Compounds and methods for treating eye disorders

Abstract

Described herein are compositions and methods for treating ocular surface disorders, including meibomian gland dysfunction, blepharitis, dry eye disease, and other inflammatory and / or infectious diseases of the anterior surface of the eye. The compositions and methods include keratolytic conjugates that demonstrate keratolytic activity and anti-inflammatory or other desirable activity. Topical administration of the compositions to the eyelid margin or surrounding area provides therapeutic benefit to patients with ocular surface disorders.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 835,963, filed Apr. 18, 2019, which is incorporated herein by reference in its entirety.

Background Art

[0002] Restasis (0.05% cyclosporine A, Allergan) has been approved by the Food and Drug Administration (FDA) to increase tear production in patients in whom tear production is presumed to be suppressed due to eye inflammation associated with dry eye keratoconjunctivitis. Xiidra® (lifitegrast ophthalmic solution) 5% is indicated for the signs and symptoms of dry eye disease (DED).

Summary of the Invention

[0003] In certain embodiments herein, compounds, pharmaceutical (e.g., ophthalmic) compositions, and treatment methods are provided. In specific embodiments, the treatment methods provided herein include treating indications or abnormalities of the eye and / or periocular region. In some embodiments, the indications or abnormalities of the eye and / or periocular region treated by or with the compositions or compounds provided herein are indications or abnormalities having multifactorial etiologies and / or interactions. In certain embodiments herein, compounds (and compositions containing such compounds) having multifactorial effects are provided, such as when administered to the eye or its surroundings (e.g., the eyelids such as the ocular surface, eyelid margin, or inner eyelid surface).

[0004] In one embodiment, the method provided herein relates to a method of treating meibomian gland dysfunction (MGD).

[0005] Currently, there are no approved pharmacological agents useful for the treatment of MGD. The recognition that terminal duct obstruction resulting from hyperkeratosis of the ductal epithelium of the meibomian glands is the central mechanism underlying MGD is consistent with clinical experience demonstrating that the restoration of ductal obstruction and the removal of glandular contents are necessary for effective treatment of MGD (Nichols et al, 2011; Lane et al, 2012; Blackie et al, 2015). Warm compresses and thermal / mechanical devices (e.g., LipiFlow) have been used in an attempt to raise the internal temperature of the meibomian glands above the normal melting point of meibum (32°C - 40°C) to restore terminal duct obstruction (Lane et al, 2012). Unfortunately, warm compresses are unable to achieve such benefits for severely obstructed glands that may have a melting point below 40°C. Current techniques for removing keratinous obstruction of the meibomian glands also include physical removal methods (e.g., debridement and gland probing) that are associated with significant pain for the patient.

[0006] After MGD, inflammatory or bacterial diseases at various stages are observed on the ocular surface. The reason is that meibomian gland obstruction may cause a series of events including further deterioration of the gland due to stasis of meibum in the secretory gland (Knop, IOVS, 2011), mechanical pressure and stress due to gland obstruction, and an increase in bacterial growth associated with the downstream release of bacterial lipase, toxic mediators, and / or inflammatory mediators. All of these factors can reduce the quality and / or quantity of meibum that the gland can secrete, cause chronic mechanical damage to the conjunctival tissue, corneal tissue, and eyelid tissue, and subsequently lead to tissue damage and the release of inflammatory mediators. Therefore, many MGD patients also have inflammatory diseases that affect the conjunctiva, cornea, lacrimal gland, eyelid, or goblet cells, causing concurrent conditions such as dry eye syndrome or blepharitis that have unmet medical needs.

[0007] For example, in the literature, the terms posterior blepharitis and MGD are used as if they have the same meaning, but these terms are not interchangeable. Posterior blepharitis describes the inflammatory condition of the posterior eyelid margin, and one possible cause for this is MGD. In its earliest stage, MGD may not be associated with the clinical symptom characteristics of posterior blepharitis. At this stage, the affected individual may be symptomatic or asymptomatic, and the condition is considered subclinical. As MGD progresses, symptoms develop, and lid margin signs such as the expressivity and quality changes of meibomian glands and lid margin erythema may become more visible. At this point, it is said that there is MGD-related posterior blepharitis.

[0008] In certain embodiments herein, methods are provided for treating eye (or dermatological) disorders associated with keratosis (such as lid keratosis, ocular surface keratosis, and / or glandular blockage in MGD, etc.), microbial infiltration / infection (such as bacterial infiltration / infection), and / or inflammation (inflammation associated with or not associated with keratosis). In one example, disorders of the skin and / or eye (and / or surrounding tissue / skin) are difficult to differentially diagnose and / or have multiple etiologies. For example, in some cases, it can be difficult to distinguish between (1) inflammation only, (2) inflammation associated with keratolytic activity, (3) inflammation associated with both keratolytic activity (such as inducing keratosis) and microbial infiltration, (4) having keratolytic activity but no inflammation and / or microbial infiltration, or various other combinations. In some cases, the compounds and compositions provided herein can be used for such eye and / or dermatological indications without performing differential diagnosis (which may be difficult due to, for example, similar symptom scores, etc.). Furthermore, many eye and / or dermatological disorders are associated with multiple etiologies such as inflammation, microbial infiltration, keratolytic activity, or various combinations thereof. As a result, therapeutic agents that target multiple etiologies, such as those described herein, are beneficial in providing therapeutic benefit by targeting both the underlying disease (such as keratolytic activity and / or microbial infiltration) and symptoms such as inflammation or dry eye.

[0009] Therefore, the present specification provides compounds, compositions, methods, and formulations for treating ocular (e.g., periorbital) or dermatological disorders, such as those having an abnormality with a multifactorial etiology. In specific embodiments, non-limiting examples of ocular disorders include surface disorders such as MGD, dry eye, and related inflammatory and bacterial diseases.

[0010] In certain embodiments herein, a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, is provided,

[0011]

Chemical formula

[0012] In some embodiments, L' comprises one or more linker groups, and each linker group is selected from the group consisting of a single bond, -O-, -S-, halo, alkyl(alkenyl), heteroalkyl(heteroalkenyl), disulfide, ester, and carbonyl (>C=O). In some embodiments, each linker group is selected from the group consisting of a single bond, -O-, -S-, halo, alkyl(alkenyl), heteroalkyl(heteroalkenyl), and ester. In some embodiments, each linker group is selected from alkyl(alkylene) and heteroalkyl(heteroalkylene), and the alkyl(alkylene) and heteroalkyl(heteroalkylene) are optionally substituted. In some embodiments, L' substituted with oxo and one or more of alkyl and heteroalkyl is alkyl(alkylene). In some embodiments, alkyl or heteroalkyl is substituted with one or more halo, alkyl, or haloalkyl. In some embodiments, alkyl or heteroalkyl is substituted with one or more alkyl or haloalkyl. In some embodiments, L' is a single bond, -O-, -S-, halo, (C=O), -(C=O)alkyl-, -(C=O)heteroalkyl-, -(C=O)O-, -(C=O)Oalkyl-, -(C=O)Oheteroalkyl-, -(C=O)S-, -(C=O)Salkyl-, -(C=O)Sheteroalkyl-, alkylene, or heteroalkylene, and alkyl, heteroalkyl, alkylene, or heteroalkylene are each optionally substituted. In some embodiments, L' is (C=O), -(C=O)alkyl-, -(C=O)heteroalkyl-, -(C=O)O-, -(C=O)Oalkyl-, -(C=O)Oheteroalkyl-, -(C=O)S-, -(C=O)Salkyl-, -(C=O)Sheteroalkyl-, alkylene, or heteroalkylene.

[0013] In some embodiments, the linker has the structure of formula (A),

[0014]

Chemical formula

[0015] In some embodiments, the compound comprises more than one linker of formula (A). In some embodiments, Z is a single bond or -O-. In some embodiments, Z is a single bond, and G 1 and G 2 are each independently hydrogen, alkyl, or cycloalkyl, and the alkyl or cycloalkyl is optionally substituted. In some embodiments, Z is -O-, and G 1 and G 2 are each independently hydrogen, alkyl, or cycloalkyl, and the alkyl or cycloalkyl is optionally substituted. In some embodiments, Z is a single bond or -O-, G 1 is hydrogen, and G 2 is alkyl or haloalkyl. In some embodiments, Z is a single bond or -O-, G 1 is hydrogen, and G 2 is methyl. In some embodiments, Z is a single bond or -O-, G 1 and G 2 are each independently hydrogen. In some embodiments, Z is a single bond, G 1 is hydrogen, and G 2 is methyl. In some embodiments, Z is a single bond, G 1 and G 2They are each independently hydrogen. In some embodiments, Z is -O-, and G 1 is hydrogen, and G 2 is methyl. In some embodiments, Z is -O-, and G 1 and G 2 are each independently hydrogen.

