FOGLER WILLIAM E (US)
GIRARD ARMAND F (US)
FOGLER WILLIAM E (US)
GIRARD ARMAND F (US)
WO2006083322A2 | 2006-08-10 | |||
WO1998009976A1 | 1998-03-12 | |||
WO2009073911A1 | 2009-06-18 | |||
WO2013096926A1 | 2013-06-27 | |||
WO2016089872A1 | 2016-06-09 | |||
WO2019133878A1 | 2019-07-04 | |||
WO2018068010A1 | 2018-04-12 | |||
WO2017095904A1 | 2017-06-08 | |||
WO2019133878A1 | 2019-07-04 | |||
WO2020139962A1 | 2020-07-02 | |||
WO2020219419A1 | 2020-10-29 | |||
WO2020219417A1 | 2020-10-29 |
US20100279965A1 | 2010-11-04 | |||
US20070054870A1 | 2007-03-08 | |||
US202063001185P | 2020-03-27 | |||
US9254322B2 | 2016-02-09 | |||
US9486497B2 | 2016-11-08 | |||
US9109002B2 | 2015-08-18 | |||
US8410066B2 | 2013-04-02 | |||
US10519181B2 | 2019-12-31 | |||
US20190233458A1 | 2019-08-01 | |||
USRE44778E | 2014-02-25 | |||
US20180369205A1 | 2018-12-27 |
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What is claimed is: 1. A method of treating COVID-19 in a patient in need thereof, the method comprising administering to the patient an effective amount of at least one E-selectin antagonist or a pharmaceutical composition comprising an effective amount of at least one E-selectin antagonist. 2. A method of treating a disease, disorder, and/or condition associated with COVID-19 in a patient in need thereof, the method comprising administering to the patient an effective amount of at least one E-selectin antagonist or a pharmaceutical composition comprising an effective amount of at least one E-selectin antagonist. 3. The method according to claim 2, wherein the disease, disorder, and/or condition associated with COVID-19 is acute lung injury. 4. The method according to claim 2, wherein the disease, disorder, and/or condition associated with COVID-19 is acute respiratory distress syndrome. 5. The method according to claim 2, wherein the disease, disorder, and/or condition associated with COVID-19 is pneumonia. 6. The method according to claim 2, wherein the disease, disorder, and/or condition associated with COVID-19 is ARDS pneumonia. 7. A method of treating acute respiratory distress syndrome in a patient in need thereof, the method comprising administering to the patient an effective amount of at least one E-selectin antagonist or a pharmaceutical composition comprising an effective amount of at least one E-selectin antagonist. 8. A method of treating pneumonia in a patient in need thereof, the method comprising administering to the patient an effective amount of at least one E-selectin antagonist or a pharmaceutical composition comprising an effective amount of at least one E-selectin antagonist. 9. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from , and pharmaceutically acceptable salts of any of the foregoing. 10. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (I): (I) isomers of Formula (I), tautomers of Formula (I), and pharmaceutically acceptable salts of any of the foregoing, wherein: R1 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; R2 is chosen from H, -M, and –L-M; R3 is chosen from –OH, –NH2, –OC(=O)Y1, –NHC(=O)Y1, and –NHC(=O)NHY1 groups, wherein Y1 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C6-18 aryl, and C1-13 heteroaryl groups; R4 is chosen from -OH and -NZ1Z2 groups, wherein Z1 and Z2, which may be identical or different, are each independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups, wherein Z1 and Z2 may together form a ring; R5 is chosen from C3-8 cycloalkyl groups; R6 is chosen from -OH, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; R7 is chosen from -CH2OH, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; R8 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; L is chosen from linker groups; and M is a non-glycomimetic moiety chosen from polyethylene glycol, thiazolyl, chromenyl, -C(=O)NH(CH2)1-4NH2, C1-8 alkyl, and -C(=O)OY groups, wherein Y is chosen from C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl groups. 11. The method according to claim 10, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (I), wherein the non-glycomimetic moiety comprises polyethylene glycol. 12. The method according to claim 10 or 11, wherein L is -C(=O)NH(CH2)1-4NHC(=O)-. 13. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (Ia): and pharmaceutically acceptable salts thereof, wherein n is chosen from integers ranging from 1 to 100. 14. The method according to claim 13, wherein n is chosen from 4, 8, 12, 16, 20, 24, and 28. 15. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from Compound A: Compound A and pharmaceutically acceptable salts thereof. 16. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (II): isomers of Formula (II), tautomers of Formula (II), and pharmaceutically acceptable salts of any of the foregoing, wherein: R1 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; R2 is chosen from –OH, –NH2, –OC(=O)Y1, –NHC(=O)Y1, and –NHC(=O)NHY1 groups, wherein Y1 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C6-18 aryl, and C1-13 heteroaryl groups; R3 is chosen from -CN, -CH2CN, and -C(=O)Y2 groups, wherein Y2 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -OZ1, -NHOH, -NHOCH3, -NHCN, and –NZ1Z2 groups, wherein Z1 and Z2, which may be identical or different, are independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups, wherein Z1 and Z2 may together form a ring; R4 is chosen from C3-8 cycloalkyl groups; R5 is independently chosen from H, halo, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups; n is chosen from integers ranging from 1 to 4; and L is chosen from linker groups. 17. The method according to claim 16, wherein the at least one E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (IIa): and pharmaceutically acceptable salts thereof. 18. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional antagonist chosen from Compound B: Compound B and pharmaceutically acceptable salts thereof. 19. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional pan-selectin antagonist chosen from compounds of Formula (III): (III) isomers of Formula (III), tautomers of Formula (III), and pharmaceutically acceptable salts of any of the foregoing, wherein: R1 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl groups; R2 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, –OH, – OX1, halo, –NH2, –OC(=O)X1, –NHC(=O)X1, and –NHC(=O)NHX1 groups, wherein X1 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, C2-12 heterocyclyl, C6-18 aryl, and C1-13 heteroaryl groups; R3 is chosen from –CN, –CH2CN, and –C(=O)X2 groups, wherein X2 is chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, –OY2, –NHOH, –NHOCH3, –NHCN, and – NY2Y3 groups, wherein Y2 and Y3, which may be identical or different, are independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C4-16 cycloalkylalkyl groups, wherein Y2 and Y3 may join together to form a ring; R6 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, and –C(=O)R7 groups; each R7 is independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C4-16 cycloalkylalkyl, , , , , , , , groups, wherein each X3 is independently chosen from H, –OH, Cl, F, N3, –NH2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C6-14 aryl, –OC1-8 alkyl, –OC2-8 alkenyl, –OC2-8 alkynyl, and –OC6-14 aryl groups, wherein any of the above ring compounds may be substituted with one to three groups independently chosen from Cl, F, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C6-14 aryl, and –OY4 groups, wherein Y4 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, and C6-14 aryl groups; n is chosen from integers ranging from 0 to 2; p is chosen from integers ranging from 0 to 3; L is chosen from linker groups; and Z is chosen from benzyl amino sulfonic acid groups. 20. The method according to claim 19, wherein the at least one E-selectin antagonist is chosen from Formula (IIIa): tautomers of Formula (IIIa), and pharmaceutically acceptable salts of any of the foregoing. 21. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional pan-selectin antagonist chosen from Compound C: , tautomers of Compound C, and pharmaceutically acceptable salts of any of the foregoing. 22. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (IV): prodrugs of Formula (IV), isomers of Formula (IV), tautomers of Formula (IV), and pharmaceutically acceptable salts of any of the foregoing, wherein each R1, which may be identical or different, is independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, and –NHC(=O)R5 groups, wherein each R5, which may be identical or different, is independently chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-18 aryl, and C1-13 heteroaryl groups; each R2, which may be identical or different, is independently chosen from halo, – OY1, –NY1Y2, –OC(=O)Y1, –NHC(=O)Y1, and –NHC(=O)NY1Y2 groups, wherein each Y1 and each Y2, which may be identical or different, are independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2- 12 haloalkynyl, C6-18 aryl, and C1-13 heteroaryl groups, wherein Y1 and Y2 may join together along with the nitrogen atom to which they are attached to form a ring; each R3, which may be identical or different, is independently chosen from wherein each R6, which may be identical or different, is independently chosen from H, C1-12 alkyl and C1-12 haloalkyl groups, and wherein each R7, which may be identical or different, is independently chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -OY3, -NHOH, -NHOCH3, –NHCN, and –NY3Y4 groups, wherein each Y3 and each Y4, which may be identical or different, are independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups, wherein Y3 and Y4 may join together along with the nitrogen atom to which they are attached to form a ring; each R4, which may be identical or different, is independently chosen from -CN, C1-4 alkyl, and C1-4 haloalkyl groups; m is chosen from integers ranging from 2 to 256; and L is chosen from linker groups. 23. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (V): prodrugs of Formula (V), isomers of Formula (V), tautomers of Formula (V), and pharmaceutically acceptable salts of any of the foregoing, wherein each R1, which may be identical or different, is independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, and –NHC(=O)R5 groups, wherein each R5, which may be identical or different, is independently chosen from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-18 aryl, and C1-13 heteroaryl groups; each R2, which may be identical or different, is independently chosen from halo, – OY1, –NY1Y2, –OC(=O)Y1, –NHC(=O)Y1, and –NHC(=O)NY1Y2 groups, wherein each Y1 and each Y2, which may be identical or different, are independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C2-12 haloalkenyl, C2- 12 haloalkynyl, C6-18 aryl, and C1-13 heteroaryl groups, wherein Y1 and Y2 may join together along with the nitrogen atom to which they are attached to form a ring; each R3, which may be identical or different, is independently chosen from wherein each R6, which may be identical or different, is independently chosen from H, C1-12 alkyl and C1-12 haloalkyl groups, and wherein each R7, which may be identical or different, is independently chosen from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, -OY3, -NHOH, -NHOCH3, –NHCN, and –NY3Y4 groups, wherein each Y3 and each Y4, which may be identical or different, are independently chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, and C2-8 haloalkynyl groups, wherein Y3 and Y4 may join together along with the nitrogen atom to which they are attached to form a ring; each R4, which may be identical or different, is independently chosen from -CN, C1-4 alkyl, and C1-4 haloalkyl groups; m is 2; and L is chosen from , wherein R8 is chosen from H, C1-8 alkyl, C6-18 aryl, C7-19 arylalkyl, and C1-13 heteroaryl groups and each p, which may be identical or different, is independently chosen from integers ranging from 0 to 250. 24. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from Compound D: . Compound D. 25. The method according to any one of claims 1 to 8, wherein the at least one E-selectin antagonist is chosen from Compound E: Compound E. 26. The method according to any one of claims 1 to 25, further comprising administering at least one additional therapeutic agent. 27. The method according to claim 26, wherein the at least one additional therapeutic agent is chosen from antiviral and antiretroviral drugs. 28. The method according to claim 26, wherein the at least one additional therapeutic agent is molnupiravir. 29. The method according to claim 26, wherein the at least one additional therapeutic agent is chosen from anti-protozoal agents. 30. The method according to claim 26, wherein the at least one additional therapeutic agent is chosen from IL-6 inhibitors. 31. The method according to any one of claims 1 to 30, further comprising administering at least one COVID-19 vaccine. |
isomers of Formula (II), tautomers of Formula (II), and pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; R 2 is chosen from –OH, –NH 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NHY 1 groups, wherein Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups; R 3 is chosen from -CN, -CH 2 CN, and -C(=O)Y 2 groups, wherein Y 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OZ 1 , -NHOH, -NHOCH3, -NHCN, and –NZ 1 Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Z 1 and Z 2 may together form a ring; R 4 is chosen from C3-8 cycloalkyl groups; R 5 is independently chosen from H, halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; n is chosen from integers ranging from 1 to 4; and L is chosen from linker groups. 17. The method according to Embodiment 16, wherein the at least one E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (IIa):
and pharmaceutically acceptable salts thereof. 18. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional antagonist chosen from Compound B: Compound B (GMI-1359) and pharmaceutically acceptable salts thereof. 19. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional pan-selectin antagonist chosen from compounds of Formula (III): (III) isomers of Formula (III), tautomers of Formula (III), and pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl groups; R 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, –OH, – OX 1 , halo, –NH 2 , –OC(=O)X 1 , –NHC(=O)X 1 , and –NHC(=O)NHX 1 groups, wherein X 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C 1-13 heteroaryl groups; R 3 is chosen from –CN, –CH 2 CN, and –C(=O)X 2 groups, wherein X 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, –OY 2 , –NHOH, –NHOCH 3 , –NHCN, and – NY 2 Y 3 groups, wherein Y 2 and Y 3 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 4-16 cycloalkylalkyl groups, wherein Y 2 and Y 3 may join together to form a ring; R 6 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, and –C(=O)R 7 groups; each R 7 is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, , , , , , , , groups, wherein each X 3 is independently chosen from H, –OH, Cl, F, N3, –NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-14 aryl, –OC 1-8 alkyl, –OC 2-8 alkenyl, –OC 2-8 alkynyl, and –OC6-14 aryl groups, wherein any of the above ring compounds may be substituted with one to three groups independently chosen from Cl, F, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C6-14 aryl, and –OY 4 groups, wherein Y 4 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 6-14 aryl groups; n is chosen from integers ranging from 0 to 2; p is chosen from integers ranging from 0 to 3; L is chosen from linker groups; and Z is chosen from benzyl amino sulfonic acid groups. 20. The method according to Embodiment 19, wherein the at least one E-selectin antagonist is chosen from Formula (IIIa): tautomers of Formula (IIIa), and pharmaceutically acceptable salts of any of the foregoing. 21. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is a heterobifunctional pan-selectin antagonist chosen from Compound C: , Compound C (GMI-1070) tautomers of Compound C, and pharmaceutically acceptable salts of any of the foregoing. 22. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (IV):
prodrugs of Formula (IV), isomers of Formula (IV), tautomers of Formula (IV), and pharmaceutically acceptable salts of any of the foregoing, wherein each R 1 , which may be identical or different, is independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and –NHC(=O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups; each R 2 , which may be identical or different, is independently chosen from halo, – OY 1 , –NY 1 Y 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2- 12 haloalkynyl, C 6-18 aryl, and C1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring; each R 3 , which may be identical or different, is independently chosen from wherein each R 6 , which may be identical or different, is independently chosen from H, C 1-12 alkyl and C 1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OY 3 , -NHOH, -NHOCH 3 , –NHCN, and –NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from -CN, C 1-4 alkyl, and C 1-4 haloalkyl groups; m is chosen from integers ranging from 2 to 256; and L is chosen from linker groups. 23. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is chosen from compounds of Formula (V): prodrugs of Formula (V), isomers of Formula (V), tautomers of Formula (V), and pharmaceutically acceptable salts of any of the foregoing, wherein each R 1 , which may be identical or different, is independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and –NHC(=O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups; each R 2 , which may be identical or different, is independently chosen from halo, – OY 1 , –NY 1 Y 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2- 12 haloalkynyl, C 6-18 aryl, and C1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring; each R 3 , which may be identical or different, is independently chosen from wherein each R 6 , which may be identical or different, is independently chosen from H, C1-12 alkyl and C1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OY 3 , -NHOH, -NHOCH3, –NHCN, and –NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from -CN, C 1-4 alkyl, and C 1-4 haloalkyl groups; m is 2; and L is chosen from
