Pharmacological Agents for Preventing and Treating Cataract and Presbyopic Eye Diseases

Abstract

A method for treating presbyopia or cataracts in a subject in need thereof is provided. The method involves administering to the subject an effective amount of a composition comprising a compound that inhibits the formation or dissolves high molecular weight aggregates of human α-A-crystallin. The composition containing certain compounds is also believed to be effective in treating transthyretin (TTR)-related amyloidosis, prion disease, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and eyelid synechiae-ectodermal dysplasia-cleft lip / palate syndrome.

Description

[Technical field]

[0001]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 215,818, filed June 28, 2021, the entire contents of which are expressly incorporated herein by reference.

[0002] Disclosed herein are 4-phosphono-butyric acid 2-hydroxy-5-(4-methyl-benzoyl)-3-nitro-phenyl ester sodium salt, as well as other compounds useful for treating presbyopia or cataract eye disease. [Background technology]

[0003] According to the World Health Organization (WHO), cataracts are the leading cause of blindness (51%) worldwide, especially in low- and middle-income countries. Data dating back to the beginning of this millennium showed that cataracts are responsible for 30-60% of blindness in Africa and 60-80% in Southeast Asia. In the United States, the current number of people with cataracts is estimated to be over 25.7 million. Projections from Prevent Blindness research estimate that the number will increase to 38.5 million by 2032 and 45.6 million by 2050. A cataract is a clouding of the lens of the eye that blocks or alters the passage of light to the eye. Cataracts usually form in both eyes, but not at the same rate. They may progress slowly or rapidly, or may progress to a point and then nothing worse happens. Besides aging, other factors can cause cataracts to form. Eye infections, certain medicines (such as steroids), smoking, injury, trauma, or exposure to intense heat or radiation can cause cataracts. Excessive exposure to invisible sunlight (called UV or ultraviolet light), and various diseases such as diabetes or metabolic disorders can also contribute to the formation of cataracts.

[0004] The only treatment currently available is surgical removal of the lens and replacement with an intraocular lens, which carries a high public health burden. Although cataract surgery is generally considered safe, there are significant complications: (i) 30-50% of patients who undergo cataract surgery in the United States develop opacification of the posterior lens capsule within two years, requiring laser treatment; (ii) 0.8% have retinal detachment; (iii) 0.6-1.3% are hospitalized with corneal edema or require a corneal transplant; and (iv) about 1% present with endophthalmitis. In addition, in many remote and poor areas of the developing and underdeveloped regions of the world, people are still going blind from cataracts, mainly due to lack of access to eye care.

[0005]

[0005] Presbyopia is the loss of the eye's ability to accommodate, resulting in the inability to focus on nearby objects. Presbyopia affects everyone over the age of 45 and has a significant negative impact on quality of life. Current treatments for presbyopia include (i) non-invasive techniques that utilize devices to help improve near and far vision, but do nothing to restore the natural process of accommodation and require constant use of the device, and (ii) invasive surgical procedures that are associated with major complications including reduced quality of vision, regression effects, anisometropia, corneal ectasia, and clouding. Most importantly, none of these methods can reverse presbyopia. Furthermore, there are no treatment options that prevent or delay the onset of presbyopia.

[0006]

[0006] Sclerosis of the ocular lens, as well as changes in the elasticity of the lens capsule, the dimensions of the ocular lens, the dimensions of the zonular attachment, and the contraction of the ciliary muscle (CM) have all been proposed as contributing factors to presbyopia. However, human and non-human primate studies suggest that CM function is normal long past the onset of presbyopia. In contrast, the human lens increases in stiffness with age in a manner that directly correlates with the loss of accommodative power. The loss of accommodative power can be restored by implanting an intraocular lens made of a flexible polymer, suggesting that restoration of lens flexibility is sufficient to restore accommodation. Thus, a pharmacological agent that can prevent or reverse lens sclerosis would be a promising avenue for novel non-invasive treatment of presbyopia.