[0016] In some embodiments, g is from 1 to 20. In some embodiments, g is from 1 to 10. In some embodiments, g is from 1 to 5. In some embodiments, g is 2. In some embodiments, g is 1.

[0017] In some embodiments, g is 1 or 2, Z is a single bond, and G 1 is hydrogen, and G 2 is methyl. In some embodiments, g is 1 or 2, Z is a single bond, and G 1 and G 2 are each independently hydrogen. In some embodiments, g is 1 or 2, Z is -O-, and G 1 is hydrogen, and G 2 is methyl. In some embodiments, g is 1 or 2, Z is -O-, and G 1 and G 2 are each independently hydrogen.

[0018] In some embodiments, the linker is a single bond, -O-, methylene,

[0019]

Chemical formula

[0020] In some embodiments, the linker is a single bond, methylene,

[0021]

Chemical formula

[0022] In some embodiments, D is selected from alkyl and heteroalkyl, and the alkyl or heteroalkyl is optionally substituted. In some embodiments, D is an alkyl substituted with one or more groups selected from oxo and substituted alkyl and substituted heteroalkyl. In some embodiments, the alkyl is substituted with one or more groups selected from -SH, -OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, D is a heteroalkyl substituted with one or more groups selected from oxo and substituted alkyl and substituted heteroalkyl. In some embodiments, the heteroalkyl is substituted with one or more groups selected from -SH, -OH, or substituted or unsubstituted heteroalkyl. In some embodiments, the heteroalkyl is substituted with one or more groups selected from -SH, -OH, alkyl, (C=O)alkyl, (C=O)heteroalkyl, and -NH(C=O)alkyl.

[0023] In some embodiments, D is -CH2OH, -CH(CH3)OH, -CH2(OCH2CH2)4OH, -CH2CH2(OCH2CH2)4OH,

[0024]

Chemical formula

[0025]

Chemical formula

[0026] In some embodiments, D is -CH2OH, -CH(CH3)OH, -CH2(OCH2CH2)4OH, -CH2CH2(OCH2CH2)4OH,

[0027]

Chemical formula

[0028]

Chem.

[0029] In some embodiments, D is

[0030]

Chem.

[0031]

Chem.

[0032] In some embodiments, D is

[0033]

Chem.

[0034] In some embodiments, D or the keratolytic agent is

[0035]

Chem.

[0036] In some embodiments, D is a "keratolytic agent" radical that, upon release, hydrolysis, or other mechanism, produces or otherwise generates an active keratolytic agent (e.g., when administered to an individual or patient, such as in or around the eye like the eyelid margin). In some examples, upon release (e.g., by hydrolysis or other mechanism), D produces a plurality of active keratolytic agents. In some examples, the active keratolytic agent includes one or more of -SH, -OH, COOH (or COO-), or disulfide. In some embodiments, the active keratolytic agent is a carboxylic acid. In some embodiments, the active keratolytic agent is selected from the group consisting of acetic acid, glycolic acid, lactic acid, lipoic acid, pivalic acid, isobutyric acid, butyric acid, propionic acid, formic acid, and carbonic acid. In some embodiments, the active keratolytic agent is a thiol.

[0037] In some embodiments, L is attached to D by a single bond.

[0038] In one example, a combination of an anti-inflammatory and / or antimicrobial moiety (e.g., having the structure of the formula provided herein minus R') and a keratolytic moiety (e.g., represented by and / or having the structure of D) is provided. In certain embodiments, such moieties are radicals connected by a linker that is a single bond, and the keratolytic moiety is hydrolysable to produce both (1) an anti-inflammatory and / or antimicrobial agent and (2) one or more active keratolytic agents. In some embodiments, such moieties are radicals connected by a hydrolysable linker that is hydrolysable such that both (1) an anti-inflammatory and / or antimicrobial agent and (2) one or more active keratolytic agents are released (e.g., in vivo, such as after therapeutic (e.g., topical) administration to the eye and / or skin).

[0039] In certain embodiments herein, a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, is provided.

[0040] [Chemical formula] In the formula, R 1 is aryl, cycloalkyl, heterocyclyl, or heteroaryl, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted, R 2 , R 3 , and R 4 are each independently H, cyano, halo, ester, alkoxy, alkyl, heteroalkyl, cycloalkyl, or heterocyclyl, and the alkoxy, alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted, R 5 is -L-R 5a where L is a single bond, alkyl, or heteroalkyl, and R 5a is absent or is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted, R 6 is H, alkyl, or heteroalkyl, each R 7 is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl, cycloalkyl, or haloalkyl, n is from 0 to 6, and R is alkyl or heteroalkyl substituted with at least one oxo and is further optionally substituted.

[0041] In some embodiments, R 1 is optionally substituted alkyl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R 1 is optionally substituted aryl or heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1is benzofuran. In some embodiments, R 1 is

[0042]

Chemical formula

[0043] In some embodiments, R 2 and R 4 are each independently H, halo, alkoxy, or alkyl. In some embodiments, R 2 and R 4 are each independently H, halo, or alkyl. In some embodiments, R 2 and R 4 are halo. In some embodiments, R 2 and R 4 are each independently chloro. In some embodiments, R 3 is H, alkyl, halo, heteroalkyl, or cycloalkyl. In some embodiments, R 3 is H, alkyl, or halo. In some embodiments, R 3 is H. In some embodiments, R 2 and R 4 are each independently chloro, and R 3 is H.

[0044] In some embodiments, L is a single bond. In some embodiments, L is a bond, and R 5a is optionally substituted aryl or heteroaryl. In some embodiments, L is alkyl and R 5a is absent. In some embodiments, L is alkyl and R 5a is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R 5 is optionally substituted aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl. In some embodiments, R 5is an optionally substituted aryl-alkyl or heteroaryl-alkyl. In some embodiments, R 5 is a substituted aryl-alkyl or heteroaryl-alkyl. In some embodiments, R 5 is a substituted aryl-alkyl. In some embodiments, R 5 is an aryl-alkyl substituted with sulfonyl. In some embodiments, R 5 is an aryl-alkyl substituted with monosulfonyl. In some embodiments, the sulfonyl substituent is methylsulfone. In some embodiments, R 5 is

[0045]

Chemical formula

[0046] In some embodiments, R 6 is heteroalkyl. In some embodiments, R 6 is -(C=O)alkyl or -(C=O)heteroalkyl. In some embodiments, R 6 is alkyl. In some embodiments, R 6 is H.

[0047] In some embodiments, each R 7 is independently H, halo, alkyl, heteroalkyl, or cycloalkyl. In some embodiments, each R 7 is independently H, halo, or alkyl. In some embodiments, n is 1 and R 7 is halo or alkyl. In some embodiments, n is 2 and R 7 is independently halo or alkyl. In some embodiments, n is 0.

[0048] In some embodiments, R 1 is heteroaryl, and R 2 and R 4 are each independently halo,5 is a substituted aryl-alkyl. In some embodiments, R 1 is heteroaryl, R 2 and R 4 are each independently halo, R 3 is H, R 5 is a substituted aryl-alkyl, R 6 is H or alkyl, and n is 0. In some embodiments, R 1 is benzofuran, R 2 and R 4 are each independently halo, R 3 is H, R 5 is an aryl-alkyl substituted with sulfonyl, R 6 is H, and n is 0. In some embodiments, R 1 is benzofuran, R 2 and R 4 are each chloro, R 3 is H, R 5 is an aryl-alkyl mono-substituted with sulfonyl, R 6 is H, and n is 0. In some embodiments, R 1 is

[0049]

Chemical formula

[0050]

Chemical formula

[0051] In some embodiments, the compound has the structure of formula (Ib) or a pharmaceutically acceptable salt thereof.

[0052]

Chemical formula

[0053] In some embodiments, the alkyl or heteroalkyl of R is substituted with one or more substituents, each substituent independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, halo, oxo, heterocyclyl, and cycloalkyl, and the heterocyclyl and cycloalkyl are optionally substituted (e.g., by one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, selenide, diselenide, sulfone, amide, halo, and oxo). In some embodiments, the alkyl of R is substituted with one or more substituents, each substituent independently selected from alkyl, oxo, heteroalkyl, haloalkyl, hydroxyl, thiol, thioether, disulfide, and heterocycloalkyl.

[0054] In some embodiments, R is

[0055]

Chemical formula

[0056] In some embodiments, X is -O-, and R 8 is alkyl or haloalkyl. In some embodiments, X is -O-, and R 8 is alkyl. In some embodiments, X is -O-, and R 8is methyl. In some embodiments, X is a single bond, and R 8 is alkyl or haloalkyl. In some embodiments, X is a single bond, and R 8 is alkyl. In some embodiments, X is a single bond, and R 8 is methyl.

[0057] In some embodiments, the compound has the structure of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof.