, wherein R 8 is chosen from H, C 1-8 alkyl, C 6-18 aryl, C 7-19 arylalkyl, and C 1-13 heteroaryl groups and each p, which may be identical or different, is independently chosen from integers ranging from 0 to 250. 24. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is chosen from Compound D: . Compound D. 25. The method according to any one of Embodiments 1 to 8, wherein the at least one E-selectin antagonist is chosen from Compound E: Compound E. 26. The method according to any one of Embodiments 1 to 25, further comprising administering at least one additional therapeutic agent. 27. The method according to Embodiment 26, wherein the at least one additional therapeutic agent is chosen from antiviral and antiretroviral drugs. 28. The method according to Embodiment 26, wherein the at least one additional therapeutic agent is molnupiravir. 29. The method according to Embodiment 26, wherein the at least one additional therapeutic agent is chosen from anti-protozoal agents. 30. The method according to Embodiment 26, wherein the at least one additional therapeutic agent is chosen from IL-6 inhibitors. 31. The method according to any one of Embodiments 1 to 30, further comprising administering at least one COVID-19 vaccine. 32. The method according to any one of Embodiments 1 to 31, wherein the patient is intravenously administered the at least one E-selectin antagonist. 33. The method according to any one of Embodiments 1 to 32, wherein the administration begins within 48 hours of administration of supplemental oxygen to the patient. 34. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist. 35. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist once a day. 36. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist twice a day. 37. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist for 7 days. 38. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist once a day for 7 days. 39. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist twice a day for 7 days. 40. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist for less than 7 days. 41. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist once a day for less than 7 days. 42. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist twice a day for less than 7 days. 43. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist for more than 7 days. 44. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist once a day for more than 7 days. 45. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg of the at least one E-selectin antagonist twice a day for more than 7 days. 46. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day. 47. The method according to any one of Embodiments 10 to 15, wherein the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day for 7 days. 48. The method according to any one of Embodiments 1 to 8, wherein the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day, wherein the at least one E-selectin antagonist is chosen from Compound A:
Compound A and pharmaceutically acceptable salts thereof. 49. The method according to any one of Embodiments 1 to 8, wherein the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day for 7 days, wherein the at least one E-selectin antagonist is chosen from Compound A: Compound A and pharmaceutically acceptable salts thereof. 50. The method according to any one of Embodiments 1 to 49, wherein the patient possesses one or more of the following characteristics: an age in the range of 18 to 75 years; documented COVID-19 pneumonia, defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and imaging (CXR/CT scan) suggestive of COVID-19 pneumonia; confirmed coronavirus (SARS-CoV-2) infection; within 48 hours of beginning supplemental oxygen; currently hospitalized; requiring supplemental oxygen; having severe COVID-19 according to the World Health Organization (WHO) Interim Guidance with confirmation by real-time RT-PCR assay; respiratory distress; respiratory rate (RR) ^30 beats/min; oxygen saturation level less than 93% in resting state; partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ^ 300 mmHg. 51. The method according to any one of Embodiments 1 to 50, wherein the patient does not possess one or more of the following characteristics: in the opinion of at least two investigators, unlikely to survive for >48 hours from screening; severe chronic respiratory disease (e.g. COPD or other) requiring supplemental oxygen and/or having required mechanical ventilation pre-COVID-19 infection; currently on invasive mechanical ventilation; hypotension defined as systolic blood pressure < 90 mmHg on two sequential readings at least 4 hours apart; total Bilirubin ^ 3 x upper limit of normal (ULN), Creatinine Clearance ^ 30 mL/min/1.73m 2 ; pregnant or breastfeeding; known diagnosis of an acute thrombosis on admission; concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylactic dose is permitted); concomitant use of thrombolytic therapy; concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors); history of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH); history of bleeding disorder thought to impose excessive bleeding risk, as per investigator discretion; hemodynamic instability, defined as inability to maintain mean arterial pressure. [0056] In some embodiments, a method of treating COVID-19 patients with antagonists of E-selectin is disclosed, the method comprising administering to a COVID-19 patient an effective amount of at least one E-selectin antagonist and/or a pharmaceutical composition comprising at least one E-selectin antagonist. [0057] In some embodiments, a method of treating a disease, disorder, and/or condition associated with COVID-19 with antagonists of E-selectin is disclosed, the method comprising administering to a COVID-19 patient an effective amount of at least one E-selectin antagonist and/or a pharmaceutical composition comprising at least one E-selectin antagonist. [0058] In some embodiments, the disease, disorder, and/or condition associated with COVID-19 is acute lung injury. In some embodiments, the disease, disorder, and/or condition associated with COVID-19 is acute respiratory distress syndrome. In some embodiments, the disease, disorder, and/or condition associated with COVID-19 is pneumonia. In some embodiments, the disease, disorder, and/or condition associated with COVID-19 is ARDS pneumonia. [0059] In some embodiments, a method of treating acute respiratory distress syndrome with antagonists of E-selectin is disclosed, the method comprising administering to an acute respiratory distress syndrome patient an effective amount of at least one E-selectin antagonist and/or a pharmaceutical composition comprising at least one E-selectin antagonist. [0060] In some embodiments, a method of treating acute lung injury with antagonists of E-selectin is disclosed, the method comprising administering to an acute lung injury patient an effective amount of at least one E-selectin antagonist and/or a pharmaceutical composition comprising at least one E-selectin antagonist. [0061] In some embodiments, a method of treating pneumonia with antagonists of E-selectin is disclosed, the method comprising administering to a pneumonia patient an effective amount of at least one E-selectin antagonist and/or a pharmaceutical composition comprising at least one E-selectin antagonist. In some embodiments, the pneumonia is ARDS pneumonia. [0062] In some embodiments, the patient is intravenously administered the at least one E-selectin antagonist. In some embodiments, the patient is intravenously administered the at least one E-selectin antagonist once a day. In some embodiments, the patient is intravenously administered the at least one E-selectin antagonist twice a day. [0063] In some embodiments, the patient possesses one or more (e.g., one, two, three, four, five, six, seven, eight, or nine) of the following characteristics: an age in the range of 18 to 75 years; documented COVID-19 pneumonia, defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and imaging (CXR/CT scan) suggestive of COVID-19 pneumonia; confirmed coronavirus (SARS-CoV-2) infection; within 48 hours of beginning supplemental oxygen; currently hospitalized; requiring supplemental oxygen; having severe COVID-19 according to the World Health Organization (WHO) Interim Guidance with confirmation by real-time RT-PCR assay; respiratory distress; respiratory rate (RR) ^30 beats/min; oxygen saturation level less than 93% in resting state; partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ^ 300 mmHg. [0064] In some embodiments, the patient does not possess