| WO/2024/073409 | METHODS FOR TREATING EARLY ALZHEIMER'S DISEASE |
| WO/2019/236436 | PROCESSES FOR THE PREPARATION OF SUGAMMADEX |
| JP2023541583 | Manufacturing method of sugammadex |
MONTGOMERY CHARLES (US)
BROCKMAN ADAM (US)
| CLAIMS We claim: 1. A pharmaceutical composition comprising: a compound capable of scavenging or trapping an aldehyde by formation of an adduct; and a compound of general formula II’’: II’’ or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin or a modified cyclodextrin; X is a covalent bond, nitrogen, oxygen, or sulfur; or a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O), -C(O)O-, -OC(O)-, -C(S)-, - C(RX)2, -C(F)2, -N(RX)-, -C(O)N(RX)-, -RXNC(O)-, -OC(O)N(RX)-, -N(RX)C(O)N(RX)-, or -Cy-; R is absent, H, -NO2, -CN, or optionally substituted C1-C12 alkyl; each RX is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Y is a modifier–(C=O)N(RX)N(RX)2, –(C=S)N(RX)N(RX)2, –(C=O)N(RX)N(RX)OH, - , , a pharmaceutically acceptable anion. 2. A pharmaceutical composition according to claim 1, wherein the compound capable of scavenging or trapping an aldehyde by formation of an adduct is a compound of general formula X-I: or a pharmaceutically acceptable salt thereof, wherein W is N or CR4; X is S, NH, or O; Y is N or CR6; provided that, if X is S or O, then Y is CR6; each of R1, R2, R3, R4, R5, and R6 is independently hydrogen, deuterium, halogen, -NH2, -CN, - OR’, -SR’, optionally substituted C1-6 aliphatic, or , provided that one of R1, R2, R3, R4, R5, and R6 is –NH2 and another one of R1, R2, R3, R4, R5, and R6 is ; Ra is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; and Rb is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or Ra and Rb, taken together with the carbon atom to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3. A pharmaceutical composition according to claim 1, wherein the compound capable of scavenging or trapping an aldehyde by formation of an adduct is a compound of general formula X-VI: or a pharmaceutically acceptable salt thereof, each of R7, R8, R9, and R10 is independently hydrogen, deuterium, halogen, -N(R’)2, -CN, -OR’, -SR’, or optionally substituted C1-6 aliphatic; Rc is hydrogen or C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; Rd is hydrogen or C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or Rc and Rd, taken together with the carbon atom to which they are attached, form a 3-8 membered, saturated cycloalkyl or heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; and each R’ is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4. A pharmaceutical composition according to claim 1, wherein the compound capable of scavenging or trapping an aldehyde by formation of an adduct is a compound of general formula Y-I: Y-I or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -N(R’)2, -CN, -OR’, -SR’, or optionally substituted C1-6 aliphatic; Rc is hydrogen or C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; Rd is hydrogen or C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or Rc and Rd, taken together with the carbon atom to which they are attached, form a 3-8 membered, saturated cycloalkyl or heterocyclyl ring having 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; L1 is -C(O)NR’-CR’2- or -NR’C(O)-CR’2-, wherein either end of L1 may be covalently bound to Ring A; Ring A is selected from a cyclic group selected from phenyl and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic group is substituted with n instances of R4; each instance of R4 is independently halogen, –CN, –NO2, –OR’, –CR’2OR’, -SR’, -NR’2, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -S(O)NR’2, -C(O)R’, -C(O)OR’, –C(O)NR’2, -C(O)N(R’)OR’, -OC(O)R’, -OC(O)NR’2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)C(NR’)NR’2, -N(R’)S(O)2NR’2, –N(R’)S(O)2R’, an optionally substituted C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; or two R4 on adjacent carbon atoms, together with the adjacent carbon atoms, form a 4- to 7- membered ring that is fused to Ring A, wherein the ring that is fused to Ring A comprises 0- 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R’ is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R’ groups on the same atom are taken together with the atom to form an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic ring that is optionally bridged bicyclic or spirocyclic (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and n is 0, 1, 2, 3, 4, or 5. 5. A pharmaceutical composition according to claim 1, wherein the compound capable of scavenging or trapping an aldehyde by formation of an adduct is a compound of general formula Y-II: Y-II or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -N(R’)2, -CN, -OR’, -SR’, or optionally substituted C1-6 aliphatic; Rc is hydrogen or C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; Rd is hydrogen or C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or Rc and Rd, taken together with the carbon atom to which they are attached, form a 3-8 membered, saturated cycloalkyl or heterocyclyl ring having 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; L1 is -C(O)NR’-CR’2- or -NR’C(O)-CR’2-, wherein either end of L1 may be covalently bound to Ring A; Ring A is selected from a cyclic group selected from phenyl and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic group is substituted with n instances of R4; each instance of R4 is independently halogen, –CN, –NO2, –OR’, –CR2OR’, -SR’, -NR’2, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -S(O)NR’2, -C(O)R’, -C(O)OR’, –C(O)NR’2, -C(O)N(R’)OR’, -OC(O)R’, -OC(O)NR’2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)C(NR’)NR’2, -N(R’)S(O)2NR’2, –N(R’)S(O)2R’, an optionally substituted C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; or two R4 on adjacent carbon atoms, together with the adjacent carbon atoms, form a 4- to 7- membered ring that is fused to Ring A, wherein the ring that is fused to Ring A comprises 0- 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R’ is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R’ groups on the same atom are taken together with the atom to form an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic ring that is optionally bridged bicyclic or spirocyclic (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and n is 0, 1, 2, 3, 4, or 5. 6. A pharmaceutical composition according to claim 1, wherein the compounds of scavenging or trapping aldehydes by formation of an adduct is a compound of general formula Y-III: Y-III or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -NH2, -CN, -OR’, -SR’, -S(O)R’, -S(O)2R’, or optionally substituted C1-6 aliphatic; Ra is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; and Rb is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or Ra and Rb, taken together with the carbon atom to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; L1 is -C(O)NR’-CR’2- or -NR’C(O)-CR’2-, wherein either end of L1 may be covalently bound to Ring A; Ring A is selected from a cyclic group selected from phenyl and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic group is substituted with n instances of R4; each instance of R4 is independently halogen, –CN, –NO2, –OR’, –CR’2OR’, -SR’, -NR’2, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -S(O)NR’2, -C(O)R’, -C(O)OR’, –C(O)NR’2, -C(O)N(R’)OR’, -OC(O)R’, -OC(O)NR’2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)C(NR’)NR’2, -N(R’)S(O)2NR’2, –N(R’)S(O)2R’, an optionally substituted C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; or two R4 on adjacent carbon atoms, together with the adjacent carbon atoms, form a 4- to 7- membered ring that is fused to Ring A, wherein the ring that is fused to Ring A comprises 0- 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R’ is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R’ groups on the same atom are taken together with the atom to form an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic ring that is optionally bridged bicyclic or spirocyclic (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and n is 0, 1, 2, 3, 4, or 5. 7. A pharmaceutical composition according to claim 1, wherein the compound capable of scavenging or trapping an aldehyde by formation of an adduct is a compound of general formula Y-IV: Y-IV or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -NH2, -CN, -OR’, -SR’, -S(O)R’, -S(O)2R’, or optionally substituted C1-6 aliphatic; Ra is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; and Rb is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or Ra and Rb, taken together with the carbon atom to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; L1 is -C(O)NR’-CR’2- or -NR’C(O)-CR’2-, wherein either end of L1 may be covalently bound to Ring A; Ring A is selected from a cyclic group selected from phenyl and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic group is substituted with n instances of R4; each instance of R4 is independently halogen, –CN, –NO2, –OR’, –CR’2OR’, -SR’, -NR’2, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -S(O)NR’2, -C(O)R’, -C(O)OR’, –C(O)NR’2, -C(O)N(R’)OR’, -OC(O)R’, -OC(O)NR’2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)C(NR’)NR’2, -N(R’)S(O)2NR’2, –N(R’)S(O)2R’, an optionally substituted C1-6 aliphatic group, an optionally substituted C1-6 aliphatic-Cy group, or Cy; or two R4 on adjacent carbon atoms, together with the adjacent carbon atoms, form a 4- to 7- membered ring that is fused to Ring A, wherein the ring that is fused to Ring A comprises 0-3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; each Cy is independently an optionally substituted cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); each R’ is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6- membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R’ groups on the same atom are taken together with the atom to form an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic ring that is optionally bridged bicyclic or spirocyclic (having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); and n is 0, 1, 2, 3, 4, or 5. 8. The pharmaceutical composition of claim 1, wherein the composition is an aqueous composition. 9. The pharmaceutical composition of any one of claims 1-8 , wherein the compound of general formula II’’ is present at a concentration of 20-40% (weight/volume) based on the total weight of the composition. 10. The pharmaceutical composition of any one of claims 2, 3, 8 or 9, wherein the compound of general formula X-I or X-VI is selected from: X-I-5 X-I-7 X-I-6 X-I-8 X-I-10 X-I-9 X-I-11 X-I-12 X-I-13 X-I-16 X-I-14 X-I-15 X-I-17 X-I-18 X-I-19 X-I-20 X-I-22 X-I-21 X-I-23 X-I-24 X-I-25 or a pharmaceutically acceptable salt thereof. 11. The pharmaceutical composition of any one of claims 4-7 or 8-9, wherein the compound of general formula Y-I, Y-II, Y-III, or Y-IV is selected from: Y-I-17 Y-I-18 Y-I-19 Y-I-20 Y-I-21 Y-I-22 Y-I-23 Y-I-24 Y-I-25 Y-I-26 Y-I-27 Y-I-28 Y-I-43 Y-I-44 Y-I-45 Y-I-46 Y-I-47 Y-I-48 Y-I-49 Y-I-50 OH O H N O H N O N O H O Y-I-51 Y-I-52 Y-I-54 Y-I-53 Y-I-69 or a pharmaceutically acceptable salt thereof. 12. The pharmaceutical composition of claim 10, wherein the compound the compound of general formula X-I or X-VI is selected from: or a pharmaceutically acceptable salt thereof. 13. The pharmaceutical composition of any one of claims 1-12, wherein the compound of general formula II’’ is selected from one of those described in Table 1. 14. The pharmaceutical composition of any one of claims 1-12, wherein the compound of general formula II’’ is selected from any one of formula III-A, III-B, or III-C: or a pharmaceutically acceptable salt thereof. 15. The pharmaceutical composition of any one of claims 1-14, wherein the cyclodextrin of general formula II’’ is selected from a modified α-cyclodextrin, a modified β-cyclodextrin, or a modified γ cyclodextrin. 16. The pharmaceutical composition of claim 15, wherein the cyclodextrin of general formula II’’ is a modified β-cyclodextrin. 17. The pharmaceutical composition of claim 1, wherein Y in general formula II’’ is – . 18. The pharmaceutical composition of claim 1, wherein the compound of general formula II’’ is a compound of formula III-A, R is H and Y is –(C=O)NHNH2, –(C=S)NHNH2, – 19. The pharmaceutical composition of claim 1, wherein the compound of general formula II’’ is: . 20. The pharmaceutical composition of any one of claims 1-19, wherein the administration of the composition to an eye increases the residency time of the compound of general formula I in the eye compared to administration of a composition that does not comprise a compound of general formula II’’. 21. A method of treating an ocular disorder, comprising administering an effective amount of the composition of any one of claims 1-20 to a subject in need thereof. 22. The method of claim 21, wherein the ocular disorder is selected from the group consisting of dry eye disease, Age-related macular degeneration (AMD), retinitis pigmentosa (RP), dark adaptation impairment, cataracts, keratoconus, bullous and other keratopathy, Fuch’s endothelial dystrophy, allergic conjunctivitis, ocular cicatricial pemphigoid, a condition associated with PRK healing and other corneal healing, a condition associated with tear lipid degradation or lacrimal gland dysfunction, uveitis, scleritis, Stargardt’s disease, ocular Stevens Johnson Syndrome, and ocular rosacea. 23. The method of claim 22, wherein the ocular disorder is selected from the group consisting of uveitis, scleritis, ocular Stevens Johnson Syndrome, and ocular rosacea. 24. The method of claim 21, wherein the ocular disorder is selected from the group consisting of keratoconus, cataracts, bullous and other keratopathy, Fuchs’ endothelial dystrophy, ocular cicatricial pemphigoid, and allergic conjunctivitis. 25. The method of claim 21, wherein the ocular disorder is diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), retinitis pigmentosa (RP), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, noninfectious anterior uveitis, posterior uveitis, pan-uveitis, post-surgical ocular pain and inflammation. 26. The method of claim 25, wherein the ocular disorder is dry eye disease (DED). 27. The method of claim 25, wherein the ocular disorder is age-related macular degeneration (AMD). 28. The method of claim 27, wherein the ocular disorder is dry age-related macular degeneration dry (AMD). 29. The method of claim 28, wherein the ocular disorder is dry age-related macular degeneration dry (AMD) with evidence of dark adaptation impairment. 30. A method of reducing levels of one or more toxic aldehydes in a subject, comprising administering an effective amount of the composition of any one of claims 1-20 to a subject in need thereof. 31. The method of claim 30, wherein the toxic aldehyde is selected from formaldehyde, acetaldehyde, acrolein, glyoxal, methylglyoxal, hexadecanal, octadecanal, hexadecenal, succinic semi-aldehyde, malondialdehyde, 4-hydroxynonenal, 4-hydroxy-2E-hexenal, 4-hydroxy-2E,6Z- dodecadienal, retinaldehyde, leukotriene B4 aldehyde, and octadecenal. 32. A compound of general formula II’’: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is a covalent bond, nitrogen, oxygen, or sulfur; or a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O), -C(O)O-, -OC(O)-, -C(S)-, -C(RX)2, -C(F)2, -N(RX)-, - C(O)N(RX)-, -R’NC(O)-, -OC(O)N(RX)-, -N(RX)C(O)N(RX)-, or -Cy-; R is absent, H, -NO2, -OH, -CN, or optionally substituted C1-C12 alkyl; each -Cy- is bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5- 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Y is a modifier. 33. The compound of claim 32, wherein the modifier is –(C=O)N(RX)N(RX)2, – (C=S)N(RX)N(RX)2, –(C=O)N(RX)N(RX)OH, -(C=O)C(RX)(NRX2)C(RX)2OH, or , , 35. The compound of claim 32, wherein the compound is selected from one of those described in Table 1. 36. The compound of claim 32, wherein the compound is selected from any one of formula III-A, III-B, or III-C: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin. 37. The compound of any one of claims 32-36, wherein the cyclodextrin is selected from a modified α-cyclodextrin, a modified β-cyclodextrin, or a modified γ cyclodextrin. 38. The compound of claim 37, wherein the cyclodextrin is a modified β-cyclodextrin. 39. The compound of claim 37, wherein the compound is: , . 40. A method for treating an ocular disorder selected from age-related macular degeneration (AMD), retinitis pigmentosa (RP), and dark adaptation impairment comprising administering to a subject in need thereof, a compound of any one of claims 32-39 or a pharmaceutically acceptable salt thereof. |
