-2267 and sLexwere inactive. Changes in PSGL-1 + cells were not statistically significant for the three treated groups. The rapid clearance of the compounds given IV being most likely the caveat of this experiment. The clinical strategy guiding the development of these molecules would most likely involve administration to hospitalized patients through infusion given that carbohydrate- based drugs are unlikely to be orally active candidates. This is however difficult to reproduce in the peritonitis model due to the practical limitations of infusing mice for a prolonged duration. Thus, the initial IV injection was complemented with subsequent intraperitoneal (IP) injections at different time points (Figs. 3A, 3C, 3E). The baseline response was determined by injecting the test compounds 10 minutes prior to the IP injection of thioglycolate (Figs. 3A and 3B). Peritoneal lavage was performed 10 minutes later and the population of neutrophils, PSGL+, CD11 b+, and macrophages / monocytes was analysed. No significant differences were observed between the control and the treated mice at this time point.

[0127] The experimental timeline was adjusted to evaluate the early stage of immune cell recruitment. As previously reported, neutrophil levels increase rapidly in this model.35’39 42A second IP injection of selectin antagonist was given 10 minutes after the thioglycolate treatment, and the peritoneal lavage was performed two hours after the first injection (Figs. 3C and 3D). At this time point, TG-treated mice not receiving selectin antagonists displayed elevated cell populations, while groups treated with compounds LCB-2248, LCB-2318, or LCB-2294 all exhibited decreased populations of neutrophils, CD11 b+, and macrophages / monocytes. Compound LCB-2294 also reduced the number of PSGL-1 positive cells. Compounds LCB-2248 and LCB-2242 were also able to reduce the total neutrophil populations (Fig. 7).

[0128] A third experimental protocol was designed to determine the effects of these compounds at a later stage of inflammation. Neutrophil levels should be lower after 48 hours,43while the macrophages / monocyte levels remain high. Compound injections were performed 24 hours after the thioglycolate IP treatment (Figs. 3E and 3F). Two and six hours later, additional IP injections of selectin antagonists were administered. Fifteen hours after the last IPinjection, a third injection was administered three hours before the peritoneal lavage. Baseline neutrophil levels were observed in all groups. The cell populations PSGL-1 +, CD11b+, and macrophage / monocytes were all significantly reduced and comparable to those observed in the natural saline solution (NSS) treated group without TG inflammatory stimulation. Thus, the investigated P- and E-selectin antagonists effectively prevent in vivo immune cell recruitment triggered by a strong inflammatory signal.

[0129] In vitro selectin mediated interactions were studied by direct SPR measurement of monomeric P- and E- selectins covalently attached to CM-5 sensor chips (Table 1). sLexand analogue solutions were passed through the flow channel at different concentrations and the change of resonance units (RU) between the ligated and the control was measured. The net binding values were then adjusted for the molecular weight differences of each molecule. Molecule LCB-110, a representative of a first generation of selectin antagonists (FIG. 1 A), was used as a standard for comparison purposes. The direct binding assay indicated that the bicyclic systems with rigidified carboxylates (LCB-2248 and LCB-2267) showed improved binding to both P- and E-selectin relative to sLexor LCB-110, with the axial carboxylic acid LCB-2248 having better binding than its equatorial counterpart LCB-2267. Compounds LCB- 2318, LCB-2294, LCB-2259 and LCB-2322 are also observed to bind significantly to the immobilized selectins (Table 1, Fig. 6).Table 1. SPR direct binding assays for sLexanalogues* Results are the mean (±SEM) of three independent experiments. The SPR signal was divided by the molecular weight and normalized RU response of LCB-110.