[0007] At the molecular level, proteins known as crystallins play a major role in the sclerosis of the ocular lens. Lens crystallins include three isoforms, α, β, and γ, and account for 90% of the protein content of the ocular lens. α-crystallin (AC), an ATP-independent chaperone and member of the small heat shock protein (sHsp) family, constitutes 40% of the crystallin protein content. It exists as a hetero-oligomer of two subunits, αA-crystallin (AAC) and αB-crystallin (ABC), and its expression is mainly restricted to the ocular lens. It recognizes conformational features exposed in partially unfolded lens proteins and segregates them from each other, thereby reducing the population of aggregation-prone species that would otherwise lead to various age-related vision disorders.

[0008]

[0008] Several studies have established a link between human lens stiffening and AC function. Dynamic mechanical analysis measurements have shown a significant increase in lens stiffness with age, with a 500- to 1000-fold decrease in elasticity observed, particularly in the lens nucleus. This increase in lens stiffness correlates with an age-related decrease in free AC chaperone concentrations, as most AC becomes incorporated into high molecular weight (HMW) aggregates by age 40-50. This conversion of soluble AC to HMW aggregates is accompanied by a large increase in lens stiffness, presumably because the low levels of soluble AC present are insufficient to chaperone denatured proteins. That an age-related decrease in free AC chaperones is responsible for lens stiffness is supported by experiments in which human lenses were subjected to heating to mimic the age-related conversion of soluble AC to HMW aggregates, and an increase in lens stiffness was observed. Similarly, purified soluble AC forms HMW aggregates and loses its chaperone-like activity when exposed to UV radiation. HMW aggregates are formed by intermolecular cross-links, particularly SS bonds, resulting from oxidation of cysteine ​​sulfhydryl groups (-SH). The formation of disulfide-bridged HMW aggregates appears to be a major contributing factor to the increase in lens stiffness and loss of accommodation amplitude.

[0009]

[0009] Presbyopia has been suggested to be the earliest observable symptom of age-related nuclear (ARN) cataract, the leading cause of blindness in the world. Summary of the Invention [Problem to be solved by the invention]

[0010]

[0010] Given that there is a need for non-invasive treatments that can protect and restore the eye's ability to accommodate that is lost in presbyopia, and that the formation of HMW AC aggregates is the primary causative factor underlying presbyopia, there is a need for the development of pharmacological agents that can selectively slow and / or reverse the formation of HMW AC aggregates. [Means for solving the problem]

[0011]

[0011] Provided herein is a rational structure-activity relationship-based approach to identify small molecule disaggregating enzymes (SMDs) that can inhibit the formation and / or dissolve HMW aggregates of human ACC (hAAC). Based on this approach, several SMDs have been identified. These SMDs are believed to be useful in the treatment and management of presbyopia, and in the treatment and / or slowing of the progression of cataracts. Cataracts can be age-related (nuclear sclerotic, cortical, and posterior subcapsular), congenital, familial, secondary, traumatic, smoking-related, and radiation cataracts.

[0012] In one aspect, provided herein is a compound for treating or managing presbyopia, or slowing the progression and / or treating cataracts in a subject in need thereof, the compound having formula (I):

[0013] [ka]

[0014] (In the formula, R1 and R2 are the same or different, and each of R1 and R2 is independently Hydrogen, R4C=O,

[0015] [ka]

[0016] selected from the group consisting of; - R 3a , R 3b , R 3c , and R 3d are each the same or different and each independently selected from the group consisting of hydrogen, branched or linear (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, and hydroxyl; - R4 is selected from the group consisting of branched or linear (C1-C6) alkyl; halo(C1-C6) alkyl; (C3-C6) cycloalkyl; halo(C3-C6) cycloalkyl; aryl; haloaryl; - R 5a and R 5b are the same or different and are each independently branched or linear (C1-C6) alkyl; R6 is a branched or linear (C1-C6) alkyl, aryl, or polyethylene glycol group; or

[0017] [ka]

[0018] (In the formula, q is 1 to 10; - p is a number from 0 to 10, - n is a number from 0 to 10, - X is C or O), or a solvate or pharma- ceutical acceptable salt thereof, comprising administering to the subject an effective amount of a composition comprising a compound having the formula:

[0019] In some embodiments, R1 and R2 are the same. In some embodiments, at least one of R1 and R2 is hydrogen. In some embodiments, R 3a , R 3b , R 3c , and R 3d At least one of R is hydrogen. 3a , R 3b , R 3c , and R 3d Each of is hydrogen.