[0088] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to general formula X-I or X-VI depicted as follows: [0089] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to general formula Y-I, Y-II, Y-III, or Y-IV depicted as follows: Y -I-1 Y-I-2 Y -I-3 Y-I-4 Y-I-57 [0090] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof depicted as follows: [0091] In certain embodiments, the present invention provides any compound described above and herein, or a pharmaceutically acceptable salt thereof. [0092] In certain embodiments, the present invention provides a compound of general formula II’: II’ or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin or a modified cyclodextrin; X is a covalent bond, nitrogen, oxygen, or sulfur; or a C 1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O), -C(O)O-, -OC(O)-, -C(S)-, -C(R X )2, -C(F)2, -N(R X )-, - C(O)N(R X )-, -R X NC(O)-, -OC(O)N(R X )-, -N(R)C(O)N(R X )-, or -Cy-; R is absent, H, -NO2, -CN, or optionally substituted C1-C12 alkyl; each R X is independently selected from hydrogen, deuterium, halogen, - OH, -O(C1-6 alkyl), -CN, -C(O)Me, -C(O)OMe, -SH, -S(C 1-6 alkyl), and an optionally substituted group selected from: C 1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5- 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;and Y is a modifier, wherein the modifier is selected from a group consisting of – - , , [0093] In certain embodiments, the present invention provides a compound of general formula II”: II” or a pharmaceutically acceptable salt thereof, wherein, CD is a cyclodextrin or a modified cyclodextrin; X is a covalent bond, nitrogen, oxygen, or sulfur; or a C 1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O), -C(O)O-, -OC(O)-, -C(S)-, -C(R X ) 2 , -C(F) 2 , -N(R X )-, - C(O)N(R X )-, -R X NC(O)-, -OC(O)N(R X )-, -N(R X )C(O)N(R X )-, or -Cy-; R is absent, H, -NO2, -CN, or optionally substituted C1-C12 alkyl; each R X is independently selected from hydrogen, deuterium, halogen, - OH, -O(C 1-6 alkyl), -CN, -C(O)Me, -C(O)OMe, -SH, -S(C1-6 alkyl), and an optionally substituted group selected from: C1-6 aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each -Cy- is bivalent optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, optionally substituted phenylene, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 5- 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Y is a modifier, wherein the modifier is selected from a group consisting (C=S)NHNH2, –(C=O)NHNHOH, -(C=O)CH(NH2)CH2OH, or - (CH2)CH(OH)CH2NH2, , -SO2H, (C=O)CH2(C=O)NH(CH2)2NH2, - , [0094] In some embodiments, the compound is a compound of general formula III-A, III-B, or III-C: III-A III-B III-C or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; R is absent, H, OH, halo, or C 1 -C 12 alkyl; and Y is a modifier. [0095] In some embodiments, Y is –(C=O)NHNH2, –(C=S)NHNH2, –(C=O)NHNHOH, or . [0096] In some embodiments, the compound is a compound of formula III-A, R is H and Y . [0097] In some embodiments, the compound is a compound of general formula IV-A, IV-B, or IV-C: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is nitrogen, oxygen, or sulfur; R is absent, H, OH, halo, or C1-C12 alkyl each R 11 , R 12 , and R 13 is independently -NR 14 N(R 15 ) 2 , -NR 14 C(R 15 ) 3 , - (CR 14 2)m(C=O)(CR 14 2)mN(CR 14 2)mN(R 15 )2, , aryl, or heteroaryl, wherein aryl and heteroaryl are unsubstituted or optionally substituted with –(R 16 )m; each m is independently an integer from 0 to 5; each R 14 is independently H, -OH, halo, or C1-C6 alkyl; R 15 is H, OH, or C1-C6 alkyl; and each R 16 is independently -NH 2 , -NHR 14 , -N(R 14 ) 2 , -NR 14 N(R 15 ) 2 , -NO 2 , - (CR 14 2 ) m (C=O)(CR 14 2 ) m N-(CR 14 2 ) m N(R 15 ) 2 , -B(OH) 2 , or –(C=O) R 14 . [0098] In some embodiments of general formula IV-A, X is N, R is H and R 11 is - NR 14 N(R 15 )2. In some embodiments of general formula IV-A, X is N, R is H and R 11 is - NHNH 2 . In some embodiments of general formula IV-A, X is N, R is H and R 11 is -NHNHOH . 1 1 In some embodiments of general formula IV-A, X is N, R is H and R is . [0099] In some embodiments of general formula IV-B, X is S, R is H, and R 11 is - NR 14 N(R 15 ) 2 . In some embodiments of general formula IV-B, X is S, R is H, and R 11 is - NHNH2. [00100] In some embodiments, the compound is a compound of general formula V-A, V-B, or V-C: V-A V-B V-C or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is nitrogen, oxygen, or sulfur; R is absent, H, OH, halo, or C 1 -C 12 alkyl; each R 14 is independently H, -OH, halo, or C1-C6 alkyl; and each R 15 is independently H or C 1 -C 6 alkyl. [00101] In some embodiments, the compound is a compound of general formula VI-A, VI-B, or VI-C: VI-A VI-B VI-C or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is nitrogen, oxygen, or sulfur; R is absent, H, OH, halo, or C1-C12 alkyl; each R 14 is independently H, -OH, halo, or C 1 -C 6 alkyl; and each R 15 is independently H or C 1 -C 6 alkyl. [00102] In some embodiments, the compound is a compound of general formula VII-A, VII- B, or VII-C: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is nitrogen, oxygen, or sulfur; R is absent, H, OH, halo, or C 1 -C 12 alkyl; Ring A is a C 4 -C 12 aryl or a C 4 -C 12 heteroaryl ring having one to 6 heteroatoms independently selected from O, N, and S; each m is independently an integer from 0 to 5; each R 16 is independently -NH 2 , -NHR 14 , -N(R 14 ) 2 , -NR 14 N(R 15 ) 2 , -NO 2 , -SO 2 , - C(R 14 )2(C=O)R 15 , -B(OH)2, or –(C=O) R 14 ; each R 14 is independently H, -OH, halo, or C1-C6 alkyl; and R 15 is H or C 1 -C 6 alkyl. [00103] In some embodiments, the compound is a compound of general formula VIII-A, VIII-B, or VIII-C: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is nitrogen, oxygen, or sulfur; R is absent, H, OH, halo, or C1-C12 alkyl; Z is C, N, O, or S; each m is independently an integer from 0 to 5; each R 14 is independently H, -OH, halo, or C1-C6 alkyl; each R 15 is independently H or C1-C6 alkyl; and each R 16 is independently -NH 2 , -NHR 14 , -N(R 14 ) 2 , -NR 14 N(R 15 ) 2 , -NO 2 , -SO 2 , - (CR 14 2 ) m (C=O)(CR 14 2 ) m N(CR 14 2 ) m N(R 15 ) 2 , -(CR 14 2 ) m (C=O)(CR 14 2 ) m (C=O)N(CR 14 2 ) m N(R 15 ) 2 , - B(OH)2, or –(C=O)R 14 . [00104] In some embodiments, the compound is a compound of general formula X-A, X-B, or X-C: X-A X-B X-C or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; R is H, -OH, halo, or C1-C12 alkyl; each R 14 is independently H, -OH, halo, or C1-C6 alkyl; R 17 is -OH, -NH 2 , -(S=O)OR 14 , -OR 14 , or R 18 ; R 18 is C 1 -C 6 alkyl or C 1 -C 6 alkenyl, wherein the C 1 -C 6 alkyl and the C 1 -C 6 alkenyl each has 0 to 5 substituents selected from halo, -OH, -SH, -OR, -SR, -NR2, and wherein the C1-C6 alkenyl has 1 to 3 double bonds. [00105] In some embodiments, the compound is a compound of general formula XII-A, XII- B, or XII-C: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; R is H, -OH, halo, or C1-C12 alkyl; R 17 is H, -OH, -NH2, -OR 18 , or R 18 ; R 18 is C 1 -C 6 alkyl or C 1 -C 6 alkenyl, wherein the C 1 -C 6 alkyl and the C 1 -C 6 alkenyl each has 0 to 5 substituents selected from halo, -OH, -SH, -OR, -SR, -NR 2 , and wherein the C 1 -C 6 alkenyl has 1, 2, or 3 double bonds. [00106] The cyclodextrin portion of formula II may be any cyclodextrin known in the art, either naturally occurring or modified. Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). Cyclodextrins may have as many as 150-membered cyclic oligosaccharides are also known. [00107] The cyclodextrin portion of formula II, II’, II”, II’” may be any cyclodextrin known in the art, either naturally occurring or modified or a compound as described herein.. [00108] An alternate way to depict the structure of a cyclodextrin (such as α-cyclodextrin) shows the glucose subunits in chair conformation:
α-cyclodextrin [00109] A cyclodextrin having six glucose subunits is an alpha cyclodextrin (α-cyclodextrin); a cyclodextrin having seven glucose subunits is a beta cyclodextrin (β-cyclodextrin); and cyclodextrin having eight glucose subunits is a gamma cyclodextrin (γ-cyclodextrin). α-cyclodextrin β-cyclodextrin γ-cyclodextrin [00110] Cyclodextrins are generally regarded as safe by the United States FDA. Cyclodextrins have toroidal shapes, with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively, as shown in this γ- cyclodextrin:
. [00111] Because of this arrangement, the interior of the toroids of native cyclodextrins is not hydrophobic, but it is considerably less hydrophilic than an aqueous environment and thus able to host other hydrophobic molecules. In contrast, the exterior is sufficiently hydrophilic to impart cyclodextrins (or their complexes) water solubility. [00112] The cyclodextrin of formula II may be any modified cyclodextrin known in the art. Common modifications include chemical modification of native hydroxyl groups in the cyclodextrin. O-methylation and acylation are common modifications, with tunability of the degree of functionalization can be controlled. Cyclodextrins react with propylene oxide to give hydroxypropylated derivatives. Further, the primary -OH moieties may be tosylated. In general, derivation of a cyclodextrin by reaction with a primary hydroxyl group results in modification at the larger opening of the toroid shape, while derivatization by reaction with a secondary hydroxyl group results in modification at the smaller opening of the toroid shape. [00113] Other suitable cyclodextrins for additional modification according to the modifiers of this invention include trimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2- hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, and β-cyclodextrin sulfobutylether sodium salt (or potassium salt) or an oligomeric or a polymeric carrier such as β- cyclodextrin sulfobutylether sodium salt. [00114] In some embodiments, the cyclodextrin of a compound of general formulas II to XI is α-cyclodextrin. In some embodiments, the cyclodextrin of a compound of general formulas II to XI is β-cyclodextrin. In some embodiments, the cyclodextrin of a compound of general formulas II to XI is γ-cyclodextrin. [00115] In some embodiments, the cyclodextrin of a compound of general formulas II to XI is an amino-α-cyclodextrin. In some embodiments, the cyclodextrin of a compound of general formulas II to XI is an amino-β-cyclodextrin. In some embodiments, the cyclodextrin of a compound of general formulas II to XI is an amino-γ-cyclodextrin. [00116] It is disclosed herein that amino-cyclodextrins may be further modified to semi- carbazido cyclodextrins, e.g., semi-carbazido-β-cyclodextrin: semi-carbazido-β-cyclodextrin [00117] In some embodiments, the cyclodextrin of a compound of general formulas II to XI is a semi-carbazido-α-cyclodextrin. In some embodiments, the cyclodextrin of a compound of general formulas II to XI is a semi-carbazido-β-cyclodextrin. In some embodiments, the cyclodextrin of a compound of general formulas II to XI is a semi-carbazido-γ-cyclodextrin. [00118] The modified cyclodextrin compounds of general formula II, II’ II” or II’” have been designed to tune the physicochemical properties of the API of general formula I, X-I, X-VI, Y-I to Y-IV: cyclodextrin compound of general formula II, II’ II” or II’” complex, resulting in enhanced overall solubility and stability. Incorporation of a polar, electron-rich “warhead” into the hydrophobic core of native amino-β-cyclodextrin achieves this goal by increasing the hydrophilicity of the overall system through introduction of new, polar, and in some cases, heteroatomic, functionality. [00119] In some embodiments, the compound of general formula II, II’ II” or II’” is:
. [00120] In another aspect, the present invention provides methods for treating an ocular disease, disorder, or condition, such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), and dark adaptation impairment with a pharmaceutical composition comprising a compound of general formula I, X-I, X-VI, Y-I to Y-IV or a pharmaceutically acceptable salt thereof, and a compound of general formula II, II’, II” or II”’ or a pharmaceutically acceptable salt thereof. [00121] In some embodiments, the method of treating an ocular disease or condition whose etiology involves accumulation of A2E and/or lipofuscin in a subject, comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound of general formula I, X-I, X-VI, Y-I to Y-IV or a pharmaceutically acceptable salt thereof, and a compound of general formula II, II’, II” or II”’ or a pharmaceutically acceptable salt thereof, and thereby reducing the level of A2E accumulation relative to the level of A2E accumulation in said subject prior to administration of the compound or composition or pharmaceutically acceptable salt thereof. [00122] In some embodiments, the method of treating, preventing, or reducing a risk of a disease, disorder, condition, or cosmetic indication in which aldehyde toxicity is implicated in a subject in need thereof, comprises administering topically or systemically to the subject a pharmaceutical composition comprising a compound of general formula I, X-I, X-VI, Y-I to Y- IV or a pharmaceutically acceptable salt thereof, and a compound of general formula II, II’, II” or II”’ or a pharmaceutically acceptable salt thereof. [00123] In some embodiments, the disease, disorder, or condition is an ocular disorder. In general, “ocular disorder” includes any disease, disorder, or condition affecting any structure of the eye. [00124] In some embodiments, the ocular disorder is selected from the group consisting of dry eye disease, age-related macular degeneration (AMD), retinitis pigmentosa (RP), dark, adaptation impairment, cataracts, keratoconus, bullous and other keratopathy, Fuch’s endothelial dystrophy, allergic conjunctivitis, ocular cicatricial pemphigoid, a condition associated with PRK healing and other corneal healing, a condition associated with tear lipid degradation or lacrimal gland dysfunction, uveitis, scleritis, Stargardt’s disease, ocular Stevens Johnson Syndrome, and ocular rosacea. [00125] In some embodiments, the ocular disorder is dry eye syndrome. [00126] In some embodiments, the ocular disorder is Age-related macular degeneration (AMD). [00127] In some embodiments, the ocular disorder is dry age-related macular degeneration (AMD). [00128] In some embodiments, the ocular disorder is dry age-related macular degeneration (AMD) with evidence of dark adaptation impairment. [00129] In some embodiments, the ocular disorder is retinitis pigmentosa (RP). [00130] In some embodiments, the ocular disorder is diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, noninfectious anterior uveitis, posterior uveitis, pan-uveitis, post-surgical ocular pain and inflammation. [00131] In some embodiments, the ocular disorder is selected from the group consisting of uveitis, scleritis, ocular Stevens Johnson Syndrome, and ocular rosacea. [00132] In some embodiments, the ocular disorder is ocular rosacea or uveitis. [00133] In some embodiments, wherein the ocular disorder is selected from the group consisting of keratoconus, cataracts, bullous and other keratopathy, Fuchs’ endothelial dystrophy, ocular cicatricial pemphigoid, and allergic conjunctivitis. [00134] In some embodiments, the present invention provides a method of reducing levels of one or more toxic aldehydes in a subject, comprises administering to the subject a a pharmaceutical composition comprising a compound of general formula I, X-I, X-VI, Y-I to Y- IV or a pharmaceutically acceptable salt thereof, and a compound of general formula II, II’, II” or II”’ or a pharmaceutically acceptable salt thereof. [00135] Any of the compounds of general formula II, II’, II” or II”’ or formulas III to XI may be used in the absence of a compound of general formula I, X-I, X-VI, Y-I to Y-IV for any ocular indication or disorder. [00136] Provided herein are compounds of general formula II: or a pharmaceutically acceptable salt thereof, wherein CD is a cyclodextrin; X is nitrogen, oxygen, or sulfur; R is absent, H, OH, halo, or C 1 -C 12 alkyl; and Y is a modifier. [00137] In some embodiments, Y is –(C=O)NHNH2, –(C=S)NHNH2, –(C=O)NHNHOH, or . [00138] In some embodiments, the compound is selected from any one of formulas III-XI. [00139] In some embodiments, the cyclodextrin is selected from a modified α-cyclodextrin, a modified β-cyclodextrin, or a modified γ cyclodextrin. [00140] In some embodiments, the cyclodextrin is a modified β-cyclodextrin. [00141] In some embodiments, the compound of general formula II is: degeneration (AMD), retinitis pigmentosa (RP), and dark adaptation impairment comprising administering to a subject in need thereof, a compound of general formula II, II’, II” or II”’ or of any one of formulas III to XII, or a pharmaceutically acceptable salt thereof. 3. Definitions [00143] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [00144] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [00145] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include: [00146] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [00147] The term “lower haloalkyl” refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [00148] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)). [00149] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [00150] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [00151] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [00152] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [00153] The term “halogen” means F, Cl, Br, or I. [00154] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. [00155] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin– 3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [00156] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4– dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl). [00157] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [00158] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [00159] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [00160] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH 2 ) 0–4 R ; º –(CH 2 ) 0–4 OR ; º -O(CH 2 ) 0-4 R o , –O– (CH 2 ) 0–4 C(O)OR°; –(CH 2 ) 0–4 CH(OR ) º 2 ; –(CH 2 ) 0–4 SR ; º –(CH 2 ) 0–4 Ph, which may be substituted with R°; –(CH 2 ) 0–4 O(CH 2 ) 0–1 Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R ) º2; –(CH2)0–4N(R ) ºC(O)R ; º –N(R ) ºC(S)R ; º –(CH2)0–4N(R ) ºC(O)NR 2 º; -N(R ) ºC(S)NR º2; –(CH2)0–4N(R ) ºC(O)OR º; –N(R ) ºN(R ) ºC(O)R ; º -N(R ) ºN(R ) ºC(O)NR 2 º; -N(R ) ºN(R ) ºC(O)OR ; º –(CH2)0–4C(O)R ; º –C(S)R ; º –(CH2)0–4C(O)OR ; º –(CH2)0–4C(O)SR ; º -(CH2)0–4C(O)OSiR 3 º; –(CH2)0–4OC(O)R ; º –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R ; º –(CH2)0–4C(O)NR 2 º; –C(S)NR 2 º; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR 2 º; -C(O)N(OR ) ºR ; º –C(O)C(O)R ; º –C(O)CH2C(O)R ; º –C(NOR ) ºR ; º -(CH2)0–4SSR ; º –(CH2)0– 4S(O)2R ; º –(CH2)0–4S(O)2OR ; º –(CH2)0–4OS(O)2R ; º –S(O)2NR 2 º; -(CH2)0–4S(O)R ; º -N(R ) ºS(O) 2 NR 2 º; –N(R ) ºS(O) 2 R ; º –N(OR ) ºR ; º –C(NH)NR 2 º; –P(O) 2 R ; º -P(O)R 2 º; -OP(O)R 2 º; –OP(O)(OR ) º 2 ; SiR 3 º; –(C 1–4 straight or branched alkylene)O–N(R ) º 2 ; or –(C 1–4 straight or branched alkylene)C(O)O–N(R ) º 2 , wherein each R º may be substituted as defined below and is independently hydrogen, C 1–6 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, -CH 2 -(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R , º taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [00161] Suitable monovalent substituents on R º (or the ring formed by taking two independent occurrences of R º together with their intervening atoms), are independently halogen, –(CH2)0–2R ^ , –(haloR ^ ), –(CH2)0–2OH, –(CH2)0–2OR ^ , –(CH2)0–2CH(OR ^ )2; -O(haloR ^ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ^ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ^ , –(CH 2 ) 0–2 SR ^ , –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ^ , –(CH2)0–2NR ^ 2, –NO2, –SiR ^ 3, –OSiR ^ 3, -C(O)SR ^ , –(C1–4 straight or branched alkylene)C(O)OR ^ , or –SSR ^ wherein each R ^ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R º include =O and =S. [00162] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , –O(C(R * 2))2–3O–, or –S(C(R * 2))2–3S–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00163] Suitable substituents on the aliphatic group of R * include halogen, –R ^ , -(haloR ^ ), -OH, –OR ^ , –O(haloR ^ ), –CN, –C(O)OH, –C(O)OR ^ , –NH2, –NHR ^ , –NR ^ 2, or –NO2, wherein each R ^ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00164] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R † , –C(O)C(O)R † , –C(O)CH2C(O)R † , -S(O)2R † , -S(O) 2 NR † 2 , –C(S)NR † 2 , –C(NH)NR † 2 , or –N(R † )S(O) 2 R † ; wherein each R † is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R † , taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00165] Suitable substituents on the aliphatic group of R † are independently halogen, –R ^ , -(haloR ^ ), –OH, –OR ^ , –O(haloR ^ ), –CN, –C(O)OH, –C(O)OR ^ , –NH2, –NHR ^ , –NR ^ 2, or -NO2, wherein each R ^ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00166] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [00167] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [00168] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. [00169] The “retina” is a region of the central nervous system with approximately 150 million neurons. It is located at the back of the eye where it rests upon a specialized epithelial tissue called retinal pigment epithelium (RPE). The retina initiates the first stage of visual processing by transducing visual stimuli in specialized neurons called “photoreceptors”. Their synaptic outputs are processed by elaborate neural networks in the retina and are then transmitted to the brain. The retina has evolved two specialized classes of photoreceptors to operate under a wide range of light conditions. “Rod” photoreceptors transduce visual images under low light conditions and mediate achromatic vision. “Cone” photoreceptors transduce visual images in dim to bright light conditions and mediate both color vision and high acuity vision. [00170] Every photoreceptor is compartmentalized into two regions called the “outer” and “inner” segment. The inner segment is the neuronal cell body containing the cell nucleus. The inner segment survives for a lifetime in the absence of retinal disease. The outer segment is the region where the light sensitive visual pigment molecules are concentrated in a dense array of stacked membrane structures. Part of the outer segment is routinely shed and regrown in a diurnal process called outer segment renewal. Shed outer segments are ingested and metabolized by RPE cells. [00171] The “macula” is the central region of the retina which contains the fovea where visual images are processed by long slender cones in high spatial detail (“visual acuity”). “Macular degeneration” is a form of retinal neurodegeneration which attacks the macula and destroys high acuity vision in the center of the visual field. Age-Related Macular Degeneration (AMD) begins in a “dry form” characterized by residual lysosomal granules called lipofuscin in RPE cells, and by extracellular deposits called “drusen”. Drusen contain cellular waste products excreted by RPE cells. “Lipofuscin” and drusen can be detected clinically by ophthalmologists and quantified using fluorescence techniques. They can be the first clinical signs of macular degeneration. [00172] Lipfuscin contains aggregations of A2E. Lipofuscin accumulates in RPE cells and poisons them by multiple known mechanisms. As RPE cells become poisoned, their biochemical activities decline and photoreceptors begin to degenerate. Extracellular drusen may further compromise RPE cells by interfering with their supply of vascular nutrients. Drusen also trigger inflammatory processes, which lead to choroidal neovascular invasions of the macula in one patient in ten who progresses to wet form AMD. Both the dry form and wet form progress to blindness. [00173] “ERG” is an acronym for electroretinogram, which is the measurement of the electric field potential emitted by retinal neurons during their response to an experimentally defined light stimulus. ERG is a non-invasive measurement which can be performed on either living subjects (human or animal) or a hemisected eye in solution that has been removed surgically from a living animal. [00174] As used herein, the term “RAL” means retinaldehyde. The term “RAL-trap” means a therapeutic compound that binds free RAL and thereby prevents the RAL from Schiff base condensation with membrane phosphatidylethanolamine (PE). “Free RAL” is defined as RAL that is not bound to a visual cycle protein. The terms “trans-RAL” and “all-trans-RAL” are used interchangeably and mean all trans-retinaldehyde. [00175] A2E is a reaction by-product of a complex biochemical pathway called the “visual cycle” which operates collaboratively in both RPE cells and photoreceptor outer segments. The visual cycle recycles a photoreactive aldehyde chromophore called “retinaldehyde” which is derived from vitamin A and is essential for vision. In simplified terms, the visual cycle has four principal steps: 1) it converts vitamin A in the RPE into an aldehyde chromophore with one photoreactive strained double bond (11-cis-RAL); 2) it transports 11-cis-RAL to the retina where it binds to a specialized photoreceptor protein called opsin; 3) light photoisomerizes bound 11-cis-RAL to trans-RAL, which initiates the release of bound RAL from the opsin binding site; and 4) it converts trans-RAL (an aldehyde) to vitamin A (an alcohol) and transports vitamin A back to the RPE where the cycle begins again. [00176] The aldehyde group of RAL helps bind the molecule to opsin by forming a reversible chemical bond to an amino acid sidechain in the opsin binding site. While the aldehyde group on RAL is essential for anchoring the molecule to the opsin binding site, it is otherwise hazardous because of its propensity to form Schiff bases with other biological amines. The first three reactions take place in photoreceptor outer segments and produce an intermediary product called A2PE. Once formed, A2PE partitions into the lipid phase and accumulates in photoreceptor outer segment membranes. [00177] As described above, macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin may be treated or prevented by lowering the amount of A2E formed. Compounds useful for doing so include RAL-traps such as certain compounds disclosed herein. RAL-traps lower the amount of A2E formed, for example by forming a covalent bond with RAL that has escaped sequestering. RAL that has reacted with a RAL-trap compound is thereby unavailable to react with phosphatidylethanolamine. [00178] The phrases “parenteral administration” and “administered parenterally” are art- recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [00179] As used herein, “about” or “approximately” in reference to a numerical value means that the stated numerical value may vary by up to 10% of the stated value. For example, “about 10” refers to a value of 9.9 to 10.1 (10 +/- 0.1). [00180] The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. 4. Uses of Compounds and Pharmaceutically Acceptable Compositions Thereof [00181] Certain compounds described herein are found to be useful in scavenging toxic aldehydes, such as MDA and HNE. Without wishing to be bound by theory, it is believed that the compounds described herein undergo a Schiff base condensation with MDA, HNE, or other toxic aldehydes, and form a complex with the aldehydes in an energetically favorable reaction, thus reducing or eliminating aldehydes available for reaction with a protein, lipid, carbohydrate, or DNA. Importantly, compounds described herein can react with aldehydes to form a compound having a cyclic structure that contains the aldehydes, thus trapping the aldehydes and preventing the aldehydes from being released back into the cellular milieu. [00182] In one aspect, the present invention provides a method for reducing levels of one or more toxic aldehydes in a subject, comprising administering to a subject in need thereof a disclosed compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein. [00183] In another aspect, the present invention provides a method for reducing levels of one or more toxic aldehydes in a biological sample, comprising contacting the biological sample with a disclosed compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein. In some embodiments, the method is carried out in vitro. [00184] In some embodiments, the toxic aldehyde is selected from formaldehyde, acetaldehyde, acrolein, glyoxal, methylglyoxal, hexadecanal, octadecanal, hexadecenal, succinic semi-aldehyde, malondialdehyde, 4-hydroxynonenal, 4-hydroxy-2E-hexenal, 4-hydroxy-2E,6Z- dodecadienal, retinaldehyde, leukotriene B4 aldehyde, and octadecenal. [00185] In some embodiments, the toxic aldehyde is formaldehyde. In some embodiments, the toxic aldehyde is acetaldehyde. In some embodiments, the toxic aldehyde is acrolein. In some embodiments, the toxic aldehyde is glyoxal. In some embodiments, the toxic aldehyde is methylglyoxal. In some embodiments, the toxic aldehyde is hexadecanal. In some embodiments, the toxic aldehyde is octadecanal. In some embodiments, the toxic aldehyde is hexadecenal. In some embodiments, the toxic aldehyde is succinic semi-aldehyde (SSA). In some embodiments, the toxic aldehyde is malondialdehyde (MDA). In some embodiments, the toxic aldehyde is 4-hydroxynonenal. In some embodiments, the toxic aldehyde is retinaldehyde. In some embodiments, the toxic aldehyde is 4-hydroxy-2E-hexenal. In some embodiments, the toxic aldehyde is 4-hydroxy-2E,6Z-dodecadienal. In some embodiments, the aldehyde is leukotriene B4 aldehyde. In some embodiments, the aldehyde is octadecenal. [00186] In some embodiments, the compound reduces systemic inflammation in the patient. [00187] In some embodiments, the compound reduces plasma levels of a biomarker selected from IL-1β, IL-6, IL-10, and tumor necrosis factor alpha. In some embodiments, the compound reduces plasma levels of a biomarker selected from a RASP. In some embodiments, the RASP is malondialdehyde (MDA) and/or 4-hydroxynonenal (4-HNE). [00188] In some embodiments, the method further comprises a reduction in the level of a reactive aldehyde species (RASP) in the patient’s blood, such as malondialdehyde (MDA) or 4- hydroxynonenal (HNE). [00189] In some embodiments, the level of RASP is reduced by at least 30%, at least 40%, or at least 50%. In some embodiments, the level of RASP is reduced by about 30% to 75%. In some embodiments, the level of RASP is reduced by about 20% to about 60%, or about 20% to about 50%, or about 20% to about 30%. [00190] In another aspect, the present invention provides a method for treating a disease, disorder, or condition described herein, comprising administering to a subject in need thereof a disclosed compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein. [00191] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). In some embodiments, treatment is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence. [00192] The invention relates to compounds described herein for the treatment, prevention, and/or reduction of a risk of diseases, disorders, or conditions in which aldehyde toxicity is implicated in the pathogenesis. [00193] Examples of the diseases, disorders, or conditions in which aldehyde toxicity is implicated include an ocular disease, disorder, or condition, including, but not limited to, a corneal disease (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid degradation or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens Johnson Syndrome, ocular rosacea (with or without meibomian gland dysfunction)). In a further example, the ocular disease, disorder, or condition is dry eye syndrome, ocular rosacea, or uveitis. [00194] In some embodiments, the invention relates to the treatment, prevention, and/or reduction of a risk of an ocular disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound described herein. The ocular disease, disorder, or condition includes, but is not limited to, a corneal disease (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy in the cornea), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid degradation or lacrimal gland dysfunction), and other ocular conditions where inflammation leads to high aldehyde levels (e.g., uveitis, scleritis, ocular Stevens Johnson Syndrome, ocular rosacea (with or without meibomian gland dysfunction)). In some embodiments, the ocular disease, disorder, or condition is macular degeneration. In some embodiments, the ocular disease, disorder, or condition is AMD or Stargardt’s disease. In one illustration, in the ocular disease, disorder, or condition, the amount or concentration of MDA or HNE is increased in the ocular tissues or cells. For example, the amount or concentration of aldehydes (e.g., MDA or HNE) is increased for at least 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 5 fold, 10 fold as compared to that in normal ocular tissues or cells. Compounds described herein decrease aldehyde (e.g., MDA and/or HNE) concentration in a concentration-dependent manner. The amount or concentration of aldehydes (e.g., MDA or HNE) can be measured by methods or techniques known in the art, such as those described in Tukozkan et al., Furat Tip Dergisi 11: 88- 92 (2006). [00195] In some embodiments, the ocular disease, disorder, or condition is dry eye syndrome. In a second class, the ocular disease, disorder, or condition is a condition associated with PRK healing and other corneal healing. For example, the invention is directed to advancing PRK healing or other corneal healing, comprising administering to a subject in need thereof a compound described herein. In a third class, the ocular disease, disorder, or condition is an ocular condition associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens Johnson Syndrome, and ocular rosacea (with or without meibomian gland dysfunction). In a fourth class, the ocular disease, disorder, or condition is keratoconus, cataracts, bullous and other keratopathy, Fuchs’ endothelial dystrophy, ocular cicatricial pemphigoid, or allergic conjunctivitis. The compound described herein may be administered topically or systemically, as described herein below. [00196] The present invention is also directed to the use of a compound described herein in the manufacture of a medicament for the treatment, prevention, and/or reduction of a risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis. More specifically, this aspect of the invention is directed to the use of a compound described herein in the manufacture of a medicament for the treatment, prevention, and/or reduction of a risk of (1) an ocular disease, disorder, or condition, including, but not limited to, a corneal disease (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid degradation or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens Johnson Syndrome, and ocular rosacea (with or without meibomian gland dysfunction)), (2) a skin disorder or condition or a cosmetic indication. [00197] The present invention is also directed to the use of a compound described herein in treating, preventing, and/or reducing a risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis. More specifically, this aspect of the invention is directed to the use of a compound described herein in treating, preventing, and/or reducing a risk of an ocular disease, disorder, or condition, including, but not limited to, a corneal disease (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuch’s endothelial dystrophy), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid degradation or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens Johnson Syndrome, and ocular rosacea (with or without meibomian gland dysfunction)). [00198] In some embodiments, the atopic dermatitis treated is in the acute phase. In some embodiments, acute atopic dermatitis presents with a vesicular, weeping, crusting eruption. [00199] In some embodiments, the atopic dermatitis treated is in the subacute phase. In some embodiments, subacute atopic dermatitis presents with dry, scaly, erythematous papules and plaques. [00200] In some embodiments, the DME treated is clinically significant macular edema (CSME). Clinically, CSME is defined as DME meeting at least one of the criteria presented as follows: (a) thickening of the retina at or within 500 μm of the center of the macula; (b) hard exudates at or within 500 μm of the center of the macula, if associated with thickening of adjacent retina (not counting residual hard exudates remaining after disappearance of retinal thickening); and (c) any zone(s) of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula. [00201] In some embodiments, the DME treated is center-involved DME. In center-involved DME, the central macula is generally the thickest portion of the retina and is an inversion of the normal morphology. [00202] In some embodiments, the DME treated is non-center-involved DME. Non-central DME lack involvement of the center of the macula. [00203] In some embodiments, the DME treated is focal DME. Focal edema often occurs associated with a cluster of microaneurysms, sometimes surrounded by an incomplete ring of hard exudates. It may be associated with less macular thickening, better visual acuity, and less severe retinopathy severity. [00204] In some embodiments, the DME treated is diffuse type DME. Diffuse macular edema occurs from dilated retinal capillaries in the retina and involve a larger area of retinal thickening. [00205] In some embodiments, the DME treated is accompanied by retinal detachment or severe non-clearing vitreous hemorrhage. [00206] In some embodiments, the patient treated has undergone focal laser photocoagulation therapy. [00207] In some embodiments, the patient treated has undergone grid laser photocoagulation therapy. [00208] In some embodiments, a method of the disclosure is directed to treatment of Stargardt’s disease. In some embodiments, a method of treating or reducing the risk of Stargardt’s disease comprises administering to a patient in need thereof an effective amount of a compound disclosed herein. Generally, Stargardt’s disease is inherited form of macular dystrophy characterized by bilateral vision loss, including dyschromatopsia and central scotomata, with characteristic macular atrophy and yellow-white flecks at the level of the retinal pigment epithelium (RPE) at the posterior pole. Stargardt’s disease may also be referred to as Stargardt macular dystrophy, juvenile macular degeneration, or fundus flavimaculatus. Onset of Stargardt’s disease occurs most commonly in childhood, with the next peak being early adulthood, and least frequently in later adulthood. Better prognosis is generally associated with a later onset. [00209] In some embodiments, the Stargardt’s disease treated is childhood-onset Stargardt’s disease. [00210] In some embodiments, the Stargardt’s disease treated is adult-onset or late onset Stargardt’s disease. [00211] In some embodiments, the severity of Stargardt’s disease can be classified based on electrophysiological assessment (see, e.g., Tanna et al., British Journal of Ophthalmology 2017; 101:25-30). [00212] In some embodiments, the Stargardt’s disease treated is classified in Group 1. Stargardt’s disease in Group 1 display a severe pattern electroretinogram (ERG) abnormality (macular dysfunction) with normal full-field ERGs. [00213] In some embodiments, the Stargardt’s disease treated is classified in Group 2. Stargardt’s disease in Group 2 display the characteristics of Group 1 and have in addition generalised loss of cone function. Patients in Group 2 have intermediate variable prognosis. [00214] In some embodiments, the Stargardt’s disease treated is classified in Group 3. Stargardt’s disease in Group 3 display an additional generalised loss of both cone and rod function. Patients in Group 3 show the worst prognosis. [00215] In some embodiments, the patient treated is identified as having a mutation in retina- specific