Methods of treating ophthalmic diseases

Abstract

In some embodiments, a method of treating an ophthalmic disorder, or a complication thereof, in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of a compound as described herein.

Description

PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WOMETHODS OF TREATING OPHTHALMIC DISEASESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 687,234, filed August 26, 2024, the content of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are methods for treating ophthalmic diseases, e.g. retinal degeneration.BACKGROUND

[0003] Glutamatergic synapses are a key feature of the retinal circuitry. Further synapse loss occurs in retinal degenerative disorders, e.g. diabetic retinopathy, glaucoma, age-related macular degeneration (AMD), and aging. A need exists for additional therapies for these retinal degenerative disorders.SUMMARY

[0004] Provided herein are novel methods for treating ophthalmic disorders in patients in need thereof by pharmacological regeneration of retinal synapses. In some embodiments, the ophthalmic disorder is a retinal degeneration disorder. In one embodiment, the disorder is diabetic retinopathy, glaucoma, age-related macular degeneration (AMD), and other ophthalmic disorders related to aging. In one embodiment, the method comprises administering to a patient in need thereof a compound as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] FIG. 1 A- IB show immunostaining results of the effects of Compound 1 in preventing Glaucoma-associated increases in the postsynaptic protein PSD95 (FIG. 1A) with corresponding bar chart (FIG. IB).

[0006] FIG. 2A-2B show immunostaining results of the effects of Compound 1 in preventing Glaucoma- Associated Increases in the presynaptic protein Bassoon by immunostaining (FIG. 2A) with corresponding bar chart (FIG. 2B).

[0007] FIG. 3A-3B show immunostaining results of the effects of Compound 1 in enhancing survival of RGCs during elevated IOP by immunostaining (FIG. 3A) with corresponding bar chart (FIG. 3B).

[0008] FIG. 4A-4B show electrical microscopy results of Compound 1 in preventing IGP-associated axon loss (FIG. 4A) with corresponding bar chart (FIG. 4B).

[0009] FIG. 5A-5C show pERG amplitude (FIG. 5A), pVEP amplitude (FIG. 5B) and latency (FIG. 5C) between the treatment groups.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0010] FIGS. 6A-6B show body weight (FIG. 6A) and relative body weight (FIG. 6B) measured during the treatment period with Compound 1. Data are presented as mean + SEM.

[0011] FIGS. 7A-7B show fasting blood glucose levels measured at baseline (FIG. 7A) and during the treatment period (FIG. 7B) with Compound 1. Data are presented as mean + SEM.

[0012] FIGS. 8A-8B show glucose tolerance test results in Db / + (FIG. 8A) and Db / Db (FIG. 8B) mice following treatment with Compound 1. Data are presented as mean + SEM.

[0013] FIGS. 9A-9B show insulin tolerance test results in Db / + (FIG. 9A) and Db / Db (FIG. 9B) mice following treatment with Compound 1. Data are presented as mean + SEM.

[0014] FIGS. 10A-10C show survival analysis of Compound 1 treated mice.

[0015] FIGS. 11A-11B show the effects of Compound 1 in enhancing survival of RGCs (FIG. 11A) and the corresponding bar chart (FIG. 11B).

[0016] FIG. 12 shows the effects of Compound 1 in mitigating both the loss of pERG responses and the delay in VEP. Statistical significance: *P < 0.05, **P < 0.01, ****P < 0.0001.

[0017] FIG. 13 shows the effects of Compound 1 in promoting synaptic markers in retina.

[0018] FIGS. 14A-14B show the effects of Compound 1 in mitigating the loss of PSD95 (FIG. 14A) and synaptophysin (FIG. 14B).

[0019] FIGS. 15A-15B show the effects of Compound 1 in reversing glial cell activation (reducing GFAP expression).

[0020] FIG. 16A shows that Compound 1 suppresses the increase of Bax and pBad, and reverses the decrease of Bcl-XL. FIG. 16B demonstrates that the effect on Bax is supported by immunofluorescence imaging.DETAILED DESCRIPTION

[0021] Generally the compounds and methods described herein provide for the administration of compounds that provide benefit in the treatment of ophthalmic disorders, or a complication thereof. Generally, the active ingredient or principal ingredient will include an agent, such as a compound, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers of a compound as described herein. The compound described herein may also be administered with one or more additional pharmaceutically active materials or in combination with one or more non-drug therapies.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WOI. Definitions

[0022] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0023] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0024] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

[0025] The prefix “Cu v” indicates that the following group has from u to v carbon atoms. For example, “Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0026] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount + 10%. In other embodiments, the term “about” includes the indicated amount + 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0027] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHs^CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CHs CHCFfc-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CHs^C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0028] “Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substitutedPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy nitro, -SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0029] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce- Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1 -pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl,1.4-pentadienyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1 ,4-hexadienyl, 1,5-hexadienyl,2.4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0030] “Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy and thiol and with the proviso that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0031] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-. Acyl includes the “acetyl” group CH3C(O)-.

[0032] “Acylamino” refers to the groups -NR47C(O) alkyl, -NR47C(O)substituted alkyl, -NR47C(O)cycloalkyl, -NR47C(O) substituted cycloalkyl, -NR47C(O)cycloalkenyl, -NR47C(O) substituted cycloalkenyl, -NR47C(O)alkenyl, -NR47C(O)substituted alkenyl, -NR47C(O)aryl, -NR47C(O) substituted aryl, -NR47C(O)heteroaryl, -NR47C(O)substituted heteroaryl, -NR47C(O)heterocyclic, and -NR47C(O) substituted heterocyclic, wherein R47is hydrogen or alkyl.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0033] “Acyloxy” refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic -C(O)O-.

[0034] “Alkynyl” refers to an unbranched or branched hydrocarbon group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2 s alkynyl), 2 to 6 carbon atoms (i.e., C26 alkynyl), or 2 to 4 carbon atoms (i.e., C24 alkynyl). The term “alkynyl” also includes those groups having at least one carbon-carbon triple bond and a carbon-carbon double bond.

[0035] “Alkoxy” refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. “Substituted alkoxy” refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.

[0036] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0037] “Alkylthio” refers to the group “alkyl-S-”.

[0038] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N- amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0039] “Amino” refers to the group -NH2. “Substituted amino” refers to the group -NR48R49wherein R48and R49are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SC -alkyl, -SCh-substituted alkyl, -SCh-alkenyl, -SCh-substituted alkenyl, -SCh-cycloalkyl, -SCh-substituted cycloalkyl, -SCh-cycloalkenyl, -SCh-substituted cycloalkenyl, -SC -aryl, -SCh-substituted aryl, -SCh-heteroaryl, -SCh-substituted heteroaryl, -SCh-heterocyclic, and -SCh-substituted heterocyclic, and wherein R48and R49are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R48and R49are both not hydrogen.