one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or eleven) of the following characteristics: in the opinion of at least two investigators, unlikely to survive for >48 hours from screening; severe chronic respiratory disease (e.g. COPD or other) requiring supplemental oxygen and/or having required mechanical ventilation pre-COVID-19 infection; currently on invasive mechanical ventilation; hypotension defined as systolic blood pressure < 90 mmHg on two sequential readings at least 4 hours apart; total Bilirubin ^ 3 x upper limit of normal (ULN), Creatinine Clearance ^ 30 mL/min/1.73m 2 ; pregnant or breastfeeding; known diagnosis of an acute thrombosis on admission; concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylactic dose is permitted); concomitant use of thrombolytic therapy; concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors); history of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH); history of bleeding disorder thought to impose excessive bleeding risk, as per investigator discretion; hemodynamic instability, defined as inability to maintain mean arterial pressure. [0065] In some embodiments, the patient possesses one or more (e.g., one, two, three, four, five, six, seven, eight, or nine) of the following characteristics: an age in the range of 18 to 75 years; documented COVID-19 pneumonia, defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and imaging (CXR/CT scan) suggestive of COVID-19 pneumonia; confirmed coronavirus (SARS-CoV-2) infection; within 48 hours of beginning supplemental oxygen; currently hospitalized; requiring supplemental oxygen; having severe COVID-19 according to the World Health Organization (WHO) Interim Guidance with confirmation by real-time RT-PCR assay; respiratory distress; respiratory rate (RR) ^30 beats/min; oxygen saturation level less than 93% in resting state; partial pressure of oxygen (PaO 2 )/oxygen concentration (FiO 2 ) ^ 300 mmHg; and the patient does not possess one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or eleven) of the following characteristics: in the opinion of at least two investigators, unlikely to survive for >48 hours from screening; severe chronic respiratory disease (e.g. COPD or other) requiring supplemental oxygen and/or having required mechanical ventilation pre-COVID-19 infection; currently on invasive mechanical ventilation; hypotension defined as systolic blood pressure < 90 mmHg on two sequential readings at least 4 hours apart; total Bilirubin ^ 3 x upper limit of normal (ULN), Creatinine Clearance ^ 30 mL/min/1.73m 2 ; pregnant or breastfeeding; known diagnosis of an acute thrombosis on admission; concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylactic dose is permitted); concomitant use of thrombolytic therapy; concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors); history of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH); history of bleeding disorder thought to impose excessive bleeding risk, as per investigator discretion; hemodynamic instability, defined as inability to maintain mean arterial pressure. [0066] In some embodiments, the administration begins within 48 hours of administration of supplemental oxygen to the patient. [0067] In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist for less than 7 days. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist for 7 days. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist for more than 7 days. [0068] In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist once a day. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist once a day for less than 7 days. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist once a day for 7 days. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist once a day for more than 7 days. [0069] In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist twice a day. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist twice a day for less than 7 days. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist twice a day for 7 days. In some embodiments, the patient is administered a dose in the range of 5 mg/kg to 100 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg; e.g., 5 mg/kg to 50 mg/kg, 10 mg/kg to 30 mg/kg, 10 mg/kg to 50 mg/kg, etc.) of the at least one E-selectin antagonist twice a day for more than 7 days. [0070] In some embodiments, the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day. In some embodiments, the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day for less than 7 days. In some embodiments, the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day for 7 days. In some embodiments, the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day for more than 7 days. [0071] In some embodiments, the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day, wherein the at least one E-selectin antagonist is chosen from Compound A:
Compound A and pharmaceutically acceptable salts thereof. [0072] In some embodiments, the patient is administered a dose of 20 mg/kg of the at least one E-selectin antagonist twice a day for 7 days, wherein the at least one E-selectin antagonist is chosen from Compound A: Compound A and pharmaceutically acceptable salts thereof. [0073] The E-selectin ligand is a carbohydrate structure that contains the epitope shared by sialyl Le a and sialyl Le x . Carbohydrates are secondary gene products synthesized by enzymes known as glycosyltransferases which are the primary gene products coded for by DNA. Each glycosyltransferase adds a specific monosaccharide in a specific stereochemical linkage to a specific donor carbohydrate chain. [0074] Non-limiting examples of suitable E-selectin antagonists include small molecules, such as nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, glycomimetics, lipids and other organic (carbon containing) or inorganic molecules. Suitably, the E-selectin antagonist is selected from antigen-binding molecules that are immuno-interactive with a selectin, peptides that bind to the selectin and that block cell-cell adhesion, and carbohydrate or peptide mimetics of selectin ligands. In some embodiments, the E-selectin antagonist reduces the expression of a selectin gene or the level or functional activity of an expression product of that gene. For example, the E-selectin antagonist may antagonize the function of the selectin, including reducing or abrogating the activity of at least one of its ligand-binding sites. [0075] In some embodiments, the E-selectin antagonist inhibits an activity of E-selectin or inhibits the binding of E-selectin to one or more E-selectin ligands (which in turn may inhibit a biological activity of E-selectin). [0076] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (I): isomers of Formula (I), tautomers of Formula (I), and pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; R 2 is chosen from H, -M, and –L-M; R 3 is chosen from –OH, –NH 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NHY 1 groups, wherein Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups; R 4 is chosen from -OH and -NZ 1 Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are each independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Z 1 and Z 2 may together form a ring; R 5 is chosen from C3-8 cycloalkyl groups; R 6 is chosen from -OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; R 7 is chosen from -CH 2 OH, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; R 8 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; L is chosen from linker groups; and M is a non-glycomimetic moiety chosen from polyethylene glycol, thiazolyl, chromenyl, -C(=O)NH(CH 2 )1-4NH 2 , C 1-8 alkyl, and -C(=O)OY groups, wherein Y is chosen from C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl groups. [0077] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (I), wherein the non-glycomimetic moiety comprises polyethylene glycol. [0078] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (I), wherein L is -C(=O)NH(CH 2 ) 1-4 NHC(=O)- and the non-glycomimetic moiety comprises polyethylene glycol. [0079] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (Ia): and pharmaceutically acceptable salts thereof, wherein n is chosen from integers ranging from 1 to 100. In some embodiments, n is chosen from 4, 8, 12, 16, 20, 24, and 28. In some embodiments n is 12. [0080] In some embodiments, the E-selectin antagonist is chosen from Compound A: Compound A and pharmaceutically acceptable salts thereof. [0081] In some embodiments, the E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (II): (II) isomers of Formula (II), tautomers of Formula (II), and pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; R 2 is chosen from –OH, –NH 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NHY 1 groups, wherein Y 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups; R 3 is chosen from -CN, -CH 2 CN, and -C(=O)Y 2 groups, wherein Y 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OZ 1 , -NHOH, -NHOCH 3 , -NHCN, and –NZ 1 Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Z 1 and Z 2 may together form a ring; R 4 is chosen from C 3-8 cycloalkyl groups; R 5 is independently chosen from H, halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups; n is chosen from integers ranging from 1 to 4; and L is chosen from linker groups. [0082] In some embodiments, the E-selectin antagonist is a heterobifunctional antagonist chosen from compounds of Formula (IIa): Br O OH R 2 N HN O O L 4 O O R OH R 1 NH HN O H O OH Me O H OH (IIa) and pharmaceutically acceptable salts thereof. [0083] In some embodiments, the E-selectin antagonist is chosen from Compound B: Compound B and pharmaceutically acceptable salts thereof. [0084] In some embodiments, the E-selectin antagonist is a heterobifunctional pan- selectin antagonist chosen from compounds of Formula (III): isomers of Formula (III), tautomers of Formula (III), and pharmaceutically acceptable salts of any of the foregoing, wherein: R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl , , , groups; R 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, –OH, – OX 1 , halo, –NH 2 , –OC(=O)X 1 , –NHC(=O)X 1 , and –NHC(=O)NHX 1 groups, wherein X 1 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C1-13 heteroaryl groups; R 3 is chosen from –CN, –CH 2 CN, and –C(=O)X 2 groups, wherein X 2 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, –OY 2 , –NHOH, –NHOCH3, –NHCN, and – NY 2 Y 3 groups, wherein Y 2 and Y 3 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C 4-16 cycloalkylalkyl groups, wherein Y 2 and Y 3 may join together to form a ring; R 6 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, and –C(=O)R 7 groups; each R 7 is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, , , , , , , , groups, wherein each X 3 is independently chosen from H, –OH, Cl, F, N 3 , –NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C6-14 aryl, –OC 1-8 alkyl, –OC 2-8 alkenyl, –OC 2-8 alkynyl, and –OC 6-14 aryl groups, wherein any of the above ring compounds may be substituted with one to three groups independently chosen from Cl, F, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-14 aryl, and –OY 4 groups, wherein Y 4 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, and C6-14 aryl groups; n is chosen from integers ranging from 0 to 2; p is chosen from integers ranging from 0 to 3; L is chosen from linker groups; and Z is chosen from benzyl amino sulfonic acid groups. [0085] Benzyl amino sulfonic acids (BASAs) are low molecular weight sulfated compounds which have the ability to interact with a selectin. The interaction modulates or assists in the modulation (e.g., inhibition or enhancement) of a selectin-mediated function (e.g., an intercellular interaction). They exist as either their protonated acid form, or as a sodium salt, although sodium may be replaced with potassium or any other pharmaceutically acceptable counterion. [0086] Further disclosure regarding BASAs suitable for the disclosed compounds may be found in U.S. Reissue Patent No. RE44,778, issued Feb. 25, 2014, and U.S. Publication No. US2018/0369205, published Dec. 27, 2018, which are hereby incorporated by reference. [0087] In some embodiments, the E-selectin antagonist is a heterobifunctional pan- selectin antagonist chosen from compounds of Formula (IIIa): tautomers of Formula (IIIa), and pharmaceutically acceptable salts of any of the foregoing. [0088] In some embodiments, the E-selectin antagonist is a heterobifunctional pan- selectin antagonist chosen from Compound C: , tautomers of Compound C, and pharmaceutically acceptable salts of any of the foregoing. [0089] In some embodiments, the linker groups of Formula (I), Formula (II), and/or Formula (III) are independently chosen from groups comprising spacer groups, such spacer groups as, for example, -(CH 2 )p- and -O(CH 2 )p-, wherein p is chosen from integers ranging from 1 to 30. In some embodiments, p is chosen from integers ranging from 1 to 20. [0090] Other non-limiting examples of spacer groups include carbonyl groups and carbonyl-containing groups such as, for example, amide groups. [0091] In some embodiments, the linker group of Formula (I), Formula (II), and/or Formula (III) is chosen from [0092] In some embodiments, the linker group of Formula (I), Formula (II), and/or Formula (III) is chosen from [0093] Other linker groups, such as, for example, polyethylene glycols (PEGs) and -C(=O)-NH-(CH 2 ) p -C(=O)-NH-, wherein p is chosen from integers ranging from 1 to 30, or wherein p is chosen from integers ranging from 1 to 20, will be familiar to those of ordinary skill in the art and/or those in possession of the present disclosure. [0094] In some embodiments, the linker group of Formula (I), Formula (II), and/or Formula (III) is chosen from [0095] In some embodiments, the linker group of Formula (I), Formula (II), and/or Formula (III) is chosen from [0096] In some embodiments, the linker group of Formula (I), Formula (II), and/or Formula (III) is chosen from . [0097] In some embodiments, the linker group of Formula (I), Formula (II), and/or Formula (III) is chosen from –C(=O)NH(CH 2 ) 2 NH-, -CH 2 NHCH 2 -, and –C(=O)NHCH 2 -. In some embodiments, the linker group is -C(=O)NH(CH 2 )2NH-. [0098] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (IV): prodrugs of Formula (IV), isomers of Formula (IV), tautomers of Formula (IV), and pharmaceutically acceptable salts of any of the foregoing, wherein e ach R1, which may be identical or different, is independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and –NHC(=O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C1-13 heteroaryl groups; each R 2 , which may be identical or different, is independently chosen from halo, – OY 1 , –NY 1 Y 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NY 1 Y 2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C1-12 haloalkyl, C 2-12 haloalkenyl, C2- 12 haloalkynyl, C 6-18 aryl, and C1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring; each R 3 , which may be identical or different, is independently chosen from wherein each R 6 , which may be identical or different, is independently chosen from H, C1-12 alkyl and C1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OY 3 , -NHOH, -NHOCH3, –NHCN, and –NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from -CN, C 1-4 alkyl, and C 1-4 haloalkyl groups; m is chosen from integers ranging from 2 to 256; and L is chosen from linker groups. [0099] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (V):
prodrugs of Formula (V), isomers of Formula (V), tautomers of Formula (V), and pharmaceutically acceptable salts of any of the foregoing, wherein each R 1 , which may be identical or different, is independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, and –NHC(=O)R 5 groups, wherein each R 5 , which may be identical or different, is independently chosen from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-18 aryl, and C 1-13 heteroaryl groups; each R 2 , which may be identical or different, is independently chosen from halo, – O Y1, –NY1Y2, –OC(=O)Y1, –NHC(=O)Y1, and –NHC(=O)NY1Y2 groups, wherein each Y 1 and each Y 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2- 12 haloalkynyl, C 6-18 aryl, and C1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring; each R 3 , which may be identical or different, is independently chosen from wherein each R 6 , which may be identical or different, is independently chosen from H, C 1-12 alkyl and C 1-12 haloalkyl groups, and wherein each R 7 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OY 3 , -NHOH, -NHOCH 3 , –NHCN, and –NY 3 Y 4 groups, wherein each Y 3 and each Y 4 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, wherein Y 3 and Y 4 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from -CN, C 1-4 alkyl, and C 1-4 haloalkyl groups; m is 2; and L is chosen from , wherein Q is a chosen from , wherein R 8 is chosen from H, C 1-8 alkyl, C 6-18 aryl, C7-19 arylalkyl, and C1-13 heteroaryl groups and each p, which may be identical or different, is independently chosen from integers ranging from 0 to 250. [00100] In some embodiments, the E-selectin antagonist of Formula (IV) or Formula (V) is chosen from compounds of the following Formula (IVa/Va) (see definitions of L and m for Formula (IV) or (V) above): (IVa/Va) [00101] In some embodiments, the E-selectin antagonist of Formula (IV) or Formula (V) is chosen from compounds of the following Formula (IVb/Vb) (see definitions of L and m for Formula (IV) or (V) above): (IVb/Vb) [00102] In some embodiments, the E-selectin antagonist is Compound D: . Compound D [00103] In some embodiments, the E-selectin antagonist is a heterobifunctional inhibitor of E-selectin and Galectin-3, chosen from compounds of Formula (VI): prodrugs of Formula (VI), isomers of Formula (VI), tautomers of Formula (VI), and pharmaceutically acceptable salts of any of the foregoing, wherein