[0130] A competitive SPR protocol was then developed to have a more discriminating model (Table 2). In this protocol, sLexanalogues and PSGL-1 compete for binding to homodimeric P-selectin in solution. The complex formed by the ligated homodimeric human PSGL-1 -Fc and the homodimeric human P-selectin exhibits a high response difference when bound together. The active analogues prevent dimeric P-selectin from binding to immobilized PSGL-1 , resulting in an important reduction of the measured RU. This SPR protocol is believed to more accurately represent an in vivo scenario, where multivalent interactions occur between dimeric selectins on the vessel wall and dimeric PSGL-1 (or clusters thereof) on the surface of neutrophils.44The formation of these high- avidity complexes is more difficult to disrupt and the experimental conditions used require a high concentration of analogues to compete with PSGL-1 . In this assay, sLexwas inactive even at a concentration of 1 mM, whereas bimosiamose, a known P-selectin antagonist, displays an IC50 of 249 piM.45The first-generation molecule LCB-110gave a significantly improved IC50 of 162 piM.46Compounds LCB-2248, LCB-2318 and LCB-2294 were the most active molecules tested with IC50 values of 108, 55 and 125 piM, respectively.Table 2. SPR Screening of Selectin Antagonists for Competitive Inhibition of P-Selectin Binding to Homodimeric Human PSGL-1 at 500 piM and ICso-aaHomodimeric human PSGL-1-Fc (100-150 kDa) was immobilized with surface density of 2000 RU and the homodimeric recombinant human P-selectin-Fc 2.8 pg / mL (~10 nM) was incubated for 30 min with or without analytes at 7 concentrations from 500 pM to 7.8 pM in running buffer before injection. Selectin binding inhibition data for each assay were normalized with the binding response of P-selectin-Fc without antagonist (0% inhibition) and in the absence of calcium (100% inhibition), and the mean (±SEM) of 2 injection cycles was plotted as a function of analyte concentration.bTwo independent experiments were performed.cThree independent experiments were performed (n=3).dIC50 for compound LCB-110 was obtained from a single experiment.

[0131] The in vitro activity of the compounds was also investigated using a more functional HL-60 cell assay. In this assay, HL-60 cells labeled with LeukoTracker™ were incubated on plates with immobilized monomeric P- or E- selectin, in the presence or absence of the test compounds (Figs. 4 and 5). Active compounds that bind to E- or P- selectin will displace the HL-60 cells, which are removed in the wash step. The remaining bound, LeukoTracker™ labeled cells are then visualised and counted with fluorescence microscopy. Compounds LCB-2248, LCB-2318, LCB-2294, LCB-2321, and LCB2376 were significantly more active than sLexat all concentrations against P- selectin. Interestingly, compounds LCB-2318, LCB-2294, LCB-2321, and LCB2376 were also active against E- selectin.

[0132] The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.REFERENCES

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Claims

CLAIMS:1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein:Ri and R2 independently represent -O-R20, or -NR21R22, wherein R20 represents alkyl, and R21 and R22 independently represent H, alkyl, or aryl, or R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group,R3 represents H, -CH2-O-R23, or -CH2-NR24R25, wherein: R23 represents H, benzoyl (Bz), or aryl unsubstituted or substituted with one or more halogen or haloalkyl (preferably the halogen is -F; preferably the haloalkyl is CF3),R24 represents H, andR25 represents -C(=O)-R26, wherein R26 represents alkyl, or aryl, each of which being unsubstituted or substituted with one or more halogen atoms, R4 represents -O-R27, wherein R27 represents H, or benzoyl (Bz),R? represents H, with the proviso that when Re representsat least one of R1 and R2 (preferably both) represents -NR21R22, and / or R3 represents -CH2-NR24R25, and with the proviso that when R5 and Re together form cycle A and Rw represents -COOH, then: at least one of R1 and R2 (preferably both) represents -NR21R22, and / orRe represents -CH2-NR24R25, and / orR11 represents benzyl (Bn).

2. The compound of claim 1, wherein R1 and R2 represent identical substituents.

3. The compound of claim 1 or 2, wherein R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl.

4. The compound of claim 1 or 2, wherein R1 and R2 represent -NR21R22.

5. The compound of any one of claims 1 to 4, wherein R21 and R22 represent identical substituents.

6. The compound of any one of claims 1 to 4, wherein R21 and R22 represent different substituents, preferably wherein one of R21 and R22 represents H, the other of R21 and R22 represents alkyl or aryl.

7. The compound of any one of claims 1 to 6, wherein the alkyl in R21 and R22 is methyl or propyl (preferably isopropyl).