[0040] “Aminocarbonyl” refers to the group -C(O)NR50R51, wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group. “Aminocarbonylamino” refers to the group -NR47C(O)NR50R51, wherein R47is hydrogen or alkyl; R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0041] “Aminocarbonyloxy” refers to the group -O-C(O)NR50R51, wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0042] “Aminosulfonyl” refers to the group -SC>2NR50R51, wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0043] “Aminosulfonyloxy” refers to the group -O-SC>2NR50R51wherein R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0044] “Aminosulfonylamino” refers to the group -NR47SC>2NR50R51, wherein R47is hydrogen or alkyl; R50and R51are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and, wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0045] ‘ ‘Amidino” refers to the group -C(=NR52)NR50R51, wherein R50, R51, and R52are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and wherein R50and R51PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0046] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). The condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl. “Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0047] “Arylene” refers to a divalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. “Substituted arylene” refers to an arylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for aryl groups.

[0048] “Aryloxy” refers to the group -O-aryl, wherein aryl is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy. “Substituted aryloxy” refers to the group -O-(substituted aryl).

[0049] “Carbonyl” refers to the divalent group -C(O)- (i.e., -C(=O)-).

[0050] “Aralkyl” refers to an aryl group pendant to an alkyl group. Examples of aralkyl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0051] “C arbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O- C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0052] “Carboxyl” or “carboxy” refers to -COOH, or salts thereof.

[0053] “Carboxyl ester” or “carboxy ester” refers to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO-C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -C(O)(O)-substituted heterocyclic. “(Carboxyl ester)amino” refers to the group -NR47C(O)(O)-alkyl,-NR47C(O)(O)-substituted alkyl, -NR47C(O)O-alkenyl, -NR47C(O)(O)-substituted alkenyl, -NR47C(O)(O)-aryl, -NR47C(O)(O)-substituted-aryl, -NR47C(O)(O)-cycloalkyl, -NR47C(O)(O)-substituted cycloalkyl, -NR47C(O)(O)-cycloalkenyl, -NR47C(O)(O)-substituted cycloalkenyl, -NR47C(O)(O)-heteroaryl, -NR47C(O)(O)-substituted heteroaryl, -NR47C(O)(O)-heterocyclic, and -NR47C(O)(O)-substituted heterocyclic. “(Carboxyl ester)oxy” refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, - O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic.

[0054] “Cyano” refers to the group -CN.

[0055] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11 , and C3-12. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. “Cycloalkenyl” refers to cycloalkyl groups which are partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4- isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.Cycloalkyl and cycloalkenyl groups can be substituted or unsubstituted. “Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substitutedPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0056] “Cycloalkyloxy” refers to -O-cycloalkyl. “Substituted cycloalkyloxy” refers to -O-(substituted cycloalkyl). “Cycloalkenyloxy” refers to -O-cycloalkenyl. “Substituted cycloalkenyloxy” refers to -O-(substituted cycloalkenyl).

[0057] ‘ ‘Guanidino” refers to the group -NHC(=NH)NH2.

[0058] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0059] “Imino” refers to a group -C(NR)R, wherein each R is independently alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0060] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0061] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include - OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0062] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. ThePCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8,3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, which may or may not contain a heteroatom, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, benzofuran, indolizine or benzothiene. The heteroaryl groups can be fused to non-aromatic ring systems, which may or may not contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group. For example, the nitrogen and / or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N— >0), sulfinyl, or sulfonyl moieties. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thiazolyl, and furanyl. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[0063] “Heteroarylene” refers to a divalent heteroaryl. “Substituted heteroarylene” refers to a heteroarylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for heteroaryl groups.

[0064] “Heteroaryloxy” refers to -O-heteroaryl. “Substituted heteroaryloxy” refers to the group -O-(substituted heteroaryl).

[0065] “Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, or partially saturated, ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-.Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8,4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with Ci-6 alkyl, oxo (=0), nitro (-NO2), or sulfonyl (-S(0)2-), among many others. “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0066] “Heterocyclyloxy” refers to the group -O-heterocyclyl. “Substituted heterocyclyloxy” refers to the group -O-(substituted heterocyclyl).

[0067] ‘ ‘Oxo” refers to the group (=0) or (O).

[0068] “Spirocycloalkyl” and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:

[0069] “Sulfonyl” refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. “Substituted sulfonyl” refers to the group -SC -alkyl, -SCh-substituted alkyl, -SC>2-alkenyl, -SCh-substitutcd alkenyl, -SCh-cycloalkyl, -SCh-substitutcd cycloalkyl, -SCh-cycloalkcnyl, -SCh-substituted cycloalkenyl, -SCh-aryl, -SCh-substitutcd aryl, -SCh-heteroaryl, -SCh-substituted heteroaryl, -SCh-heterocyclic, -SCh-substituted heterocyclic. Substituted sulfonyl includes groups such as mcthyl-SCh-. phcnyl-SO -. and 4-methylphenyl-SO2-. “Substituted sulfonyloxy” refers to the group -OSCh-alkyl, -OSCE-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substitutedPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSCE-substituted heterocyclic.

[0070] “Alkylsulfonyl” refers to the group -S(O)2R, where R is alkyl.

[0071] “Alkylsulfinyl” refers to the group -S(O)R, where R is alkyl.

[0072] As used herein, the term “saccharide” refers to a sugar, such as a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide. Monosaccharides include, but are not limited to, glucose, ribose and fructose. Disaccharides include, but are not limited to, sucrose and lactose. Oligosaccharides refers to 2 to 10 sugars linked together preferably through an alpha linkage. Examples of oligosaccharides include maltose, lactose, sucrose, and the like. Polysaccharides include, but are not limited to, cellulose, hemicellulose and lignocellulose or starch. Saccharides or sugars useful in the present invention include any and all naturally occurring sugars, such as, but not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N- acetylglucosamine, fructose, sialic acid, including aldol and pyranose forms thereof, as well as D and L isomers thereof.

[0073] “Thiocyanate” refers to the group -SCN.

[0074] ‘ ‘Thioxo” or “thione” refer to the group (=S) or (S).

[0075] A substituted ring can be substituted with one or more fused and / or spiro cycles. Such fused cycles include a fused cycloalkyl, a fused heterocyclyl, a fused aryl, a fused heteroaryl ring, each of which rings can be unsubstituted or substituted. Such spiro cycles include a fused cycloalkyl and a fused heterocyclyl, each of which rings can be unsubstituted or substituted.

[0076] The groups defined above can optionally be substituted by any suitable number and type of substituents. Representative substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, haloalkyl, haloalkoxy, -OR’, =0, -OC(O)R’, -(O)R’, -O2R’, -ONR’R”, -OC(O)NR’R”, =NR’, =N-OR’, -NR’R”, -NR”C(O)R’, -NR’-(O)NR”R”’, -NR”C(O)OR’, -NH-(NH2)=NH, -NR’C(NH2)=N H, -NH-(NH2)=NR’, -SR’, -S(O)R’, -S(O)2R’, -S(O)2NR’R”, -NR’S(O)2R”, -N3and -NO2. R’, R” and R’” each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted Ci-6 alkyl. Alternatively, R’ and R”, or R” and R’”, when attached to the same nitrogen, are combined with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring, as defined above.