R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, groups, wherein n is chosen from integers ranging from 0 to 2, R 6 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, and –C(=O)R 7 groups, and each R 7 is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, and C1-13 heteroaryl groups; R 2 is chosen from –OH, –OY 1 , halo, –NH 2 , –NY 1 Y 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NHY 1 groups, wherein Y 1 and Y 2 , which may be the same or different, are independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C1-13 heteroaryl groups, wherein Y 1 and Y 2 may join together along with the nitrogen atom to which they are attached to form a ring; R 3 is chosen from -CN, -CH 2 CN, and -C(=O)Y 3 groups, wherein Y 3 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OZ 1 , -NHOH, -NHOCH 3 , -NHCN, and –NZ 1 Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, and C 7-12 arylalkyl groups, wherein Z 1 and Z 2 may join together along with the nitrogen atom to which they are attached to form a ring; R 4 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, and C 6-18 aryl groups; R 5 is chosen from –CN, C 1-8 alkyl, and C 1-4 haloalkyl groups; M is chosen from groups, wherein X is chosen from O and S, and R 8 and R 9 , which may be identical or different, are independently chosen from C 6-18 aryl, C 1-13 heteroaryl, C 7-19 arylalkyl, C7-19 arylalkoxy, C2-14 heteroarylalkyl, C2-14 heteroarylalkoxy, and –NHC(=O)Y 4 groups, wherein Y 4 is chosen from C 1-8 alkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C 1-13 heteroaryl groups; and L is chosen from linker groups. [00104] In some embodiments, the E-selectin antagonist is chosen from compounds having the following Formulae:
. [00105] In some embodiments, the E-selectin antagonist is chosen from compounds having the following Formulae: ,
pharmaceutically acceptable salts of any of the foregoing. [00106] In some embodiments, the E-selectin antagonist is chosen from compounds having the following Formulae:
, , , [00107] In some embodiments, the E-selectin antagonist is chosen from compounds having the following Formulae: , , ,
pharmaceutically acceptable salts of any of the foregoing. [00108] In some embodiments, the E-selectin antagonist is Compound E: Compound E. [00109] In some embodiments, the E-selectin antagonist is chosen from compounds of Formula (VII): prodrugs of Formula (VII), isomers of Formula (VII), tautomers of Formula (VII), and pharmaceutically acceptable salts of any of the foregoing, wherein R 1 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, , , , groups, wherein n is chosen from integers ranging from 0 to 2, R 6 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, and –C(=O)R 7 groups, and each R 7 is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, and C1-13 heteroaryl groups; R 2 is chosen from –OH, –OY 1 , halo, –NH 2 , –NY 1 Y 2 , –OC(=O)Y 1 , –NHC(=O)Y 1 , and –NHC(=O)NHY 1 groups, wherein Y 1 and Y 2 , which may be the same or different, are independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 2-12 heterocyclyl, C 6-18 aryl, and C1-13 heteroaryl groups, or Y 1 and Y 2 join together along with the nitrogen atom to which they are attached to form a ring; R 3 is chosen from -CN, -CH 2 CN, and -C(=O)Y 3 groups, wherein Y 3 is chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OZ 1 , -NHOH, -NHOCH 3 , -NHCN, and –NZ 1 Z 2 groups, wherein Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, and C 7-12 arylalkyl groups, or Z 1 and Z 2 join together along with the nitrogen atom to which they are attached to form a ring; R 4 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, and C 6-18 aryl groups; R 5 is chosen from –CN, C 1-8 alkyl, and C 1-4 haloalkyl groups; M is chosen from groups, wherein X is chosen from –O–, –S–, –C–, and –N(R 10 )–, wherein R 10 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, and C 2-8 haloalkynyl groups, Q is chosen from H, halo, and –OZ 3 groups, wherein Z 3 is chosen from H and C 1-8 alkyl groups, R 8 is chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, C1-13 heteroaryl, C7-19 arylalkyl, and C2-14 heteroarylalkyl groups, wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, C 1-13 heteroaryl, C 7-19 arylalkyl, and C 2-14 heteroarylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 haloalkyl, C 6-18 aryl, –OZ 4 , –C(=O)OZ 4 , –C(=O)NZ 4 Z 5 , and – SO2Z 4 groups, wherein Z 4 and Z 5 , which may be identical or different, are independently chosen from H, C 1-8 alkyl, and C 1-8 haloalkyl groups, or Z 4 and Z 5 join together along with the nitrogen atom to which they are attached to form a ring, R 9 is chosen from C 6-18 aryl and C 1-13 heteroaryl groups, wherein the C 6-18 aryl and C 1- 13 heteroaryl groups are optionally substituted with one or more groups independently chosen from R 11 , C 1-8 alkyl, C 1-8 haloalkyl, –C(=O)OZ 6 , and –C(=O)NZ 6 Z 7 groups, wherein R 11 is independently chosen from C 6-18 aryl groups optionally substituted with one or more groups independently chosen from halo, C 1-8 alkyl, –OZ 8 , – C(=O)OZ 8 , and –C(=O)NZ 8 Z 9 groups, wherein Z 6 , Z 7 , Z 8 and Z 9 , which may be identical or different, are independently chosen from H and C 1-8 alkyl groups, or Z 6 and Z 7 join together along with the nitrogen atom to which they are attached to form a ring and/or Z 8 and Z 9 join together along with the nitrogen atom to which they are attached to form a ring, and wherein each of Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , and Z 9 is optionally substituted with one or more groups independently chosen from halo and –OR 12 groups, wherein R 12 is independently chosen from H and C 1-8 alkyl groups; and L is chosen from linker groups. [00110] In some embodiments of Formula (VII), M is chosen from groups. [00111] In some embodiments of Formula (VII), M is chosen from groups. [00112] In some embodiments of Formula (VII), linker groups may be chosen from groups comprising spacer groups, such spacer groups as, for example, -(CH 2 ) t - and -O(CH 2 ) t -, wherein t is chosen from integers ranging from 1 to 20. Other non-limiting examples of spacer groups include carbonyl groups and carbonyl-containing groups such as, for example, amide groups. A non-limiting example of a spacer group is . [00113] In some embodiments of Formula (VII), the linker group is chosen from . [00114] In some embodiments of Formula (VII), the linker group is chosen from polyethylene glycols (PEGs), -C(=O)NH(CH 2 )vO- , -C(=O)NH(CH 2 ) v NHC(=O), -C(=O)NHC(=O)(CH 2 )NH-, and -C(=O)NH(CH 2 ) v C(=O)NH- groups, wherein v is chosen from integers ranging from 2 to 20. In some embodiments, v is chosen from integers ranging from 2 to 4. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. [00115] In some embodiments of Formula (VII), the linker group is . [00116] In some embodiments of Formula (VII), the linker group is . [00117] In some embodiments of Formula (VII), the linker group is . [00118] In some embodiments of Formula (VII), the linker group is . [00119] In some embodiments of Formula (VII), the linker group is . [00120] In some embodiments of Formula (VII), the linker group is . [00121] In some embodiments of Formula (VII), the linker group is . [00122] In some embodiments of Formula (VII), the linker group is . [00123] In some embodiments of Formula (VII), the linker group is . [00124] Figures and examples illustrating the synthesis of compounds of Formula (VII) are shown in PCT International Application Publication No. WO 2020/139962, which is incorporated by reference herein. [00125] In some embodiments, the E-selectin antagonist is a multimeric inhibitor of E- selectin, Galectin-3, and/or CXCR4, chosen from compounds of Formula (VIII):