8. The compound of any one of claims 1 to 7, wherein the aryl in R21 and R22 is phenyl.

9. The compound of any one of claims 1 to 8, wherein R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably wherein said nitrogen atom is the only heteroatom in the heterocycloalkyl group.

10. The compound of any one of claims 1 to 9, wherein R21 and R22 together with the nitrogen atom to which they are attached form I I — —NI or, more preferably11 . The compound of any one of claims 1 to 8, wherein R21 and R22 represent alkyl.

12. The compound of any one of claims 1 to 8, wherein R21 and R22 represent aryl.

13. The compound of any one of claims 1 to 12, wherein the one or more halogen atom substituting the aryl in R23 is fluorine.

14. The compound any one of claims 1 to 13, wherein the one or more halogen atom substituting the one or more alkyl substituting the aryl in R23 is fluorine.

15. The compound any one of claims 1 to 14, wherein the one or more alkyl substituted with one or more halogen atom in R23 is CF3.

16. The compound of any one of claims 1 to 15, wherein R23 represents H.

17. The compound of any one of claims 1 to 15, wherein R23 represents benzoyl (Bz).

18. The compound of any one of claims 1 to 15, wherein R23 represents aryl unsubstituted or substituted with one or more halogen atom and / or alkyl substituted with one or more halogen atoms.

19. The compound of any one of claims 1 to 18, wherein the alkyl in R26 is methyl unsubstituted or substituted with one or more halogen atoms.

20. The compound of any one of claims 1 to 19, wherein the aryl in R26 is phenyl unsubstituted or substituted with one or more halogen atoms.21 . The compound of any one of claims 1 to 20, wherein the halogen atoms substituting the alkyl and / or the aryl in R26 are fluorine atoms.

22. The compound of any one of claims 1 to 21 , wherein R26 is methyl or trihalomethyl, preferably methyl or -CF3.

23. The compound of any one of claims 1 to 21, wherein R26 is phenyl or para-halophenyl, preferably phenyl or parafluorophenyl.

24. The compound of any one of claims 1 to 23, wherein R3 represents H.

25. The compound of any one of claims 1 to 23, wherein R3 represents -CH2-O-R23.

26. The compound of any one of claims 1 to 23, wherein R3 represents -CH2-NR24R25.

27. The compound of any one of claims 1 to 26, wherein R27 represents H.

28. The compound of any one of claims 1 to 26, wherein R27 represents benzoyl (Bz).

29. The compound of any one of claims 1 to 28, wherein Rs represents H, and Re represents30. The compound of any one of claims 1 to 29, wherein Re represents31 . The compound of any one of claims 1 to 29, wherein Re represents32. The compound of any one of claims 1 to 28, wherein R5 and Re together form cycle A.

33. The compound of any one of claims 1 to 32, wherein R10 represents -COOH. W34. The compound of any one of claims 1 to 33, wherein R10 represents N N35. The compound of any one of claims 1 to 34, wherein Rn represents H.

36. The compound of any one of claims 1 to 34, wherein Rn represents benzyl (Bn).

37. The compound of any one of claims 1 to 36, wherein when Re represents, then at least one of R1 and R2 (preferably both) represents -NR21R22.

38. The compound of any one of claims 1 to 37, wherein when R5 and Re together form cycle A and Rw represents -COOH, then at least one of R1 and R2 (preferably both) represents -NR21R22.

39. The compound of any one of claims 1 to 38, wherein when R5 and Re together form cycle A and Rw represents -COOH, then R3 represents -CH2-NR24R25.

40. The compound of any one of claims 1 to 39, wherein when R5 and Re together form cycle A and Rw represents-COOH, then Rn represents benzyl (Bn).41 . The compound of any one of claims 1 to 40, wherein R5 and Re together form cycle A and Rw represents theMWN^^NH\ _ I tetrazolyl: N N , preferably wherein Rn represents H, and / or R1 and R2 represent identical substituents, and / or R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl, and / or R3 represents -CH2-O- R23, preferably wherein R23 represents H, or benzoyl (Bz), and / or R27 represents H.

