CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/216,429, which was filed on June 29, 2021, and the entire contents of which is expressly incorporated by reference herein.

FIELD OF THE DISCLOSURE

[0002] The disclosure relates to compounds and methods of treating ophthalmic diseases and disorders.

BACKGROUND

[0003] Cataracts are the leading cause of blindness worldwide according to the World Health Organization (WHO), particularly in low- and middle-income countries. Data dating back to the beginning of this millennium shows that 30-60% of blindness in Africa and 60-80% in South East Asia is attributable to cataracts. In the United States, the current number of those with cataracts is estimated to be more than 25.7 million. Projections from Prevent Blindness research estimate that the number will increase to 38.5 million by 2032, and to 45.6 million by the year 2050. Cataract is a clouding of the eye’s lens which blocks or changes the passage of light into the eye. Cataract usually forms in both eyes, but not at the same rate. It can develop slowly or quickly, or progress to a certain point, then not get any worse. Besides aging, other factors may cause cataracts to form. Eye infections, certain medicines (e.g., steroids), injuries, and exposure to intense heat or radiation may cause cataracts. Too much exposure to non-visible sunlight (called UV or ultraviolet light) and various diseases, such as diabetes or metabolic disorders, may also contribute to formation of cataracts.

[0004] The only cataracts treatment currently available is surgical extraction and replacement of eye lens with intraocular lens. This treatment represents a high public health burden. Although cataracts surgery is generally considered to be safe, there are significant complications: (i) 30-50% of patients in the US who have undergone cataracts surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% develop endophthalmitis. In addition, in many remote and poor areas of the developing and underdeveloped regions of the world, people still remain blind from cataract, primarily due to lack of access to eye care.

[0005] Presbyopia is the loss of accommodative ability of the eye resulting in the inability to focus on near objects. Presbyopia affects everyone over the age of 45 and has significant negative impacts on the quality of life. Current treatments for presbyopia include: (i) non-invasive approaches that utilize devices to help improve near and distance vision but do nothing to restore the natural process of accommodation and require constant use of the devices, and (ii) invasive surgical procedures which are associated with major complications including decrease in vision quality, regression effects, anisometropia, corneal ectasia, and haze. Most importantly, none of these methods can reverse presbyopia. Moreover, no treatment option exists that can either prevent or delay the onset of presbyopia.

[0006] Stiffening of eye lens and changes in the elasticity of the lens capsule, dimension of eye lens, dimension of the zonular attachment, and ciliary muscle (CM) contractions, have all been proposed as contributing factors for presbyopia. However, human and non-human primate studies suggest that CM function is normal well beyond the onset of presbyopia. By contrast, the human lens increases in stiffness with age in a manner that directly correlates with a loss in accommodative power [FIGS. lA-lD] The loss in accommodative power can be restored by implanting intraocular lenses made from a flexible polymer, suggesting that restoration of lens flexibility is sufficient to restore accommodation. Therefore, pharmacological agents that prevent or reverse the hardening of the crystalline lens hold promise for novel non-invasive treatment of presbyopia.

[0007] At the molecular level, proteins known as crystallins play a major role in the stiffening of the eye lens. The lens crystallins comprise three isoforms, a, b, and g and make up 90% of the eye lens protein content a crystalline (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, aA-crystallin (AAC) and aB-crystallin (ABC) and its expression is primarily restricted to the eye lens. It recognizes exposed conformational features in partially unfolded lens proteins and sequesters them from one another, thereby reducing the population of aggregation-prone species that would otherwise lead to various age-related vision impairment. [0008] Multiple studies have established a link between stiffening of the human lens and AC function. Dynamic mechanical analysis measurements have shown that there is a significant increase in the stiffness of the lens with age, particularly in the lens nucleus where a 500- to 1000- fold decrease in elasticity is observed. This increase in lens stiffness correlates with the age-related decline in free AC chaperone concentration as most AC becomes incorporated into high molecular weight (HMW) aggregates by the age of 40-50. This conversion of soluble AC into HMW aggregates is accompanied by a large increase in lens stiffness, presumably because the low level of soluble AC present is not sufficient to chaperone denatured proteins. That age-related decrease in free AC chaperone is responsible for lens stiffness is supported by experiments where human lenses were subjected to heating to mimic the age-related conversion of soluble AC into HMW aggregates and an increase in lens stiffness was observed. Similarly, purified soluble AC forms HMW aggregates when exposed to UV radiation with a loss in chaperone like activity. The HMW aggregate is formed due to the intermolecular cross-linking, particularly S-S bonds, resulting from the oxidation of cysteine sulfhydryl groups (-SH). The formation of this disulfide cross-linked HMW aggregate is thought to be a major contributor in increasing the stiffness and loss of accommodation amplitude of the lens.

[0009] It has been suggested that presbyopia is the earliest observable symptom of age-related nuclear (ARN) cataract, a major cause of blindness in the world.

[0010] Given the need for noninvasive treatment that can protect and restore the accommodative ability of the eye lost in presbyopia and given that formation of HMW AC aggregates is a major causative factor underlying presbyopia, there is a need for the development of pharmacological agents that can selectively delay and/or reverse the HMW AC aggregate formation.

BRIEF DESCRIPTION OF THE FIGURES

[0011] FIG 1A: Stiffness values of cortex and nucleus as a function of lens age. Nuclear and cortical modulus values plotted on a log scale as a function of age for individual lenses. Nuclear values are shown in blue and cortical values in red. The curves were fitted using SigmaPlot. This figure was adapted from Heys KR, et. al Molecular Vision 2004; 10:956-963.