[0077] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. In otherPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO words, each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0078] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0079] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. The term “optionally substituted” with reference to a group is intended to be construed as describing the unsubstituted group and the group substituted by the indicated or defined substituent(s).

[0080] A protecting group may be any known in the art, for example, as described in Peter G. M. Wuts and Theodora W. Greene, Greene's protective groups in organic synthesis (Wiley-Interscience, 2007).

[0081] Some compounds exist as tautomers. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise all tautomers.

[0082] Any formula or structure given herein is also intended to represent isotopically labeled forms of the compounds as well as unlabeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an isotope having the indicated atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure, or counter-ions thereto, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium), ”C,13C,14C,15N,18F,31P,32P,35S,36C1 and125I. Various isotopically labeled compounds are possible under the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single -photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0083] The disclosure also includes “deuterated analogs” of compounds, and counter-ions thereto, in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of a compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0084] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound.

[0085] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent enrichment of deuterium above a naturally occurring level at the indicated position.

[0086] Compounds described herein may be present as a salt, such as a pharmaceutically acceptable salt. Compounds are capable of forming salts such as acid and / or base salts. Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. Salts of compounds described herein can be prepared according to procedures described herein and as known in the art.

[0087] The term “pharmaceutically acceptable salt” of a given compound, refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically orPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, isobutyric acid, suberic acid, lactic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NHs( alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)s), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri( substituted alkyl) amines (i.e., N(substituted alkyl)s), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di( substituted alkenyl) amines (i.e., HN(substituted alkenyl^), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl^, mono-, di- or bi- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)s), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Methods of preparing a salt also include mixing a compound by redox reaction with an active metal, or by exchange of ions, for example, due to differing solubility of salts.

[0088] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. If not specified, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, aryl, -Ns, carbamoyl, carboxyl, carboxyl ester, -CN, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, -OH, imino,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO oxo, -NO2, alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorine atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0089] A “solvate” is a solid form of a compound in which solvent molecules are incorporated. A solvate is formed by the interaction of a solvent and a compound. A hydrate is a solvate in which the solvent is water. Solvates of salts of compounds described herein are also provided.

[0090] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0091] “Treatment” or “treating” provides a beneficial or desired result, e.g., an improvement in one or more clinical indicia of a disorder. Beneficial or desired results may include one or more of the following: decreasing or ameliorating one or more symptoms of the disorder, and / or diminishing the extent of the disorder; (e.g., stabilizing the disorder, preventing or delaying the worsening or progression of the disorder); providing partial or total remission of the disorder; enhancing effect of another medication; increasing the quality of life; and / or prolonging survival in a population of patients.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0092] “Prevention” or “preventing” means blocking development of a disorder, or symptoms thereof. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk of or has a family history of the disorder. Prevention may comprise delay in reaching predefined disease milestones or reduction in appearance or progression of a marker.

[0093] “Subject” refers to an animal, such as a mammal, e.g. a human that may benefit from administration of a compound described herein. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. When the subject is a human person, the subject may be referred to as a “patient.”

[0094] The term “therapeutically effective amount” or “effective amount” of a compound described herein means an amount sufficient to effect treatment when administered to a subject, to provide a benefit as described herein. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a mood disorder. The therapeutically effective amount may vary depending on the subject, the disorder being treated, the weight and age of the subject, the severity of the disorder, and the manner of administering, which can readily be determined by a medical practitioner.Treatment Methods and Uses

[0095] It is contemplated by administering to patient a compound as described herein, glutamatergic synapses may be rapidly restored both in early and late stages of the disease. It is further contemplated that the compounds described herein will have tolerability in the eye when applied locally. It is further contemplated that the therapy described herein may be used in conjunction with other therapies for the disorders described herein. Other therapies may include IOP and ROCK inhibitors, VEGF, complement inhibitors, stem cell therapies, and glucagon like peptides.

[0096] In some embodiments, is provided a method of treating an ophthalmic disorder. In some embodiments, the ophthalmic disorder is a retinal degeneration disorder. In one embodiment, the disorder is diabetic retinopathy, glaucoma, age-related macular degeneration (AMD), and other ophthalmic disorders related to aging. In one embodiment, the method comprises administering to a patient in need thereof a compound as described herein.

[0097] As used herein, "diabetic retinopathy (DR)" refers to changes in the retina due to the micro vascular changes seen in diabetes, which is an ocular disorder characterized by excessive angiogenesis that develops in diabetes due to thickening of capillary basement membranes, and lack of contact between pericytes and endothelial cells of the capillaries. Loss of pericytes increases leakage of the capillaries and leads to breakdown of the blood-retina barrier.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0098] Hyperglycemia-induced pericyte death and thickening of the basement membrane lead to incompetence of the vascular walls. These damages change the formation of the blood-retinal barrier and also make the retinal blood vessels become more permeable. Small blood vessels - such as those in the eye - are especially vulnerable to poor blood sugar (blood glucose) control. An overaccumulation of glucose and / or fructose damages the tiny blood vessels in the retina. Macular edema can also develop when the damaged blood vessels leak fluid and lipids onto the macula. These fluids make the macula swell, which blurs vision. This damage also results in a lack of oxygen at the retina.

[0099] The disease generally develops slowly over a period of months but over time, diabetic retinopathy can get worse and cause vision loss. Diabetic retinopathy usually affects both eyes. Diabetic retinopathy progresses from mild non-proliferative abnormalities, characterized by increased vascular permeability, to moderate and severe non-proliferative diabetic retinopathy (NPDR), characterized by vascular closure, to proliferative diabetic retinopathy (PDR), characterized by the growth of new blood vessels on the retina and posterior surface of the vitreous. Macular edema, characterized by retinal thickening from leaky blood vessels, can develop at all stages of retinopathy. Furthermore conditions such as pregnancy, puberty, blood glucose control, hypertension, and cataract surgery can accelerate these changes.

[0100] Signs and symptoms of diabetic retinopathy include, but are not limited to, one or more of the following: changes in the blood vessels; retinal swelling (macular edema); pale deposits on the retina; damaged nerve tissue; visual appearance of leaking blood vessels; loss of central or peripheral vision; temporary or permanent vision loss; spotty, blurry, hazy or double vision; eye pain; floaters; impaired color vision; vision loss; a dark or blind spot in the central vision; venous dilation and intraretinal micro vascular abnormalities; neuropathy; fluctuating and progressive deterioration of vision; macular edema; macular ischemia; traction retinal detachment; endothelial cell proliferation; photopsias; rubeosis or nvi; micro aneurysms; hard exudates; haemorrhages; and cotton wool spots.