[0058]

Chemical formula

[0059] In some embodiments, X is a single bond. In some embodiments, X is -O-. In some embodiments, X is a single bond or -O-, and the alkyl or heteroalkyl of said R 9 is substituted with one or more substituents, each substituent being independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, ester, carboxylic acid, halo, oxo, heterocyclyl, and cycloalkyl, and said heterocyclyl and cycloalkyl are optionally substituted (e.g., by one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, sulfone, amide, ester, halo, and oxo). In some embodiments, the alkyl or heteroalkyl of said R 9 is substituted with one or more substituents, each substituent being independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, ester, oxo, and heterocyclyl.

[0060] In some embodiments, X is -O-, and R 9 is C1-6 alkyl, -(CR d R e )p (C=O)O(C1-C6-alkyl), -(CR d R e ) p carbocyclic, -(CR d R e ) p heterocyclic, or

[0061] [Chemical formula] and R d and R e are each independently H, halo, alkyl, alkoxy, hydroxyl, thioether, sulfide, thiol, disulfide, seleno, heteroalkyl, carbocyclic, carbocyclic alkyl, carbocyclic alkoxy, carboxyl, heterocyclic, heterocycloalkyl, or heterocyclic alkoxy, R 10 is H, -(C=O)C1-6 alkyl, and each R 10 combines to optionally form a substituted heterocycloalkyl, p is from 1 to 6, and C1-6 is optionally substituted by halo, alkyl, heteroalkyl, alkoxy, hydroxyl, thiol, disulfide, selenide, diselenide, amide, heterocyclic, or heterocyclic alkyl.

[0062] In some embodiments, X is -O-, and R 9 is C1-6 alkyl. In some embodiments, the C1-6 alkyl is optionally substituted by alkyl, heteroalkyl, alkoxy, hydroxyl, heterocyclic, or heterocyclic alkyl.

[0063] In some embodiments, X is -O-, and R 9 is

[0064] [Chemical formula] is as follows.

[0065] In some embodiments, each R 10 is independently hydrogen or -(C=O)C1-6 alkyl. In some embodiments, each R 10 is hydrogen. In some embodiments, each R 10 is -(C=O)C1-6 alkyl. In some embodiments, the alkyl of the -(C=O)C1-6 alkyl is methyl, ethyl, propyl, isopropyl, or tert-butyl. In some embodiments, the alkyl of the -(C=O)C1-6 alkyl is methyl. In some embodiments, the alkyl of the -(C=O)C1-6 alkyl is ethyl. In some embodiments, the alkyl of the -(C=O)C1-6 alkyl is propyl. In some embodiments, the alkyl of the -(C=O)C1-6 alkyl is isopropyl. In some embodiments, the alkyl of the -(C=O)C1-6 alkyl is tert-butyl.

[0066] In some embodiments, each R 10 combines to form an optionally substituted heterocycloalkyl. In some embodiments, R d and R e are each independently hydrogen, halo, or alkyl. In some embodiments, R d and R e are each hydrogen. In some embodiments, p is from 1 to 5. In some embodiments, p is from 1 to 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, the heterocycloalkyl is 2,2-dimethyl-1,3-dioxane, 2-methyl-1,3-dioxane, or 1,3-dioxane.

[0067] In some embodiments, X is a single bond, and R 9is C1-6 alkyl, heteroalkyl, or heterocyclylalkyl, wherein the C1-6 alkyl may be straight-chain or branched-chain and is optionally substituted with halo, alkyl, heteroalkyl, alkoxy, hydroxyl, thiol, disulfide, selenide, diselenide, amide, heterocyclyl, or heterocyclylalkyl. In some embodiments, X is a single bond, and R 9 is heteroalkyl. In some embodiments, X is a single bond, the heteroalkyl is -(C=O)alkyl, and the alkyl is optionally substituted with -OH or heterocycloalkyl. In some embodiments, the heterocycloalkyl is dithiolane.

[0068] In some embodiments, X is a single bond or -O-, and R 9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0069] In some embodiments, X is a single bond, and R 9 is CH2OH, -CH(CH3)OH, -CH2(OCH2CH2)4OH, -CH2CH2(OCH2CH2)4OH.

[0070] In some embodiments, X is -O-, and R 9 is

[0071]

Chemical formula

[0072] In some embodiments, R 9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, CH2OH,

[0073]

Chemical formula

[0074] One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0075]

Chemical formula

[0076] One embodiment provides a compound having the structure of formula (I') or a pharmaceutically acceptable salt thereof.

[0077]

Chemical formula

[0078] One embodiment provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0079]

Chemical formula

[0080] One embodiment provides a pharmaceutical composition comprising a compound provided herein, such as a compound of any one of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Another embodiment provides a pharmaceutical composition suitable for ocular administration. Another embodiment provides a pharmaceutical composition suitable for topical ocular administration. In some embodiments, topical ocular administration is administration to the inside and / or around the eye, such as the lid margin. In some embodiments, topical ocular administration is administration to the ocular surface and the inner surface of the eyelid.

[0081] In some embodiments, a compound provided herein, such as a compound of any one of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, is hydrolytically substantially stable (e.g., stable in an aqueous composition (e.g., solution) such as a buffer or an ophthalmically acceptable aqueous composition). In some embodiments, said compound or pharmaceutical composition is formulated in an aqueous solvent. In some embodiments, said compound or pharmaceutical composition is formulated and stored in an aqueous solvent. In some examples, the compositions or formulations provided herein are chemically and / or physically stable in an aqueous composition.

[0082] In some embodiments, a compound provided herein, such as a compound of any one of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II), or a pharmaceutically acceptable salt thereof, is hydrolyzed to an active pharmaceutical (e.g., the free form of the radical of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II), where R is a negative charge or H) and a keratolytic agent. In some embodiments, said compound or pharmaceutical composition is hydrolyzed to an active pharmaceutical and a keratolytic agent in the ocular space. In some embodiments, said compound or pharmaceutical composition is hydrolyzed to an active pharmaceutical and a keratolytic agent by an esterase in the ocular space. In some embodiments, the pro-active pharmaceutical is an anti-inflammatory agent. In some embodiments, said anti-inflammatory agent is lifitegrast. In some embodiments, said keratolytic agent is a carboxylic acid. In some embodiments, said carboxylic acid is selected from the group consisting of acetic acid, glycolic acid, lactic acid, lipoic acid, pivalic acid, isobutyric acid, butyric acid, propionic acid, formic acid, and carbonic acid. In some embodiments, said active keratolytic agent is a thiol.

[0083] In some embodiments, provided herein are compounds such as any one of the compounds of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising said compounds. In certain embodiments, said composition further comprises a certain amount of the free form of any radical of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II) (said free form being a radical where R is a negative charge or H). In some embodiments, the compositions provided herein are in a ratio of about 1:99 to about 100:0 (e.g., by weight or mole) of the compounds provided herein or pharmaceutically acceptable salts thereof and the free form of any radical of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II) (e.g., where R is a negative charge or H) (e.g., the amount of the free form of said radical relative to the total amount of the free form and conjugate of said radical is from 0% (by weight or mole) to 99%). In some embodiments, the relative amount of the free form of said radical is from 0% to about 50%, such as 0% to about 20%, 0% to about 10%, about 0.1% to about 10%, about 0.1% to about 5%, less than 5%, less than 2.5%, less than 2%, etc. (the percentages being weight / weight or mole / mole percentages). In some examples, such aqueous compositions are pre-manufactured or manufactured at the time of application to maintain a high concentration of the compound relative to its free form of the radical. In some embodiments, such a concentration of the compound is present in the aqueous composition (such as an aqueous composition under the conditions described herein, e.g., HEPES buffer, etc.) for at least 45 minutes in the composition. Tables 2 and 3 of the examples illustrate the good stability of the compositions provided herein, and these listings are incorporated into their disclosure. Further in some examples, the compounds provided herein release the free form of the radical of the compounds of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II) (e.g., where R is a negative charge or H) upon administration to an individual (e.g., upon administration to the eye (e.g., periorbitally) or skin).In a more specific example, when administered at the location where esterase is present in an individual, the active (free) form of the radicals of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II) (for example, R is a negative charge or H) (and keratolytic agents and / or agents that further produce active keratolytic agents (for example, by further hydrolysis thereof)) are rapidly released.

[0084] One embodiment provides a method of treating an eye disease or disorder in a patient, the method comprising administering to the patient a composition comprising a compound provided herein, such as any one of the compounds of formula (Ia), formula (Ib), formula (Ic), formula (I), formula (I'), or formula (II), or a pharmaceutically acceptable salt thereof. Another embodiment provides a method wherein the eye disease or disorder is selected from dry eye, lid wiper epitheliopathy (LWE), contact lens discomfort (CLD), contact lens discomfort, dry eye syndrome, evaporative dry eye syndrome, aqueous tear-deficient dry eye syndrome, blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland disorders, inflammation of the anterior eye surface, infectious diseases of the anterior eye surface, infectious diseases of the eyelids, demodex blepharitis, lid wiper epitheliopathy, and autoimmune disorders of the anterior eye surface.