, prodrugs of Formula (VIII), and pharmaceutically acceptable salts of any of the foregoing, wherein each R 1 , which may be identical or different, is independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-8 haloalkyl, C 2-8 haloalkenyl, C 2-8 haloalkynyl, , groups, wherein each n, which may be identical or different, is chosen from integers ranging from 0 to 2, each R 6 , which may be identical or different, is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, and – C(=O)R 7 groups, and each R 7 , which may be identical or different, is independently chosen from H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 4-16 cycloalkylalkyl, C 6-18 aryl, and C1-13 heteroaryl groups; each R 2 , which may be identical or different, is independently chosen from H, a non- glycomimetic moiety, and a linker-non-glycomimetic moiety, wherein each non- glycomimetic moiety, which may be identical or different, is independently chosen from galectin-3 inhibitors, CXCR4 chemokine receptor inhibitors, polyethylene glycol, thiazolyl, chromenyl, C 1 - 8 alkyl, R 8 , C 6-18 aryl-R 8 , C 1-12 heteroaryl-R 8 , wherein each Y 1 , which may be identical or different, is independently chosen from C 1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl groups and wherein each R 8 , which may be identical or different, is independently chosen from C 1-12 alkyl groups substituted with at least one substituent chosen from –OH, –OSO3Q, –OPO3Q2, –CO2Q, and –SO3Q groups and C 2-12 alkenyl groups substituted with at least one substituent chosen from –OH, –OSO3Q, –OPO3Q2, –CO2Q, and –SO3Q groups, wherein each Q, which may be identical or different, is independently chosen from H and pharmaceutically acceptable cations; each R 3 , which may be identical or different, is independently chosen from –CN, – CH 2 CN, and –C(=O)Y 2 groups, wherein each Y 2 , which may be identical or different, is independently chosen from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, –OZ 1 , –NHOH, – NHOCH3, –NHCN, and –NZ 1 Z 2 groups, wherein each Z 1 and Z 2 , which may be identical or different, are independently chosen from H, C 1-12 alkyl, C 2-12 alkenyl, C 2- 12 alkynyl, C1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, and C 7-12 arylalkyl groups, wherein Z 1 and Z 2 may join together along with the nitrogen atom to which they are attached to form a ring; each R 4 , which may be identical or different, is independently chosen from H, C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 2-12 haloalkenyl, C 2-12 haloalkynyl, C 4-16 cycloalkylalkyl, and C 6-18 aryl groups; each R 5 , which may be identical or different, is independently chosen from –CN, C 1-12 alkyl, and C1-12 haloalkyl groups; each X, which may be identical or different, is independently chosen from –O– and –N(R 9 )–, wherein each R 9 , which may be identical or different, is independently chosen from H, C1–8 alkyl, C2–8 alkenyl, C2–8 alkynyl, C1–8 haloalkyl, C2–8 haloalkenyl, and C2–8 haloalkynyl groups; m is chosen from integers ranging from 2 to 256; and L is independently chosen from linker groups. [00126] In some embodiments of Formula (VIII), at least one linker groups is chosen from groups comprising spacer groups, such spacer groups as, for example, -(CH 2 )z- and - O(CH 2 )z-, wherein z is chosen from integers ranging from 1 to 250. Other non-limiting examples of spacer groups include carbonyl groups and carbonyl-containing groups such as, for example, amide groups. A non-limiting example of a spacer group is . [00127] In some embodiments of Formula (VIII), at least one linker group is chosen from , , , ,
, ,
[00128] Other linker groups for certain embodiments of Formula (VIII), such as, for example, polyethylene glycols (PEGs) and -C(=O)-NH-(CH 2 )z-C(=O)-NH-, wherein z is chosen from integers ranging from 1 to 250, will be familiar to those of ordinary skill in the art and/or those in possession of the present disclosure. [00129] In some embodiments of Formula (VIII), at least one linker group is . [00130] In some embodiments of Formula (VIII), at least one linker group is . [00131] In some embodiments of Formula (VIII), at least one linker group is chosen from –C(=O)NH(CH 2 )2NH–, –CH 2 NHCH 2 –, and –C(=O)NHCH 2 –. In some embodiments of Formula (VIII), at least one linker group is –C(=O)NH(CH 2 ) 2 NH–. [00132] In some embodiments of Formula (VIII), L is chosen from dendrimers. In some embodiments of Formula (VIII), L is chosen from polyamidoamine (“PAMAM”) dendrimers. In some embodiments of Formula (VIII), L is chosen from PAMAM dendrimers comprising succinamic. In some embodiments of Formula (VIII), L is PAMAM GO generating a tetramer. In some embodiments of Formula (VIII), L is PAMAM G1 generating an octamer. In some embodiments of Formula (VIII), L is PAMAM G2 generating a 16-mer. In some embodiments of Formula (VIII), L is PAMAM G3 generating a 32-mer. In some embodiments of Formula (VIII), L is PAMAM G4 generating a 64-mer. In some embodiments, L is PAMAM G5 generating a 128-mer. [00133] In some embodiments of Formula (VIII), m is 2 and L is chosen from groups, wherein U is chosen from
groups, wherein R 14 is chosen from H, C 1-8 alkyl, C 6-18 aryl, C 7-19 arylalkyl, and C 1-13 heteroaryl groups and each y, which may be identical or different, is independently chosen from integers ranging from 0 to 250. In some embodiments of Formula (VIII), R 14 is chosen from C 1-8 alkyl. In some embodiments of Formula (VIII), R 14 is chosen from C 7-19 arylalkyl. In some embodiments of Formula (VIII), R 14 is H. In some embodiments of Formula (VIII), R 14 is benzyl. [00134] In some embodiments of Formula (VIII), L is chosen from ,
wherein y is chosen from integers ranging from 0 to 250. [00135] In some embodiments of Formula (VIII), L is chosen from groups, wherein y is chosen from integers ranging from 0 to 250. [00136] In some embodiments of Formula (VIII), L is . [00137] In some embodiments of Formula (VIII), L is chosen from wherein y is chosen from integers ranging from 0 to 250. [00138] In some embodiments of Formula (VIII), L is chosen from roups, wherein y is chosen from integers ranging from 0 to 250. [00139] In some embodiments of Formula (VIII), L is chosen from . [00141] In some embodiments of Formula (VIII), L is chosen from groups, wherein y is chosen from integers ranging from 0 to 250. [00142] In some embodiments of Formula (VIII), L is . [00143] In some embodiments of Formula (VIII), L is
. [00144] In some embodiments of Formula (VIII), L is . [00145] In some embodiments of Formula (VIII), L is chosen from ,
. [00146] In some embodiments of Formula (VIII), L is
. [00147] In some embodiments of Formula (VIII), L is chosen from wherein each y, which may be identical or different, is independently chosen from integers ranging from 0 to 250. [00148] In some embodiments of Formula (VIII), L is chosen from
, wherein each y, which may be identical or different, is independently chosen from integers ranging from 0 to 250. [00149] In some embodiments of Formula (VIII), L is chosen from . [00150] In some embodiments, at least one compound is chosen from compounds of Formula (VIII), wherein each R 1 is identical, each R 2 is identical, each R 3 is identical, each R 4 is identical, each R 5 is identical, and each X is identical. In some embodiments, at least one compound is chosen from compounds of Formula (VIII), wherein said compound is symmetrical. [00151] Figures and examples illustrating the synthesis of compounds of Formula (VIII) are shown in PCT International Application Publication No. WO 2020/219417, which is incorporated by reference herein. [00152] Also provided are pharmaceutical compositions comprising at least one compound chosen from compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (V), (IVa/Va), (IVb/Vb), (VI), (VII), and (VIII). These compounds and compositions may be used in the methods described herein. In some embodiments, provided are pharmaceutical compositions comprising at least one compound chosen from Compound A, Compound B, Compound C, Compound D, and Compound E. These compounds and compositions may be used in the methods described herein. [00153] Also provided are pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and at least one compound chosen from compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (V), (IVa/Va), (IVb/Vb), (VI), (VII), and (VIII) and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, provided are pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and at least one compound chosen from Compound A, Compound B, Compound C, Compound D, and Compound E, and pharmaceutically acceptable salts of any of the foregoing. These compounds and compositions may be used in the methods described herein. [00154] In some embodiments, the at least one E-selectin antagonist is chosen from compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (V), (IVa/Va), (IVb/Vb), (VI), (VII), and (VIII). In some embodiments, the at least one E-selectin antagonist is chosen from compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (V), (IVa/Va), (IVb/Vb), (VI), (VII), and (VIII) and pharmaceutically acceptable salts of any of the foregoing. [00155] In some embodiments, the at least one E-selectin antagonist is Compound A. In some embodiments, the at least one E-selectin antagonist is Compound B. In some embodiments, the at least one E-selectin antagonist is Compound C. In some embodiments, the at least one E-selectin antagonist is Compound D. In some embodiments, the at least one E-selectin antagonist is Compound E. [00156] In some embodiments, the method further comprises administering at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is chosen from antiviral and antiretroviral drugs. In some embodiments, the at least one additional therapeutic agent is molnupiravir. In some embodiments, the at least one additional therapeutic agent is chosen from anti-protozoal agents. In some embodiments, the at least one additional therapeutic agent is chosen from IL-6 inhibitors. [00157] In some embodiments, the at least one additional therapeutic agent is remdesivir. In some embodiments, the at least one additional