[0012] FIG IB: Change in accommodative power (diopters) as function of age. Accommodative power of human subjects expressed as a function of age. The data points on the graph represent a summary of four separate studies on human accommodation as indicated by the following references. 1 (Blue): Bruckner, R., et. al., Ophthalmo-gerontological research results. Doc. Ophthalmol 1986; 64:235-310. 2 (Red): Duane, AJ., J. Am Med Assoc. 1912; 59:1010-1013. 3 (Green): Donders FC., New Sydenham; 1864 and 4 (Open circle): Hamasaki, D., et., al., Am J Optom Arch Am Acad Optom 1965; 33: 3-14. This figure was adapted from Heys KR, et. al., Molecidar Vision 2004; 10:956-963.

[0013] FIG 1C: Mass distribution in the water-soluble fraction in young (19years) (solid line and filled circle) and aged (83 years) (broken line andopen circle) human lenses using multiangle light scattering. This figure was adapted from Santhoshkumar R, et. al., THE JOURNAL OF BIOLOGICAL CHEMISTRY (2008) 283, NO. 13: 8477-8485.

[0014] FIG ID: Changes in the content of soluble a-crystallin (O) and high molecular weight protein (●) in the lens nucleus as a function of age. This figure was adapted from Heys KR., et., al., Aging Cell (2007) 6:807-815.

[0015] FIG 2A: SDS-PAGE showing the protection against UVC induced aggregation of human a-A-crystallin (hAAC) by disulfide and related SDMs. Shown are also efficacy of non-related SDMs. The compounds were tested at 500mM concentration.

[0016] FIG 2B: Molecular weight and structures of the disulfide SDMs and related compounds tested for perotection against UVC induced aggregation of hAAC.

[0017] FIG 3A: Molecular structures of the disulfide SDMs evaluated for protection of human lens epithelial cells, SRA 01/04 against UVC and heat.

[0018] FIG 3B: Protection rendered by disulfide SDMs towards human lens epithelial cells, SRA 01/04 upon exposure to UVC (for 48 Secs). SRA 01/04 cells were pre-incubated for 2 hours with disulfide containing SDMs then exposed to UVC. Cell viability was assessed by Alamar blue 24- hours after exposure. Graphed are mean±SD.

[0019] FIG 3C: Protection rendered by disulfide SDMs towards human lens epithelial cells, SRA 01/04 upon exposure to Heat (50°C for 30 mins). SRA 01/04 cells were pre-incubated for 2 hours with disulfide containing SDMs then exposed to UVC. Cell viability was assessed by Alamar blue 24-hours after exposure. Graphed are mean±SD.

SUMMARY OF VARIOUS ASPECTS

[0020] Small molecules that can inhibit the formation of high molecular weight (HMW) aggregates of human aA-crystallin (hAAC) are disclosed. These small molecules are called disaggregates (SMDs). It is believed that these SMDs would be useful in the treatment of presbyopia and also in the treatment of cataract including cataract that is age-related (nuclear sclerotic, cortical, and posterior subcapsular), congenital, secondary, traumatic, or caused by radiation.

[0021] Accordingly, compounds having the formula (I), (II), (III), (IV), or (V) shown below, and pharmaceutically acceptable salt thereof, method of making these compounds, and methods of using these compounds are disclosed. In some aspects, methods of treating eye-related conditions such as cataract or presbyopia using SMDs are provided. In some aspects, methods comprise administering an effective amount of a compound having the formula (I), (II), (III), (IV), or (V) shown below, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, are provided. In some aspects, pharmaceutical compositions comprising a compound having the formula (I), (II), (III), (IV), or (V) shown below, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, are provided. In some aspects, the methods of administration disclosed herein comprise administration of the compounds having the formula (I), (II), (III), (IV), or (V), or administration of prodrug compounds that convert to these compounds in the body.

[0022] Compounds having formula (I), (II), (III), (IV), and (V), and prodrugs thereof are provided. [0023] A compound of formula (I) is provided: wherein R _1a , R _1b , A ₁ , A ₂ , m, and n are as described herein below.

[0024] A compound of formula (II) is provided: wherein R ₁ , A, X, W, r, and t, are as described herein below. [0025] A compound of formula (III) is provided: wherein R ₁ , R _3, R _4, and A ₃ are as described herein below. [0026] A compound of formula (IV) is provided: wherein R _1a , R _1b , R _3a , R _3b , X ₁ , X ₂ , A ₄ , and A ₅ are as described herein below. [0027] A compound of formula (V) is provided: wherein R _1c , R _4a, R _4b , R ₅ , R ₆ , X _A , X _B , X _C , V, and x, are as described herein below.

DETAILED DESCRIPTION OF VARIOUS ASPECTS

General Description of Compounds

[0028] In a first aspect, the present disclosure provides a compound of formula (I), and a method of use of these compounds. In one aspect, the present disclosure provides a method of treating, preventing, reducing the severity of, or reducing or alleviating the symptoms associated with, an eye-related disease or condition, including but not limited to cataract or presbyopia, in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula (I): or a pharmaceutically acceptable salt thereof, wherein

- A ₁ and A2 are, each independently, a six-membered aromatic or heteroaromatic ring comprising at least one heteroatom and at least one carbon atom;

- each of m and n is, independently, any number from 0 to 4;

- R _1a is attached to one or more carbon atoms of A ₁ ; and R _1b is attached to one or more carbon atoms of A ₂ ;

- R _1a and R _1b are, each independently, selected from the group consisting of: hydrogen; (C ₁ - C ₆ )alkyl; halo(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy; halo(C ₁ -C ₆ )alkoxy; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ - C ₆ )alkoxy(C ₁ -C ₆ )alkyl; (C ₂ -C ₅ )alkenyl; (C ₂ -C ₅ )alkynyl; SO ₂ R ₂ ; CO ₂ R ₂ ; NH ₂ ; (R ₂ )(R ₂ ) wherein each R ₂ may be the same or different, (C ₁ -C ₆ )alkylamine; (C ₁ -C ₆ )dialkylamine; NHCOR ₂ ; hydroxyl; halogen; CN; NO ₂ ; (C ₃ -C ₆ )cycloalkyl, halo(C ₃ -C ₆ )cycloalkyl, and hydroxy(C ₃ - C ₆ )cycloalkyl;

- wherein more than one R _1a may exist, and if more than one R _1a is present, then each R _1a may be the same or different,

- wherein more than one R _1b may exist, and if more than one R _1b is present, then each R _1b may be the same or different,

- wherein R ₁ is selected from hydrogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(C ₃ -C ₆ )cycloalkyl, hydroxy(C ₃ - C ₆ )cycloalkyl, and (CH ₂ ) _1-3 CO ₂ H.