[0085] In certain embodiments herein, methods of treating eye (e.g., periorbital) or dermatological indications (e.g., related to keratolytic activity, inflammation, and / or microbial infiltration) are provided, the methods comprising administering a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the compositions provided herein (e.g., used in the methods provided herein) comprise a therapeutically effective amount (e.g., a concentration effective to treat keratosis / keratolytic activity, inflammation, and / or microbial infiltration) of a compound provided herein for the eye, surrounding tissues, or skin. In one embodiment, the compositions provided herein (e.g., pharmaceutical and / or ophthalmic) comprise from about 0.1 wt% to about 10 wt% of a compound provided herein.

[0086] As ophthalmic and / or dermatological disorders, inflammatory diseases of the eyelids (such as hordeolum (sty), blepharitis, and chalazion), the ocular surface (such as dry eye disease and anterior uveitis), and the posterior segment of the eye (such as posterior and panuveitis), abnormalities of the periocular glands (such as meibomian gland dysfunction (MGD)), allergic diseases (such as eczema, atopic dermatitis, atopic keratoconjunctivitis resistant to topical steroid therapy, and vernal keratoconjunctivitis), surgical complications (such as corneal transplant rejection, glaucoma after corneal transplantation, cataract associated with phakic corneal transplantation, fungal infections in corneal transplant patients, and dry eye after LASIK, and / or poor refractive outcome), corneal abnormalities (such as inflammatory corneal ulcer, rheumatic corneal ulcer, and Thygeson superficial punctate keratitis), conjunctival abnormalities (such as iridocyclitis, ligneous conjunctivitis), ocular complications due to systemic therapy and / or autoimmune diseases (such as pauciarticular juvenile rheumatoid arthritis, graft-versus-host disease, and Sjogren's syndrome), and / or infections of the anterior surface of the eye are included. Compositions and methods for treating ocular and periocular abnormalities known to have multifactorial etiologies and interactions are provided herein.

[0087] One embodiment provides a compound having the structure of formula (III), or a pharmaceutically acceptable salt or solvate thereof,

[0088] [Chemical formula] X is a single bond or -O-, R 8 is hydrogen, alkyl, heteroalkyl, or haloalkyl, R 9 is alkyl or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted.

[0089] In some embodiments, R 8 is hydrogen, alkyl, or haloalkyl. In some embodiments, R 8 is C1-C4 alkyl. In some embodiments, R 8 is methyl.

[0090] In some embodiments, X is a single bond. In some embodiments, R 9 is alkyl optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of -OH and optionally substituted alkyl. In some embodiments, the alkyl is substituted by alkyl or heterocycloalkyl. In some embodiments, the heterocycloalkyl is further optionally substituted. In some embodiments, R 9 is alkyl substituted by OH. In some embodiments, R 9 is alkyl substituted by OH and alkyl. In some embodiments, R 9 is alkyl substituted by dithiolane. In some embodiments, R 9 is C1-C4 alkyl.

[0091] In some embodiments, R 9 is C1-C4 alkyl, -CH(CH3)OH, -CH2OH, or

[0092]

Chemical formula

[0093] In some embodiments, X is -O-. In some embodiments, R 8 is methyl and R 9 is alkyl further optionally substituted by one or more substituents, each substituent being independently selected from the group consisting of alkyl, heteroalkyl (such as hydroxymethyl or ester), and heterocycloalkyl, and the heteroalkyl (such as hydroxymethyl or ester) or heterocycloalkyl being further optionally substituted. In some embodiments, R 9 is alkyl further substituted by optionally substituted 1,3-dioxane. In some embodiments, R 9is alkyl further substituted with 1,3 - dioxane. In some embodiments, R 9 is alkyl further substituted with 2,2 - dimethyl - 1,3 - dioxane or 2 - methyl - 1,3 - dioxane. In some embodiments, R 9 is alkyl further substituted with one or more heteroalkyl substituents. In some embodiments, the heteroalkyl substituent is - CH2OH or - O(C = O)C1 - C4 alkyl. In some embodiments, R 9 is alkyl further substituted with alkyl, where the alkyl is further substituted with an ester substituted with alkyl, and the alkyl is optionally further substituted with one or more substituents, each substituent being independently selected from the group consisting of - OH and alkyl. In some embodiments, R 9 is C1 - C4 alkyl. In some embodiments, R 9 is alkyl further substituted with methyl and - O(C = O)C1 - C4 alkyl.

[0094] In some embodiments, R 9 is C1 - C4 alkyl,

[0095]

Chemical formula

[0096] In some embodiments, the C1 - C4 alkyl is methyl, ethyl, propyl, isopropyl, or tert - butyl.

[0097] In certain embodiments described herein, a method of treating a disorder or condition (e.g., any disorder or condition described herein) of an individual (e.g., the eye or skin) is described, the method comprising administering (e.g., topically to the eye and / or skin) to the individual a composition (e.g., any composition described herein) comprising a compound provided herein such as a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0098] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference for the specific purposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

[0099] Specific Definitions As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, references to "an agent" include plural such agents, references to "a cell" include one or more cells (or plural cells), and references to equivalents known to those skilled in the art, etc. When ranges are used herein with respect to physical properties such as molecular weight or chemical properties such as chemical formula, all combinations of the range and specific embodiments therein, and subcombinations, are intended to be encompassed. The term "about" when referring to a number or range of numbers means that the recited number or range of numbers is an approximation within the range of experimental variation (or within statistical experimental error), and thus the number or range of numbers may vary by 1% to 15% of the recited number or range of numbers. The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is intended not to exclude, in other specific embodiments, embodiments such as any composition, composition of matter, method, or process described herein that may consist of or consist essentially of the recited features.

[0100] As used herein, the terms "treat", "treating", or "treatment" include the reduction, attenuation, alleviation, amelioration, mitigation, or decrease of symptoms associated with a disease, disease state, or indication (e.g., MGD) in either a chronic or acute treatment scenario. In one embodiment, treatment includes the reduction of terminal duct occlusion. Further, treatment of a disease or disease state described herein includes the disclosure of the use of the foregoing compounds or compositions for the treatment of such disease, disease state, or indication.

[0101] The term "open" refers to the removal (at least partial) of an occluded meibomian gland duct or orifice and / or the maintenance of the patency of the meibomian gland duct or orifice.

[0102] The terms "keratolytic agent" and / or "keratoplastic agent", as used herein, refer to an agent that softens, disrupts, dissolves, solubilizes, or alleviates keratinization occlusion or prevents the formation of keratinization occlusion. Specifically, the term "keratolytic agent" refers to an agent used to promote the softening and dissolution of keratin, and the term "keratoplastic agent" refers to an agent used to reduce keratin production.

[0103] "Amino" refers to the -NH2 radical.

[0104] "Cyano" refers to the -CN radical.

[0105] "Nitro" refers to the -NO2 radical.

[0106] "Oxo" refers to the =O radical.

[0107] "Thioxo" refers to the =S radical.

[0108] "Imino" refers to the =N-H radical.

[0109] "Imino" refers to the =N-H radical.

[0110] "Oximo" refers to the =N-OH radical.

[0111] "Hydrazino" refers to the =N-NH2 radical.

[0112] "Alkyl" generally refers to a straight-chain or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, such as having 1 to 15 carbon atoms (e.g., C1-C 15 alkyl). Unless otherwise specified, alkyl is saturated or unsaturated (e.g., alkenyl containing at least one carbon-carbon double bond). The disclosure of "alkyl" provided herein is intended to include a separate detailed description of saturated "alkyl" unless otherwise specified. The alkyl groups described herein are generally monovalent, but may also be divalent (sometimes also described herein as "alkylene" groups or "alkylenyl" groups). In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 alkyl). In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15It contains (alkyl). In other embodiments, the alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is bonded to the rest of the molecule by a single bond. Usually, each alkyl group is independently substituted or unsubstituted. Each detailed description of "alkyl" provided herein includes a specific and explicit description of an unsaturated "alkyl" group unless otherwise specified. Similarly, unless otherwise specified herein, an alkyl group has the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2) and is optionally substituted by one or more of them, and each R aindependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0113] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where the alkyl is an alkyl chain as defined above.

[0114] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. The alkenyl is optionally substituted as described for the "alkyl" group.

[0115] "Alkylene" or "alkylene chain" generally refers to a straight-chain or branched-chain divalent alkyl group having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, i-propylene, n-butylene, etc., which binds the remainder of the molecule to a radical group. Unless otherwise specified herein, the alkylene chain is optionally substituted as described for the alkyl group herein.