[0101] Diabetic retinopathy include three main types: non-proliferative diabetic retinopathy, proliferative diabetic retinopathy and diabetic maculopathy.

[0102] Non-Proliferative Diabetic Retinopathy (NDPR) is considered as the early stage of retinopathy and is the most common seen in diabetics. The tiny blood vessels in the retina are only mildly affected, but may form bulges (micro aneurysms) and connections with each other (intraretinal micro vascular anomalies) and / or leak fluid (edema), protein deposits (exudates) and blood (hemorrhage). Another typical sign of nonproliferative diabetic retinopathy (NPDR) is the presence of puffy white patches on the retina (cotton wool spots). These changes can occur anywhere throughout the retina, including the macula.

[0103] There are three stages of non-proliferative diabetic retinopathy which are detailed below:PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0104] (1) Mild Non-proliferative Diabetic Retinopathy: At this earliest stage, at least one micro aneurysm may occur. Micro aneurysms are small areas of balloon- like swelling in the retina's blood vessels.

[0105] (2) Moderate Non-proliferative Diabetic Retinopathy: As the disease progresses, some blood vessels that nourish the retina are blocked.

[0106] (3) Severe Non-proliferative Diabetic Retinopathy: Many more blood vessels are blocked, depriving several areas of the retina of blood supply. These areas of the retina send signals to the body to grow new blood vessels for nourishment.

[0107] Non-proliferative diabetic retinopathy should not cause any problems to the patient, as the vision remains normal as long as the macula is not affected. However, as the symptoms of diabetic retinopathy are generally not visible in this stage, it is recommended that regular retinal screening eye tests should be done to monitor the signs of progression to more serious stages of retinopathy.

[0108] Proliferative Diabetic Retinopathy (PDR) emerges as an advanced phase following severe non-proliferative diabetic retinopathy, marked by the emergence of new, abnormal blood vessels within the eye. This condition arises when diabetes leads to the occlusion of blood vessels, resulting in ischemia — areas of the eye and retina are deprived of oxygen and essential nutrients. In an attempt to counteract this oxygen deficiency, the eye initiates the growth of a new blood supply to the affected regions. However, this compensatory mechanism gives rise to fragile, easily bleeding blood vessels through a process known as neovascularization. These aberrant vessels proliferate in inappropriate locations on the retina's surface and extend into the vitreous gel, the clear gel that fills the eye. A vitreous hemorrhage may ensue if these new vessels rupture, releasing blood into the vitreous cavity and obstructing the passage of light to the retina. The extent of vision impairment can range from mild to severe, contingent upon the volume of blood present within the eye. Over time, vision may progressively recover as the body gradually absorbs the hemorrhage, though this process can span several months.

[0109] Abnormal new vessels also cause the formation of scar tissue which pulls on the retina and may result in tractional retinal detachment. The retinal detachment can affect any part of the retina. If it affects the macula, the patient might lose his / her central vision and it can be treated only with surgery.

[0110] Diabetic maculopathy stands as the leading cause of vision impairment among individuals with diabetes, resulting from changes in the macula due to diabetic retinopathy. The macula, situated at the retina's core, is crucial for sharp central vision and discerning fine details. Consequently, those diagnosed with diabetic maculopathy experience compromised central vision and a diminished capacity to perceive details. This impairment might manifest as difficulty in recognizing faces from a distance or reading small text. The severity of vision loss can vary from mild to significant.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WONonetheless, even in severe cases, peripheral vision, which is essential for navigating environments both indoors and outdoors, typically remains intact.

[0100] Vision loss from diabetic maculopathy occurs in 2 ways: Diabetic macular edema (DME) and Macular ischemia.

[0101] Diabetic macular edema (DME) is the swelling and thickening of the macula. This is due to fluid leakage from the retinal blood vessels in the macula. The vision becomes blurry because the structure and function of the macular photoreceptor cells becomes disrupted. Vision loss from macular edema can be controlled with laser and injections into the eyeball.

[0102] Macular ischemia occurs when the tiny retinal blood vessels (capillaries) to the macula close up. The vision becomes blurry because the macula does not receive enough blood supply for it to work properly. Unfortunately, there are no effective treatments for macular ischemia. Macular edema is due to leakage of fluid from the retinal blood vessels. Hard exudates are the yellowish deposits seen on the retina. They are caused by leakage of protein material.

[0103] Possible causes of diabetic retinopathy include diabetes, high cholesterol, pregnancy, kidney impairment, chromosome 15q deletion, or even intraocular surgery, etc.

[0104] Among them, diabetes could be a major cause. Prolonged hyperglycemia (high blood glucose levels) affects the anatomy and function of retinal capillaries. The excess glucose is converted into sorbitol when it is diverted to alternative metabolic pathways. Sorbitol leads to death or dysfunction of the pericytes of the retinal capillaries. This weakens the capillary walls allowing for the formation of micro aneurysms, which are the earliest signs of diabetic retinopathy. The weak capillary walls can also be responsible for increased permeability and the exudates. Due to the predisposition to increased platelet aggregation and adhesion (blood clot formation) as a result of diabetes, the capillary circulation becomes sluggish or even totally impaired by an occlusion. This can also contribute to the development of diabetic retinopathy.

[0105] The retina contains photoreceptors that transduce light into a neural signal, and also has an extensive vascular supply. The clinical hallmark of retinopathy of prematurity (ROP) is abnormal retinal vasculature, which appears at the pre-term ages. This abnormal vasculature is insufficient to supply oxygen during the maturation of the rod photoreceptors, cells that are the most demanding of oxygen of any cells in the body. In the most severe ROP cases, vision loss results from retinal detachment instigated by leaky retinal blood vessels. However, milder cases of ROP, the retinal vascular abnormalities usually resolve without treatment, but the patients nevertheless suffer a range of lifelong visual impairments even with optimal optical correction.

[0106] Retinopathy of Prematurity (ROP) is a potentially blinding eye disorder that primarily affects premature infants or those born before 31 weeks of gestation, as well as infants with a very low birthPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO weight. This condition occurs when abnormal blood vessels grow and spread throughout the retina, the light-sensitive lining of the back of the eye. These abnormal vessels are fragile and can leak, leading to retinal scarring and detachment, which is the main cause of vision loss in ROP.

[0107] ROP is classified into different stages, ranging from mild (which might resolve without treatment) to severe (which may require surgical intervention to prevent vision loss or blindness). The development of ROP is closely linked to the oxygen levels in the blood, with both high and low levels of oxygen contributing to the risk of developing this condition. As such, careful monitoring of oxygen therapy in premature infants is essential for ROP prevention.