[0029] In some aspects, A ₁ and A ₂ are the same or different. In some aspects, R _1a and R _1b are the same or different. In some aspects, one to six R _1a groups, or any number from one to six, are present. In some aspects, one to six R _1b groups, or any number from one to six, are present. In some aspects, the same number of R _1a and R _1b groups is present in the compound of formula (I). [0030] In a second aspect, the present disclosure provides a compound of formula (II), and a method of use of these compounds. In one aspect, the present disclosure provides a method of treating, preventing, reducing the severity of, or reducing or alleviating the symptoms associated with, an eye-related disease or condition, including but not limited to cataract or presbyopia, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the formula (II): or a pharmaceutically acceptable salt thereof, wherein - A is a 5-10 membered heteroaryl or heteroaromatic ring comprising at least one heteroatom and at least one carbon atom, wherein A may be a monocyclic or bicyclic ring, wherein A is optionally substituted with one or more R ₁ groups, wherein each R ₁ is attached to one or more carbon atoms of A, and wherein when more than one R ₁ is present, then each R ₁ may be the same or different,

- R ₁ is optional, but when present, R ₁ is independently selected from the group consisting of: hydrogen; (C ₁ -C ₆ )alkyl; halo(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy; halo(C ₁ -C ₆ )alkoxy; hydroxy(C ₁ - C ₆ )alkyl; (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl; (C ₂ -C ₅ )alkenyl; (C ₂ -C ₅ )alkynyl; SO ₂ R ₂ ; (CH ₂ ) _0-4 C O ₂ R ₂ ; Nth; NHR2; N(R ₂ )(R2) wherein each R2 may be the same or different; (C ₁ -C ₆ )alkylamine; di(C ₁ - C6)alkylamine; NHCOR ₂ ; hydroxyl; halogen; CN; and NO ₂ ;

- wherein R ₂ is selected from: hydrogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₂ -C ₅ )alkenyl, (C ₂ -C ₅ )alkynyl, (C ₃ -C ₆ )cycloalkyl, halo(C ₃ - C ₆ )cycloalkyl, and hydroxy(C ₃ -C ₆ )cycloalkyl;

- W is a direct bond, CO, CS, or (CRARB)P, and

- X is a direct bond, O, NH, or (CRARB) _p ,

- wherein each of R _A and R _B is independently selected from the group consisting of: hydrogen, halogen, and hydroxyl, wherein RA and R _B may be the same or different,

- wherein p is any number between 0 and 4; and

- each of r and t is independently any number between 1 and 3.

[0031] In some aspects, one to ten R ₁ groups, or any number between one and ten, are present in the compound of formula (II).

[0032] In a third aspect, the present disclosure provides a compound of formula (III), and a method of use of these compounds. In one aspect, the present disclosure provides a method of treating, preventing, reducing the severity of, or reducing or alleviating the symptoms associated with, an eye-related disease or condition, including but not limited to cataract or presbyopia, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the formula (III): or a pharmaceutically acceptable salt thereof, wherein

- A ₃ is a 5- or 6-membered aromatic or heteroaromatic ring comprising at least one heteroatom and at least one carbon atom, wherein A ₃ is optionally substituted with one or more R ₁ groups, wherein each R ₁ is attached to one or more carbon atoms of A ₃ , and wherein when more than one R ₁ is present, then each R ₁ may be the same or different,

- R ₁ is attached to one or more carbon atoms of A ₃ , and R ₁ is independently selected from the group consisting of: hydrogen; (C ₁ -C ₆ )alkyl; halo(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy; halo(C ₁ -C ₆ )alkoxy; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl; (C ₂ -C ₅ )alkenyl; (C ₂ -C ₅ )alkynyl; SO ₂ R ₂ ; (CH ₂ ) ₀ - ₄ CO ₂ R ₂ ; NH ₂ ; NHR ₂ ; N(R ₂ )(R ₂ ) wherein each R ₂ may be the same or different; (C ₁ -C ₆ )alkylamine; di(C ₁ -C ₆ )alkylamine; NHCOR ₂ ; hydroxyl; halogen; CN; and NO ₂ ;

- wherein R ₂ is selected from: hydrogen, (C ₁ -C ₆ )alkyl. halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₂ -C ₅ )alkenyl, (C ₂ -C ₅ )alkynyl, (C ₃ -C ₆ )cycloalkyl, halo(C ₃ - C ₆ )cycloalkyl, and hydroxy(C ₃ -C ₆ )cycloalkyl; and

- R ₃ and R ₄ are each independently selected from the group consisting of: hydrogen; (C ₁ -C ₁₀ ) alkyl; halo(C ₁ -C ₆ )alkyl; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl; (C ₂ -C ₅ )alkenyl; (C ₂ - C ₅ )alkynyl; (C ₃ -C ₆ )cycloalkyl; halo(C ₃ -C ₆ )cycloalkyl; hydroxy(C ₃ -C ₆ )cycloalkyl; (CHR ₅ )nCO ₂ R ₅ ; or R ₃ and R ₄ together, with the nitrogen to which they are attached to, j oin together to form a 5-10 membered aromatic or heterocyclic ring or cyclic ring linked to the nitrogen with (CH ₂ ) _1-4 , optionally substituted at one or more ring atoms with (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, hydroxyl, CN, halogen, NH ₂ ; (C ₁ -C ₆ )alkylamine; di(C ₁ - C ₆ )alkylamine; and NO _2;

- wherein R ₅ is independently selected from the group consisting of: hydrogen and a (C ₁ - C ₆ )alkyl and - wherein n is any number from 0 and 4.