[0116] "Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon consisting of 5 to 18 carbon atoms, where at least one of the rings in the ring system is completely unsaturated, i.e., contains a cyclic delocalized (4n + 2)π - electron system according to Hückel's theory. Examples of the ring system from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically provided herein, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include an aryl radical optionally substituted by one or more substituents, and the one or more substituents are independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)R a 、-R b -OC(O)OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)Ra , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) and is selected from each R aEach is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond, or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise defined, the above substituents are each unsubstituted.

[0117] "Aralkyl" or "aryl-alkyl" refers to a radical of the formula -R c -aryl, where R c is an alkylene chain as defined above, such as methylene or ethylene. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as described above for the aryl group.

[0118] "Carbocyclic" or "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, and having 3 to 15 carbon atoms. In certain embodiments, carbocyclic contains 3 to 10 carbon atoms. In other embodiments, carbocyclic contains 5 to 7 carbon atoms. Carbocyclic is bonded to the remainder of the molecule by a single bond. Carbocyclic or cycloalkyl is either saturated (containing only C-C bonds) or unsaturated (containing one or more double or triple bonds). Examples of saturated cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic is also called "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclic radicals include, for example, adamantyl, norbornyl (bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically defined herein, the term "carbocyclic" is intended to include carbocyclic radicals optionally substituted by one or more substituents, said one or more substituents being independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a , -R b -OC(O)R a , -R b -OC(O)OR a , -R b -OC(O)-N(R a )2, -Rb -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) and is selected from each R ais independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond, or a straight or branched alkylene chain or alkenylene chain, and R c is a straight or branched alkylene chain or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0119] "Carbocyclic alkyl" refers to a radical of the formula -R c -carbocyclic, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic radical are optionally substituted as defined above.

[0120] "Carbocyclic alkenyl" refers to a radical of the formula -R c -carbocyclic, where R c is an alkenylene chain as defined above. The alkenylene chain and the carbocyclic radical are optionally substituted as defined above.

[0121] "Carbocyclic alkynyl" refers to a radical of the formula -R c -carbocyclic, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclic radical are optionally substituted as defined above.

[0122] "Carbocyclic alkoxy" refers to a radical bonded through an oxygen atom of -carbocyclic of the formula -O-R c where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic radical are optionally substituted as defined above.

[0123] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to, the following.

[0124] [Chemical formula]

[0125] "Halo" or "halogen" refers to a substituent of bromo, chloro, fluoro, or iodo.

[0126] "Fluoroalkyl" refers to an alkyl radical as defined above, where the alkyl radical is substituted by one or more fluoro radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0127] The term "heteroalkyl" refers to an alkyl group as defined above, where one or more skeletal carbon atoms of the alkyl are replaced by heteroatoms (which may be replaced by, for example, -CH2- by -NH- or -O- depending on the appropriate number of substituents or valences). For example, each substituted carbon atom is independently replaced by a heteroatom, where the carbon is replaced by nitrogen, oxygen, selenol, or other appropriate heteroatoms. In some examples, each substituted carbon atom is independently replaced by oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, -N(aryl)-, or those having another substituent contemplated herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-). In some embodiments, heteroalkyl is bonded to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, heteroalkyl is bonded to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, heteroalkyl is C1-C 18 is heteroalkyl. In some embodiments, heteroalkyl is C1-C 12 is heteroalkyl. In some embodiments, heteroalkyl is C1-C6 heteroalkyl. In some embodiments, heteroalkyl is C1-C4 heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCH2OMe or -CH2CH2OMe. In some embodiments, heteroalkyl, as defined herein, includes alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl. Unless otherwise specifically defined herein, heteroalkyl groups are optionally substituted as defined above for alkyl groups.

[0128] "Heteroalkylene" refers to a divalent heteroalkyl group as defined above that connects one part of a molecule to another part thereof. Unless otherwise specifically defined, heteroalkylene is optionally substituted as defined above for alkyl groups.

[0129] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including a fused or bridged ring system. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. Heterocyclyl is attached to the remainder of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified herein, the term "heterocyclyl" is intended to include heterocyclyl radicals as defined above optionally substituted by one or more substituents, said substituents being alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a 、-R b -OC(O)R a 、-Rb -OC(O)OR a 、 -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a 、 -R b -C(O)OR a 、 -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a 、 -R b -N(R a )C(O)R a 、 -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2) and is selected from each R ais independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond, or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0130] “N - heterocyclyl” or “N - bonded heterocyclyl” refers to a heterocyclyl radical as defined above that includes at least one nitrogen, and the point of attachment of the heterocyclyl radical to the remainder of the molecule is through a nitrogen atom in the heterocyclyl radical. The N - heterocyclyl radical is optionally substituted as described above for the heterocyclyl radical. Examples of such N - heterocyclyl radicals include, but are not limited to, 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0131] "C - Heterocyclyl" or "C - bonded heterocyclyl" refers to a heterocyclyl radical as defined above that includes at least one heteroatom, and the point of attachment of the heterocyclyl radical to the remainder of the molecule is through a carbon atom in the heterocyclyl radical. The C - heterocyclyl radical is optionally substituted as described above for the heterocyclyl radical. Examples of such C - heterocyclyl radicals include, but are not limited to, 2 - morpholinyl, 2 - or 3 - or 4 - piperidinyl, 2 - piperazinyl, 2 - or 3 - pyrrolidinyl, etc.

[0132] "Heterocyclylalkyl" refers to a radical of the formula - R c -heterocyclyl, where R c is an alkylene chain as defined above. When the heterocyclyl is a nitrogen - containing heterocyclyl, this heterocyclyl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl radical is optionally substituted as defined above for the heterocyclyl group.

[0133] "Heterocyclylalkoxy" refers to a radical bonded through the oxygen atom of the formula - O - R c -heterocyclyl, where R c is an alkylene chain as defined above. When the heterocyclyl is a nitrogen - containing heterocyclyl, this heterocyclyl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkoxy radical is optionally substituted as defined above for the heterocyclyl group.

[0134] "Heteroaryl" refers to a radical derived from an aromatic ring radical having 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and having 3 to 18 ring members. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings in the ring system is fully unsaturated, i.e., it encompasses a cyclic delocalized (4n + 2)π - electron system according to Hückel's theory. Heteroaryl includes fused ring systems or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 - benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2 - d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7 - dihydro - 5H - cyclopenta[4,5]thieno[2,3 - d]pyrimidinyl, 5,6 - dihydrobenz[h]quinazolinyl, 5,6 - dihydrobenz[h]cinnolinyl, 6,7 - dihydro - 5H - benz[6,7]cyclohepta[1,2 - c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2 - c]pyridinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d] pyridinyl, and thiophenyl (i.e., thienyl), among others, but not limited thereto. Unless otherwise specified herein, the term "heteroaryl" is intended to include heteroaryl radicals as defined above that are optionally substituted with one or more substituents, said one or more substituents being alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R, b -OR a 、-R b -OC(O)R a 、-R b -OC(O)OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b-S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2(where t is 1 or 2), and each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl, (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond, or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and unless otherwise defined, the above substituents are each unsubstituted.

[0135] "N - heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen, and the point of attachment of the heteroaryl radical to the remainder of the molecule is through a nitrogen atom in the heteroaryl radical. The N - heteroaryl radical is optionally substituted as described above for the heteroaryl radical.

[0136] "C-Heteroaryl" refers to a heteroaryl radical as defined above, and the point of attachment of the heteroaryl radical to the remainder of the molecule is via a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0137] "Heteroarylalkyl" has the formula -R c -heteroaryl radical, where R c is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, this heteroaryl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for alkylene chains. The heteroaryl moiety of the heteroarylalkyl radical is optionally substituted as defined above for heteroaryl groups.

[0138] "Heteroarylalkoxy" refers to a radical attached through the oxygen atom of the formula -O-R c -heteroaryl, where R c is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, this heteroaryl is optionally attached to the alkyl radical at a nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for alkylene chains. The heteroaryl moiety of the heteroarylalkoxy radical is optionally substituted as defined above for heteroaryl groups.

[0139] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined as (R) or (S) from the perspective of absolute stereochemistry. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be embraced by the present disclosure. When the compounds described herein contain an alkene double bond and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, in addition to all possible isomers, their racemic and optically pure forms, and all tautomers are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers of an alkene double bond (e.g., cis or trans). The term "positional isomer" refers to structural isomers around a central ring, such as ortho isomers, meta isomers, and para isomers around a benzene ring.

[0140] Typically, the optionally substituted groups are each independently substituted or unsubstituted. Each detailed description of the optionally substituted groups provided herein, unless otherwise specified, includes independent and explicit details of both unsubstituted groups and substituted groups (e.g., substituted in certain embodiments and unsubstituted in other embodiments). Unless otherwise specified, a substituted group is selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a 、-SR a 、-OC(O)R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t ORa (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a )2(where t is 1 or 2), and is optionally substituted by one or more of them, and each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0141] In the compounds disclosed herein, any reference to an atom includes a reference to its isotope. For example, a reference to H includes a reference to any isotope of H, such as 1 H, 2 H, 3 H, or a mixture thereof.