[0108] The incidence and severity of ROP are inversely related to the gestational age and birth weight of the infant; the more premature and lighter the infant is at birth, the higher the risk of developing ROP. Advances in neonatal care have significantly improved the outcomes for infants affected by ROP, particularly with the early detection and appropriate treatment of the condition.

[0109] In certain embodiments, Compound I of the present disclosure can be used to treat or prevent disorder associated with neovascularization in the eye, such as retinopathy of prematurity (ROP), age- related macular degeneration, choroidal neovascularization, or retinal neovascularization.

[0110] Age-related Macular Degeneration (AMD) typically occurs in older adults and refers to a disease that causes abnormality in the macula of the retina; it is the leading cause of vision loss in Europe and the United States. In Japan, the disease is also steadily increasing because of the aging population. The macula is located in the center of the retina, and the region is densely populated with cone cells among the photoreceptor cells. Rays of light coming from outside are refracted by the cornea and crystalline lens, and then converge on the macula, the central fovea in particular. The ability to read letters depends on the function of this area. In age-related macular degeneration, the macula, which is an important area as described above, degenerates with age and results in visual impairment, mainly in the form of image distortion (anorthopia) and central scotoma.

[0111] The "dry" form of advanced AMD, results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. Neovascular or exudative AMD, the "wet" form of advanced AMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris, through Bruch's membrane, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated. The wet form of age-related macular degeneration is a disease with a poor prognosis, which results in rapid and severe visual impairment. The major pathological condition is choroidal neovascularization.

[0112] Choroidal Neovascularization (CNV) refers to the creation of new blood vessels in the choroid layer of the eye. CNV can occur rapidly in individuals with defects in Bruch's membrane, thePCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO innermost layer of the choroid. It is also associated with excessive amounts of vascular endothelial growth factor (VEGF). As well as in wet AMD, CNV can also occur frequently with the rare genetic disease pseudoxanthoma elasticum and rarely with the more common optic disc drusen. CNV has also been associated with extreme myopia or malignant myopic degeneration, where in choroidal neovascularization occurs primarily in the presence of cracks within the retinal (specifically) macular tissue known as lacquer cracks.

[0113] Choroidal neovascularization (CNV) commonly occurs in macular degeneration in addition to other ocular disorders and is associated with proliferation of choroidal endothelial cells, overproduction of extracellular matrix, and formation of a fibrovascular subretinal membrane. Retinal pigment epithelium cell proliferation and production of angiogenic factors appears to effect choroidal neovascularization. CNV has proven recalcitrant to treatment in most cases. Laser treatment can ablate CNV and help to preserve vision in selected cases not involving the center of the retina, but this is limited to only about 10%> of the cases. Unfortunately, even with successful laser photocoagulation, the neovascularization recurs in about 50-70%> of eyes (50% over 3 years and >60% at 5 years). (Macular Photocoagulation Study Group, Arch. Ophthalmol. 204:694-701 (1986)). In addition, many patients who develop CNV are not good candidates for laser therapy because the CNV is too large for laser treatment, or the location cannot be determined so that the physician cannot accurately aim the laser.

[0114] Retinal neovascularization (RNV) refers to the proliferation of new blood vessels in the retina, which is usually an abnormal response to ischemic (lack of oxygen) conditions in the eye. This process can occur in a variety of retinal diseases where blood flow to the retina is compromised, leading to oxygen deprivation. The body responds by producing growth factors, such as vascular endothelial growth factor (VEGF), which stimulate the growth of new, often fragile and leaky, blood vessels in an attempt to increase oxygen supply to the affected areas.

[0115] However, these new vessels can lead to complications, including vitreous hemorrhage (bleeding into the clear gel that fills the space between the lens and the retina), retinal detachment, and ultimately, severe vision loss or blindness. Retinal neovascularization is a key feature of proliferative diabetic retinopathy, a severe form of diabetic eye disease, and can also occur in conditions such as retinal vein occlusion, sickle cell retinopathy, and retinopathy of prematurity.

[0116] RNV develops in numerous retinopathies associated with retinal ischemia, such as sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteriolitis, radiation retinopathy, retinal vein occlusion, retinal artery occlusion, retinal embolism. Retinal neovascularization can also occur with inflammatory diseases (birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO toxoplasmosis, and uveitis), choroidal melanoma, chronic retinal detachment, incontinentia pigmenti, and rarely in retinitis pigmentosa.

[0117] A factor common to almost all RNV is retinal ischemia, which releases diffusible angiogenic factors (such as VEGF). The neovascularization begins within the retina and then breaches the retinal internal limiting membrane. The new vessels grow on the inner retina and the posterior surface of the vitreous after it has detached (vitreous detachment). Neovascularization may erupt from the surface of the optic disk or the retina. RNV commonly progresses to vitreoretinal neovascularization. Iris neovascularization often follow retinal neovascularization.

[0118] In certain embodiments, one or more symptoms of the patient can be treated or prevented, including, but are not limited to defects in Bruch's membrane, increases in amount of ocular vascular endothelial growth factor (VEGF), myopia, myopic degeneration, deterioration of central vision, metamorphopsia, color disturbances, hemorrhaging of blood vessels, or a combination thereof.

[0119] In the ophthalmic disease, the density of retinal ganglion cell (RGC) axon and density of synapse can be used to measure the structure or function of the neuron cells in the retina.Administration of the compounds described herein increases the density of RGC in a patient suffering from a ophthalmic disease of from about 5%-80%, from about 10%-80%, from about 10%-70%, from about 10%-60%, from about 10%-50%, from about 10%-40%, from about 10%-30%, or from about 10%-20%, or at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.

[0120] In certain embodiments, administration of the compounds described herein increases the density of RGC axon in a patient suffering from a ophthalmic disease of from about 5%-80%, from about 10%-80%, from about 10%-70%, from about 10%-60%, from about 10%-50%, from about 10%-40%, from about 10%-30%, or from about 10%-20%, or at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.

[0121] In certain embodiments, administration of the compounds described herein increases the density of synapse in a patient suffering from a ophthalmic disease from about 5%-80%, from about 10%-80%, from about 10%-70%, from about 10%-60%, from about 10%-50%, from about 10%-40%, from about 10%-30%, or from about 10%-20%, or at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.

[0122] Glaucoma is associated with increased expression of PSD95, a key postsynaptic scaffolding protein, as glutamatergic synapse loss develops. In further embodiments, administration of the compounds described herein decreases the density of PSD95 in a patient suffering from a glaucoma atPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.

[0123] Bassoon is a presynaptic scaffolding protein, which is also associated with glaucoma. In further embodiments, administration of the compounds described herein decreases the density of bassoon in a patient suffering from a glaucoma at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.

[0124] Electroretinogram (ERG) is a diagnostic test that measures the electrical activity of the retina in response to a light stimulus. The ERG arises from currents generated directly by retinal neurons in combination with contributions from retinal glia. Importantly, the ERG is an objective measure of retinal function that can be recorded non-invasively under physiological conditions. The pattern ERG (pERG) uses contrast reversing pattern stimuli (sinewave gratings or checkerboards) to assess macular retinal ganglion cell (RGC) activity. Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) tests are commonly used in ophthalmology to estimate bioelectrical function of the retina and optic nerve.