[0033] In some aspects, one to six R ₁ groups, or any number between one and six, are present. [0034] In a fourth aspect, the present disclosure provides a compound of formula (IV), and a method of use of these compounds. In one aspect, the present disclosure provides a method of treating, preventing, reducing the severity of, or reducing or alleviating the symptoms associated with, an eye-related disease or condition, including but not limited to, cataract or presbyopia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the formula (IV): or a pharmaceutically acceptable salt thereof, wherein

- A ₄ and As are each independently a 6-14 membered aromatic or heteroaromatic ring comprising at least one heteroatom and at least one carbon atom, wherein each of A ₄ and As are independently optionally substituted with R _1a and R _1b , respectively,

- wherein R _1a and R _1b are each independently optionally attached to one or more carbon atoms of the A ₄ and As, respectively, and R _1a and R _1b are each independently selected from the group consisting of: hydrogen; (C ₁ -C ₆ )alkyl; halo(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy; halo(C ₁ -C ₆ )alkoxy; hydroxy(C ₁ -C ₆ )alkyl; (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl; (C ₂ -C ₅ )alkenyl; (C ₂ -C ₅ )alkynyl; CO ₂ R ₂ ; NH ₂ ; NHR ₂ ; N(R ₂ )(R ₂ ) wherein each R ₂ may be the same or different (C ₁ -C ₆ )alkylamine; di(C ₁ - C ₆ )alkylamine; NHCOR ₂ ; hydroxyl; halogen; CN; and NO ₂ ;

- wherein R ₂ is selected from the group consisting of: hydrogen, (C ₁ -C ₆ )alkyl _, halo(C ₁ - C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(C ₃ - C ₆ )cycloalkyl, and hydroxy(C ₃ -C ₆ )cycloalkyl;

- each of R ₃ a and R _3b is independently hydrogen or (C ₁ -C ₃ )alkyl; and

- each of Xi and X ₂ is independently CHR ₄ , wherein R ₄ is hydrogen or (C ₁ -C ₃ )alkyl, wherein Xi and X ₂ are the same or different. [0035] In a fifth aspect, the present disclosure provides a compound of formula (V), and a method of use of these compounds. In one aspect, the present disclosure provides a method of treating, preventing, reducing the severity of, or reducing or alleviating the symptoms associated with, an eye-related disease or condition, including but not limited to cataract or presbyopia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the formula (V). or a pharmaceutically acceptable salt thereof, wherein:

- X _A is N or O;

- X _B is S or CH;

- X _C is N or CH;

- R _1c is selected from the group consisting of: (CH ₂ ) _1-3 NH ₂ , (CH ₂ ) _1-3 NH(R ₂ ), (CH ₂ ) _1-3 NR ₂ R ₃ , (CH ₂ ) _1-3 (C ₁ -C ₆ )alkylamine, and (CH ₂ ) _1-3 di(C ₁ -C ₆ )alkylamine, and N=CR ₂ R _3, wherein R ₂ and R ₃ are independently hydrogen or (C ₁ -C ₆ )alkyl and may be the same or different;

- R _4a and R _4b are each independently hydrogen or (C ₁ -C ₆ )alkyl, and R _4a and R _4b may be the same or different,

- R ₅ is (C ₁ -C ₆ )alkyl, (C ₂ -C ₅ )alkenyl, (C ₂ -C ₅ )alkynyl, or CH ₂ CN;

- R ₆ is NH ₂ , NHR ₂ N(R ₂ )(R ₂ ) wherein each R ₂ may be the same or different, NO ₂ or (C ₁ -C ₆ )alkyl, wherein R ₂ is selected from the group consisting of: hydrogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, halo(C ₃ -C ₆ )cycloalkyl, and hydroxy(C ₃ -C ₆ )cycloalkyl;

- v is any number from 0 to 3; and

- x is any number from 0 to 3. Compounds and Definitions

[0036] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0037] The term "alkyl", used alone or as a part of a larger moiety such as e.g., "haloalkyl", means a saturated monovalent straight or branched hydrocarbon radical having, unless otherwise specified, 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. "Monovalent" means attached to the rest of the molecule at one point.

[0038] As used herein, either alone or in combination, the term “alkenyl” refers to a functional group comprising a straight-chain or branched-chain hydrocarbon containing, unless otherwise specified, from 2 to 20 carbon atoms and having one or more carbon-carbon double bonds and not having any cyclic structure. An alkenyl group may be optionally substituted as defined herein. Examples of alkenyl groups include, without limitation, 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 can be on the double bond carbon or on any single bond carbon.

[0039] As used herein, either alone or in combination, the term “alkynyl” refers to a functional group comprising a straight-chain or branched-chain hydrocarbon containing, unless otherwise specified, from 2 to 20 carbon atoms and having one or more carbon-carbon triple bonds and not having any cyclic structure. An alkynyl group may be optionally substituted as defined herein. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-l-yl, butyn-2-yl, 3-methylbutyn-l-yl, pentynyl, pentyn-l-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 can be on the triple bond carbon or on any single bond carbon.