[0142] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Any one of the pharmaceutically acceptable salts of the dual-action drugs for myoboom gland dysfunction described herein is intended to encompass all pharmaceutically appropriate salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0143] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effects and properties of the free base, which salts are not biologically or otherwise undesirable and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Similarly included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Accordingly, typical salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Similarly contemplated are salts of amino acids such as alginates, gluconates, and galacturonates (e.g., Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). The acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques well known to those of skill in the art.

[0144] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effects and properties of the free acid, and these salts are not unwanted in biological or other respects. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are formed in some embodiments with metals or amines such as alkali metals, alkaline earth metals, or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum. Examples of salts derived from organic bases include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins. See Berge et al. supra.

[0145] Meibomian gland Meibomian glands are large sebaceous glands in the eyelids and are not associated with hair as opposed to the skin. Meibomian glands produce the lipid layer of the tear film that protects the tear film from evaporation of the aqueous phase. The meibomian gland orifice is located on the epithelial side of the eyelid margin and is only a few hundred microns from the mucosal side. Meibomian glands are present in both the upper and lower eyelids, and the number of meibomian glands is greater in the upper eyelid. One meibomian gland consists of a mass of secretory acini arranged annularly around a long central duct and connected to the central duct by a short duct. The terminal part of the central duct is covered by the ingrowth of the epidermis, which forms a short excretory duct that covers the free eyelid margin and opens as an orifice at the posterior part of the eyelid margin just in front of the mucocutaneous transition of the inner eyelid near the border. The oily secretion composed of lipids is synthesized in the secretory acini. The lipid secretion is a liquid close to body temperature and is delivered to the skin of the eyelid margin as a clear fluid called "meibum". The lipid secretion forms shallow reservoirs at the edges of the upper and lower eyelids and consists of a complex mixture of cholesterol, wax, cholesterol esters, phospholipids, and small amounts of triglycerides, triacylglycerols, and hydrocarbons. Separate meibomian glands are arranged parallel and in a single row over the length of the tarsal plates in the upper and lower eyelids. The extent of the glands approximately corresponds to the dimensions of the tarsal plates.

[0146] As used herein, the term "keratin plugging" refers to the blockage of the meibomian glands regardless of the location of the blockage. In some embodiments, this blockage is complete, while in other embodiments it is partial. Regardless of the degree of blockage, such keratin plugging causes meibomian gland dysfunction. In some embodiments, keratin plugging is composed of keratinized material and lipids. In some embodiments, keratin plugging is a blockage at the meibomian gland orifice and the excretory duct. In some embodiments, keratin plugging is caused by keratinization of the epithelium at the eyelid margin and the meibomian glands. In one example, keratin obstruction is affected by the migration or abnormal differentiation of stem cells. In some embodiments, keratin plugging causes a decrease in the delivery of oil to the eyelid margin and the tear film, as well as stasis within the meibomian glands that causes elevated blood pressure, resulting in dilation, atrophy of the glandular acini, and a decrease in the secretion volume. In one example, keratinization of the meibomian glands causes degenerative glandular dilation and atrophy.

[0147] Ocular surface diseases or disorders Ocular surface diseases include, but are not limited to, a group of diseases such as dry eye syndrome (evaporative DES and / or aqueous tear-deficient DES), blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland disorders, contact lens-related diseases, and inflammatory, infectious, or autoimmune diseases or disorders of the anterior surface of the eye. The term "meibomian gland dysfunction" as used herein refers to a chronic and extensive abnormality of the meibomian glands characterized by terminal duct blockage, qualitative or quantitative changes in glandular secretion, or both. MGD may cause changes in the tear film, ocular irritation symptoms, inflammation, or ocular surface diseases. The most prominent aspects of MGD are the blockage of the meibomian gland openings and the terminal ducts and changes in meibomian gland secretion.

[0148] In some cases, meibomian gland dysfunction (MGD) is a chronic and extensive abnormality of the meibomian glands, typically characterized by terminal duct obstruction and / or qualitative / quantitative changes in glandular secretion. Terminal duct obstruction is caused by hyperkeratosis of the ductal epithelium (Nichols et al, Inv. Oph. & Vis. Sci. (2011); 52(4): 1922 - 1929). Such changes in both the quality and expression of meibum can lead to changes in the tear film, ocular irritation symptoms, and ocular surface diseases such as evaporative dry eye. The main clinical outcome of MGD is evaporative dry eye syndrome, and based on large - scale population - based studies (Bankok Study and Shihpai Eye Study), it is estimated that over 60% of patients with dry eye symptoms also have MGD (Schaumberg et al, Investigative Ophthalmology and Visual Science. (2011); 52(4): 1994 - 2005).

[0149] MGD is a major cause of dry eye syndrome. The occurrence of dry eye syndrome is widespread, and in the United States alone, approximately 20 million patients are affected. Dry eye syndrome is an ocular surface disorder caused by either inadequate tear production or excessive evaporation of moisture from the ocular surface. Since the cornea has no blood vessels and relies on tears for the supply of oxygen and nutrients, tears are essential for corneal health. Tear fluid and the tear film are composed of lipids, water, and mucus, and dry eye may occur if any of these is disrupted. Excessive evaporation can occur due to an inappropriate amount of lipid outflow from the meibomian glands, such as that caused by keratinizing occlusion, which can lead to dry eye syndrome.

[0150] In some embodiments, changes in meibomian gland secretion are detected by physically compressing the meibomian glands by applying digital pressure to the tarsal plate. In subjects without MGD, the meibum is a collection of clear oil. In MGD, both the quality of the expressed material and the expressibility change. The changes in meibum, also known as meibomian gland discharge, consist of a mixture of altered secretions and keratinized epithelial material. In MGD, the appearance of the expressed lipids changes from a clear fluid to a viscous fluid containing particulate matter and a thick, opaque toothpaste-like material. The meibomian gland orifices may exhibit a bulge above the surface height of the eyelid, which is referred to as plugging or pouting and is caused by terminal duct obstruction and extrusion of a mixture of meibomian gland lipids and keratinized material.

[0151] Obstructive MGD is characterized by all or some of the following: 1) chronic ocular discomfort, 2) anatomical abnormalities around the meibomian gland orifices (one or more of vascular congestion, anterior or posterior displacement of the mucocutaneous junction, or irregularity of the eyelid margin), and 3) obstruction of the meibomian glands (finding of gland orifice obstruction (bulging, plugging, or elevation) by slit-lamp biomicroscopy, decreased meibum expressibility with moderate digital pressure).

[0152] Examples of methods for assessing and monitoring current MGD symptoms include, but are not limited to, patient questionnaires, meibomian gland expression, tear film stability break-up time, and determination of the number of glands in the patient as confirmed by digital pressure.

[0153] In some embodiments, the patient's symptoms are evaluated by asking the patient a series of questions. A questionnaire can be used to evaluate the range of symptoms related to ocular discomfort. In some embodiments, this questionnaire is the SPEED questionnaire. The SPEED questionnaire is used to evaluate the frequency and severity of the patient's dry eye symptoms. This questionnaire examines the occurrence of symptoms on the day, 72 hours later, and in the past three months. The SPEED score is aggregated based on the patient's answers to the questions to provide a range of the severity of the patient's symptoms. The SPEED questionnaire includes questions such as 1) what dry eye symptoms occurred and when, 2) how frequent is the dryness, grittiness, or itchiness of the eyes, 3) how frequent is the eye pain or irritation, 4) how frequent is the eye burning or tearing, 5) how frequent is the eye fatigue, and 6) how severe are the symptoms.

[0154] The meibomian gland squeeze degree is optionally determined to evaluate meibomian gland function. The meibum of a normal patient is a transparent to light yellow oil. When pressure is applied to the gland, the meibum is secreted from the gland. A change in the meibomian gland squeeze degree is one of the possible MGD indications. In some embodiments, the quantification of the amount of physical force applied during squeezing is monitored in addition to the evaluation of the lipid volume and lipid mass.

[0155] Tear breakup time (TBUT) is a surrogate marker for tear stability. Tear film instability is a central mechanism in dry eye and MGD. A short TBUT suggests a compromise of the lipid layer and the possibility of MGD. TBUT is optionally measured by examining the fluorescein breakup time, which is defined as the time to the first disruption in the tear film after a blink. Fluorescein is optionally applied by wetting a commercially available fluorescein-impregnated strip with saline and applying it to the lower lid or bulbar conjunctiva. The patient is then asked to blink several times and move the eyes. The disruption is then analyzed using a slit lamp, cobalt blue filter, and a 4 mm beam width. The patient is instructed to blink, and the time from the upward movement of the last blink to the first tear film disruption or dry spot formation is recorded as the measurement.