[0020] In one embodiment, a compound of formula (1) is provided, wherein at least one of R1 and R2 is

[0021] [ka]

[0022] (In the formula, R 5a is (C1-C6) alkyl, R6 is (C1-C6) alkyl, aryl, or

[0023] [ka]

[0024] (wherein q is 1 to 10), The compound or a solvate or pharma- ceutically acceptable salt thereof. In one aspect, there is provided a compound of formula (I): - One of R1 and R2 is

[0025] [ka]

[0026] (wherein X is C and p is 1 or 2; the other of R1 and R2 is hydrogen; - R 3a , R 3b , R 3c , and R 3d each of which is hydrogen) It is.

[0027] In one aspect, there is provided a compound of formula (I): - one of R1 and R2 is R4C=O, where R4 is a branched (C3-C6) alkyl, e.g. isopropyl; - the other of R1 and R2 is hydrogen; - R 3a , R 3b , R 3c , and R 3d Each of R is hydrogen. In one embodiment, R is R C=O, where R is isopropyl, and R, R 3a , R 3b , R 3c , and R 3dEach of is hydrogen.

[0028] In one aspect, there is provided a compound of formula (I): - R1 and R2 are the same or different and each independently represent R4C=O, where R4 is a branched (C3-C6) alkyl, e.g., isopropyl; - R 3a , R 3b , R 3c , and R 3d In one embodiment, R1 and R2 are each R4C=O, where R4 is isopropyl, and R 3a , R 3b , R 3c , and R 3d Each of is hydrogen.

[0029] In one aspect, there is provided a compound of formula (I): R1 and R2 are the same or different and each independently represent

[0030] [ka]

[0031] (wherein R6 is a branched (C3-C6) alkyl, such as isopropyl); - R 3a , R 3b , R 3c , and R 3d Each of is hydrogen. In one aspect, there is provided a compound of formula (I): - One of R1 and R2 is

[0032] [ka]

[0033] (wherein R6 is a branched (C3-C6) alkyl, such as isopropyl); - the other of R1 and R2 is hydrogen; - R 3a , R 3b , R 3c , and R 3d Each of is hydrogen. In some embodiments, R1 is

[0034] [ka]

[0035] (wherein R6 is isopropyl), and R2, R 3a , R 3b , R 3c , and R 3d Each of is hydrogen. In another aspect, the present invention relates to a compound of formula (Ia):

[0036] [ka]

[0037] or a solvate or pharma- ceutically acceptable salt thereof is provided. In another aspect, the present specification provides a compound of formula (Ib):

[0038] [ka]

[0039] or a solvate or pharma- ceutically acceptable salt thereof is provided. In another aspect, the present specification provides a compound of formula (Ic):

[0040] [ka]

[0041] or a solvate or pharma- ceutically acceptable salt thereof is provided. In another aspect, the present specification provides a compound of formula (Id):

[0042] [ka]

[0043] or a solvate or pharma- ceutically acceptable salt thereof is provided. In another aspect, the present specification provides a compound of formula (Ie):

[0044] [ka]

[0045] or a solvate or pharma- ceutically acceptable salt thereof is provided. In another aspect, the present specification provides a compound of formula (If):

[0046] [ka]

[0047] or a solvate or pharma- ceutically acceptable salt thereof is provided. In another aspect, the following:

[0048] [ka]

[0049] or a solvate or pharma- ceutically acceptable salt thereof is provided. In one embodiment, compounds of formula (I) are produced by the following general reaction: General scheme for making prodrugs:

[0050] [ka]

[0051] In one aspect, a method of treating, preventing, reducing the incidence or reducing, ameliorating, or alleviating symptoms associated with presbyopia, cataracts, transthyretin (TTR)-related amyloidosis, or other eye-related conditions or disorders is provided, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), including each of the disclosed compounds and compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), and (If). In some aspects, a pharmaceutical composition is provided that includes a compound of formula (I), including each of the disclosed compounds and compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), and (If), and one or more pharmaceutical excipients. In some embodiments, the compounds of formula (I), including each of the disclosed compounds and compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), and (If), may be administered to a subject in need thereof in an amount effective to reduce or inhibit the formation of or dissolve high molecular weight aggregates of human α-A-crystallin, or to treat, prevent, or reduce the incidence, or reduce, ameliorate, or alleviate symptoms associated with conditions related to human α-A-crystallin, including, but not limited to, transthyretin (TTR)-related amyloidosis, prion, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and eyelid synechiae-ectodermal hypoplasia-cleft lip / palate syndrome.