[0040] As used herein, either alone or in combination, the term "alkoxy" refers to -O-alkyl, -O- alkenyl, or -O-alknyl, wherein alkyl, alkenyl, and alkynyl are as defined above.

[0041] As used herein, either alone or in combination, the term “alkoxyalkyl" means an alkyl as defined above substituted with an alkoxy group as defined above (in some embodiments one or two alkoxy groups). C2-6 alkoxyalkyl means the total number of carbon atoms. Examples include but not limited to 2-m ethoxy ethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxy ethyl, and the like.

[0042] The terms "cycloalkyl" used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Bicyclic cycloalkyl groups include e.g., cycloalkyl group fused to another cycloalkyl group, such as decalin or a cycloalkyl group fused to an aryl group (e.g., phenyl) or heteroaryl group, such as tetrahydronaphthalenyl, indanyl, 5,6,7,8-tetrahydroquinoline, and 5,6,7,8-tetrahydroisoquinoline. It will be understood that the point of attachment for bicyclic cycloalkyl groups can be either on the cycloalkyl portion or on the aryl group (e.g., phenyl) or heteroaryl group that results in a stable structure. It will be further understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.

[0043] The term "heterocyclyl" means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", may be used interchangeably. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxetanyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Aheterocyclyl group may be mono-or bicyclic. Unless otherwise specified, bicyclic heterocyclyl groups include, e.g., unsaturated or saturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aromatic or heteroaryl ring, such as for example, chromanyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, tetrahydronaphthyridinyl, indolinonyl, dihydropyrrol otriazolyl, imidazopynmidinyl, quinolinonyl, dioxaspirodecanyl. It will be understood that the point of attachment for bicyclic heterocyclyl groups can be on the heterocyclyl group or aromatic ring that results in a stable structure. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.

[0044] As used herein, either alone or in combination, the term "aryl" refers to monocyclic, bicyclic (fused), and tricyclic (fused or spiro) hydrocarbon ring system having a total of five to fourteen ring atoms. When aryl is monocyclic, the monocyclic is aromatic and contains no heteroatom. When aryl is bicyclic or tricyclic, at least one of the ring in the bicyclic or tricyclic is aromatic and contains no heteroatom, and when the other ring(s) is aromatic, the other ring(s) does not contain a heteroatom, but when the other ring(s) is not aromatic, the other ring(s) may or may not contain a heteroatom. The point of attachment can be on any ring atom. Examples of aryl include, without limitation, benzene, naphthalene, indane, 1,2,3,4-tetrahydronaphthalene, chromane, isochromane, 1,2,3,4-tetrahydroquinoline, thiochromane 1,1-dioxide, 6, 7,8,9- tetrahydro-5H-benzo[7]annulene, and 2,3-dihydrobenzofuran.

[0045] As used herein, either alone or in combination, the term "aralkyl" refers to a 5 to 12 membered heteroaryl or 6 to 12 membered aryl, as defined herein, substituted for a hydrogen of an Ci- ₆ alkyl.

[0046] The term "heteroaryl" used alone or as part of a larger moiety as in "heteroarylalkyl", "heteroarylalkoxy", or "heteroarylaminoalkyl", refers to a 5-10 -membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". The terms "heteroaryl" and "heteroar- ", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, and quinoxalinyl. A heteroaryl group may be mono- or bicyclic. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.

[0047] For any structure disclosed herein, the scope of a compound also includes any tautomer which may be formed. Unless otherwise indicated, reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.

[0048] A prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by [tailor this part to the structure being claimed], or some other biologically labile group. Prodrug preparation is well known in the art. For example, “Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action , 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

[0049] Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.

[0050] Unless stereochemistry is explicitly depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.

[0051] Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein. For example, alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.

[0052] Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.

[0053] When ranges of values are disclosed, and the notation “from m . . . to n ₂ ” or “n ₁ . . . to n ₂ ” is used, where n ₁ and n ₂ are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “3 to If membered cycloalkyl” is intended to include cycloalkyl having three, four, five, six, seven, eight, nine, ten, or eleven ring atoms. When n is set at 0 in the context of “0 carbon atoms”, it is intended to indicate a bond or null.

[0054] As used herein the terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0055] The compounds described herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds described herein refer to non- toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.

[0056] Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine salts.

[0057] Pharmaceutically acceptable acidic/anionic salts include, e.g., the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.

Description of Exemplary Compounds

[0058] In some embodiments, the present disclosure provides a compound of formula (I), pharmaceutical compositions comprising a compound of formula (I), and a method of use of the compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0059] In some embodiments, m and n are the same, A ₁ and its R _1a substituents are the same as A ₂ and its R _1b substituents.

[0060] In some embodiments, A ₁ and A ₂ are the same. [0061] In some embodiments, A ₁ is a benzene ring, and at least one R _1a substituent occurs at the ortho position. In some embodiments, A ₁ is a benzene ring, and at least one R _1a substituent occurs at the meta position. In some embodiments, A ₁ is a benzene ring, and at least one R _1a substituent occurs at the para position. In some embodiments, A ₁ is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the ortho position and one R _1a substituent occurs at the para position. In some embodiments, A ₁ is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the ortho position and one R _1a substituent occurs at the meta position. In some embodiments, A ₁ is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the meta position and one R _1a substituent occurs at the para position. In some embodiments, A ₁ is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the one ortho position and one R _1a substituent occurs at the other ortho position. In some embodiments, A ₁ is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the one meta position and one R _1a substituent occurs at the other meta position.