[0125] In certain embodiments, the pERG amplitude is increased by at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to the level prior to administration of the compounds or compositions provided herein.Compounds

[0126] It is contemplated that the compounds described herein are capable of regenerating retinal synapses. The compound may be a compound described in International Patent Publication No. WO 2019 / 028164, which is hereby incorporated by reference herein. In some embodiments, the compound is of formula I or formula la:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1 or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxylPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro;A is an arylene or heteroarylene, having 1 to 4 heteroatoms;W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is as defined above, provided that when A is arylene, and Y is -S- or -NR2-, then X is not -S-;Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-, wherein R2is as defined above; andZ is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R3)O)q-T, wherein subscript q is an integer from 1 to 100, R3is selected from the group consisting of hydrogen and methyl, and T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.

[0127] In some embodiments, A is phenylene or pyridylene. In some embodiments, X is S. In some embodiments, Y is -O-. In some embodiments, X is S, Y is -O-, and A is phenylene.

[0128] In some embodiments, provided is a compound according to Formula lb, Formula Ic, Formula Id, Formula le, and / or Formula Ig:PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:R1, R2, A, Y, Z, n and p are as defined above with respect to formula I and formula la; and subscript m is 0, 1 or 2.

[0129] In some embodiments, provided is a compound selected from:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0130] In some embodiments, the compound is a compound of formula Ik:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are each independently 0, 1 or 2; subscript q is an integer from 2 to 8; and each R41and each R42are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

[0131] In some embodiments, each of subscripts n and p is 0.

[0132] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, as described herein, selected from:PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WOPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WOPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0133] In some embodiments, provided is a compound according to Formula Ij:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscript q is an integer from 4 or 6;R3, R4, R5, and R6are independently selected from the group consisting of hydrogen halo, -CH3, and -OCH3; andR7, R8, R9, and R10are independently selected from the group consisting of hydrogen, halo, -CH3, -CF3, -OCH3, -OCF3, phenyl, and -NO2; wherein at least six of R3-R10 are hydrogen.

[0134] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, selected from:

[0135] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0136] In some embodiments, the compound is a compound described in International PublicationNo. WO 2017 / 120198. In some embodiments, the compound is a compound of formula II:PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WOor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:Y is -NR33-, or -S-;R31is independently halogen, -CX313, -CHX312, -CH2X31, -OCX313, -OCHX312, -OCH2X31, - CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,- C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;; each R32is independently halogen, -CX323, -CHX322, -CH2X32, -OCX323, -OCHX322, -OCH2X32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R33is H, alkyl, or substituted alkyl; each of X31and X32is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

[0137] In some embodiments, Y is S. In some embodiments, each of zl and z2 is 0.

[0138] In some embodiments, the compound is a compound of formula Ila:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: each R1is independently halogen, -CXS, -CHXS, -CH2X1, -OCX ,-OCHX>2, -OCH2X1, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H,-SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO-NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; each R2is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCHX22,-OCH2X2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;; each of X1and X2is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and n is an integer from 1 to 12.

[0139] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0140] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0141] In some embodiments, Y is NH or NMe. In some embodiments, zl is 1 , z2 is 0, and R31is alkyl.

[0142] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0143] In some embodiments, the compound isor a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0144] In some embodiments, the compound is a compound described in US Patent No. 8,741,883.In some embodiments, the compound is a compound of formula III:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: each of R,-R8are independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of Rs-R8and one of R1-R4 is H; andP is selected from the group consisting ofwherein: m is an integer from 1 and 20; n is 0, 1, or 2; q is an integer from 1 and 20; each of R9-R16 is independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of R9-R12 and one of R13-R16 is H; andX is hydrogen, methyl, or ethyl.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0145] In some embodiments, the compound of formula Illa:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: each of Ri-Rs is independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of Rs-Rs and one of R1-R4 is H; andwherein m is an integer from 1 and 20; q is an integer from 1 and 20; each of R9-R16 are independently selected from the group consisting of hydrogen, deuterium, tritium, fluoro, chloro, bromo, iodo, hydroxyl, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, and trifluoromethyl, wherein at least one of R9-R12 and one of R13-R16 is H; andX is hydrogen, methyl, or ethyl.

[0146] In some embodiments, the compound is selected from:PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0147] In some embodiments, the compound is a compound described in US Patent Publication No. 2015 / 0299191. In some embodiments, the compound is a compound described in US Patent Publication No. 2014 / 0080843.

[0148] In some embodiments, the compound is a compound described in International Patent Publication No. WO 2013 / 013240. In some embodiments, the compound is a compound described in US Patent Publication No. 2014 / 0024705.

[0149] In some embodiments, the compound is G2 (or G2-044), having the name N-(l-(4-(trifluoromethyl)benzyl)-lH-indazol-3-yl)furan-2-carboxamide:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0150] In some embodiments, the compound is imipramine or semapimod or a or a pharmaceutically acceptable salt of each thereof.Kits

[0151] Provided herein are also kits that include compounds described herein, or a pharmaceutically acceptable salt thereof, optionally a second active ingredient, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound, or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the pharmaceutical composition in the treatment of the indications, including the diseases or conditions, described herein.

[0152] Provided herein are also articles of manufacture that include a compound described herein, or a pharmaceutically acceptable salt thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, nebulizer, aerosol dispensing device, dropper, or intravenous bag.Pharmaceutical Compositions and Modes of Administration

[0153] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain a compound described herein, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0154] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain some embodiments, the pharmaceutical composition may be administered by intra-vitreal injection, intravenously, intraperitoneally (“i.p.”), parenterally, intramuscularly, subcutaneously, or topically. In one embodiment, the composition is administered topically wherein optionally the formulation is a suspension or alternatively, a scleral patch (e.g. microneedles). In one embodiment, the administration is via intravitreal injection.

[0155] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0156] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0157] The pharmaceutical composition and any container in which it is distributed may be sterilized. The pharmaceutical composition may also contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for varying the osmotic pressure, viscosity alerting agents, or buffers.

[0158] The compositions that include at least one compound described herein, such as a compound described herein, or a pharmaceutically acceptable salt thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein inPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0159] Solid compounds, or a salt or crystal thereof, may be present in a formulation in a selected average particle size. The particles may have an average particle size (in longest dimension) of 10 nm, 100 nm, 300 nm, 500 nm, 1 pm, 10 pm, 50 pm, 100 pm, 300 pm, or 500 pm, or a range between any two values.