[0156] Other methods for evaluating other MGD symptoms include, but are not limited to, Schirmer test, ocular surface staining, eyelid morphology analysis, meibography, meibometry, interferometry, evaporimetry, tear lipid composition analysis, fluorescence analysis, meiscometry, osmolality analysis, tear film dynamics, evaporation, and tear turnover indices.

[0157] Current MGD treatments include eyelid warming, eyelid massage, eyelid hygiene, lid expression, and meibomian gland probing. Pharmacological methods have not been used prior to the methods described herein.

[0158] Eyelid hygiene is considered a primary treatment for MGD and consists of three elements: 1) warm compresses, 2) mechanical massage of the eyelids, and 3) eyelid cleansing. Eyelid warming procedures improve meibomian gland secretion by melting the pathologically altered lipids of the meibomian glands. Warming is achieved by warm compresses or devices. Mechanical eyelid hygiene includes the use of scrubs, mechanical expression, and cleansing of the eyelashes and eyelid margins with various solutions. The eyelid margins are optionally cleansed with a low-allergy solid soap, diluted baby shampoo, or commercially available eyelid scrubs. Physical expression of the meibomian glands is performed in the physician's office or by the patient at home. This technique exists in various forms, from a gentle massage of the eyelids against the eyeball to forcibly squeezing the eyelids between each other or between a rigid object on the inner eyelid surface and a finger, thumb, or rigid object (such as a glass rod, cotton swab, or metal paddle) on the outer eyelid surface. The rigid object on the inner eyelid surface protects the eyeball from the forces transmitted through the eyelid during expression and provides stable resistance to increase the amount of force applied to the glands.

[0159] Eyelid warming is limited because the lipids melt with warming and does not address the movement of the keratinized material. Additionally, eyelid warming causes temporary vision loss due to corneal distortion. Mechanical eyelid hygiene is also limited. This is because the force required to remove the obstruction is significant and can cause severe pain to the patient. The effectiveness of mechanical eyelid hygiene is limited by the patient's ability to tolerate the associated pain during treatment. Other treatments for MGD are limited.

[0160] Physical opening of meibomian gland obstruction by meibomian gland expression is an acceptable method for improving meibomian gland secretion and dry eye symptoms. In addition, probing of the meibomian gland ducts has been used to open blocked ducts. However, both methods of expression and probing are limited by the pain induced by this procedure, possible physical trauma to the gland and duct structures, and the transient effects expected over days and weeks. Therefore, there is a need for a method to improve patient comfort, which will not harm the meibomian glands and ducts, reduce the dependence on frequent clinic visits, and improve meibomian secretion.

[0161] U.S. Patent No. 9,463,201, entitled "Compositions and methods for the treatment of meibomian gland dysfunction," describes a method of treating meibomian gland dysfunction that includes topical administration of a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier. This patent includes keratolytic agents that are inorganic selenium (Se) compounds such as selenium disulfide (SeS2) or organic selenium compounds such as ebselen (2-phenyl-1,2-benzoselenazol-3-one). This agent treats the underlying cause of MGD rather than the "plus" inflammatory disease as described by the DEWS report for MGD.

[0162] The role of inflammation in the etiology of MGD has been debated. The terms posterior blepharitis and MGD are not synonymous. Posterior blepharitis describes an inflammatory disease of the posterior eyelid margin, which has various causes, but one possible cause is MGD (Nichols et al 2011). In its earliest stages, MGD is not associated with the characteristics of the clinical symptoms of posterior blepharitis. As MGD progresses, it is said that there is MGD-related posterior blepharitis. MGD-related posterior blepharitis affects the meibomian glands and the meibomian gland orifices. MGD-related posterior blepharitis is characterized by flora changes, esterase release, lipase release, lipid changes, and eyelid inflammation. Hyperkeratosis of the meibomian gland epithelium (thickening of the inner lining of the gland) may cause obstruction and a decrease in the quality of meibomian gland secretion, and may also cause MGD-related posterior blepharitis. The diagnosis of MGD-related posterior blepharitis includes evidence regarding changes in the quality of the expressed secretions and / or meibomian gland expression due to loss of gland function (decrease or loss of expressibility). In the TFOS report on meibomian gland disorders, it is noted that anterior blepharitis and worsening inflammatory ocular surface diseases are "plus" diseases associated with MGD managed by topical steroids (Nichols et al 2011). Since these "plus" diseases can exist at various severities from the early to the late stages of MGD, treatments and / or combination treatments that can target both the fundamental non-inflammatory pathophysiology of MGD and the inflammation associated with these co-existing diseases are needed.

[0163] MGD-related inflammatory eye diseases may involve different mechanisms from MGD associated with blepharitis. MGD-related inflammatory eye diseases are characterized by an inflammatory cascade that involves the activation of T lymphocytes and their migration into inflamed tissues. T lymphocyte infiltration may lead to lacrimal gland stimulation and upregulation of cytokines. Exemplary cytokines that may be involved in MGD-related inflammatory eye diseases include, but are not limited to, interleukin 1, interleukin 4, interleukin 6, interleukin 8, interferon γ, macrophage inflammatory protein 1α, and tumor necrosis factor α. Kinase pathways, including the mitogen-activated protein kinase (MAPK) pathway, are also activated in the inflammatory cascade. This inflammatory process results in the loss of mucin-producing goblet cells and may lead to ocular surface disruption that can cause further damage.

[0164] Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), is considered a self-sustaining disease that is gradually separated from its initial causes. Dry eye syndrome is associated with inflammation of the ocular surface and the tissues surrounding the eye. The inflammation is characterized by the activation of T lymphocytes and their migration into inflamed tissues, including tissues in the conjunctiva and lacrimal gland. Inflammatory cytokines, chemokines, and matrix metalloproteinases have also been identified as being increased.

[0165] Animal models of dry eye disease have been established and studied (Barabino, et al., (Invest. Ophthalmol. Vis. Sci. 2004, 45:1641-1646)). Barabino, et al. (Invest. Ophthalmol. Vis. Sci. 2005, 46:2766-2771) described that exposing normal mice to a low humidity environment in a controlled environmental chamber resulted in significant changes in tear secretion, goblet cell density, and the acquisition of dry eye-related ocular surface signs. However, a single animal model does not fully incorporate the immune, endocrine gland, neuronal, and environmental factors that contribute to the etiology of dry eye.

[0166] Anti-inflammatory agents can be used to treat ocular surface diseases or disorders including dry eye syndrome. Corticosteroids are effective anti-inflammatory therapeutic agents for dry eye disease. For example, in a 4-week double-blind randomized trial of 64 patients with dry eye and delayed tear clearance, four times daily administration of a 0.5% ophthalmic suspension of loteprednol etabonate (Lotemax [Bausch and Lomb, Rochester, NY]) was found to be more effective than its vehicle in improving some signs and symptoms (Pflugfelder et al, Am J Ophthalmol (2004);138:444-57). In the TFOS 2007 report on dry eye disease, it was concluded that "in the US Federal Regulations, ophthalmic corticosteroids that receive 'classified labeling' are indicated for'steroid-responsive inflammatory diseases' such as allergic conjunctivitis, blepharitis, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infectious conjunctivitis, etc. in the eyelids and bulbar conjunctiva, cornea and anterior uveal tract of the eye. In some examples, KCS is included in this list of steroid-responsive inflammatory diseases (Therapy Subcommittee of the International Dry Eye WorkShop, 2007. Management and Therapy of Dry Eye Disease: Report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). 2007;5:163-178)". Although the US FDA does not concur with this conclusion, the steroid, Lotemax, is commonly used to treat inflammation associated with dry eye disease for short periods.

[0167] Other anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the activity of cyclooxygenase, including cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are enzymes involved in the synthesis of prostaglandins and thromboxanes from arachidonic acid. Prostaglandin and thromboxane signaling are involved in the modification of inflammation and immunity. In some cases, NSAIDs are used to treat dry eye disease by treating inflammation of the ocular surface.

[0168] Treatment of dry eye can also be achieved with agents that enhance tear and mucin production. For example, agonists of the P2Y2 receptor have been shown to increase tear and mucin secretion. This mechanism is thought to involve P2Y2 signaling, which raises intracellular calcium and opens chloride channels in the apical cell membrane. The P2Y2 receptor belongs to the family of purinergic receptors, which are classified as P1 and P2 receptors based on their native agonism by purine nucleosides and pyrimidine nucleotides, respectively. The P2 receptors are further physiologically divided into two types, P2X and P2Y receptors. The P2Y receptors are involved in diverse signaling, including platelet aggregation, immunity, lipid metabolism, and bone activity. Some studies have also demonstrated the presence of P2X and P2Y receptors in ocular tissues, including the retina, ciliary body, and lens. These studies suggest that the P2Y2 receptor is likely the major subtype of purinergic receptor located on the ocular surface. The P2Y2 receptor has further been demonstrated to be located in goblet and serous cells of the conjunctival epithelium in ocular tissues, as well as in acinar and duct epithelial cells of the meibomian glands of rhesus monkeys.