[0062] In some embodiments, A2 is a benzene ring, and at least one R _1b substituent occurs are the ortho position. In some embodiments, A2 is a benzene ring, and at least one R _1b substituent occurs at the meta position. In some embodiments, A2 is a benzene ring, and at least one R _1b substituent occurs at the para position. In some embodiments, A2 is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the ortho position and one R _1b substituent occurs at the para position. In some embodiments, A2 is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the ortho position and one R _1b substituent occurs at the meta position. In some embodiments, A2 is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the meta position and one R _1b substituent occurs at the para position. In some embodiments, A2 is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the one ortho position and one R _1b substituent occurs at the other ortho position. In some embodiments, A2 is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the one meta position and one R _1b substituent occurs at the other meta position. [0063] In some embodiments, in formula (I), R _1a and R _1b are the same or different and are each CO ₂ R ₂ , and R ₂ is as defined above. In some embodiments, in formula (I), R _1a and R _1b are the same or different and are each CO ₂ R ₂ , and R ₂ is hydrogen or a (C ₁ -C ₃ )alkyl.

[0064] In some embodiments, in formula (I), R _1a and R _1b are each CO ₂ R _2, R _1a and R _1b are the same or different, and R2 is (C ₁ -C ₆ )alkyl.

[0065] In some embodiments, in formula (I), R _1a and R _1b are each (C ₁ -C ₆ )alkoxy, and R _1a and R _1b are the same or different.

[0066] In some embodiments, in formula (I), R _1a and R _1b are each NHCOR ₂ , and R _1a and R _1b are the same or different, and R ₂ is as defined above

[0067] In some embodiments, in formula (I), R _1a and R _1b are each NHCOR ₂ , R _1a and R _1b are the same or different, and R ₂ is (C ₁ -C ₆ )alkyl.

[0068] In some embodiments, in formula (I), R _1a and R _1b are each SO ₂ R ₂ , R _1a and R _1b are the same or different, and R2 is as defined above.

[0069] In some embodiments, in formula (I), R _1a and R _1b are each SO ₂ R _2, and R _1a and R _1b are the same or different, and R ₂ is halo(C ₁ -C ₆ )alkyl.

[0070] In some embodiments, in formula (I), A ₁ with its R _1a substitutions is identical to A ₂ with its R _1b substitutions.

[0071] In some embodiments, the compound of formula (I) is one of

or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the present disclosure provides a compound of formula (II), pharmaceutical compositions comprising a compound of formula (II), and a method of use of the compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0073] In some embodiments, A is a benzene ring, and at least one R ₁ substituent occurs at the ortho position. In some embodiments, A is a benzene ring, and at least one R ₁ substituent occurs at the meta position. In some embodiments, A is a benzene ring, and at least one R ₁ substituent occurs at the para position. In some embodiments, A is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the ortho position and one R ₁ substituent occurs at the para position. In some embodiments, A is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the ortho position and one R ₁ substituent occurs at the meta position. In some embodiments, A is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the meta position and one R ₁ substituent occurs at the para position. In some embodiments, A is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the one ortho position and one R ₁ substituent occurs at the other ortho position. In some embodiments, A is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the one meta position and one R ₁ substituent occurs at the other meta position.

[0074] In some embodiments, in formula (II), X is NH.

[0075] In some embodiments, in formula (II), W is CO.

[0076] In some embodiments, in formula (II), X and W are the same or different. In some embodiments, in formula (II), at least one of X and W represent a direct bond. In some embodiments, both X and W represent a direct bond.

[0077] In some embodiments, in formula (II), A is pyridine, pyrimidine, or pyrazine.

[0078] In some embodiments, in formula (II), A is a 5-10 membered heteroaryl or heteroaromatic ring. In some embodiments, in formula (II), A is a 5 or 6-membered heteroaromatic ring comprising at least one nitrogen heteroatom. In some embodiments, in formula (II), A is a monocyclic or bicyclic 5-10 membered heteroaryl or heteroaromatic ring.

[0079] In some embodiments, in formula (II), there are at least two R ₁ groups, and R ₁ is NO ₂ at one position and NO ₂ or (C 1 -C>,)alkyl at another position.

[0080] In some embodiments, in formula (II), there are at least two R ₁ groups, R ₁ is NO ₂ at one position and NO ₂ or NH ₂ at another position.

[0081] In some embodiments, in formula (II), A is pyridine.

[0082] In some embodiments, in formula (II), A is Isoindole-1,3-dione ring.

[0083] In some embodiments, in formula (II), r and t are the same or different. In some embodiments, r and t are each 1.

[0084] In some embodiments, the compound of formula (II) is one of,

, and or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the present disclosure provides a compound of formula (III), pharmaceutical compositions comprising a compound of formula (III), and a method of use of the compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0086] In some embodiments, A ₃ is a benzene ring, and at least one R ₁ substituent occurs at the ortho position. In some embodiments, A ₃ is a benzene ring, and at least one R ₁ substituent occurs at the meta position. In some embodiments, A ₃ is a benzene ring, and at least one R ₁ substituent occurs at the para position. In some embodiments, A ₃ is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the ortho position and one R ₁ substituent occurs at the para position. In some embodiments, A ₃ is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the ortho position and one R ₁ substituent occurs at the meta position. In some embodiments, A ₃ is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the meta position and one R ₁ substituent occurs at the para position. In some embodiments, A ₃ is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the one ortho position and one R ₁ substituent occurs at the other ortho position. In some embodiments, A ₃ is a benzene ring, and there are two R ₁ substituents, wherein one R ₁ substituent occurs at the one meta position and one R ₁ substituent occurs at the other meta position.

[0087] In some embodiments, in formula (III), at least one R ₁ is present, and each R ₁ is independently CO ₂ H, CO ₂ R ₂ , OH, or (CH ₂ ) _1-4 C O ₂ R _2.

[0088] In some embodiments, in formula (III), R ₁ is CO ₂ R ₂

[0089] In some embodiments, in formula (III), at least one of R ₃ and R ₄ is cyclopropane.