ATP-binding cassette transporter (ABCA4) gene resulting in reduction or defect in ABCA4 function. Mutations in ABCA4 are the most common forms of inherited Stargardt’s disease. [00216] In some embodiments, the patient treated is identified as having mutation in ABCA4 gene that are associated with childhood-onset Stargardt’s disease. Exemplary mutations associated with childhood-onset Stargardt’s disease include, among others, 634C>T, 768G>T, 1317G>A, 1531C>T, 1557C>A, 5308T>G, 6088C>T, or 6449G>A. [00217] In some embodiments, the patient treated is identified as having mutation in ABCA4 gene that are associated with adult-onset or late onset Stargardt’s disease. Exemplary mutations associated with adult-onset or late onset Stargardt’s disease include, among others, 769-784C>T, 2486C>T, 5603A>T, or 5882G>A. [00218] As further discussed below, the compound or pharmaceutically acceptable salt thereof described herein can be administered systemically to treat the indications described herein. In some embodiments, the pharmaceutical composition is a liquid. [00219] In some embodiments, the disease, disorder, or condition for treatment with the compounds of the disclosure is an ocular inflammatory disorder. In some embodiments, the ocular inflammatory disorder is diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), retinitis pigmentosa (RP), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, noninfectious anterior uveitis, posterior uveitis, pan-uveitis, post-surgical ocular pain and inflammation. [00220] In some embodiments, the disease, disorder, or condition is one of those described in WO 2019/075136, which is hereby incorporated by reference. [00221] In some embodiments, the disease, disorder, or condition is one of those described in WO 2023/278816, which is hereby incorporated by reference. [00222] In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered once, twice, thrice, or four times per day. In some embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice per day. [00223] In some embodiments, the dose of the compound or pharmaceutically acceptable salt thereof is administered systemically. [00224] In some embodiments, the dose of the compound or pharmaceutically acceptable salt thereof is administered orally. [00225] In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the pharmaceutical composition is administered as a liquid via nasogastric tube. [00226] As discussed above, a disclosed compound may be administered to a subject in order to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin. Other diseases, disorders, or conditions characterized by the accumulation of A2E may be similarly treated. [00227] In one embodiment, a compound is administered to a subject that reduces the formation of A2E. For example, the compound may compete with PE for reaction with trans- RAL, thereby reducing the amount of A2E formed. In another embodiment, a compound is administered to a subject that prevents the accumulation of A2E. For example, the compound competes so successfully with PE for reaction with trans-RAL, no A2E is formed. [00228] Individuals to be treated fall into three groups: (1) those who are clinically diagnosed with macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin on the basis of visual deficits (including but not limited to dark adaptation, contrast sensitivity and acuity) as determined by visual examination and/or electroretinography, and/or retinal health as indicated by fundoscopic examination of retinal and RPE tissue for drusen accumulations, tissue atrophy and/or lipofuscin fluorescence; (2) those who are pre-symptomatic for macular degenerative disease but thought to be at risk based on abnormal results in any or all of the same measures; and (3) those who are pre-symptomatic but thought to be at risk genetically based on family history of macular degenerative disease and/or genotyping results showing one or more alleles or polymorphisms associated with the disease. The compositions are administered topically or systemically at one or more times per month, week or day. Dosages may be selected to avoid side effects, if any, on visual performance in dark adaptation. Treatment is continued for a period of at least one, three, six, or twelve or more months. Patients may be tested at one, three, six, or twelve months or longer intervals to assess safety and efficacy. Efficacy is measured by examination of visual performance and retinal health as described above. [00229] In one embodiment, a subject is diagnosed as having symptoms of macular degeneration, and then a disclosed compound is administered. In another embodiment, a subject may be identified as being at risk for developing macular degeneration (risk factors include a history of smoking, age, female sex, and family history), and then a disclosed compound is administered. In another embodiment, a subject may have dry AMD in both eyes, and then a disclosed compound is administered. In another embodiment, a subject may have wet AMD in one eye but dry AMD in the other eye, and then a disclosed compound is administered. In yet another embodiment, a subject may be diagnosed as having Stargardt’s disease and then a disclosed compound is administered. In another embodiment, a subject is diagnosed as having symptoms of other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, and then the compound is administered. In another embodiment a subject may be identified as being at risk for developing other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, and then the disclosed compound is administered. In some embodiments, a compound is administered prophylactically. In some embodiments, a subject has been diagnosed as having the disease before retinal damage is apparent. For example, a subject is found to carry a gene mutation for ABCA4 and is diagnosed as being at risk for Stargardt’s disease before any ophthalmologic signs are manifest, or a subject is found to have early macular changes indicative of macular degeneration before the subject is aware of any effect on vision. In some embodiments, a human subject may know that he or she is in need of the macular generation treatment or prevention. [00230] In some embodiments, a subject may be monitored for the extent of macular degeneration. A subject may be monitored in a variety of ways, such as by eye examination, dilated eye examination, fundoscopic examination, visual acuity test, and/or biopsy. Monitoring can be performed at a variety of times. For example, a subject may be monitored after a compound is administered. The monitoring can occur, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other time period after the first administration of a compound. A subject can be repeatedly monitored. In some embodiments, the dose of a compound may be altered in response to monitoring. [00231] In some embodiments, the disclosed methods may be combined with other methods for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin, such as photodynamic therapy. For example, a patient may be treated with more than one therapy for one or more diseases or disorders. For example, a patient may have one eye afflicted with dry form AMD, which is treated with a compound of the invention, and the other eye afflicted with wet form AMD which is treated with, e.g., photodynamic therapy. [00232] In some embodiments, a compound for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin may be administered chronically. The compound may be administered daily, more than once daily, twice a week, three times a week, weekly, biweekly, monthly, bimonthly, semiannually, annually, and/or biannually. 5. Combination Therapies [00233] In one aspect, the present invention provides a combination pharmaceutical composition comprising: a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein each of A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is as defined herein; and a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein each of CD, R, X and Y is as defined herein. [00234] In some embodiments, the present invention provides a combination pharmaceutical composition comprising an aldehyde trap; and a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein each of CD, R, X and Y is as defined herein. [00235] In one aspect, the present invention provides a combination pharmaceutical composition comprising: a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein each of A, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is as defined herein; and an aldehyde trap. [00236] An “aldehyde trap” is any compound that can react to form a covalent bond with an aldehyde moiety. In some cases, the aldehydes are by-products of a disorder or a disease process. [00237] The compounds described herein are compounds that have aldehyde trapping activity, and have been described for use in treating disorders and diseases associated with the effects of toxic aldehydes. See, e.g., PCT patent publication WO2006127945, WO2014116836, WO2017035077, and WO2017035082, each of which is hereby incorporated by reference. Synthesis of the compounds described herein are described in PCT publications WO2006127945, WO2017035082, and WO2018039192; and U.S. patent application publication US 2013/0190500, each of which is hereby incorporated by reference. As described herein, certain aldehyde trapping compounds are useful in treating a variety of diseases such as atopic dermatitis, psoriasis, diabetic macular edema, and Stargardt’s disease. Additionally, the compounds that have aldehyde trapping activity for use in treating disorders and diseases associated with the effects of toxic aldehydes and the synthesis of compounds having such aldehyde trapping activity are described in PCT publication WO 2023/278816, the contents of which is herein incorporated by references in its entirety. [00238] In some embodiments, the compound for use in a combination therapy with a compound of formula I and/or a compound of formula II is a compound of formula III: III or a pharmaceutically acceptable salt thereof, wherein: Q, T and V are independently S, N, O, or -C-R; each of R 1 , R 6 , R 7 , and R 8 is independently H, D, halogen, -NH2, -CN, -OR, -SR, optionally substituted C1-6 aliphatic, or , wherein one of R 1 , R 6 , R 7 , and R 8 is –NH2 and other one of R 1 , R 6 , R 7 , and R 8 is ; R a is C 1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; and R b is C1-4 aliphatic optionally substituted with 1, 2, or 3 deuterium or halogen atoms; or R a and R b , taken together with the carbon atom to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl ring containing 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; and each R is independently selected from hydrogen, deuterium, and an optionally substituted group selected from: C 1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aryl ring, a 3- to 8- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 10-membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [00239] In some embodiments of formula III, the –NH 2 on one of R 1 , R 6 , R 7 , and R 8 and the carbinol on the other of R 1 , R 6 , R 7 , and R 8 are on adjacent carbon atoms of the phenyl moiety. [00240] In some embodiments of formula III, one of Q, T and V is N, and other of Q, T and V is O. In some embodiments, Q is O, V is N, and T is C-R. In some embodiments, Q is N, T is O and V is C-R. [00241] In some embodiments of formula III, the compound is a compound of formula III-a or III-b: III-a III-b or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , R 7 , and R 8 when present is independently H, D, halogen, -CN, -OR, -SR, optionally substituted C1-6 aliphatic, or , wherein one of R 1 , R 6 , R 7 , and R 8 is Q, T, V, R, R a and R b are as defined in formula III. [00242] In some embodiments of formula III, the compound is a compound of formula III-c, III-d or III-e: or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , and R 7 when present is independently H, D, halogen, -CN, -OR, -SR, optionally substituted C1-6 aliphatic; and Q, T, V, R, R a and R b are as defined in formula III. [00243] In some embodiments of formula III, the compound is a compound of formula III-f, III-g, III-h or III-i: III-f III-g III-h III-i or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , R 7 , and R 8 when present is independently H, D, halogen, -CN, -OR, -SR, optionally substituted C1-6 aliphatic or , wherein one of R 1 , R 6 , R 7 , and R 8 is R, R a and R b are as defined in formula III. [00244] In some embodiments of formula III, the compound is a compound of formula III-j, III-k, III-l or III-m: or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , R 7 , and R 8 when present is independently H, D, halogen, -CN, -OR, -SR, optionally substituted C 1-6 aliphatic; and R, R a and R b are as defined in formula III. [00245] In some embodiments of formula III, the compound is a compound of formula III-n: III-n or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , R 7 , and R 8 is independently H, D, halogen, -NH 2 , -CN, -OR, -SR, optionally substituted C1-6 aliphatic, or rein one of R 1 , R 6 , R 7 , and R 8 is –NH2 and other one of R 1 , R 6 , R 7 , and R 8 R, R a , and R b are as defined in formula III. [00246] In some embodiments of formula III, the compound is a compound of formula III-o, III-p, III-q or III-r: or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , R 7 , and R 8 when present is independently H, D, halogen, -CN, -OR, -SR, optionally substituted C1-6 aliphatic, or , wherein one of R 1 , R 6 , R 7 , and R 8 is R, R a , and R b are as defined in formula III. [00247] In some embodiments of formula III, the compound is a compound of formula III-s, III-t, III-u, III-v, III-w, or III-x: or a pharmaceutically acceptable salt thereof, wherein: each of R 1 , R 6 , R 7 , and R 8 when present is independently H, D, halogen, -CN, -OR, -SR, optionally substituted C1-6 aliphatic; and R, R a and R b are as defined in formula III. [00248] In some embodiments, the compound for use in a combination therapy with a compound of formula I and/or a compound of formula II is a compound selected from the following: [00249] In some embodiments, the compound for use in combination therapy with a compound of formula I and/or a compound of formula II is a compound selected from the following:
[00250] In some embodiments, the compound for use in a combination therapy with a compound of formula I, X-I, X-VI, Y-I, Y-II, Y-III, or Y-IV and/or a compound of formula II is a compound selected from: [00251] In another aspect, the present invention provides methods for treating an ocular disorder, such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), and dark adaptation impairment with a combination pharmaceutical composition comprising a compound of formula I, X-I, X-VI, Y-I to Y-IV or a pharmaceutically acceptable salt thereof, and a compound of formula II or a modified cyclodextrin compound described herein or a pharmaceutically acceptable salt thereof. [00252] In some embodiments, a compound of formula II may be used in other combination therapies, with or without a compound of formula I, X-I, X-VI, Y-I to Y-IV present. [00253] In some embodiments, the compound of formula II or a modified cyclodextrin compound described herein is used, with or without an aldehyde trapping compound, in combination with a co-administered agent in the form of eye drops, a sustained release delivery system to the eye, a cream, a paste, or an ointment containing an anti-inflammatory agent, antihistamine, antibiotic, or other agent. [00254] For methods of treating DME, the compound of formula II or a modified cyclodextrin compound described herein , with or without an aldehyde trapping compound, can be combined with an insulin pump or other diabetes treatment. [00255] In some embodiments, a method of treating wet AMD further comprises co- administering a known treatment for AMD, such as a VEGF inhibitor or photodynamic therapy. Exemplary VEGF inhibitors include brolucizumab (Beovu®), aflibercept (Eylea®), ranibizumab (Lucentis®), pegaptanib sodium (Macugen®), faricimab-svoa (VABYSMO®), ranibizumab injection for intravitreal use via ocular implant (SUSVIMO TM ), and Avastin® (bevacizumab). In some embodiments, the co-administered treatment is RGX-314. [00256] In some embodiments, a method of treating retinitis pigmentosa (RP) further comprises co-administering a known treatment for RP, such as UV-reducing glasses or voretigene neparvovec-ryzl (Luxturna®). [00257] In the methods of treating ocular inflammatory disorders and diseases, the compound of formula II or a modified cyclodextrin compound described herein above is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents useful for treating ocular inflammation in combination with the compound of formula II or a modified cyclodextrin compound described herein include, among others, a steroid, non-steroidal anti-inflammatory compound, anti-metabolite, immunosuppressive antibiotic, alkylating agent, and an anti- inflammatory cytokine antibody. [00258] In some embodiments, the anti-inflammatory agent is a steroid, particularly a steroid with immunomodulatory, anti-inflammatory properties. In some embodiments, the anti- inflammatory is a glucocorticosteroid, which is widely used as effective treatments to control inflammatory and autoimmune diseases. In some embodiments, the glucocorticosteroid is a corticosteroid or a prodrug thereof. In some embodiments, the corticosteroid is selected from cortisol, cortisone, prednisone, prednisolone, methylprednisone, triamcinolone, betamethasone, dexamethasone and a prodrug thereof. In some embodiments, the corticosteroid prodrug is prednisolone acetate. [00259] In some embodiments, the compound of formula II or a modified cyclodextrin compound described herein is used in combination with a non-steroidal anti-inflammatory compound. These compounds generally act as inhibitors of the enzyme cyclooxygenase (COX), inhibiting the cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2) isoenzymes. Different classes of non-steroidal anti-inflammatory compounds includes salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid, anthranilic acid derivatives, and selective cox inhibitors. Exemplary non-steroidal anti-inflammatory compounds useful in the combination include, among others, acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and celecoxib. In some embodiments, for topical application to the eye, the non-steroidal anti-inflammatory compound can be selected from diclofenac, flurbiprofen, ketoprofen, bromfenac, and nepafenac. [00260] In some embodiments, the anti-inflammatory agent for use in combination with the compound of formula II or a modified cyclodextrin compound described herein is an anti- metabolite. In some embodiments, the anti-metabolite is a cytotoxic purine analog, for example, azathioprine and mercaptopurine. In some embodiments, the anti-metabolite is an anti-folate compound. Exemplary