[0052] In some embodiments, the compounds of formula (I), including each of the disclosed compounds and compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), and (If), may be administered through any route of administration, including, but not limited to, oral, nasal, intranasal, intramuscular, intravenous, subcutaneous, rectal, sublingual, intrathecal, transdermal, intraocular, inhalation, or other topical. In some embodiments, the compounds of formula (I), including each of the disclosed compounds and compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), and (If), are administered intraocularly or topically to the eye. In some embodiments, the pharmaceutical composition is an ophthalmic solution or suspension comprising a compound of formula (I) and one or more pharma- ceutically acceptable excipients suitable for administration to the eye.

[0053]

[0031] With respect to any structure disclosed herein, the scope of the compounds also includes any tautomers that may be formed. Unless otherwise indicated, reference to a compound shall be broadly interpreted to include pharma- ceutically acceptable salts, prodrugs, tautomers, alternative solid forms, non-covalent complexes, and combinations thereof, of the depicted structure or chemical entity of the chemical name.

[0054]

[0032] A pharmaceutically acceptable salt is any salt of a parent compound that is suitable for administration to animals or humans. A pharmaceutically acceptable salt also refers to any salt that may form in vivo as a result of administration of an acid, another salt, or a prodrug that is converted to an acid or salt. A salt includes one or more ionic forms of a compound, such as a conjugate acid or base, combined with one or more corresponding counterions. A salt can be formed from or incorporate one or more deprotonated acidic groups (e.g., carboxylic acids), one or more protonated basic groups (e.g., amines), or both (e.g., zwitterions).

[0055]

[0033] A prodrug is a compound that is converted into a therapeutically active compound after administration. For example, the conversion can occur by removal of a biologically labile group. The preparation of prodrugs is well known in the art. For example, the chapter "Prodrugs and Drug Delivery Systems" in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2nd Edition, Elsevier Academic Press: Amsterdam, 2004, pages 496-557, provides further details on the subject.

[0056]

[0034] Tautomers are isomers that are in rapid equilibrium with each other. For example, tautomers can be related by the migration of a proton, a hydrogen atom, or a hydride ion.

[0035] Unless specific stereochemistry is explicitly depicted, a structure is intended to include all possible stereoisomers, both pure or in any possible mixtures. An alternative solid form is a solid form that is different from that which may result from the practice of the procedures described herein. For example, an alternative solid form may be a polymorph, a different type of amorphous solid form, a glass, etc.

[0057]

[0036] A non-covalent complex is a complex that may form between a compound and one or more additional chemical species that does not involve a covalent interaction between the compound and the additional chemical species. The complex may or may not have a specific ratio between the compound and the additional chemical species. Examples may include solvates, hydrates, charge transfer complexes, etc.

[0058]

[0037] When a range of values ​​is disclosed, and when the notation "from n1...to n2" or "n1...to n2 (where n1 and n2 are numbers) is used, unless otherwise specified, the notation is intended to include the numbers themselves and the range therebetween. The range may be integer or continuous, inclusive of the end values. As an example, the range "3-11 membered cycloalkyl" is intended to include cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10, or 11 ring atoms. When n is set to 0 in the context of "0 carbon atoms", it is intended to indicate a bond or none.

[0059]

[0038] The term "alkyl", as used herein alone or in combination, refers to a functional group that contains a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms linked only by single bonds and not having any cyclic structure. The alkyl group may be optionally substituted as defined herein. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, and the like.

[0060]

[0039] The term "alkenyl", as used herein alone or in combination, refers to a functional group that includes a straight or branched chain hydrocarbon containing 2 to 20 carbon atoms, having one or more carbon-carbon double bonds, and not having any cyclic structure. The alkenyl group may be optionally substituted as defined herein. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, 2-methylpropenyl, butenyl, 1,4-butadienyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, and the like. The point of attachment may be on the double bond carbon or on any single bond carbon.