[0090] In some embodiments, in formula (III), at least one of R ₃ and R ₄ is (C ₁ -C ₆ ) alkyl.

[0091] In some embodiments, in formula (III), R3 and R4 join together to form a 5 or 6 membered heterocyclic ring, wherein the heterocyclic ring comprises a further heteroatom that is oxygen or sulfur.

[0092] In some embodiments, in formula (III), there are at least two R ₁ groups, and R ₁ is CO ₂ R ₂ in one position and hydroxyl at another position. _.

[0093] In some embodiments, A ₃ is a benzene ring.

[0094] In some embodiments, A ₃ is thiophene.

[0095] In some embodiments, the compound of formula (III) is one of or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the present disclosure provides a compound of formula (IV), pharmaceutical compositions comprising a compound of formula (IV), and a method of use of the compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein the variable are as described above.

[0097] In some embodiments, A4 is a benzene ring, and at least one R _1a substituent occurs at the ortho position. In some embodiments, A4 is a benzene ring, and at least one R _1a substituent occurs at the meta position. In some embodiments, A4 is a benzene ring, and at least one R _1a substituent occurs at the para position. In some embodiments, A4 is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the ortho position and one R _1a substituent occurs at the para position. In some embodiments, A4 is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the ortho position and one R _1a substituent occurs at the meta position. In some embodiments, A4 is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the meta position and one R _1a substituent occurs at the para position. In some embodiments, A4 is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the one ortho position and one R _1a substituent occurs at the other ortho position. In some embodiments, A4 is a benzene ring, and there are two R _1a substituents, wherein one R _1a substituent occurs at the one meta position and one R _1a substituent occurs at the other meta position.

[0098] In some embodiments, A ₅ is a benzene ring, and at least one R _1b substituent occurs are the ortho position. In some embodiments, A ₅ is a benzene ring, and at least one R _1b substituent occurs at the meta position. In some embodiments, A ₅ is a benzene ring, and at least one R _1b substituent occurs at the para position. In some embodiments, A ₅ is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the ortho position and one R _1b substituent occurs at the para position. In some embodiments, A ₅ is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the ortho position and one R _1b substituent occurs at the meta position. In some embodiments, A ₅ is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the meta position and one R _1b substituent occurs at the para position. In some embodiments, A ₅ is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the one ortho position and one R _1b substituent occurs at the other ortho position. In some embodiments, A ₅ is a benzene ring, and there are two R _1b substituents, wherein one R _1b substituent occurs at the one meta position and one R _1b substituent occurs at the other meta position.

[0099] In some embodiments, in formula (IV), A ₄ and A ₅ are the same or different, and are each independently phenyl or napthyl.

[0100] In some embodiments, in formula (IV), one or both of R _1a and R _1b is NO ₂ .

[0101] In some embodiments, in formula (IV), there are at least two R _1a groups, and R _1a is a halogen at one position and (C ₁ -C ₆ )alkyl at another position. In some embodiments, in formula (IV), there are at least two R _1b groups, and R _1b is a halogen at one position and (C ₁ -C ₆ )alkyl at another position.

[0102] In some embodiments, in formula (IV), R _1a is a halogen and R _1b is a (C ₁ -C ₆ )alkyl. In some embodiments, in formula (IV), R _1a is a (C ₁ -C ₆ )alkyl and R _1b is a halogen.

[0103] In some embodiments, in formula (IV), Xi and X2 are the same.

[0104] In some embodiments, in formula (IV), one or both of R _3a and R _3b is hydrogen.

[0105] In some embodiments, in formula (IV), R4 in one or both of Xi and X2 is methyl.

[0106] In some embodiments, in formula (IV), A4 with its R _1a substitutions is identical to A ₅ with its R _1b substitutions. [0107] In some embodiments, in formula (IV), X ₁ and X ₂ are the same, and A4 with its R _1a substitutions is identical to A ₅ with its R _1b substitutions.

[0108] In some embodiments, in formula (IV), Xi and X2 are the same; Ria and R _3b are the same; and A4 with its R _1a substitutions is identical to A ₅ with its R _1b substitutions.

[0109] In some embodiments, the compound of formula (IV) is one of and or a pharmaceutically acceptable salt thereof. [0110] In some embodiments, the present disclosure provides a compound of formula (V), pharmaceutical compositions comprising a compound of formula (V), and a method of use of the compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0111] In some embodiments, in formula (V), X _A is N and X _B is S.

[0112] In some embodiments, in formula (V), XA is 0 and XB is CH.

[0113] In some embodiments, in formula (V), R ₅ is CN.

[0114] In some embodiments, in formula (V), R ₅ is (C ₁ -C ₆ )alkyl.

[0115] In some embodiments, in formula (V), R ₆ is (C ₁ -C ₆ )alkyl, or a (C ₁ -C ₃ ) alkyl.

[0116] In some embodiments, in formula (V), R ₆ is NO ₂ .

[0117] In some embodiments, in formula (V), R _4a and R _4b are the same.

[0118] In some embodiments, in formula (V), at least one of R _4a and R ₅ is hydrogen.

[0119] In some embodiments, in formula (V), v is 2, and x is 1.