therapeutic agent is lopinavir. In some embodiments, the at least one additional therapeutic agent is ritonavir. In some embodiments, the at least one additional therapeutic agent is chloroquine. In some embodiments, the at least one additional therapeutic agent is hydroxychloroquine. In some embodiments, the at least one additional therapeutic agent is interferon-beta. In some embodiments, the at least one additional therapeutic agent is tocilizamib. [00158] In some embodiments, the method further comprises administering at least one COVID-19 vaccine. EXAMPLE [00159] The following example is intended to be illustrative and is not meant in any way to limit the scope of the disclosure. Prophetic Example 1: A Pilot Study to Assess the Safety, Tolerability and Efficacy of Selectin Inhibitor Compound A (GMI-1271) in Patients with COVID-19 Pneumonia [00160] A Phase 1 prospective, interventional, single group assignment will be conducted at a single center (University of Michigan, Ann Arbor) in the United States to assess the safety, tolerability, and efficacy of Compound A in patients with COVID-19 pneumonia. Compound A is administered as an IV formulation that has been extensively tested in humans, including in healthy volunteers, patients with calf level deep vein thrombosis (DVT), and patients with acute myeloid leukemia (AML) and multiple myeloma (MM). [00161] The primary objective of the open-label study is to evaluate if treatment with Compound A administered intravenously in addition to the best available therapy according to institutional guidelines is able to reduce the progression of acute respiratory failure, in patients with severe COVID-19 pneumonia. The primary endpoints include: (1) reduction in the progression to acute respiratory failure [Time Frame: 15 days for primary endpoint]; and (2) patients with a baseline PaO 2 /FiO 2 >= 200: progression of respiratory failure is defined by: a. severe gas transfer deficit (PaO2/FiO2 < 200); b. persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of accessory respiratory muscles, paradoxical respiratory movements). The rate will be calculated as the proportion of patients who experienced at least one of the events above by day+15 from treatment start. [00162] The secondary objectives include: (1) evaluating overall survival and all-cause mortality at day 15 and 28; (2) evaluating changes in the COVID ordinal outcomes scale; (3) assessing adverse events to evaluate the safety of Compound A; (4) assessing ventilator- free days, ICU-free days, oxygen, vasopressor free days; (5) evaluating changes in D-dimer; and (6) assessing the pharmacokinetics of Compound A used in this study. Exploratory objectives include: (1) examining the correlation of plasma soluble E-selectin concentrations with clinical outcomes; and (2) examining the correlations of other biomarkers of interest with clinical outcome. [00163] 15 subjects will be enrolled in the experimental cohort to receive Compound A, with parallel data collection on non-treated patients (concurrent control cohort n=15). Inclusion/exclusion criteria will be the same between the two groups. For subjects in the experimental cohort, Compound A (20 mg/kg BID, up to a maximum dose of 2500 mg) will be IV infused over 20 minutes on days 1-7. Protocol treatment must start within 48 hours of the admitted patient requiring supplemental oxygen for documented COVID-19 pneumonia. The concurrent control cohort, not treated with Compound A, will receive the best available therapy according to institutional guidelines. [00164] Inclusion criteria include: 1. Adults, ages 18 – 75 years. 2. Willing and able to provide informed consent prior to performing study procedures unless they have a legally authorized representative (LAR). 3. Documented COVID-19 pneumonia: defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and imaging (CXR/CT scan) suggestive of COVID-19 pneumonia. 4. Confirmed coronavirus (SARS-CoV-2) infection, enrolled ^ 48 hours of beginning oxygen need for COVID-19+ confirmed hospital admission. 5. Currently hospitalized requiring supplemental oxygen. 6. Have severe COVID-19 according to the World Health Organization (WHO) Interim Guidance with confirmation by real-time RT-PCR assay. The enrollment criteria with one of the following: respiratory distress, respiratory rate (RR) ^30 beats/min; oxygen saturation level less than 93% in resting state; or partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ^ 300 mmHg. 7. WHO, Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV) infection is suspected: Interim guidance. https://www. who.int/publications-detail/clinical-management-of-severe-ac ute-respiratory- infectionwhen-novel-coronavirus-(ncov)-infection-is-suspecte d. 8. Willing and able to participate in all required evaluations and procedures. [00165] Exclusion criteria include: 1. In the opinion of at least two investigators, unlikely to survive for >48 hours from screening. 2. Severe chronic respiratory disease (e.g. COPD or other) requiring supplemental oxygen and/or having required mechanical ventilation pre-COVID-19 infection. 3. Concurrent enrollment in a COVID-related interventional drug trial. Use of remdesivir, steroids, and convalescent plasma are permitted along with other standard of care therapies for COVID. 4. Currently on invasive mechanical ventilation. 5. Hypotension defined as systolic blood pressure < 90 mmHg on two sequential readings at least 4 hours apart. 6. Total Bilirubin ^ 3 x upper limit of normal (ULN), Creatinine Clearance ^ 30 mL/min/1.73m 2 . 7. Pregnant or breastfeeding. 8. Known diagnosis of an acute thrombosis on admission. 9. Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylactic dose is permitted). 10. Concomitant use of thrombolytic therapy. 11. Concomitant therapeutic systemic anticoagulant therapy (e.g. heparin, warfarin, direct thrombin inhibitors and direct factor Xa inhibitors). 12. History of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH). 13. History of bleeding disorder thought to impose excessive bleeding risk, as per investigator discretion. 14. Hemodynamic instability, defined as inability to maintain mean arterial pressure. 15. Hypersensitivity to the active substance or to any of the excipients of Compound A. 16. Any physical examination findings and/or history of any illness that, in the opinion of the investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study. REFERENCES [00166] The following references are hereby incorporated by reference in their respective entireties: 1. Huang C. et al 2020 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet https://doi.org/10.1016/s0140- 6736(20)30183-5. 2. Potey P., Rossi A.G., Lucas C.D. and Dorward D.A. Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential. J. Pathol. 247:672-685 (2019). 3. Lyall F., Boswell F., Young A., Clark C.J., and Greer I.A. The cytokine interleukin-6 increases expression of the cell adhesion molecules E-selectin and VCAM-1 on endothelial cells in vitro: a role in preclampsia? Hyper in Preg 16(3):403-415 (1997). 4. Vora M., Romero L.I. and Karasek M.A. Interleukin-10 induces E-selectin on small and large blood vessel endothelial cells. J. Exp. Med. 184:821-829 (1996). 5. Xu Z. et.al. Predictive value of combined LIPS and ANG-2 level in critically III patients with ARDS risk factors. Mediators Inflamm (2018). 6. Osaka D. et.al. Soluble endothelial selectin in acute lung injury complicated by severe pneumonia. Int. J. Med. Sci. 8(4):302-308 (2011). 7. Okajima K., Harada N., Sakurai G., Soga Y., Suga H., Terada T. and Nakagawa T. Rapid assay for plasma soluble E-selectin predicts the development of acute respiratory distress syndrome in patients with systemic inflammatory response syndrome. Translational Res. 148:295-300 (2006). 8. Meyer N.J. et.al. Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome. JCI insight 2(23) (2017). 9. Ruchaud-Sparagano M-H., Dorst E.M., Donnelly S.C., Bird M.I., Haslett C. and Dransfield I. Potential pro-inflammatory effects of soluble E-selectin upon neutrophil function. Eur. J. Immunol. 28:80-89 (1998). 10. Mulligan M.S., Lowe J.B., Larsen R. D., Paulson J., Zheng Z., DeFrees S., Maemura K., Fukuda M. and Ward P.A. Protective effects of sialylated oligosaccharides in immune complex-induced acute lung injury. J. Exp. Med. 179:623-631 (1993). 11. Wun T., et.al. Pan-selectin antagonist Rivipansel (GMI-1070) reduces soluble E-selectin levels while improving clinical outcomes in SCD vaso-occlusive crisis. Blood 124(21):2704 (2014). 12. DeAngelo D.J., Liesveld J.L., Jonas B.A., O’Dwyer M.E., Bixby D.L., Magnani J.L., Thackray H.M. and Becker P.S. A phase I/II study of GMI- 1271, a novel E-selectin antagonist, in combination with induction chemotherapy in relapsed/refractory and previously untreated elderly patients with acute myeloid leukemia; results to date. Blood 128(22):4049 (2016).
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