anti-folate compound is methotrexate. In some embodiments, the anti- metabolite is an inosine monophosphate dehydrogenase inhibitor (IMPDH), such as mycophenolic acid and its prodrug mycophenolate mofetil. In some embodiments, the anti- metabolite for use in the combination therapy is a dihydroorotate dehydrogenase inhibitor, such as leflunomide. [00261] In some embodiments, the anti-inflammatory agent for use in combination with the compound of formula II or a modified cyclodextrin compound described herein is an alkylating agent. Exemplary alkylating agents include, among others, cyclophosphamide and chlorambucil. [00262] In some embodiments, the anti-inflammatory agent for use in combination with the compound of formula II or a modified cyclodextrin compound described herein is an immunomodulatory antibiotic. Immunosuppressive antibiotics useful for the treatments herein include those that bind cyclophilin and/or calcineurin and inhibit T-lymphocyte activity. In some embodiments, the immunomodulatory antibiotic is selected from cyclosporine, tacrolimus, rapamycin, and derivatives thereof. [00263] In some embodiments, the anti-inflammatory agent for use in the combination therapy is an anti-inflammatory antibody, such as an antibody targeting an inflammatory cytokine, such as TNF, IL-1, IL-4, IL-5, or IL-17, or targeting an immune system cell active in the inflammatory response, such as B cells expressing CD20. In some embodiments, the anti- inflammatory biologic agent is selected from etanercept, infliximab, adalimumab, daclizumab, rituximab, toclizumab, certolizumab pegol, and golimumab. [00264] The compounds of general formula II or a modified cyclodextrin compound described herein may be used with a therapeutic agent for treating inflammatory diseases or disorders of the eye. In one aspect, the composition for treating eye inflammation comprises a cyclodextrin and a therapeutic agent selected from an anti-histamine, alpha-adrenergic agonist, non-steroidal anti-inflammatory drug (NSAID), mast cell inhibitor or stabilizer, corticosteroid, adhesion molecule inhibitor, T-cell activation inhibitor and combinations thereof. [00265] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and an anti-histamine. In some embodiments, the anti-histamine is selected from the group consisting of ketotifen, phenylephrine, tetrahydrozaline, pheniramine, alcaftadine, azelastine, emedastine, epinastine, and bepotastine. [00266] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and an alpha-adrenergic agonist. In some embodiments, the alpha-adrenergic agonist is selected from the group consisting of oxymetazoline, brimonidine, cirazoline, apraclonidine hydrochloride, and naphazoline. [00267] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and a non-steroidal anti-inflammatory drug. In some embodiments, the non-steroidal anti-inflammatory drug is selected from the group consisting of diclofenac, flurbiprofen, ketorolac, bromfenac, indomethacin and nepafenac. [00268] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and a mast cell inhibitor or stabilizer. In some embodiments, the mast cell inhibitor or stabilizer is selected from the group consisting of cromolyn, nedocromil, pemirolast, nedocromil sodium, tranilast, lodoxamide (e.g., lodoxamide tromethane), and lodoxamine (e.g., lodoxamine ethyl). [00269] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and an anti-inflammatory steroid. In some embodiments, the anti-inflammatory steroid is a corticosteroid. In some embodiments, the steroid is selected from the group consisting of lotoprednol, rimexolone, difluprednate, fluorometholone, prednisone and prednisolone. [00270] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and an adhesion molecule inhibitor, in particular an integrin antagonist. In some embodiments, the integrin agonist is lifitegrast (lymphocyte function-associated antigen 1 – LFA-1 antagonist). [00271] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and a T-cell activation inhibitor. In some embodiments, the T-cell activation inhibitor is selected from the group consisting of cyclosporine, tacrolimus, pimecrolimus, and rapamycin. [00272] In some embodiments, the composition comprises a compound of general formula II or a modified cyclodextrin compound described herein and two or more of therapeutic agents selected from anti-histamine, alpha-adrenergic agonist, non-steroidal anti-inflammatory drug (NSAID), mast cell inhibitor or stabilizer, corticosteroid, adhesion molecule inhibitor, and T-cell activation inhibitor. [00273] In some embodiments, the compound of general formula II or a modified cyclodextrin compound described herein is present in excess of the therapeutic agent. [00274] In some embodiments, the composition further comprises one or more ophthalmic pharmaceutically acceptable additive or excipient. In some embodiments, the one or more pharmaceutically acceptable additive or excipient is selected from a tonicity agent, solubilizing agent, stabilizing agent, preservative, buffering agent, wetting agent, viscosity enhancing agent, lubricating agent, chelating agent, and antioxidant. [00275] In another aspect, the composition comprising a compound of general formula II or a modified cyclodextrin compound described herein and a therapeutic agent is used for treating an eye disease or disorder having an inflammatory response, or in some embodiments, for treating an inflammatory eye disease or disorder. In some embodiments, the compositions herein are used for treating allergic conjunctivitis, scleritis, blepharitis, keratitis, retinitis, cyclitis, iridocyclitis choroiditis, dry-eye syndrome (keratoconjunctivitis sicca), iritis, meibomian gland dysfunction, sarcoidosis, or uveitis. [00276] In some embodiments, the compositions are used in treating inflammation of the eye associated with injury or trauma to the eye. In some embodiments, the compositions are used for treating inflammation associated with cataract surgery, laser surgery, keratotomy, keratoplasty, corneal surgery, accidental (non-iatrogrenic) trauma or vitrectomy. [00277] In some embodiments, the compositions herein are used for treating ocular inflammation associated with eye infections. In some embodiments, the compositions are used for treating inflammation associated with fungal (e.g., keratomycosis, fungal keratitis, etc.), bacterial, protozoal or viral infections, including conjunctivitis, keratitis, cyclitis, iridocyclitis and blepharitis associated with eye infections. [00278] In some embodiments, the compositions herein are used for treating irritation or inflammation associated with exposure of the eye to chemical irritants. These include irritants such as smoke, volatile organic compounds, cosmetics), dust, and use of computer monitors. [00279] Additional uses of cyclodextrin compounds with active agents are described in WO2020/018498, published 01/23/2020, which is incorporated by reference in its entirety. It is contemplated that the modified cyclodextrins of this disclosure may be used with any of the agents or for the indications described therein. [00280] The ocular inflammatory disorder treatable with the combination of the compound of formula II or a modified cyclodextrin compound described herein and the anti-inflammatory agent include allergic conjunctivitis, including vernal keratoconjunctivitis and atopic keratoconjunctivitis; dry eye syndrome and meibomian gland dysfunction; cataracts; keratoconus; bullous and other keratopathy; Fuch's endothelial dystrophy; ocular cicatricial pemphigoid; conditions associated with photoreactive keratotomy (PRK) healing and other corneal healing; conditions associated with tear lipid degradation or lacrimal gland dysfunction; uveitis, including anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, non- infectious uveitis, and infectious uveitis; keratitis; scleritis; iritis; cyclitis; ocular graft versus host disease (GVHD); optic neuritis; ocular Stevens Johnson Syndrome; blepharitis; ocular rosacea, with or without meibomian gland dysfunction; post cataract; persistent corneal erosion; and inflammation associated with corneal trauma, corneal transplantation, and refractive surgery. [00281] In some embodiments, the combination therapy is used to treat uveitis. In some embodiments, the uveitis treated with the combination is anterior uveitis, which includes the disorders of iridocyclitis and iritis and involves the anterior chamber and iris, with the latter indication also affecting the ciliary body. The vast majority of uveitis is anterior uveitis. In some embodiments, the uveitis treatable with the combination is intermediate uveitis, also referred to as pars planitis, which involves inflammation of cells in the vitreous cavity or deposition of inflammatory material on the pars plana. In some embodiments, the uveitis treatable with the combination is posterior uveitis, which involves inflammation of the uveal tract in the retina and the choroid. In some embodiments, the uveitis treatable with the combination is panuveitis (i.e., diffuse uveitis), which is inflammation of the uveal tract of both the anterior segment (e.g., iris and ciliary body) and the posterior segment (e.g., retina and choroid). [00282] It is to be understood that while the description above are directed to combination treatment with the compound of formula II or a modified cyclodextrin compound described herein and an anti-inflammatory agent, the data on treatment of uveitis indicates that the compound of formula II or a modified cyclodextrin compound described herein has therapeutic efficacy when used alone, i.e., as monotherapy. Thus, for the each and every one of the ocular inflammatory disorders and diseases described in the present disclosure for treatment with the combination therapy, also provided are treatment with the compound of formula II or a modified cyclodextrin compound, without adjunctive administration of the anti-inflammatory agent, for example, as monotherapy. [00283] In some embodiments, the combination of the compound of formula II and the anti- inflammatory agent is used to treat macular degeneration. Accordingly, in some embodiments, a method of treating macular degeneration comprises administering to a subject in need thereof a therapeutically effective amount a compound of formula II or a modified cyclodextrin compound described herein, particularly compound I-1, for example, and an anti-inflammatory agent, as described herein. Thus, each and every combination of the fused bicyclic compound and the anti- inflammatory agent described for treatment of ocular inflammatory disorders and diseases can also be applied to treatment of macular degeneration. In some embodiments, the form of macular degeneration which can be treated is selected from age-related macular degeneration; Stargardt disease, an inherited form of juvenile macular degeneration; wet macular degeneration; dry macular degeneration; and geographic atrophy (GA) secondary to dry age related macular degeneration. 6. Pharmaceutically Acceptable Compositions [00284] The compounds and compositions, according to the method of the present invention, are administered using any amount and any route of administration effective for treating or lessening the severity of a disease, disorder, or condition provided above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. [00285] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00286] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00287] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. [00288] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00289] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00290] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00291] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00292] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. [00293] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [00294] The compounds of the invention can also be administered topically, such as directly to the eye, e.g., as an eye-drop or ophthalmic ointment. Eye drops typically comprise an effective amount of at least one compound of the invention and a carrier capable of being safely applied to an eye. For example, the eye drops are in the form of an isotonic solution, and the pH of the solution is adjusted so that there is no irritation of the eye. In many instances, the epithelial barrier interferes with penetration of molecules into the eye. Thus, most currently used ophthalmic drugs are supplemented with some form of penetration enhancer. These penetration enhancers work by loosening the tight junctions of the most superior epithelial cells (Burstein, 1985, Trans Ophthalmol Soc U K 104(Pt 4): 402-9; Ashton et al., 1991, J Pharmacol Exp Ther 259(2): 719-24; Green et al., 1971, Am J Ophthalmol 72(5): 897-905). The most commonly used penetration enhancer is benzalkonium chloride (Tang et al., 1994, J Pharm Sci 83(1): 85-90; Burstein et al., 1980, Invest Ophthalmol Vis Sci 19(3): 308-13), which also works as preservative against microbial contamination. It is typically added to a final concentration of 0.01-0.05%. [00295] Topical administration may be in the form of a cream, suspension, emulsion, ointment, drops, oil, lotion, patch, tape, inhalant, spray, or controlled release topical formulations including gels, films, patches, and adhesives. Intra-ocular administration may take the form of subconjunctival, subtenon’s capsule, retrobulbar or intravitreal injections, depots or implants. Compounds administered by these routes may be in solution or suspension form. Administration of compounds by depot injection may contain pharmaceutically acceptable carriers or excipients; these may be natural or synthetic and may be biodegradable or non-biodegradable and facilitate drug release in a controlled manner. Implants used for controlled release of compound may be composed of natural or synthetic, biodegradable or non-biodegradable materials. The carrier is acceptable in that it is compatible with the other components of the composition and is not injurious to the patient. Some examples of carriers include (1) sugars such as lactose glucose and sucrose, (2) starches such as corn starch and potato starch, (3) cellulose and (4) cyclodextrins. A useful topical formulation is described in PCT publication WO 2011/072141, the contents of which are herein incorporated by reference. [00296] Formulations for topical administration to the skin can include, for example, ointments, creams, gels and pastes comprising the primary amine compound in a pharmaceutical acceptable carrier. The formulation of the primary amine compound for topical use includes the preparation of oleaginous or water-soluble ointment bases, as is well known to those in the art. For example, these formulations may include vegetable oils, animal fats, and, for example, semisolid hydrocarbons obtained from petroleum. Particular components used may include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, anhydrous lanolin and glyceryl monostearate. Various water-soluble ointment bases may also be used, including glycol ethers and derivatives, polyethylene glycols, polyoxyl 40 stearate and polysorbates. [00297] The formulations for topical administration may contain the compound used in the present application at a concentration in the range of 0.001-10%, 0.05-10%, 0.1-10%, 0.2-10%, 0.5-10%, 1-10%, 2-10%, 3-10%, 4-10%, 5-10%, or 7-10% (weight/volume), or in the range of 0.001-2.0%, 0.001-1.5%, or 0.001-1.0%, (weight/volume), or in the range of 0.05-2.0%, 0.05- 1.5%, or 0.05-1.0%, (weight/volume), or in the range of 0.1-5.0%, 0.1-2.0%, 0.1-1.5%, or 0.1- 1.0% (weight/volume), or in the range of 0.5-5.0%, 0.5-2.0%, 0.5-1.5%, or 0.5-1.0% (weight/volume), or in the range of 1-5.0%, 1-2.0%, or 1-1.5% (weight/volume). The formulations for topical administration may also contain the compound used in the present application at a concentration in the range of 0.001-2.5%, 0.01-2.5%, 0.05-2.0%, 0.1-2.0%, 0.2- 2.0%, 0.5-2.0%, or 1-2.0% (weight/weight), or in the range of 0.001-2.0%, 0.001-1.5%, 0.001- 1.0%, or 0.001-5% (weight/weight). [00298] In an eye drop formulation the composition may contain the active compound at a concentration of 0.01-20%, 0.02-15%, 0.04-10%, 0.06-5%, 0.08-1%, or 0.09-0.5% (weight/volume) with or without pH and/or osmotic adjustment to the solution. More particularly, the eye drop formulation may contain a compound described herein at a concentration of 0.09-0.5% (weight/volume), such as 0.1%, 0.25%, or 0.5%. [00299] The compounds described herein may be administered orally and as such the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. [00300] For oral administration in the form of a tablet or capsule (e.g., a gelatin capsule), the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum starches, agar, alginic acid or its sodium salt, or effervescent mixtures, croscarmellose or its sodium salt, and the like. Diluents, include, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine. [00301] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. [00302] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. [00303] For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. [00304] Parenteral formulations comprising a compound described herein can be prepared in aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The formulations may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutic agents. The compositions are prepared according to conventional methods, and may contain about 0.1 to 75%, preferably about 1 to 50%, of a compound described herein. [00305] In certain embodiments, the present invention is directed to a composition, as described herein, comprising a prodrug of a compound of formula I, X-I, X-VI, Y-I, Y-II, Y-III or Y-IV or II or a modified cyclodextrin compound as described herein, or a pharmaceutically acceptable salt thereof. The term “prodrug,” as used herein, means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula I, X-I, X- VI, Y-I, Y-II, Y-III or Y-IV or II or a modified cyclodextrin compound as described herein, or a pharmaceutically acceptable salt thereof. Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard- Larsen, et al., (ed). Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby incorporated by reference in its entirety. [00306] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. REFERENCES 1. Dreffs, A., Lin, C. M., Liu, X., Shanmugam, S., Abcouwer, S. F., Kern, T. S., & Antonetti, D. A. (2020). All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion. Investigative ophthalmology & visual science, 61(6), 8. 2. Flamendorf, J., Agrón, E., Wong, W. T., Thompson, D., Wiley, H. E., Doss, E. L., Al-Holou, S., Ferris, F. L., 3rd, Chew, E. Y., & Cukras, C. (2015). Impairments in Dark Adaptation Are Associated with Age-Related Macular Degeneration Severity and Reticular Pseudodrusen. Ophthalmology, 122(10), 2053–2062. 3. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins.1. Drug solubilization and stabilization. J Pharm Sci.1996 Oct;85(10):1017-25. doi: 10.1021/js950534b. PMID: 8897265. 4. Mosher G., Machatha S, Encyclopedia of Pharmaceutical Science and Technology DOI: 10.3109/9781841848204.000: Complexation: Cyclodextrins, pp 1-21. Copyright © 2012 5. Nigalye, A.K.; Hess, K.;Pundlik, S.J.; Jeffrey, B.G.; Cukras,C.A.; Husain, D. Dark Adaptation and Its Role in Age-Related Macular Degeneration.J. Clin. Med.2022,11,1358. 6. Nociari MM, Lehmann GL, Perez Bay AE, Radu RA, Jiang Z, Goicochea S, Schreiner R, Warren JD, Shan J, Adam de Beaumais S, Ménand M, Sollogoub M, Maxfield FR, Rodriguez-Boulan E. Beta cyclodextrins bind, stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium. Proc Natl Acad Sci U S A.2014 Apr 8;111(14):E1402-8. doi: 10.1073/pnas.1400530111. Epub 2014 Mar 24. PMID: 24706818; PMCID: PMC3986126. 7. Prajapati M, Christensen G, Paquet-Durand F, Loftsson T. Cytotoxicity of β-Cyclodextrins in Retinal Explants for Intravitreal Drug Formulations. Molecules.2021 Mar 9;26(5):1492. doi: 10.3390/molecules26051492. PMID: 33803405; PMCID: PMC7967144. 8. Telias M, Sit KK, Frozenfar D, Smith B, Misra A, Goard MJ, Kramer RH. Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration. Sci Adv.2022 Mar 18;8(11):eabm4643. doi: 10.1126/sciadv.abm4643. Epub 2022 March 18. PMID: 35302843; PMCID: PMC8932665. 9. Zhang D, Robinson K, Saad L, Washington I. Vitamin A cycle byproducts impede dark adaptation. J Biol Chem.2021 Sep;297(3):101074. doi: 10.1016/j.jbc.2021.101074. Epub 2021 Aug 12. PMID: 34391781; PMCID: PMC8427233. EXEMPLIFICATION [00307] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of particular compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Abbreviations equiv or eq: molar equivalents o/n: overnight rt: room temperature UV: ultra violet HPLC: high pressure liquid chromatography Rt: retention time LCMS or LC-MS: liquid chromatography-mass spectrometry NMR: nuclear magnetic resonance CC: column chromatography TLC: thin layer chromatography sat: saturated aq: aqueous Ac: acetyl ACN or MeCN: acetonitrile CDI: 1,1’-Carbonyldiimidazole DCM: dichloromethane DCE: dichloroethane DEA: diethylamine DMF: dimethylformamide DMSO: dimethylsulfoxide DIPEA: diisopropylethylamine EA or EtOAc: ethyl acetate BINAP: (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene TEA: triethylamine THF: tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: potassium hexamethyl disilylazide Tf: trifluoromethanesulfonate Ms: methanesulfonyl NBS: N-bromosuccinimide NMP: N-methyl pyrrolidinone PE: petroleum ether TFA: trifluoroacetic acid FA: formic acid MMPP: magnesium monoperoxyphthalate HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid Hexafluorophosphate Cy: cyclohexyl Tol: toluene PTSA: p-Toluenesulfonic acid NMP: N-Methyl-2-pyrrolidone TFA: 1,1,1,-trifluoroacetone Example 1 - Synthesis of Compound A: Scheme 1: Synthesis of Compound A: Synthesis of methyl 2-(bis-Boc-amino)-4-(benzamido-d5)-5-bromobenzoate 4 [00308] To a stirred suspension of benzoic acid-d 5 1 (56.89 g, 2.0 eq) in DCM (5.0 vol) was heated to reflux under azeotropic conditions and water was collected for 1-2 h, then DMF (2.0 mL) was slowly added, followed by oxalyl chloride (60 mL, 0.6 vol) at 40 – 45 °C. This temperature was maintained for 2-3 h. After completion of reaction was shown by TLC, DCM was distilled away under N2 to obtain acid chloride 2. [00309] To a stirred solution of 3 (100 g, 1.0 eq) in DCM (5.0 vol) was added DMAP (1.05 g, 0.04 eq) at room temperature under nitrogen atmosphere. The reaction mixture was cooled to 15-20 °C, acid chloride 2 was added slowly. After the reaction mixture was maintained for 10- 15 min, pyridine (140 mL, 1.4 vol) was added slowly at 10-15 °C. The reaction mixture was warmed to room temperature and maintained at room temperature for 4-5 h. After completion of the reaction, water (300 mL) was added at room temperature and the organic layer was separated. The organic layer was washed with 1N HCl (2 x 200 mL) followed by 5% sodium bicarbonate solution (200 mL). The organic layer was separated and distilled under vacuum to obtain crude product. The crude product was further purified by ethyl acetate (300 mL) slurry and the product wasdried at 50-60 °C to yield 4 (100 g, 80.3%) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.18 (s, 1H), 7.67 (s, 1H), 3.81 (s, 3H), 1.35 & 1.33 (s, 18H); Mass: 554.15 (M+H). Synthesis of methyl 5-(bis-Boc-amino)-2-(phenyl-d5)-benzo[d]oxazole-6-carboxylat e 5 [00310] To a stirred solution of 4 (110 g, 1.0 eq) in DMF (550 mL) was added CuI (17.6 g, 0.4 eq) followed by 1,10-phenanthroline (20.9 g, 0.5 eq) at room temperature under a nitrogen atmosphere. After stirring for 10-15 min, potassium carbonate (80.3 g, 2.5 eq) was added and the reaction mixture was heated to 100-110 °C and maintained at that temperature for 6-8 h. After completion of reaction was shown by TLC, the reaction mixture was cooled to room temperature and water (1.65 L) was added. After stirring for 10-15 min, ethyl acetate (550 mL) was added, and the reaction mass was filtered through celite and washed with ethyl acetate (110 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2.0 vol). The combined organic layers were washed with water (2.0 vol) and then distilled under vacuum below 50 °C to obtain the crude. IPA (550 mL) was added to crude and heated to 65-70 °C and maintained for 1-2 h, and then the contents were cooled to 0-5 °C and maintained at that temperature for 1-2 h. The precipitated solid was filtered and washed with IPA (55 mL), and then the product was dried at 50-60 °C to obtain 5 (72.5 g, 77.2% yield) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.86 (s, 1H), 3.84 (s, 3H), 1.32 (s, 18H); Mass: 496.20 (M+Na). Synthesis of methyl 5-amino-2-(phenyl-d5)-benzo[d]oxazole-6-carboxylate hydrochloride 6 [00311] To a stirred solution of 5 (90.0 g, 1.0 eq) in acetonitrile (12 vol) was added conc. HCl (1.5 vol) at room temperature. The reaction mixture was heated to 50-55 °C and maintained at that temperature for 2-3 h. After completion of the reaction was shown by TLC, the reaction mass was cooled to room temperature and the precipitated solid was filtered. The solid was washed with acetonitrile (2.0 vol) and product dried at 50-60 °C for 6-8 h to provide 6. HCl (52.0 g, 93% yield) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.24 (s, 1H), 4.89 (bs, 2H), 3.85 (s, 3H); Mass: 274.10 (M+H). Synthesis of 2-(5-amino-2-(phenyl-d5)-benzo[d]oxazol-6-yl)propan-2-ol A: [00312] To a stirred suspension of 6.HCl (55.0 g, 1.0 eq) in THF (12.0 vol) was added MeMgBr (2 M in THF, 5.0 eq) at 0-5 °C under nitrogen atmosphere. The reaction mixture was maintained at 0-5 °C for 2-3 h. After completion of reaction was shown by TLC, 10% ammonium chloride solution (12 vol) was added and maintained for 10-15 min. The reaction mass was warmed to room temperature and ethyl acetate (10.0 vol) was added. After stirring for 10-15 min, organic layer was separated and aqueous layer was extracted with ethyl acetate (2.0 vol). The combined organic layers were washed with 15% sodium chloride solution (2 x 2.0 vol). The organic layer was distilled under vacuum below 50 °C to obtain the crude product. Acetonitrile (3.0 vol) was added to the crude product and heated to 80-85 °C and maintained at that temperature for 1-2 h. Then the contents were cooled to room temperature and maintained at that temperature for 1-2 h. The precipitated solid was filtered and washed with acetonitrile (0.5 vol), and then product was dried at 50-60 °C to furnish A(40.50 g, 72.7% yield) as pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.43 (s, 1H), 6.96 (s, 1H), 5.54 (s, 2H), 5.39 (s, 1H), 1.59 (s, 6H); Mass: 274.15 (M+H); HPLC purity: 98.98%. Example 2 - Synthesis of Modified Cyclodextrins: 2.1 Synthesis of Semi-carbazido-β-cyclodextrin (I-1) Scheme 2.1: Synthesis of Synthesis of Semi-carbazido-β-cyclodextrin: Step 1: Synthesis of Boc-Semi-carbazido-β-cyclodextrin 7: [00313] To a stirred solution of CDI (5.0 eq) in DMF (5.0 mL) was added Boc-hydrazine (5.0 eq) at room temperature under nitrogen atmosphere. After stirring for 15-20 min, amino-β- cyclodextrin 6 (50.0 mg, 1.0 eq) was added and stirred the reaction mixture for 12 h at room temperature. After consumption of starting material (by TLC), acetone (2.0 mL) was added to the reaction mass and the precipitated solid was filtered. The wet material was dried to obtain Boc-Semi-carbazido-β-cyclodextrin 7 (40.0 mg, 71%) as an off white solid. Mass: m/z 1293.1 (+ve). Step 2: Synthesis of Semi-carbazido-β-cyclodextrin I-1: [00314] To a stirred solution of Boc-Semi-carbazido-β-cyclodextrin 7 (500 mg, 1.0 eq) in DCM (5.0 mL) was added trifluoro acetic acid (2.5 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at room temperature. After the starting material was depleted (as shown by TLC), volatiles were removed under reduced pressure to obtain crude. The crude material was co-distilled with water followed by toluene. The obtained solid was slurried in ethanol and filtered to obtain semi-carbazido-β-cyclodextrin I-1 (375 mg, 81%) as an off white solid. Mass: m/z 1192.8 (+ve). 2.2 Synthesis of Semi-thiocarbazido-β-cyclodextrin (I-2) Scheme 2.2: Synthesis of Semi-thiocarbazido-β-cyclodextrin: Step 1: Synthesis of Boc-Semi-thiocarbazido-β-cyclodextrin 7: Ref: 01PDP056 [00315] To a stirred solution of thiocarbonyldiimidazole 6 (5.0 eq) in DMF (5.0 mL) was added Boc-hydrazine (5.0 eq) at room temperature under nitrogen atmosphere. After stirring for 15-20 min, amino-β-cyclodextrin (50.0 mg, 1.0 eq) was added and the reaction mixture was stirred for 12 h at room temperature. After starting material was consumed (as shown by TLC), acetone (2.0 mL) was added to the reaction mass, and the precipitated solid was filtered. The wet material was dried to obtain Boc-Semi- carbazido-β-cyclodextrin 7 (28.0 mg, 49%) as an off white solid. Mass: m/z 1308.2 (+ve) Step 2: Synthesis of Semi-thiocarbazido-β-cyclodextrin I-2: [00316] To a stirred solution of Boc-Semi-carbazido-β-cyclodextrin 7 (23 mg, 1.0 eq) in DCM (5.0 mL) was added trifluoro acetic acid (2.5 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at room temperature. After starting material was consumed (as shown by TLC), volatiles were removed under reduced pressure to obtain crude. The crude material was co-distilled with water followed by toluene. The obtained solid was slurried in ethanol and filtered to obtain semi-thiocarbazido-β-cyclodextrin I-2 (20 mg, 100%) as an off white solid. Mass: m/z 1208.1 (+ve). 2.3 Synthesis of Serinol-β-cyclodextrin I-3 Scheme 2.3: Synthesis of Serinol-β-cyclodextrin:
Step 1: Synthesis of Boc-Serinol-β-cyclodextrin 8: [00317] To a stirred solution of carbonyldiimidazole 6 (5.0 eq) in DMF (5.0 mL) was added Boc-serinol (5.0 eq) at room temperature under nitrogen atmosphere. After stirring for 15-20 min, amino-β-cyclodextrin (50.0 mg, 1.0 eq) was added and stirred the reaction mixture for 12 h at room temperature. After starting material was consumed (as shown by TLC), acetone (2.0 mL) was added to the reaction mass and the precipitated solid was filtered. The wet material was dried to obtain Boc-Serinol-β-cyclodextrin 8 (36.0 mg, 62%) as an off white solid. Mass: m/z 1321.2 (+ve). Step 2: Synthesis of Serinol-β-cyclodextrin (I-3) [00318] To a stirred solution of Boc-Serinol-β-cyclodextrin 8 (30 mg, 1.0 eq) in DCM (5.0 mL) was added trifluoro acetic acid (2.5 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at room temperature. After starting material was consumed (as shown by TLC), volatiles were removed under reduced pressure to obtain crude. The crude material was co-distilled with water followed by toluene. The obtained solid was slurried in ethanol and filtered to obtain serinol-β-cyclodextrin I-3 (22 mg, 79%) as an off white solid. [00319] Mass: m/z 1221.1 (+ve) 2.4 Synthesis of 3,4-Diaminobenzoic acid amido-β-cyclodextrin (I-4) Step 1: Synthesis of Boc-3,4-Diaminobenzoic acid amido-β-cyclodextrin 9: [00320] To a stirred solution of carbonyldiimidazole 6 (5.0 eq) in DMF (5.0 mL) was added Boc-3,4-diaminobenzoic acid (5.0 eq) at room temperature under nitrogen atmosphere. After stirring for 15-20 min, amino-β-cyclodextrin (50.0 mg, 1.0 eq) was added and stirred the reaction mixture for 12 h at room temperature. After starting material was consumed (as shown by TLC), acetone (2.0 mL) was added to the reaction mass and the precipitated solid was filtered. The wet material was dried to obtain Boc-3,4-Diaminobenzoic acid amido -β-cyclodextrin 9 (18.0 mg, 28%) as an off white solid. [00321] Mass: m/z 1468.4 (+ve). Synthesis of Synthesis of 3,4-Diaminobenzoic acid amido-β-cyclodextrin I-4 [00322] To a stirred solution of Boc-3,4-Diaminobenzoic acid amido -β-cyclodextrin 9 (13 mg, 1.0 eq) in DCM (5.0 mL) was added trifluoro acetic acid (2.5 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at room temperature. After starting material was consumed (as shown by TLC), volatiles were removed under reduced pressure to obtain crude. The crude material was co-distilled with water followed by toluene. The obtained solid was slurried in ethanol and filtered to obtain 3,4-Diaminobenzoic acid amido -β- cyclodextrin I-4 (9.0 mg, 80%) as an off white solid. [00323] Mass: m/z 1268.1 (+ve). Example X.1: Synthesis of Compounds X-I-1 to X-I-37 Synthesis of 2-(6-Aminobenzo[d] [1,3] dioxol-5-yl propan-2-ol (X-I-29): Synthesis of X-I-29: [00324] To a stirred solution of 1-(6-aminobenzo[d] [1,3] dioxol-5-yl) ethanone 1 (0.5 g, 1.0 eq) in THF (15 mL) was added methyl magnesium bromide (4.0 eq, 2M solution) at 0°C under nitrogen. The reaction was stirred for 2 h at 0°C. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by silica gel column (ethyl acetate: hexane, 1:9) to obtain X-I-29 (300 mg, 55%) as gummy syrup. 1 H NMR (CDCl 3 , 400 MHz): δ 6.66 (s, 1H), 6.23 (s, 1H), 5.83 (s,2H), 1.62 (s, 6H). Synthesis of 2-(2-Amino-4-(trifluoromethyl) phenyl) propan-2-ol (X-I-31): [00325] To a stirred solution of 2 (1.0 g, 1.0 eq) in ethanol (3.6 mL) were added iron powder (3.0 eq), con. HCl (0.54 mL) and stirred the reaction mixture for 16 h at 70 °C. After consumption of starting material (by TLC), the reaction mixture cooled to room temperature, ethanol was evaporated under reduced pressure. The obtained residue was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain 3 (0.82 g, 92%) as a pale brown solid. LCMS: 252 [+ve]. [00326] Synthesis of 5-(Methylsulfonyl)-2-((trimethylsilyl)ethynyl) aniline 3: To a stirred solution of 2 (0.1 g, 1.0 eq) in diisopropyl amine (2.0 mL) were added copper iodide (0.02 eq), bis (triphenylphosphine) palladium (II) dichloride (0.04 eq), degassed the contents and TMS acetylene (3.0 eq) was added in a sealed tube. The reaction mixture was stirred for 12 h at 60 °C. After consumption of starting material (by TLC), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain 3 (0.06 g, 56%) as a pale yellow solid. LCMS: 268 [+ve]. Synthesis of 1-(2-Amino-4-(methyl sulfonyl) phenyl) ethanone 4: [00327] To a stirred solution of 3 (0.8 g, 1.0 eq) in ethanol (3.2 mL), water (0.8 mL) was added PTSA (1.0 eq). The reaction mixture was stirred for 48 h at 70 °C. After consumption of starting material (by TLC), water was added and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give 4 (0.483 g, 64%) as a pale yellow solid. LCMS: 214 [+ve]. Synthesis of X-I-31: [00328] To a stirred solution of 4 (0.3 g, 1.0 eq) in THF (3.0 mL) was added methyl magnesium bromide (4.0 eq, 2M solution) at -70 °C under nitrogen. After addition, the reaction mixture was allowed to reach room temperature and stirred for 2 h. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by silica gel column chromatography (ethyl acetate: hexane, 3:7) to obtain X-I-31(90 mg, 28%) as a pale yellow solid. 1 H NMR (CD 3 OD, 400 MHz): δ 7.32 (d, 1H), 7.18 (d, 1H), 7.08 (dd, 1H), 3.03 (s, 3H), 1.60 (s, 6H). Synthesis of other examples of general formula X-I or X-VI [00329] The compounds of general formula X-I or X-VI described herein can be prepared as described in the international publication WO 2023/278816, the contents of which are herein incorporated by reference in their entireties. Example X.2: Experimental Conditions Used for Initial Trapping Experiments [00330] Each of compounds X-I-1 through X-I-13 (0.01 moles) was tested for reactivity using 4-hydroxynonenal (4-HNE) (0.006 mol) as a model aldehyde. The experimental compound was dissolved in a 20% solution of Captisol in phosphate buffer (1 mL, pH=7.2). Then, 4-HNE in ethanol (10 mg/mL solution) was added to the solution. The ensuing reaction was monitored by HPLC analysis. After approximately 24 hours, excess formic acid was added to complete the reaction and provide the final composition of product:starting material. The relative ratio of experimental compound/4-HNE adduct to final composition was plotted against time to provide an indication of reaction rate and level of reaction completeness. Example X.3: Experimental Conditions Used for Additional Trapping Experiments [00331] Each of compounds, Reproxalap, X-I-32, X-I-8, X-I-29, and X-I-31 (0.01 moles) was tested for reactivity using 4-hydroxynonenal (4-HNE) (1.5 eq) as a model aldehyde. Each compound was dissolved in a 20% solution of Captisol in phosphate buffer (1 mL, pH=7.2). Then, 4-HNE in ethanol (10 mg/mL solution) was added to the solution. The ensuing reaction was monitored by LCMS analysis. The relative ratio of experimental compound/4-HNE adduct to final composition was plotted against time to provide an indication of reaction rate and level of reaction completeness. Rates of formation of aldehyde adducts over a 24-h time period were then measured. It was found that all samples bind (positive increase in product HPLC peak over time). X-I-29 demonstrated the best binding, followed by X-I-31, which demonstrated slightly better binding than X-I-32. Example X.4: Evaluation of Prophylactic Anti-Inflammatory Activity of Test Compounds in Acute LPS-Induced Sepsis in C57BL/6 Mice Summary [00332] The primary objective of this study was to collect plasma samples of lipopolysaccharide (LPS) challenged C57BL/6 mice after dose of test compounds to provide a cytokine profile as impacted by prophylactic treatments. This study models acute sepsis, which is a systemic inflammatory syndrome initiated by Gram-negative and Gram-positive bacteria and fungi which infect the lungs, abdomen, bloodstream, and renal or genitourinary tracts. Sepsis patients ultimately die of multiorgan failure which is caused by extensive tissue hypo- oxygenation due to ongoing microvascular leakage, disseminated intravascular coagulation, compromised energy production, and metabolic alterations. Sepsis is characterized by an early systemic inflammatory response phase featuring symptoms, such as tachycardia, fever, hyperventilation, and activation of the complement and coagulation cascades. However, it is now appreciated that a compensatory anti-inflammatory response phase follows, characterized by neuroendocrine-mediated immunosuppression. Since these processes are the result of interaction between cells of inflammation and organs, investigation of the treatment of this syndrome requires the use of intact animal models. The use of ten mice per group allows useful statistical modelling of the results. [00333] For the data shown in Table X.2A, 103 mice (female, 18-22 gram, C57BL/6) were purchased from ENVIGO. The mice were housed in 20 cages of 5 mice per cage with 1 cage of 3 mice as extra. The cages had filter tops and autoclaved bedding, and the animals were placed in quarantine with daily inspection. The treatment groups are detailed in Table 2A below. 10 mice were included in each group. The mice were dosed by oral gavage (PO) at 10 ml/kg as per the table below. MC = methyl cellulose. Table X.2A:
[00334] For the data shown in Table X.2B, 185 mice (female, 18-22 gram, C57BL/6) were purchased from ENVIGO. The mice were housed in 37 cages of 5 mice per cage. The cages had filter tops and autoclaved bedding, and the animals were placed in quarantine with daily inspection. The treatment groups are detailed in Table X.2B below. 10 mice were included in each group. The mice were dosed by oral gavage (PO) at 10 ml/kg as per the table below. MC = methyl cellulose. Table X.2B: Procedure [00335] At T = 0 h, the mice were dosed with one of the test compounds as described in the above table. [00336] At T = 0.5 h, the mice were injected IP with 1.5 mg/kg MPS (Sigma). [00337] At T = 6.5 h, all mice were anesthetized and exsanguinated into pre-chilled EDTA- treated tubes. The blood was processed to plasma which was stored in labeled 0.5 polypropylene snap-cap tubes (0.5 mL Eppendorf Safe-Lock Tubes (Fisher Scientific) at -80 °C. [00338] Preparation of vehicle: 1.0 gram of methyl cellulose (Sigma) was dissolved in 200 mL of water (USP purified) to make a solution of 0.5% methyl cellulose in water. Preparation of LPS solution: 6 mg of LPS (from Escherichia Coli 055:B5, Cat# L2880, Sigma Lot# 057m4013) was dissolved in 20 ml of saline to give a LPS solution of 0.3 mg/ml. All mice were injected with 5ml/kg (1.5 mg/kg) at the scheduled time by intraperitoneal injection. Cytokine Panel Summary [00339] A 32-plex cytokine panel was obtained from Eve Technologies. Each cytokine was assessed based against a 7 point curve range in duplicate. The average of the two replicate analyses was used for statistics. Unpaired t-tests were performed using Excel™ contrasting vehicle against each treatment group. Column plots of the treatment groups for each cytokine are shown in the Figures. One star indicates P<0.05. Two stars indicates P<0.01. Three stars indicates P<0.001. Four stars indicates P<0.0001. Most, but not all, statistically significant results are indicated with star(s). [00340] A heatmap of significant cytokine changes is shown in Table X.3A and Table X.3B below. Table X.3A:
Table X.3B:
Conclusions [00341] Significant changes were observed for the treatment groups vs. vehicle for several cytokines. Example Y.1: Synthesis of Compounds Y-I-1 to Y-I-169 Key int-1 synthesis: Synthesis of methyl 3-amino-4-((trimethylsilyl)ethynyl)benzoate 2 [00375] A mixture of methyl 3-amino-4-bromobenzoate 1 (20.0 g, 1.0 eq), copper iodide (0.33 g 0.02 eq) in DIPA (160 mL) was degassed with nitrogen for 20 min, then Pd(pph3)2Cl2 (3.67 g, 0.06 eq) followed by trimethylsilyl acetylene (25.61 g, 3.0 eq) were added at room temperature. The reaction mixture was slowly heated to 60 °C and stirred for 16 h in a sealed tube. After consumption of starting material (by TLC), the reaction mass was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water (3 x 150 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 5:95), pure fraction was distilled to give 2 (15.5 g, 71.7%) as thick syrup. 1 H NMR (400 MHz, CDCl3): δ 7.34-7.30 (m, 2H), 7.36 (s, 1H), 4.34 (bs, 2H), 3.88 (s, 3H), 0.27 (s, 9H); Mass: 248 (M+H). Synthesis of methyl 4-acetyl-3-aminobenzoate 3 [00376] A mixture of methyl 3-amino-4-((trimethylsilyl)ethynyl)benzoate 2 (15.5 g, 1.0 eq), PTSA.H 2 O (11.91 g, 1.0 eq) in water (15 mL): ethanol (160 mL) was heated to 75 °C and stirred for 16 h. After consumption of starting material (by TLC), the reaction mass was cooled to room temperature and ethanol was evaporated under reduced pressure. The crude compound was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound, which was purified by column chromatography eluted with (ethyl acetate: petroleum ether, 10:90), pure fraction was distilled to furnish 3 (8.0 g, 66.16%) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.85 (d, 1H), 7.42-7.41 (m, 1H), 7.35 (bs, 2H), 7.04 (dd, 1H), 3.84 (s, 3H), 2.54 (s, 3H); Mass: 194 (M+H). Synthesis of 4-acetyl-3-aminobenzoic acid Key int-1 [00377] To a stirred solution of methyl 4-acetyl-3-aminobenzoate 3 (8.0 g, 1.0 eq) in THF (130 mL) and water (32 mL) was added LiOH.H 2 O (10.43 g, 6.0 eq) at room temperature. The reaction was stirred for 16 h at RT. After consumption of starting material (by TLC), reaction was cooled to room temperature and volatiles were evaporated under reduced pressure to obtain crude compound. This crude was diluted with water, acidified with KHSO 4 , the obtained solid was filtered and dried under vacuum to give Key int-1 (6.0 g, 81%) as pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.6-12.0 (br, 1H), 7.83 (d, 1H), 7.39 (s, 1H), 7.32 (br, 2H), 7.03 (d, 1H), 2.53 (s, 3H); Mass: 178 (M-H). Synthesis of Y-I-34
Synthesis of 4-acetyl-3-amino-N-(4-methoxybenzyl)benzamide 2 [00378] To a stirred solution of 4-acetyl-3-aminobenzoic acid (1.0 g, 1.0 eq) and (4- methoxyphenyl)methanamine (0.84 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (3.0 mL, 3.0 eq), EDCI.HCl (1.60 g, 1.5 eq) followed by HOBt (1.13 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 70:30), pure fraction was distilled to give 2 (0.4 g, 24%) as pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.84 (d, 1H), 7.27 (d, 2H), 7.15 (d, 1H), 6.95 (dd, 1H), 6.88 (d, 2H), 4.47 (s, 2H), 3.77 (s, 3H), 2.56 (s, 3H); Mass: 299 (M+H). Synthesis of 3-amino-4-(2-hydroxypropan-2-yl)-N-(4-methoxybenzyl)benzamid e Y-I-34 [00379] To solution of 4-acetyl-3-amino-N-(4-methoxybenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 9.6 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-34 (0.2 g, 47.5%) as an off white solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.25-7.27 (m, 2H), 7.19 (d, 1H), 7.12 (d, 1H), 7.05 (dd, 1H), 6.88 (dd, 2H), 4.47 (s, 2H), 3.76 (s, 3H), 1.61 (s, 6H); Mass: 315 (M+H). Synthesis of Y-I-22
Synthesis of 4-acetyl-3-amino-N-(2,6-difluorobenzyl)benzamide 2 [00380] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and (2,6- difluorophenyl)methanamine (0.70 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.4 g, 29.5%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.86 (t, 1H), 7.77 (d, 1H), 7.43-7.35 (m, 1H), 7.27 (bs, 2H), 7.16 (s, 1H), 7.08 (t, 2H), 6.91 (dd, 1H), 4.48 (d, 2H), 2.51 (s, 3H); Mass: 305 (M+H). Synthesis of 3-amino-N-(2,6-difluorobenzyl)-4-(2-hydroxypropan-2-yl)benza mide Y-I-22 [00381] To solution of 4-acetyl-3-amino-N-(2,6-difluorobenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 9.4 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-22 (0.2 g, 47.6%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.32-7.37 (m, 1H), 7.18 (dd, 1H), 7.09 (d, 1H), 6.96-7.04 (m, 3H), 4.63 (s, 2H), 1.61 (s, 6H); Mass: 321 (M+H). Synthesis of Y-I-24 Synthesis of 4-acetyl-3-amino-N-(3,4-dichlorobenzyl)benzamide 2 [00382] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and (3,4- dichlorophenyl)methanamine (0.86 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.4 g, 26.6%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.07 (t, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 7.55-7.54 (s, 1H), 7.31-7.29 (m, 3H), 7.23 (dd, 1H), 6.93 (dd, 1H), 4.43 (dd, 2H), 2.53-2.50 (s, 3H); Mass: 337 (M+H). Synthesis of 3-amino-N-(3,4-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)benza mide Y-I-24 [00383] To solution of 4-acetyl-3-amino-N-(3,4-dichlorobenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 8.47 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-24 (0.3 g, 72%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.48-7.51 (m, 2H), 7.27-7.29 (m, 1H), 7.22 (dd, 1H), 7.15 (d, 1H), 7.09 (dd, 1H), 4.52 (s, 2H), 1.63 (s, 6H); Mass: 353 (M+H). Synthesis of Y-I-25
Synthesis of 4-acetyl-3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)benzamide 2 [00384] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and benzo[d][1,3]dioxol-5-ylmethanamine (0.74 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.4 g, 26.6%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.94 (t, 1H), 7.80 (d, 1H), 7.28 (bs, 2H), 7.21 (s, 1H), 6.95 (d, 1H), 6.87-6.84 (m, 2H), 6.78 (d, 1H), 5.97 (s, 2H), 4.34 (d, 2H), 2.51 (s, 3H); Mass: 313 (M+H). Synthesis of 3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-(2-hydroxypropa n-2- yl)benzamide Y-I-25 [00385] To solution of 4-acetyl-3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 9.2 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-25 (0.2 g, 47.6%) as a pale yellow solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.19 (d, 1H), 7.12 (d, 1H), 7.05 (dd, 1H), 6.80-6.84 (m, 2H), 6.74-6.76 (m, 1H), 5.90 (s, 2H), 4.43 (s, 2H), 1.61 (s, 6H); Mass: 329 (M+H). Synthesis of Y-I-26 Synthesis of 4-acetyl-3-amino-N-(3,4-dimethoxybenzyl)benzamide 2 [00386] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and benzo[d][1,3]dioxol-5-ylmethanamine (0.82 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.3 g, 20.5%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.92 (t, 1H), 7.80 (d, 1H), 7.28 (bs, 2H), 7.22 (s, 1H), 6.97-6.93 (m, 2H), 6.90-6.88 (m, 1H), 6.83-6.81 (m, 1H), 4.37 (d, 2H), 3.73 (d, 6H), 2.53 (s, 3H); Mass: 329 (M+H). Synthesis of 3-amino-N-(3,4-dimethoxybenzyl)-4-(2-hydroxypropan-2-yl)benz amide Y-I-26 [00387] To solution of 4-acetyl-3-amino-N-(3,4-dimethoxybenzyl)benzamide (0.3 g, 1.0 eq) in THF (15 mL) was added methyl magnesium bromide (1.4 M in THF, 6.52 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-26 (0.15 g, 47.6%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.19 (d, 1H), 7.12 (d, 1H), 7.04-7.07 (m, 1H), 6.97 (s, 1H), 6.90 (s, 2H), 4.47 (s, 2H), 3.80 (s, 6H), 1.61 (s, 6H); Mass: 345 (M+H). Synthesis of Y-I-27 Synthesis of 4-acetyl-3-amino-N-(4-(tert-butyl)benzyl)benzamide 2 [00388] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and (4-(tert- butyl)phenyl)methanamine (0.81 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.5 g, 34.7%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.96 (t, 1H), 7.80 (d, 1H), 7.35-7.33 (m, 2H), 7.28 (bs, 2H), 7.23-7.21 (m, 3H), 6.96 (dd, 1H), 4.40 (d, 2H), 2.53 (s, 3H), 1.26 (s, 9H); Mass: 325 (M+H). Synthesis of 3-amino-N-(4-(tert-butyl)benzyl)-4-(2-hydroxypropan-2-yl)ben zamide Y-I-27 [00389] To solution of 4-acetyl-3-amino-N-(4-(tert-butyl)benzyl)benzamide (0.5 g, 1.0 eq) in THF (25 mL) was added methyl magnesium bromide (1.4 M in THF, 11.0 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-27 (0.15 g, 57.2%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.37-7.39 (m, 2H), 7.27-7.29 (m, 2H), 7.22 (d, 1H), 7.15 (d, 1H), 7.09 (dd, 1H), 4.53 (s, 2H), 1.63 (s, 6H), 1.31 (s, 9H); Mass: 341 (M+H). Synthesis of Y-I-28 Synthesis of 4-acetyl-3-amino-N-(4-fluorobenzyl)benzamide 2 [00390] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and (4- fluorophenyl)methanamine (0.61 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 65:25), pure fraction was distilled to give 2 (0.4 g, 31.3%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.01 (t, 1H), 7.81 (d, 1H), 7.36-7.32 (m, 2H), 7.28 (bs, 1H), 7.23 (s, 1H), 7.15 (t, 2H), 6.96 (d, 1H), 4.42 (d, 2H), 2.53 (s, 3H); Mass: 287 (M+H). Synthesis of 3-amino-N-(4-fluorobenzyl)-4-(2-hydroxypropan-2-yl)benzamide Y-I-28 [00391] To solution of 4-acetyl-3-amino-N-(4-fluorobenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 10.0 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by column chromatography eluted with (MeOH:DCM, 2:98) to obtain Y-I-28 (0.12 g, 28.4%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.33-7.37 (m, 2H), 7.19 (d, 1H), 7.13 (d, 1H), 7.02-7.07 (m, 3H), 4.51 (s, 2H), 1.61 (s, 6H); Mass: 303 (M+H). Synthesis of Y-I-31 Synthesis of 4-acetyl-3-amino-N-(2-chloro-6-fluorobenzyl)benzamide 2 [00392] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and (2-chloro-6- fluorophenyl)methanamine (0.71 g, 1.1 eq) in EtOAc (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), followed by 50% T3P in EtOAc (3.9 mL, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.5 g, 35%) as off white solid. 1 H NMR (400 MHz, CD3OD): δ 7.84 (d, 1H), 7.36-7.29 (m, 2H), 7.16-7.11 (m, 2H), 6.93 (dd, 1H), 4.73 (s, 2H), 2.57 (s, 3H); Mass: 321 (M+H). Synthesis of 3-amino-N-(2-chloro-6-fluorobenzyl)-4-(2-hydroxypropan-2-yl) benzamide Y-I- 31 [00393] To solution of 4-acetyl-3-amino-N-(2-chloro-6-fluorobenzyl)benzamide (0.5 g, 1.0 eq) in THF (25 mL) was added methyl magnesium bromide (1.4 M in THF, 11.13 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by column chromatography eluted with (MeOH:DCM, 1:99) to obtain Y-I- 31 (0.27 g, 51.4%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.26-7.35 (m, 2H), 7.16-7.18 (m, 1H), 7.10-7.13 (m, 1H), 7.07 (d, 1H), 7.01 (dd, 1H), 4.70 (s, 2H), 1.60 (s, 6H); Mass: 337 (M+H). Synthesis of Y-I-36 Synthesis of 4-acetyl-3-amino-N-(4-methylbenzyl)benzamide 2 [00394] To a stirred solution of 4-acetyl-3-aminobenzoic acid (0.8 g, 1.0 eq) and p- tolylmethanamine (0.54 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 65:25), pure fraction was distilled to give 2 (0.3 g, 26.3%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.95 (t, 1H), 7.80 (d, 1H), 7.28 (bs, 2H), 7.22 (s, 1H), 7.20-7.18 (m, 2H), 7.13-7.11 (m, 2H), 6.96 (d, 1H), 4.39 (d, 2H), 2.53 (s, 3H), 2.27 (s, 3H); Mass: 283 (M+H). Synthesis of 3-amino-4-(2-hydroxypropan-2-yl)-N-(4-methylbenzyl)benzamide Y-I-36 [00395] To solution of 4-acetyl-3-amino-N-(4-methylbenzyl)benzamide (0.3 g, 1.0 eq) in THF (15 mL) was added methyl magnesium bromide (1.4 M in THF, 7.6 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by di ethyl ether wash to obtain Y-I-36 (0.11 g, 34.7%) as a pale yellow solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.20 (t, 3H), 7.12-7.13 (m, 3H), 7.05 (dd, 1H), 4.49 (s, 2H), 2.30 (s, 3H), 1.61 (s, 6H); Mass: 299 (M+H). Key int-2 synthesis: Synthesis of methyl 4-amino-3-((trimethylsilyl)ethynyl)benzoate 2 [00396] A mixture of methyl 4-amino-3-bromobenzoate 1 (30.0 g, 1.0 eq), copper iodide (0.496 g 0.02 eq) in DIPA (240 mL) was degassed with nitrogen for 20 min, then Pd(pph3)2Cl2 (5.50 g, 0.06 eq) followed by trimethylsilyl acetylene (38.33 g, 3.0 eq) were added at room temperature. The reaction mixture was slowly heated to 60 ° C and stirred for 16 h in a sealed tube. After consumption of starting material (by TLC), the reaction mass was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water (3 x 180 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 5:95), pure fraction was distilled to give 2 (20.0 g, 62.0%) as thick syrup. 1 H NMR (400 MHz, DMSO-d6): δ 7.71 (d, 1H), 7.63 (dd, 1H), 6.74 (d, 1H), 6.15 (bs, 2H), 3.74 (s, 3H), 0.23 (s, 9H); Mass: 248 (M+H). Synthesis of methyl 3-acetyl-4-aminobenzoate 3 [00397] A mixture of methyl 4-amino-3-((trimethylsilyl)ethynyl)benzoate 2 (20.0 g, 1.0 eq), PTSA.H2O (15.37 g, 1.0 eq) in water (40 mL): ethanol (200 mL) was heated to 75 °C and stirred for 16 h. After consumption of starting material (by TLC), the reaction mass was cooled to room temperature and ethanol was evaporated under reduced pressure. The crude compound was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound, which was purified by column chromatography eluted with (ethyl acetate: petroleum ether, 10:90), pure fraction was distilled to furnish 3 (10.6 g, 68%) as an off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.34 (d, 1H), 7.85 (bs, 2H), 7.77 (dd, 1H), 6.81 (d, 1H), 3.79 (s, 3H), 2.56 (s, 3H); Mass: 194 (M+H). Synthesis of 3-acetyl-4-aminobenzoic acid (Key int-2) [00398] To a stirred solution of methyl 3-acetyl-4-aminobenzoate 3 (10.6 g, 1.0 eq) in THF (172 mL) and water (43 mL) was added LiOH.H2O (13.83 g, 6.0 eq) at room temperature. The reaction was stirred for 16 h at RT. After consumption of starting material (by TLC), reaction was cooled to room temperature and volatiles were evaporated under reduced pressure to obtain crude compound. This crude was diluted with water, acidified with KHSO4, the obtained solid was filtered and dried under vacuum to give Key int-2 (7.6 g, 78%) as pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.5 (br, 1H), 8.33 (s, 1H), 7.75 (dd, 3H), 6.78 (d, 1H), 2.55 (s, 3H); Mass: 178 (M+H). Synthesis of Y-I-55 Synthesis of 3-acetyl-4-amino-N-(4-methoxybenzyl)benzamide 2 [00399] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.5 g, 1.0 eq) and (4- methoxyphenyl)methanamine (0.42 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (1.5 mL, 3.0 eq), EDCI.HCl (0.8 g, 1.5 eq) followed by HOBt (0.57 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.4 g, 48%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.76 (t, 1H), 8.31 (d, 1H), 7.79 (dd, 1H), 7.60 (bs, 2H), 7.23 (d, 2H), 6.88 (d, 2H), 6.77 (d, 1H), 4.39 (d, 2H), 3.72 (s, 3H), 2.56 (s, 3H); Mass: 299 (M+H). Synthesis of 4-amino-3-(2-hydroxypropan-2-yl)-N-(4-methoxybenzyl)benzamid e Y-I-55 [00400] To solution of 3-acetyl-4-amino-N-(4-methoxybenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 9.57 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-55 (0.11 g, 26.1%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.69 (d, 1H), 7.51 (dd, 1H), 7.25 (d, 2H), 6.85-6.88 (m, 2H), 6.66 (d, 1H), 4.46 (s, 2H), 3.76 (s, 3H), 1.63 (s, 6H); Mass: 315 (M+H). Synthesis of Y-I-55 Synthesis of 3-acetyl-4-amino-N-(2,6-difluorobenzyl)benzamide 2 [00401] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.5 g, 1.0 eq) and (2,6- difluorophenyl)methanamine (0.44 g, 1.1 eq) in DMF (10 mL) cool to 0 o C, added the DIPEA (1.5 mL, 3.0 eq), EDCI.HCl (0.8 g, 1.5 eq) followed by HOBt (0.57 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.4 g, 47.1%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.64 (t, 1H), 8.27 (d, 1H), 7.75 (dd, 1H), 7.59 (bs, 2H), 7.40-7.34 (m, 1H), 7.08 (t, 2H), 6.74 (d, 1H), 4.50 (d, 2H), 2.54 (s, 3H); Mass: 305 (M+H). Synthesis of 4-amino-N-(2,6-difluorobenzyl)-3-(2-hydroxypropan-2-yl)benza mide Y-I-55 [00402] To solution of 3-acetyl-4-amino-N-(4-methoxybenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 9.38 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by di ethyl ether wash to obtain Y-I-55 (0.18 g, 42.7%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.64 (d, 