[0160] The pharmaceutical composition may comprise a liquid suspension or solution comprising about 0.05%, about 0.1%, about 0.3%, about 0.5%, about 0.7%, about 1%, about 2%, about 3%, about 4%, or about 5% w / w of active ingredients. The liquid may comprise water and / or an alcohol. The liquid may include a pH adjusting agent such that the pH is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, or a range of values therebetween.

[0161] The pharmaceutical composition may comprise a pharmaceutically acceptable preservative. Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate. In certain some embodiments, the pharmaceutical composition comprises from about 0.01% to about 1.0% w / w of benzalkonium chloride, or from about 0.01% and about 1% v / w phenylethyl alcohol. Preserving agents may also be present in an amount from about 0.01% to about 1%, preferably about 0.002% to about 0.02% by total weight or volume of the composition.

[0162] The pharmaceutical composition may also comprise from about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 1 % w / w of one or more of an emulsifying agent, a wetting agent or a suspending agent. Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane- 1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methyl cellulose; hydroxypropylcellulose ; hydroxypropylmethylcellulose ; ethylmethylcellulose ; carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; mono-and di-glycerides of fatty acids; acetic acid esters of mono- and di-glycerides of fatty acids; lactic acid esters of mono-PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO and di-glycerides of fatty acids; citric acid esters of mono-and di-glycerides of fatty acids; tartaric acid esters of mono-and di-glycerides of fatty acids; mono-and diacetyltartaric acid esters of mono-and diglycerides of fatty acids; mixed acetic and tartaric acid esters of mono-and di-glycerides of fatty acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids; polyglycerol esters of polycondensed fatty acids of castor oil; propane- 1,2-diol esters of fatty acids; sodium stearoyl- 21actylate; calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; extract of quillaia; polyglycerol esters of dimerized fatty acids of soya bean oil; oxidatively polymerized soya bean oil; and pectin extract.Dosing

[0163] The specific dose level of an active ingredient of the present application, for example a compound described herein, of a salt thereof, for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.01 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0164] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound described herein, or a salt thereof, may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day.

[0165] When administered nasally, the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day. In various embodiments, the daily dosage is about 10 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or a range of values therebetween.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0166] The active ingredients of the present application or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. The treatment cycles, may be continuous. Administration or treatment may be continued indefinitely.

[0167] In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.Example 1: In Vivo Effects of Compound I in Treating Glaucoma

[0168] Microbeads can cause increase in the intraocular pressure (IOP), and are used for generating animal models of glaucoma. Prior to the experiment, microbeads were injected into one eye of the mice, and the contralateral eye serves as internal control. Compound 1 or DMSO (vehicle) was dosed daily (i.p.) at 30mg / kg for 8 weeks. Thus, there are 4 treatment groups: Vehicle-control (CNT), Vehicle-Microbeads (MB), Compound 1-CNT, and Compound 1- MB.

[0169] The intraocular pressure (IOP) was monitored weekly during the experiment. The mice were sacrificed on Week 8, and the tissues for retinal and optic nerve were collected for analysis with axon density via electronic microscope and immunostaining for synaptic and retinal ganglion cell (RGC) marker density. Electroretinogram (ERG) was also conducted to measure the electrical activity of the retina (in response to a light stimulus).

[0170] Decreased PSD95 and Bassoon

[0171] Glaucoma has been associated with increased expression of PSD95, a key postsynaptic scaffolding protein and Bassoon, a large presynaptic scaffolding protein, as glutamatergic synapse loss develops. The immunostaining results in FIG. 1A and FIG.2A and corresponding intensity chart FIG. IB and FIG.2B showed that microbead treatment elevated PSD95 (upper right panel of FIG. 1A and 2ndbar of FIG. IB) expression in the inner plexiform layer (IPL) of the retina, and elevated Bassoon (upper right panel of FIG. 2A and 2ndbar of FIG. 2B) expression in the inner plexiform layer (IPL) and ganglion cell layer (GCL) of the retina, this could be a potential homeostatic response to synaptic compromise.

[0172] By contrast, the Compound 1 treatment prevented the increase of PSD95 (lower left panel of FIG. 1A) and Bassoon (lower left panel of FIG. 2A) caused by the microbeads and showed a significantly reduced intensity of IPL PSD95 and Bassoon as compared with the vehicle + MB groupPCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO(3rdbar vs. 2ndbar in FIG. IB and FIG. 2B, respectively). This indicates that the synaptic regenerative effect may obviate need for homeostatic increases in postsynaptic proteins.

[0173] Enhanced survival of RGCs

[0174] Compound 1 also exerted a significant protective effect on RGCs. As shown in FIG. 3A and 3B, the microbeads (DMSO-MB) induced RGC loss in middle and peripheral retina and Compound 1 (Compound I) treatment reduced this effect.

[0175] Increased RGCs axon density

[0176] Loss of RGC axons is a hallmark pathological feature of glaucoma that contributes to blindness. As observed in FIG. 4A, the microbeads treatment has damaged axons in the optic nerve, as reflected by the reduced axon density in optic nerve cross sections and the abnormal morphology of remaining axons (upper right panel of FIG. 4A), while Compound I treatment group preserved axon density and exhibited potential normalization of morphology (lower left and lower right panel of FIG. 4A). The axon density of FIG. 4B reflected the same result. This indicated that the synaptogenic drug Compound 1 has efficacy in preventing IGP-associated axon loss.

[0177] Attenuated reduction in RGC pERG amplitude

[0178] Compound 1 also improved RGC function as measured by a translationally relevant ERG readout. As can be seen from FIG. 5A-5C, the microbead treatment greatly reduced pattern ERG (pERG) amplitude (FIG. 5A), while having little or no effect on pattern visual evoked potential (pVEP) amplitude (FIG. 5B) or latency (FIG. 5C). The Compound 1 treatment attenuated IOP- associated reductions in pERG amplitude of RGC (FIG. 5A).Example 2: Protective effect on Retinal Degeneration

[0179] Studies will be conducting using a bead-based model of rodent diabetic retinopathy (Db / Db mice) with systemic delivery of Compound 1. A total of 50 animals will be included: a. 15 Db / Db mice with administration of study drug vehicle b. 15 Db / Db mice with administration of Compound 1 c. 10 Db / + control mice with administration of study drug vehicle d. 10 Db / + control mice with administration of Compound 1

[0180] Compound 1 will be administered by an intraperitoneal route at a dose of 30 mg / kg. Data will be provided from mice at ~24 weeks of age after starting treatment at ~16 weeks (total: 8-week treatment time). It is contemplated that the following measurements will be taken:PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO a. Histological sections or flat mounts for immunolabeling of synaptic markers in the inner retina, retinal ganglion cell counting, TUNEL stain, optic nerve nerve fiber layer makers, and glial astrocyte reaction (at the final timepoint). b. Functional electrophysiology of PERG and VEP (at the final timepoint).Example 3: In Vivo Effects of Compound I on Diabetes Mellitus Related Retinal Complications

[0181] An in vivo study was conducted using Db / Db mice to evaluate the protective effect of Compound 1 on diabetes mellitus related retinal complications.