[0061]

[0040] The term "alkynyl", as used herein alone or in combination, refers to a functional group that includes a straight or branched chain hydrocarbon containing 2 to 20 carbon atoms, having one or more carbon-carbon triple bonds, and not having any cyclic structure. The alkynyl group may be optionally substituted as defined herein. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-1-yl, butyn-2-yl, 3-methylbutyn-1-yl, pentynyl, pentyn-1-yl, hexynyl, hexyn-2-yl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, eicosynyl, and the like. The point of attachment may be on a triple bond carbon or on any single bond carbon.

[0062]

[0041] As used herein, alone or in combination, the term "alkoxy" refers to -O-alkyl, -O-alkenyl, or -O-alknyl, where alkyl, alkenyl, and alkynyl are as defined above.

[0063]

[0042] The term "alkoxyalkyl", as used herein, alone or in combination, means an alkyl, as defined above, substituted with an alkoxy group, as defined above (in one embodiment, one or two alkoxy groups). 2~6 Alkoxyalkyl refers to the total number of carbon atoms. Examples include, but are not limited to, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0064]

[0043] The term "aryl", as used herein alone or in combination, refers to monocyclic, bicyclic (fused), and tricyclic (fused or spiro) hydrocarbon ring systems having a total of 5 to 14 ring atoms. When an aryl is monocyclic, the monocyclic is aromatic and does not contain heteroatoms. When an aryl is bicyclic or tricyclic, at least one of the rings in the bicyclic or tricyclic is aromatic and does not contain heteroatoms, and when the other ring(s) is aromatic, the other ring(s) does not contain heteroatoms, but when the other ring(s) is not aromatic, the other ring(s) may or may not contain heteroatoms. The point of attachment may be on any ring atom. Examples of aryl include, but are not limited to, benzene, naphthalene, indane, 1,2,3,4-tetrahydronaphthalene, chroman, isochroman, 1,2,3,4-tetrahydroquinoline, thiochroman 1,1-dioxide, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, and 2,3-dihydrobenzofuran.

[0065] As used herein, alone or in combination, the term "aralkyl" refers to any of the following: 1~6 It refers to a 5-12 membered heteroaryl or a 6-12 membered aryl, as defined herein, substituted in place of a hydrogen on an alkyl.

[0066] The term "cycloalkyl," as used herein, alone or in combination, refers to a monocyclic, bicyclic (fused, bridged, or spiro), or tricyclic (fused or spiro) hydrocarbon ring system having a total of 3 to 14 ring atoms, which is fully saturated or contains one or more units of unsaturation, but none of the individual rings in the monocyclic, bicyclic, or tricyclic hydrocarbon ring system are aromatic, and none of the ring atoms are heteroatoms. The point of attachment may be on a saturated or unsaturated carbon. A bridged bicyclic cycloalkyl refers to two hydrocarbon rings that share three or more carbon atoms, with the two bridgehead carbon atoms separated by a bridge containing at least one atom. Examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.5]decane, and spiro[5.5]undecane.

[0067]

[0046] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl, as defined above, in which one or one to five hydrogens have been replaced with a halogen atom(s), including those substituted with different halogen atoms. Examples of haloalkyl include, but are not limited to, -CF3, -CH2Cl, -CHF2, and -CF2CF3.

[0068]

[0047] The term "haloalkoxy", as used herein alone or in combination, refers to an alkoxy as defined above in which one or one to five hydrogens have been replaced with a halogen atom(s), including those substituted with different halogen atoms. Examples of haloalkoxy include, but are not limited to, -OCF3 and -OCHF2.

[0069] The terms "halo" or "halogen," as used herein, alone or in combination, mean fluoro, chloro, bromo, or iodo, and in one embodiment, fluoro or chloro.