1H), 7.47 (dd, 1H), 7.28-7.34 (m, 1H), 6.93-6.97 (m, 2H), 6.63 (d, 1H), 4.61 (s, 2H), 1.61 (s, 6H); Mass: 321 (M+H). Synthesis of Y-I-57 Synthesis of 3-acetyl-4-amino-N-(3,4-dichlorobenzyl)benzamide 2 [00403] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.8 g, 1.0 eq) and (3,4- dichlorophenyl)methanamine (0.86 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 65:25), pure fraction was distilled to give 2 (0.7 g, 46.6%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.87 (t, 1H), 8.33 (d, 1H), 7.79 (dd, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.30 (dd, 1H), 6.78 (d, 1H), 4.45 (d, 2H), 2.57 (s, 3H); Mass: 337 (M+H). Synthesis of 4-amino-N-(3,4-dichlorobenzyl)-3-(2-hydroxypropan-2-yl)benza mide Y-I-55 [00404] To solution of 3-acetyl-4-amino-N-(3,4-dichlorobenzyl)benzamide (0.7 g, 1.0 eq) in THF (35 mL) was added methyl magnesium bromide (1.4 M in THF, 14.82 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by n-pentane wash to obtain Y-I-55 (0.4 g, 54.5%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.72 (d, 1H), 7.56 (dd, 1H), 7.47-7.50 (m, 2H), 7.28 (dd, 1H), 6.70 (d, 1H), 4.52 (s, 2H), 1.65 (s, 6H); Mass: 353 (M+H). Synthesis of Y-I-58 Synthesis of 3-acetyl-4-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)benzamide 2 [00405] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.8 g, 1.0 eq) and benzo[d][1,3]dioxol-5-ylmethanamine (0.74 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 70:30), pure fraction was distilled to give 2 (0.7 g, 50.2%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.75 (t, 1H), 8.31 (s, 1H), 7.78 (d, 1H), 7.60 (bs, 2H), 6.87-6.84 (m, 2H), 6.79-6.76 (m, 2H), 5.97 (s, 2H), 4.36 (d, 2H), 2.56 (s, 3H); Mass: 313 (M+H). Synthesis of 4-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(2-hydroxypropa n-2- yl)benzamide Y-I-58 [00406] To solution of 3-acetyl-4-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)benzamide (0.7 g, 1.0 eq) in THF (35 mL) was added methyl magnesium bromide (1.4 M in THF, 16.0 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by n-pentane wash to obtain Y-I-58 (0.52 g, 70.27%) as a pale yellow solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.71 (d, 1H), 7.54 (dd, 1H), 6.81-6.85 (m, 2H), 6.77 (d, 1H), 6.69 (d, 1H), 5.92 (s, 2H), 4.46 (s, 2H), 1.65 (s, 6H); Mass: 329 (M+H). Synthesis of Y-I-59 Synthesis of 3-acetyl-4-amino-N-(3,4-dimethoxybenzyl)benzamide 2 [00407] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.8 g, 1.0 eq) and (3,4- dimethoxyphenyl)methanamine (0.82 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 70:30), pure fraction was distilled to give 2 (0.7 g, 47.7%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.75 (t, 1H), 8.32 (d, 1H), 7.78 (dd, 1H), 7.60 (bs, 2H), 6.93 (d, 1H), 6.89 (d, 1H), 6.82 (dd, 1H), 6.77 (dd, 1H), 4.39 (d, 2H), 3.72 (s, 6H), 2.56 (s, 3H); Mass: 329 (M+H). Synthesis of 4-amino-N-(3,4-dimethoxybenzyl)-3-(2-hydroxypropan-2-yl)benz amide Y-I-59 [00408] To solution of 3-acetyl-4-amino-N-(3,4-dimethoxybenzyl)benzamide (0.7 g, 1.0 eq) in THF (35 mL) was added methyl magnesium bromide (1.4 M in THF, 15.2 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by n-pentane wash to obtain Y-I-59 (0.49 g, 66.7%) as a pale yellow solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.72 (d, 1H), 7.55 (dd, 1H), 6.99 (s, 1H), 6.91 (s, 2H), 6.69 (d, 1H), 4.50 (s, 2H), 3.82 (s, 6H), 1.65 (s, 6H); Mass: 345 (M+H). Synthesis of Y-I-60 Synthesis of 3-acetyl-4-amino-N-(4-(tert-butyl)benzyl)benzamide 2 [00409] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.8 g, 1.0 eq) and (4-(tert- butyl)phenyl)methanamine (0.8 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:40), pure fraction was distilled to give 2 (0.45 g, 31%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.77 (t, 1H), 8.32 (d, 1H), 7.78 (dd, 1H), 7.60 (bs, 2H), 7.33 (d, 2H), 7.23 (d, 2H), 6.77 (d, 1H), 4.42 (d, 2H), 2.56 (s, 3H), 1.26 (s, 9H); Mass: 325 (M+H). Synthesis of 4-amino-N-(4-(tert-butyl)benzyl)-3-(2-hydroxypropan-2-yl)ben zamide Y-I-60 [00410] To solution of 3-acetyl-4-amino-N-(4-(tert-butyl)benzyl)benzamide (0.45 g, 1.0 eq) in THF (25 mL) was added methyl magnesium bromide (1.4 M in THF, 9.9 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by n-pentane wash to obtain Y-I-60 (0.15 g, 31.7%) as off white solid. 1 H NMR (400 MHz, CD3OD): δ 7.72 (d, 1H), 7.55 (dd, 1H), 7.36-7.39 (m, 2H), 7.27 (d, 2H), 6.69 (d, 1H), 4.53 (s, 2H), 1.65 (s, 6H), 1.32 (s, 9H); Mass: 341 (M+H). Synthesis of Y-I-61 Synthesis of 3-acetyl-4-amino-N-(4-fluorobenzyl)benzamide 2 [00411] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.8 g, 1.0 eq) and (4- fluorophenyl)methanamine (0.61 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), EDCI.HCl (1.27 g, 1.5 eq) followed by HOBt (0.9 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 50:50), pure fraction was distilled to give 2 (0.35 g, 27.3%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.83 (t, 1H), 8.33 (s, 1H), 7.79 (dd, 1H), 7.61 (bs, 2H), 7.36-7.33 (m, 2H), 7.17-7.12 (m, 2H), 6.78 (d, 1H), 4.44 (d, 2H), 2.56 (s, 3H); Mass: 287 (M+H). Synthesis of 4-amino-N-(4-fluorobenzyl)-3-(2-hydroxypropan-2-yl)benzamide Y-I-61 [00412] To solution of 3-acetyl-4-amino-N-(4-fluorobenzyl)benzamide (0.35 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 8.7 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by n-pentane wash to obtain Y-I-61 (0.26 g, 70.4%) as a pale yellow solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.69 (d, 1H), 7.52 (dd, 1H), 7.32-7.36 (m, 2H), 7.03 (t, 2H), 6.67 (d, 1H), 4.51 (s, 2H), 1.63 (s, 6H); Mass: 303 (M+H). Synthesis Y-I-63 Synthesis of 3-acetyl-4-amino-N-(2-chloro-6-fluorobenzyl)benzamide 2 [00413] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.8 g, 1.0 eq) and (2-chloro-6- fluorophenyl)methanamine (0.71 g, 1.1 eq) in EtOAc (10 mL) cool to 0 o C, added the DIPEA (2.36 mL, 3.0 eq), followed by 50% T3P in EtOAc (3.9 mL, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 60:30), pure fraction was distilled to give 2 (0.7 g, 49%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.52 (t, 1H), 8.26 (d, 1H), 7.75 (dd, 1H), 7.59 (bs, 2H), 7.39-7.32 (m, 2H), 7.25-7.21 (m, 1H), 6.74 (d, 1H), 4.56 (d, 2H), 2.54 (s, 3H); Mass: 321 (M+H). Synthesis of 4-amino-N-(2-chloro-6-fluorobenzyl)-3-(2-hydroxypropan-2-yl) benzamide Y-I- 63 [00414] To solution of 3-acetyl-4-amino-N-(2-chloro-6-fluorobenzyl)benzamide (0.7 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 15.58 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by n-pentane wash to obtain Y-I-63 (0.39 g, 53.0%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.65 (d, 1H), 7.48 (dd, 1H), 7.25-7.34 (m, 2H), 7.07-7.12 (m, 1H), 6.64 (d, 1H), 4.69 (s, 2H), 1.62 (s, 6H); Mass: 337 (M+H). Synthesis of Y-I-67 Synthesis of 3-acetyl-4-amino-N-(3,4,5-trimethoxybenzyl)benzamide 2 [00415] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.6 g, 1.0 eq) and (3,4,5- trimethoxyphenyl)methanamine (0.73 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (1.8 mL, 3.0 eq), EDCI.HCl (0.96 g, 1.5 eq) followed by HOBt (0.68 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 70:30), pure fraction was distilled to give 2 (0.4 g, 33.3%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.75 (t, 1H), 8.32 (d, 1H), 7.79 (dd, 1H), 7.60 (bs, 2H), 6.78 (d, 1H), 6.64 (s, 2H), 4.40 (d, 2H), 3.74 (s, 6H), 3.62 (s, 3H), 2.56 (s, 3H); Mass: 359 (M+H). Synthesis of 4-amino-3-(2-hydroxypropan-2-yl)-N-(3,4,5-trimethoxybenzyl)b enzamide Y-I- 67 [00416] To solution of 3-acetyl-4-amino-N-(3,4,5-trimethoxybenzyl)benzamide (0.4 g, 1.0 eq) in THF (20 mL) was added methyl magnesium bromide (1.4 M in THF, 8.0 mL, 10.0 eq) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated under reduced pressure to give crude compound which was purified by diethyl ether wash to obtain Y-I-67 (0.25 g, 59.8%) as a pale yellow solid. 1 H NMR (400 MHz, CD3OD): δ 7.71 (d, 1H), 7.54 (dd, 1H), 6.66-6.69 (m, 3H), 4.48 (s, 2H), 3.81 (s, 6H), 3.73 (s, 3H), 1.63 (s, 6H); Mass: 375 (M+H). Synthesis of Y-I-68 Synthesis of 3-acetyl-4-amino-N-(4-methylbenzyl)benzamide 2 [00417] To a stirred solution of 3-acetyl-4-aminobenzoic acid (0.5 g, 1.0 eq) and p- tolylmethanamine (0.37 g, 1.1 eq) in DMF (15 mL) cool to 0 o C, added the DIPEA (1.5 mL, 3.0 eq), EDCI.HCl (0.78 g, 1.5 eq) followed by HOBt (0.57 g, 1.5 eq) and the reaction mixture was continued for 16 h at RT. After consumption of starting material (by TLC), the reaction mass was quenched with water extracted with ethyl acetate. The organic layer was washed with water (2 x 20 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to obtain crude compound which was purified by column chromatography eluted with (ethyl acetate: Hexane, 70:30), pure fraction was distilled to give 2 (0.2 g, 25.4%) as off white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.78 (t, 1H), 8.32 (d, 1H), 7.78 (dd, 1H), 7.60 (bs, 2H), 7.19 (d, 2H), 7.12 (d, 2H), 6.77 (d, 1H), 4.42 (d, 2H), 2.56 (s, 3H), 2.27 (s, 3H); Mass: 283 (M+H). Synthesis of 4-amino-3-(2-hydroxypropan-2-yl)-N-(4-methylbenzyl)benzamide Y-I-68 To solution of 3-acetyl-4-amino-N-(4-methylbenzyl)benzamide (0.2 g, 1.0 eq) in THF (10 mL) was added methyl magnesium bromide (1.4 M in THF, 5.1 mL, 10.0 eq ) for 10 min under nitrogen atmosphere at 0 °C. The reaction mass was continued for another 30 min at same temperature. After consumption of starting material (by TLC), the reaction mixture was quenched with NH 4 Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude compound which was purified by di ethyl ether wash to obtain Y-I-68 (0.25 g, 59.8%) as a pale yellow solid (hygroscopic nature). 1 H NMR (400 MHz, CD3OD): δ 7.69 (d, 1H), 7.52 (dd, 1H), 7.19-7.21 (m, 2H), 7.11-7.13 (m, 2H), 6.67 (d, 1H), 4.49 (s, 2H), 2.30 (s, 3H), 1.63 (s, 6H); Mass: 299 (M+H). Example Y.2: Experimental Conditions Used for Initial Trapping Experiments [00418] Each of compounds of the disclosure may be tested for reactivity using 4- hydroxynonenal (4-HNE) (0.006 mol) as a model aldehyde. The experimental compound is to be dissolved in a 20% solution of Captisol in phosphate buffer (1 mL, pH=7.2). Then, 4-HNE in ethanol (10 mg/mL solution) is added to the solution. The ensuing reaction is monitored by HPLC analysis. After approximately 24 hours, excess formic acid is added to complete the reaction and provide the final composition of product:starting material. The relative ratio of experimental compound/4-HNE adduct to final composition is plotted against time to provide an indication of reaction rate and level of reaction completeness. Example Y.3: Experimental Conditions Used for Additional Trapping Experiments [00419] Each compound (0.01 moles) may be tested for reactivity using 4-hydroxynonenal (4-HNE) (1.5 eq) as a model aldehyde. Each compound may be dissolved in a 20% solution of Captisol in phosphate buffer (1 mL, pH=7.2). Then, 4-HNE in ethanol (10 mg/mL solution) is added to the solution. The ensuing reaction is monitored by LCMS analysis. The relative ratio of experimental compound/4-HNE adduct to final composition is plotted against time to provide an indication of reaction rate and level of reaction completeness. Example Y.4: Evaluation of Prophylactic Anti-Inflammatory Activity of Test Compounds in Acute LPS-Induced Sepsis in C57BL/6 Mice Summary [00420] The primary objective of this study is to collect plasma samples of lipopolysaccharide (LPS) challenged C57BL/6 mice after dose of test compounds to provide a cytokine profile as impacted by prophylactic treatments. This study models acute sepsis, which is a systemic inflammatory syndrome initiated by Gram-negative and Gram-positive bacteria and fungi which infect the lungs, abdomen, bloodstream, and renal or genitourinary tracts. Sepsis patients ultimately die of multiorgan failure which is caused by extensive tissue hypo- oxygenation due to ongoing microvascular leakage, disseminated intravascular coagulation, compromised energy production, and metabolic alterations. Sepsis is characterized by an early systemic inflammatory response phase featuring symptoms, such as tachycardia, fever, hyperventilation, and activation of the complement and coagulation cascades. However, it is now appreciated that a compensatory anti-inflammatory response phase follows, characterized by neuroendocrine-mediated immunosuppression. Since these processes are the result of interaction between cells of inflammation and organs, investigation of the treatment of this syndrome requires the use of intact animal models. The use of ten mice per group allows useful statistical modelling of the results. [00421] For example, 103 mice (female, 18-22 gram, C57BL/6) may be purchased from ENVIGO. The mice housed in 20 cages of 5 mice per cage with 1 cage of 3 mice as extra. The cages have filter tops and autoclaved bedding, and the animals are placed in quarantine with daily inspection. 10 mice are included in each group. The mice are dosed by oral gavage (PO) at 10 ml/kg. For further example, 185 mice (female, 18-22 gram, C57BL/6) may be purchased from ENVIGO. The mice housed in 37 cages of 5 mice per cage. The cages having filter tops and autoclaved bedding, and the animals placed in quarantine with daily inspection. 10 mice may be included in each group. The mice are to be dosed by oral gavage (PO) at 10 ml/kg. Procedure [00422] At T = 0 h, the mice are dosed with one of the test compounds. [00423] At T = 0.5 h, the mice are injected IP with 1.5 mg/kg MPS (Sigma). [00424] At T = 6.5 h, all mice are anesthetized and exsanguinated into pre-chilled EDTA- treated tubes. The blood is processed to plasma which is stored in labeled 0.5 polypropylene snap-cap tubes (0.5 mL Eppendorf Safe-Lock Tubes (Fisher Scientific) at -80 °C. [00425] Preparation of vehicle: 1.0 gram of methyl cellulose (Sigma) is dissolved in 200 mL of water (USP purified) to make a solution of 0.5% methyl cellulose in water. Preparation of LPS solution: 6 mg of LPS (from Escherichia Coli 055:B5) is dissolved in 20 ml of saline to give a LPS solution of 0.3 mg/ml. All mice are injected with 5ml/kg (1.5 mg/kg) at the scheduled time by intraperitoneal injection. Cytokine Panel Summary [00426] A 32-plex cytokine panel of results is obtained. Each cytokine is assessed based against a 7 point curve range in duplicate. The average of the two replicate analyses is used for statistics. Unpaired t-tests are performed using Excel™ contrasting vehicle against each treatment group. Column plots of the treatment groups for each cytokine may be generated. A heatmap of significant cytokine changes is generated. Example Y.5: ALDH2 Agonism of Exemplary Compounds [00427] ALDH2 is a NAD(p)+-dependent mitochondrial matrix enzyme. Major substrates (high affinity) of ALDH2 are short-chain aliphatic lipid aldehydes (e.g., 4-HNE, acetaldehyde, malondialdehyde and acrolein). ALDH2 dysfunction has been associated with neurodegeneration, apoptotic cell death, pain and the process of aging (Chen Y, He Y, DeVivo MJ. Changing demographics and injury profile of new traumatic spinal cord injuries in the United States, 1972-2014. Arch Phys Med Rehabil. 2016b;97:1610–1619). ALDH2 KO mice had a significantly high 4-HNE load, increased cytokine levels, and persistent behavioral deficits after closed head traumatic brain injury, supporting the anti-inflammatory and antioxidant role of ALDH2 activity in neurotrauma (Knopp RC, Lee SH, Hollas M, Nepomuceno E, Gonzalez D, Tam K, Aamir D, Wang Y, Pierce E, BenAissa M, Thatcher GRJ. Interaction of oxidative stress and neurotrauma in ALDH2(-/-) mice causes significant and persistent behavioral and pro- inflammatory effects in a tractable model of mild traumatic brain injury. Redox Biol. 2020;32:101486). ALDH2 is an established druggable target, and it can be selectively and robustly activated by Alda-1 and inhibited by daidzin (Chen et al., 2014). See Khan, M. et al., Neural Regen Res.2022 Jan; 17(1): 185–193 for an assay procedure. [00428] Compounds Y-I-36, Y-I-55, and Y-I-68 showed an increased in ALDH activity (agonism). EC50s: Y-I-36: 0.29 µM; Y-I-55: 0.56 µM; Y-I-68: 0.83 µM. Example 3 - Rabbit Vitreous PK Profile [00429] Ocular PK was conducted with a non-deuterated analog of Compound A. A single injection of 500 micrograms of the non-deuterated version was administered to New Zealand White rabbits. The vitreous humor was collected at various time points and analyzed by LCMS. The half-life of non-deuterated Compound A was determined to be approximately 24 hours as shown in FIG.1. Fit parameters for the data in FIG.1 are shown below. Parameter Unit Value Example 4 - Retinaldehyde Binding Profile of Compound A [00342] Compound A is designed to trap reactive aldehydes species (RASP) in diverse ocular regions and inhibit RASP-mediated toxicity. Compound A is a small, membrane-permeable molecule that should readily reach the Bruch's membrane and retinal pigment epithelium (RPE), where excess retinaldehyde is thought to form toxic precipitates. [00343] All-trans-retinaldehyde, is a highly reactive intermediate, that is toxic retina cells and contributes to retinal and macular degenerations (Dreffs, et al., 2020). Retinol is converted into retinaldehyde by retinol dehydrogenase, which is expressed in RPE cells. Retinaldehyde is converted into retinoic acid by the enzyme retinaldehyde dehydrogenase (RALDH), which is expressed in RPE, and retina. Therefore, modulating retinaldehyde and inhibiting retinoic acid may mitigate further vision loss (Telias, et al., 2022). Compound A is designed to prevent retinal toxicity by sequestering aldehydes before they can form reactive precipitates in the eye. An in vitro study was executed demonstrating the irreversible covalent binding of retinaldehyde by Compound A. Compound A (2mM) was added to a buffered solution (pH~7.4) of retinaldehyde (1mM). The loss of free Compound A and increase in Compound A -CD complex formation was monitored at various time points to determine completeness of the reaction as shown in FIG.2. Example 5 - In Vitro ADMET Assays [00344] The following in-vitro ADMET assessments have been performed and reported below in Table 2. Table 2: Additional Planned ADMET Studies [00345] Metabolite ID 2 Time Points with Hepatocytes (Human, Beagle Dog, Rat, NZW Rabbit) [00346] Plasma Protein Binding (rat, rabbit, dog, human) Example 6 - Clinical Study [00347] Protocol Synopsis:
Example 9 - In vitro Binding Data for Compounds I-1, I-2, I-3, and I-4 and Amino-CD Compound I-1/4-HNE Binding Data [00348] Fig 3A shows Compound I-1 binding with 4-HNE (4-hydroxynonenol) as a model aldehyde. 3-Amino-β-Cyclodextrin/4-HNE Binding Data [00349] Fig 3B shows Compound 6 of Example 2.1 binding with 4-HNE (4-hydroxynonenol) as a model aldehyde. Conclusions [00350] Aldehyde traps, including Compound A, have increased residency time in the eye when delivered in a composition having a modified cyclodextrin of this disclosure.
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