42. The compound of claim 41 , wherein R23 represents H.

43. The compound of claim 41 , wherein R23 represents benzoyl (Bz).

44. The compound of any one of claims 1 and 41 to 43, being of formula (II):wherein Bz is benzoyl, iPr is isopropyl and Bz is benzoyl and R; represents H, or benzoyl (Bz), or a pharmaceutically acceptable salt thereof.

45. The compound of any one of claims 1 to 40, wherein R5 represents H, Re represents, and R1 and R2 represent -NR21 R22, preferably wherein R28 represents -COOH, and / or R1 and R2 represent identical substituents, and / or the alkyl in R21 and R22 is methyl, and / or the aryls inR21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R3 represents -CH2-O-R23.

46. The compound of claim 45, wherein R21 and R22 represent identical substituents,47. The compound of claim 45 or 46, wherein R21 and R22 represent alkyl.

48. The compound of claim 45, R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably, more preferably49. The compound of any one of claims 45 to 48, wherein R23 represents H.

50. The compound of any one of claims 45 to 48, wherein R23 represents benzoyl (Bz).51 . The compound of any one of claims 45 to 50, wherein R27 represents H.

52. The compound of any one of claims 45 to 50, wherein R27 represents benzoyl (Bz).

53. The compound of any one of claims 1 and 45 to 52, being of formula (III):or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 1 to 40, wherein R5 and Re together form cycle A, R10 represents -COOH,represents H, and R1 and R2 represent -NR21R22, preferably wherein R1 and R2 representidentical substituents, and / or the alkyl in R21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R3 represents -CH2-O-R23.

55. The compound of claim 54, wherein R21 and R22 represent identical substituents.

56. The compound of claim 54 or 55, wherein R21 and R22 represent alkyl.

57. The compound of claim 54, wherein R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably58. The compound of any one of claims 54 to 57, wherein R23 represents H.

59. The compound of any one of claims 54 to 57, wherein R23 represents benzoyl (Bz).

60. The compound of any one of claims 57 to 59, wherein R27 represents H.61 . The compound any one of claims 1 and 57 to 60, being of formula (IV):, , , , or a pharmaceutically acceptable salt thereof.

62. The compound of any one of claims 1 to 40, wherein R5 and Re together form cycle A, R10 represents -COOH,represents H, and R3 represents -CH2-NR24R25, wherein R25 represents -C(=O)-R26, preferably wherein the alkyl in R26 is methyl unsubstituted or substituted with one or more halogen atoms, preferably methyl or trihalomethyl, and / orthe aryl in R26 is phenyl unsubstituted or substituted with one or more halogen atoms, preferably phenyl or para-halophenyl, the one or more halogen atoms in R26 is fluorine, the alkyl in R21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R27 represents H.

63. The compound of claim 62, wherein R1 and R2 represent identical substituents.

64. The compound of claim 62 or 63, wherein R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl.

65. The compound of claim 62 or 63, wherein R1 and R2 represent -NR21R22.

66. The compound of any one of claims 62, 63, and 65, wherein R21 and R22 represent alkyl.

67. The compound of any one of claims 62, 63, and 65, wherein R21 and R22 represent aryl.

68. The compound of any one of claims 62, 63, and 65, wherein R21 and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably, more preferably69. The compound of any one of claims 62 to 68, being of formula (V):or a pharmaceutically acceptable salt thereof.

70. The compound of any one of claims 1 to 40, wherein R5 represents H, and Re represents, preferably wherein R1 and R2represent identical substituents, and / or the alkyl in R21 and R22is methyl, and / or the aryl in R21 and R22is phenyl, and / or the nitrogen atom to which R21 and R22are both attached is the only heteroatom in the heterocycloalkyl group, and / or R2? represents H.71 . The compound of claim 70, wherein R1 and R2represent -O-R20, preferably wherein R2o represents isopropyl.