[0070] The term "spiro," as used herein, alone or in combination, refers to a moiety containing two rings which share one common atom. [Brief description of the drawings]

[0071] [Figure 1]

[0050] Figure 1A shows the absorbance at 600 nm of various concentrations of CAP1160 exposed to UV light. Figure 1B shows the absorbance at 600 nm of various concentrations of CAP1160 exposed to UV light. EXAMPLES

[0072] Example 1 Prevention of UVC / H2O2-induced aggregation of bovine lens extract by CAP1160 Bovine lens lysate (2 mg / ml, 50 μl) was incubated with various concentrations of CAP1160 (structure shown below) or vehicle (0.5% DMSO) and then left unexposed (unexposed) or exposed to UV (UV irradiation). See FIG. 1A. At various time points, wells containing bovine lens lysate were photographed and the corresponding absorbance at 600 nm (A600) was measured. See FIGS. 1A and 1B. Representative bright field images of wells 7 minutes after the first UV exposure (FIG. 1A) and the corresponding A600 (FIG. 1B).

[0073]

[0054] The results show that CAP1160 dose-dependently delays the opacification of bovine lens protein lysate induced by UV irradiation.

[0074] [ka]

[0075] Example 2 General scheme for making prodrugs The prodrugs described herein are prepared according to the following general scheme.

[0076] [ka]

[0077] In the above scheme, the starting compound 1 and the reagents used to react with the OH group are merely examples, and each can be appropriately selected based on the desired end product.

Claims

1. 【Fig. 1】 (wherein, R １ and R ２ are the same or different, and each of R １ and R ２ is independently hydrogen, R ４ C=O, [Chemical Formula 2] is selected from the group consisting of; -R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ are each the same or different and each independently is selected from the group consisting of hydrogen, branched or linear (C １ -C ６ ) alkyl, halo(C １ -C ６ ) alkyl, (C ３ -C ６ ) cycloalkyl, halo(C ３ -C ６ ) cycloalkyl, and hydroxyl; -R ４ is selected from the group consisting of branched or linear (C １ -C ６ )alkyl; halo(C １ -C ６ )alkyl; (C ３ -C ６ )cycloalkyl; halo(C ３ -C ６ )cycloalkyl; aryl; haloaryl; -R ５ａ and R ５ｂ are each the same or different and independently are branched or linear (C １ to C ６ ) alkyl, -R ６ is a branched or linear (C １ -C ６ ) alkyl, aryl, or polyethylene glycol group, or [Chemical Formula 3] (wherein, q is from 1 to 10; - p is a number from 0 to 10, - n is a number from 0 to 10, - X is C or O)), or a solvate or pharmaceutically acceptable salt thereof. **Claim 2** R １ and R ２ at least one of them is 【Chemical 4】 (wherein, R ５ａ is (C １ - C ６ ) alkyl, and R ６ is (C １ - C ６ ) alkyl, aryl, or 【Chemical Formula 5】 selected from the group consisting of (wherein q is from 1 to 10), the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof. **Claim 3** Compound of formula (Ia): 【Chemical Formula 6】 or a solvate or pharmaceutically acceptable salt thereof. **Claim 4** Compound of formula (Ib): 【Chemical Formula 7】 or a solvate or pharmaceutically acceptable salt thereof. **Claim 5** Compound of formula (Ic): 【Chemical 8】 or a solvate or pharmaceutically acceptable salt thereof. **Claim 6** Compound of formula (Id): 【Chemical Formula 9】 or a solvate or pharmaceutically acceptable salt thereof. **Claim 7** Compound of formula (Ie): 【Chemical 10】 or a solvate or pharmaceutically acceptable salt thereof. **Claim 8** Compound of formula (If): 【Chemical 11】 or a solvate or pharmaceutically acceptable salt thereof.

9. 【Fig. 12】 A compound selected from the group consisting of, or a solvate or pharmaceutically acceptable salt thereof. **Claim 10** A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients. **Claim 11** For use in a method of treating, preventing, reducing the incidence of, or reducing, ameliorating, or alleviating symptoms associated with presbyopia, cataract, transthyretin (TTR)-related amyloidosis, or other conditions or disorders related to the eye, the compound according to any one of claims 1 to 9, **Claim 12** For use in a method of treating, preventing, reducing the incidence of, or reducing, ameliorating, or alleviating symptoms associated with presbyopia, cataract, transthyretin (TTR)-related amyloidosis, or other conditions or disorders related to the eye, the pharmaceutical composition according to claim 10.

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