[0120] In some embodiments, in formula (V), X _A is N; X _B is S; v is 2, and x is 1; Xc is CH, R _4a is a (C ₁ -C ₃ ) alkyl; R ₅ is hydrogen; R ₆ is NO ₂ , NH2, NHR2R3, or CH ₃ ; and R _1c is CHNHR ₂ or CHNR ₂ R ₃ , wherein R ₂ and R ₃ are the same or different and are each independently (C ₁ -C ₃ )alkyl. [0121] In some embodiments, in formula (V), X _A is O; X _B is CH; v is 2, and x is 1; Xc is CH, R _4a is a (C ₁ -C ₃ ) alkyl; R ₅ is hydrogen; R ₆ is NO ₂ , NH ₂ , NHR ₂ R ₃ , or CH ₃ ; and R _1c is CHNHR ₂ or CHNR ₂ R ₃ , wherein R ₂ and R ₃ are the same or different and are each independently (C ₁ -C ₃ )alkyl. [0122] In some embodiments, in formula (V), X _A is O; X _B is CH; v is 2, and x is 1; X _C is N, R _4a is hydrogen; R ₅ is CH ₂ CN; R ₆ is (C ₁ -C ₃ )alkyl; and R _1c is N=CR ₂ R ₃ , wherein R ₂ and R ₃ are the same or different and are each independently (C ₁ -C ₃ )alkyl or hydrogen.

[0123] In some embodiments, the compound of formula (V) is one of and or a pharmaceutically acceptable salt thereof.

[0124] In one aspect, the compounds of the present disclosure can be produced by the following general methods.

GENERAL METHODS FOR OBTAINING COMPOUNDS OF THE PRESENT DISCLOSURE

[0125] Reaction Schemes A, B, C and D illustrate general methods for obtaining the compounds of present disclosure.

Reaction Scheme A ¹ Reaction Scheme B

Reaction Scheme C

Ref:

1. J.K. Vandavasi et al., Tetrahedron 67 (2011), p. 8895-8901

[0126] Further, U.S. Patent No. 5,700,945, which is incorporated by reference in its entirety, discloses method of making compounds of Formula (V).

Prodrug Synthesis Example

Reaction Scheme D [0127] In one aspect, provided is a method of treating, preventing, reducing the occurrence of, or reducing, ameliorating, or alleviating the symptoms associated with presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, or other conditions or disorders associated with the eye, comprising administering to a subject in need thereof, an effective amount of the compounds of the present disclosure, including the disclosed compounds of formula (I), (II), (III), (IV), and (V), or pharmaceutically acceptable salts thereof, or prodrugs thereof, or any of the disclosed compounds. In some aspects, provided is a pharmaceutical composition the disclosed compounds of formula (I), (II), (III), (IV), and (V), or pharmaceutically acceptable salts thereof, or prodrugs thereof, or any of the disclosed compounds, and one or more pharmaceutically excipients.

[0128] In some aspects, the compounds of the present disclosure may be administered through any route of administration, including but not limited to oral, nasal, intranasal, intramuscular, intravenous, subcutaneous, rectal, sublingual, intrathecal, transdermal, intraocularly, inhalation or other topical. In some aspects, the compounds are administrated intraocularly or topically to the eye. In some aspects, the pharmaceutically composition is an ophthalmic solution or suspension comprising the compound and one or more pharmaceutically acceptable excipients suitable for administration to the eye.

EXAMPLES

Example 1: Measurement of biochemical potency of compounds

[0129] The potency of compounds to provide protection from Ca ⁺² and UVC induced aggregation of alpha-A crystalline (ACC) was measured by monitoring the effect of Ca ⁺² and UVC on recombinant human hAAC. hAAC forms HMW aggregates when exposed to UVC radiation in the presence of 10 mM Ca ⁺² . The aggregates lead to increased absorbance. Stock compound solutions (made in DMSO) were added to recombinant hAAC (100ug/ml) at desired concentrations. The hAAC, with the added compound, was incubated at room temperature for 1 hour, followed by addition of 10 μl of 200 mM CaCl ₂ and further incubation for 5 minutes. Then, absorbance was recorded at 400 nM (T=0 Minute) followed by exposure to UVC (254 nm, 480 mJ/cm ² per minute). Absorbance was measured again at 15 and 30 minutes. To control for compound related effects, assays were performed with or without AAC in triplicate. Percent protection or change in fold- decrease in aggregation were computed using the measured differences in absorbance. DMSO was used as control. Results obtained are shown below in Table 1. EC ₅₀ values were calculated using the SDS-PAGE, which is defined as the concentration of SMD needed to prevent 50% of hAAC from forming HMW aggregates when exposed to UVC in presence of Ca ⁺² [FIGS 2A-2B]

Example 2: Cellular activity of AC based evaluation and optimization of SMDs:

[0130] A mild heating assay using human lens epithelial (HLE) cells has been previously used as a model system for mimicking lens aging, where the time of heating is correlated with a loss in AC function and cell death. SRA 01/04 cells were pre-incubated for 2 hours with or without compounds and then exposed to UV light or heat and cell viability was assessed by Alamar blue 24-hours after exposure. The percent viability was calculated relative to untreated drug [FIGS 3A- 3C] Correspondingly, heating of intact human lenses dramatically promotes conversion of soluble AC into HMW aggregates and induces opacity.

Example 3: Ex vivo lens culture-based evaluation and optimization of SMDs:

[0131] To predict whether SMDs could prevent opacification in animal models and ultimately in human patients, we assessed their ability to protect intact lenses cultured ex vivo from UV-induced opacification. As fresh human lenses are difficult to obtain, porcine lenses were used for the ex vivo studies. Porcine lenses are easy to acquire (Sierra for Medical Science, Inc., Whittier, CA) and have been used previously in ex vivo models of Presbyopia. As predicted by our biochemical assays, SMDs prevents UV-induced opacification of porcine lenses ex vivo.

Table 1 : Compound with data

Note: = 20% or less unaggregated AAC

“+” score= >20% to 50% unaggregated AAC “++” score= >50% unaggregated AAC Cell data: % activity at 500uM; n/a = not active

OTHER EMBODIMENTS

[0132] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0133] From the above description, one skilled in the art can easily ascertain the essential characteristics of the described compounds, products and methods, and without departing from the spirit and scope thereof, can make various changes and modifications thereof to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.