[0182] Mice received intraperitoneal (IP) daily injections of Compound 1 for eight weeks, beginning at 16 weeks of age and concluding at 24 weeks. Compound 1 was administered at a concentration of 30 milligrams per kilogram body weight, dissolved in PBS containing 2% DMSO (vehicle). Control mice received daily IP injections of the vehicle solution (PBS with 2% DMSO) alone.• Cohort 1: Db / Db mice (diabetic model, 10 mice, started with 15 mice) were administered with Compound 1.• Cohort 2: Db / Db mice (12 mice, started with 15 mice) were administered with vehicle.• Cohort 3: Db / + mice (control, 8 mice, started with 8 mice) were administered with Compound 1.• Cohort 4: Db / + mice (2 mice, started with 8mice) were administered with vehicle.

[0183] All animals were housed and handled under lACUC-approved protocols. Metabolic data were collected, after which the animals were sacrificed and their eyes harvested for subsequent analyses.Metabolic Assessments

[0184] Body Weight Monitoring (FIGS. 6A-6B). Weekly body weights were recorded throughout the treatment period. No significant differences were observed between Compound 1 treated Db / Db and Db / + mice (control). Body weight remained stable, and Compound 1 treatment did not adversely affect weight gain or loss patterns.

[0185] Basa Blood Glucose Levels (FIGS. 7A-7B). Fasting blood glucose was measured at baseline and during the treatment period. Db / Db mice exhibited elevated blood glucose levels compared to Db / + mice. Compound 1 treatment did not significantly altered basal glucose levels in either group.

[0186] Glucose Tolerance Test (GTT) (FIGS. 8A-8B). A single GTT was performed during the treatment. In consultation with the attending veterinarian, repeated testing was avoided due to the poor health and high baseline glucose levels of the Db / Db mice. GTT curves indicated no improvement in the glucose clearance with Compound 1 treatment. Area under the curve (AUC) analysis confirmed no significant differences.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO

[0187] Insulin Tolerance Test (ITT) (FIGS. 9A-9B). Similarly, a single ITT was performed. Compound 1 treatment did not improve insulin sensitivity. Db / Db mice exhibited insulin resistance, and treatment did not ameliorate this phenotype.

[0188] Survival Outcomes (FIGS. 10A-10C). A reduction in survival was observed among Compound 1 treated Db / Db mice (re-constituted Compound 1 was administered via IP injections). This finding contrasts with prior studies and human clinical trials, suggesting that the decreased survival may be specific to this particular mouse model.Analyses of the Eye

[0189] FIGS. 11A-11B demonstrate that loss of inner retinal ganglion cells (RGCs) was observed in Db / Db mice, and treatment with Compound 1 mitigated this loss.

[0190] FIG. 12 demonstrates that loss of pattern electroretinography (pERG) responses and delayed visual evoked potentials (VEP) were observed in Db / Db mice. Treatment with Compound 1 mitigated these effects.

[0191] FIG. 13 demonstrates that loss of synaptic markers in retina was observed in Db / Db mice, and treatment with Compound 1 promotes these markers.

[0192] FIGS. 14A-14B demonstrates that loss of PSD95 (FIG. 14A) and synaptophysin (FIG. 14B) in the inner plexiform layer (IPL) was observed in Db / Db mice, and treatment with Compound 1 reduced these effects.

[0193] Without being bound by theory, it is believed that glial cell activation (or GFAP expression) represent a stress response under disease conditions. FIGS. 15A-15B demonstrates that glial cell activation (or GFAP expression) was observed in Db / Db mice, and treatment with Compound 1 reversed this effect.

[0194] Without being bound by theory, it is believed that Bcl-XL inhibits cell death, while Bax and pBad promote cell death. FIG. 16A demonstrates that increased Bax and pBad were observed in Db / Db mice, and treatment with Compound 1 suppressed these effects. Additionally or alternatively, FIG. 16A shows that decreased Bcl-XL was observed in Db / Db mice, and treatment with Compound 1 reversed this effect. FIG. 16B further supports the effect on Bax through immunofluorescence imaging.* * *

[0195] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0196] The disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example,PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible.

[0197] Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

Claims

PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WOWHAT IS CLAIMED IS:

1. A method of treating an ophthalmic disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound that is capable of regenerating retinal synapses in the patient.

2. The method of claim 1 , wherein the compound of formula I or la:I la or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1, or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro;A is an arylene or heteroarylene, having 1 to 4 heteroatoms;W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, provided that when A is arylene, and Y is -S- or -NR2-, then X is not -S-;Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-; andZ is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R3)O)q-T, wherein subscript q is an integer selected from 1 to 100, R3is selected from the group consisting of hydrogen and methyl, and T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide, and -L-oligosaccharide, wherein L is selected from the group consisting of a bond, phosphate, and sulfate.

3. The method of claim 2, wherein A is phenylene or pyridylene in the compound of formula I or la.

4. The method of claim 2, wherein X is S in the compound of formula I.

5. The method of claim 2, wherein Y is -O- in the compound of formula I or la.PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO6. The method of claim 2, wherein X is S, Y is -O-, and A is phenylene in the compound of formula I.

7. The method of claim 2, wherein the compound of formula I is a compound of formula Ik:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are each independently 0, 1, or 2; subscript q is an integer from 2 to 8; and each R41and each R42are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

8. The method of claim 7, wherein each of subscripts n and p is 0.

9. The method of claim 2, wherein the compound is:Compound 1 or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

10. The method of claim 1, wherein the compound is of formula II:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein:Y is -NR33- or -S-; each R31is independently halogen, -CX31, -CHX31, -CH2X31, -OCX313, -OCHX312, -OCH2X31, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,- C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;PCT / US25 / 43607 26 August 2025 (26.08.2025)Attorney Docket No. 62WD-350735-WO each R32is independently halogen, -CX323, -CHX322, -CH2X32, -OCX323, -OCHX322, -OCH2X32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R33is H, alkyl, or substituted alkyl; each of X31and X32is independently halogen; each of zl and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

11. The method of claim 10, wherein Y is S.

12. The method of claim 10, wherein each of zl and z2 is 0.

13. The method of claim 10, wherein the compound of formula II is:or a pharmaceutically acceptable salt or solvate thereof.

14. The method of claim 10, wherein Y is NH.

15. The method of claim 10, wherein zl is 1 , z2 is 0, and R31is alkyl.

16. The method of claim 10, wherein the compound is:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

17. The method of any preceding claim wherein the disorder is a retinal degenerative disorder.

18. The method of claim 1, wherein the compound is G2-044, imipramine, or semapimod.

19. The method of any preceding claim wherein the disorder is selected from diabetic retinopathy, glaucoma, age-related macular degeneration (AMD), and aging.

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