72. The compound of claim 70, wherein R1 and R2represent -NR21R22.

73. The compound of any one of claims 70 to 72, wherein R2I and R22represent identical substituents.

74. The compound of any one of claims 70 to 73, wherein R2I and R22represent alkyl.

75. The compound of any one of claims 70 to 73, wherein R2I and R22represent aryl.

76. The compound of any one of claims 70 to 72, wherein R2I and R22together with the nitrogen atom to which theyX k are attached form a heterocycloalkyl group, preferably I I — —NI or *\ - ] , more preferably77. The compound of any one of claims 70 to 76, wherein R3 represents -CH2-O-R23, preferably wherein R23 represents H.

78. The compound of any one of claims 70 to 76, wherein R23 represents benzoyl (Bz).

79. The compound of any one of claims 70 to 78, being of formula (VI):(VI), wherein Bz is benzyl, Bz is benzoyl, R1 and R2 are as defined in any one of claims 70 to 78, R23 represents H, or benzoyl (Bz), and R27 represents H, or benzoyl (Bz), or a pharmaceutically acceptable salt thereof.

80. The compound of any one of claims 1 to 40, wherein R5 and Re together form cycle A, R10 represents -COOH,represents benzyl (Bn), preferably wherein R1 and R2 represent identical substituents, and / or the alkyl in R21 and R22 is methyl, and / or the aryl in R21 and R22 is phenyl, and / or the nitrogen atom to which R21 and R22 are both attached is the only heteroatom in the heterocycloalkyl group, and / or R27 represents H.81 . The compound of claim 81 , wherein R1 and R2 represent -O-R20, preferably wherein R20 represents isopropyl.

82. The compound of claim 81 , wherein R1 and R2 represent -NR21R22.

83. The compound of any one of claims 81 to 83, wherein R21 and R22 represent identical substituents.

84. The compound of any one of claims 81 to 84, wherein R21 and R22 represent alkyl.

85. The compound of any one of claims 81 to 84, wherein R21 and R22 represent aryl.

86. The compound of any one of claims 81 to 83, wherein R2I and R22 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, preferably87. The compound of any one of claims 81 to 87, wherein R3represents -CH2-O-R23, preferably wherein R23 represents H.

88. The compound of any one of claims 81 to 87, wherein R23 represents benzoyl (Bz).

89. The compound of any one of claims 81 to 89, being of formula (VII):(VII), wherein Bz is benzyl, Ph is phenyl, R1 and R2 are as defined in any one of claims 81 to 89, R23 represents H, or benzoylof a pharmaceutically acceptable salt thereof.

90. The compound of any one of claims 1 to 90, being:(LCB-2318) (LCB-2294), or a pharmaceutically acceptable salt thereof.

91. A pharmaceutical composition comprising the compound of any one of claims 1 to 91 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

92. The compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for use as a medicament.

93. The compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for use in the prevention or treatment of hyperinflammation, for example lung or respiratory hyperinflammation, in a subject.

94. A method for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, comprising administering to a subject in need thereof an effective amount of compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92.

95. Use of the compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, in a subject.

96. Use of the compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for the manufacture of a medicament for preventing or treating hyperinflammation, for example lung or respiratory hyperinflammation, in a subject.

97. The compound or pharmaceutical composition of claim 94, the method of claim 95, or the use of claim 96 or 97, wherein the hyperinflammation is caused by a virus.

98. The compound, pharmaceutical composition, method, or use of claim 98, wherein the virus is a rhinovirus, an influenza virus, a respiratory syncytial virus (RSV) or a coronavirus.

99. The compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for use in the prevention or treatment of SIRS, for example SIRS caused by sepsis, in a subject.

100. A method for preventing or treating systemic inflammatory response syndrome (SIRS) comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92.101 . Use of the compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for preventing or treating SIRS in a subject.

102. Use of the compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92, for the manufacture of a medicament for preventing or treating SIRS in a subject.

103. The compound or pharmaceutical composition of claim 100, the method of claim 101, or the use of claim 102 or 103, wherein the SIRS is associated or caused by sepsis.

104. The compound, pharmaceutical composition, method, or use of claim 104, wherein the SIRS is caused by a viral infection, for example an infection by an influenza virus or a severe acute respiratory syndrome (SARS) virus such as SARS-CoV-2.

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