[0169] Lifitegrast The chemical name of lifitegrast is, molecular formula C 29 H 24(S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propionic acid having Cl2N2O7S, with a molecular weight of 615.5. Lifitegrast is generally administered as a 5% ophthalmic solution having a pH of 7.0 to 8.0 and an osmolarity range of 200 to 330 mOsmol / kg. The structural formula of lifitegrast is as follows.

[0170] [Chemical formula]

[0171] Lifitegrast is indicated for the treatment of the signs and symptoms of dry eye disease (DED). Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on white blood cells, and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. The LFA-1 / ICAM-1 interaction may contribute to the formation of immunological synapses that lead to T cell activation and migration to target tissues. In in vitro tests, lifitegrast has been demonstrated to inhibit the adhesion of T cells to ICAM-1 in human T cell lines and to inhibit the secretion of inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in dry eye disease is not known. More information on lifitegrast can be found in U.S. Patent Nos. 10,124,000; 7,314,938; 7,745,460; 7,790,743; 7,928,122; 8,084,047; 8,168,655; 8,367,701; 8,592,450; 8,927,574; 9,085,553; 9,216,174; 9,353,088; 9,447,077; and 9,890,141, below.

[0172] GW-559090 The chemical name of GW-559090 is (S)-3-(4-((4-carbamoylpiperidine-1-carbonyl)oxy)phenyl)-2-((S)-4-methyl-2-(2-(o-tolyloxy)acetamido)pentaamide)propanoic acid with the molecular formula C 31 H 40 N4O8 and a molecular weight of 596.7. The structural formula of GW-559090 is as follows:

[0173] [Chemical formula]

[0174] GW-559090 is a potent integrin α4 antagonist that has demonstrated improvement of the objective signs of dry eye in a mouse DS model (Ravensberg et al, Allergy (2006) 61, 1097 - 1103). This potent integrin α4 antagonist is thought to act locally at the ocular surface by presumably preventing antigen-presenting cells from migrating to the draining lymph nodes and consequently disrupting the immune cycle of dry eye (Invest. Ophthalmol. Vis. Sci. (2015) 56(10), 5888 - 5895).

[0175] Drug for meibomian gland dysfunction and dry eye disease Keratolytic conjugate as a dual-action agent This specification describes a non-inflammatory keratolytic blocking component for meibomian gland dysfunction and a dual-action agent that simultaneously addresses inflammatory-related dry eye diseases including the lacrimal fluid reduction type. The keratolytic conjugate described in this specification is useful either as an emergency treatment (e.g., by a trained professional or physician) or as a long-term treatment (e.g., under the management of a patient or alternatively by a trained professional or physician). In certain embodiments, this keratolytic conjugate is tested using the assays and methods described in this specification (e.g., as described in this example). The keratolytic conjugate described in this specification represents a significant advance in the art because the primary metabolism obtained from the metabolism of the agent acts on both the keratolytic component and the inflammatory component of dry eye disease.

[0176] One embodiment provides a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof,

[0177] [Chemical formula] wherein, R 1 is aryl, cycloalkyl, heterocyclyl, or heteroaryl, and the aryl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted, R 2 , R 3 , and R 4 are each independently H, cyano, halo, ester, alkoxy, alkyl, heteroalkyl, cycloalkyl, or heterocyclyl, and the alkoxy, alkyl, heteroalkyl, cycloalkyl, or heterocyclyl is optionally substituted, R 5 is -L-R 5a where L is a single bond, alkyl, or heteroalkyl, and R 5a is absent or is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted, R 6 is H, alkyl, or heteroalkyl, each R 7 is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl, cycloalkyl, or haloalkyl, n is from 0 to 6, R is -L'-D, D is a keratolytic, and L' is a linker.

[0178] In some embodiments, L' comprises one or more linker groups, each linker group being selected from the group consisting of a single bond, -O-, -S-, alkyl(alkylenyl), heteroalkyl(heteroalkylenyl), disulfide, ester, and carbonyl. In some embodiments, the keratolytic comprises one or more groups (e.g., keratolytic groups), each group (e.g., keratolytic group) being independently selected from the group consisting of thiol, disulfide, selenol (e.g., selenide, diselenide), and carboxylic acid.

[0179] In one aspect, the present disclosure provides a compound having the structure of formula (Id), or a pharmaceutically acceptable salt or solvate thereof,

[0180]

Chemical formula

[0181] In one aspect, the disclosure provides a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof,

[0182]

Chemical formula

[0183] In some embodiments, said alkyl or heteroalkyl of R is substituted with one or more substituents, each substituent being independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, halo, oxo, heterocyclyl, and cycloalkyl, said heterocyclyl and cycloalkyl being optionally substituted (e.g., by one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, selenide, diselenide, sulfone, amide, halo, and oxo).

[0184] In some embodiments, R is

[0185]

Chemical formula

[0186] In some embodiments, said R 9 alkyl or heteroalkyl is substituted with one or more substituents, each substituent being independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, ester, carboxylic acid, halo, oxo, heterocyclyl, and cycloalkyl, and said heterocyclyl and cycloalkyl being optionally substituted (e.g., by one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, sulfone, amide, ester, halo, and oxo).

[0187] In some embodiments, R 6 is H. In some embodiments, R 3 is H. In some embodiments, n is 0. In some embodiments, R 1 is optionally substituted alkyl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is benzofuran. In some embodiments, R 2 and R 4 are each independently H, halo, alkoxy, or alkyl. In some embodiments, R 2 and R 4 are halo. In some embodiments, R 2 and R 4 are chloro. In some embodiments, R 5 is optionally substituted aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl. In some embodiments, R 5 is optionally substituted aryl-alkyl. In some embodiments, R 5 is substituted aryl-alkyl. In some embodiments, R 5 is aryl-alkyl substituted with sulfonyl.

[0188] In certain embodiments, the compound has the structure of formula (Ib) or a pharmaceutically acceptable salt thereof.

[0189]

Chemical formula

[0190] In certain embodiments, the compound has the structure of formula (Ic) or a pharmaceutically acceptable salt or solvate thereof.

[0191]

Chemical formula

[0192] In some embodiments, X is -O-, and R 9 is C1-6 alkyl, -(CR d R e )(C=O)O(C1-C6-alkyl), -(CR p R d R e )(carbocyclyl), -(CR p R d R e )(heterocyclyl), or p

Chemical formula

[0193]

Chemical formula

[0194] In some embodiments, X is a single bond and R 9 is C1-6 alkyl, heteroalkyl, or heterocyclylalkyl, said C1-6 alkyl may be straight-chain or branched-chain and is optionally substituted by halo, alkyl, heteroalkyl, alkoxy, hydroxyl, thiol, disulfide, selenide, diselenide, amide, heterocyclyl, or heterocyclylalkyl. In some embodiments, R 9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH(CH3)OH, -CH2(OCH2CH2)4OH, -CH2CH2(OCH2CH2)4OH,

[0195]

Chemical formula

[0196] In some embodiments, R 9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, CH2OH,

[0197]

Chemical formula

[0198] One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0199]

Chemical formula

[0200] One embodiment provides a compound having the structure of formula (I’) or a pharmaceutically acceptable salt thereof.

[0201]

Chemical formula

[0202] One embodiment provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0203]

Chemical formula

[0204] In one embodiment, a keratolytic conjugate having the structure provided in Table 1 or a pharmaceutically acceptable salt thereof is provided.

[0205]

Table 1-1

[0206]

Table 1-2

[0207]

Table 1-3

[0208]

Table 1-4

[0209]

Table 1-5

[0210] Preparation of the compound The compounds used in the reactions described in this specification are prepared from commercially available chemical substances and / or compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. "Commercially available chemical substances" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U..), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR) t R aObtained from standard commercial sources, including ns World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA).

[0211] Appropriate reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described in this specification, or provide references to papers describing this preparation, include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York, S.R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983, H.O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972, T.L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992, J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Other appropriate reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described in this specification, or provide references to papers describing this preparation, include, for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5, Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5, Larock, R.C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4, March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992), Interscience, ISBN: 0-471-93022-9; Solomons, T.W.G., "Organic Chemistry" 7th Edition (2000), John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2000), John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups", John Wiley & Sons, in 73 volumes are included.

[0212] Certain and similar reactants are optionally identified by indices of known chemical products prepared by the Chemical Abstract Service of the American Chemical Society, which are available via online databases, in addition to most public and university libraries (for details, please contact the American Chemical Society in Washington, DC). Chemical substances that are known but not commercially available in catalogs are optionally prepared by special chemical substance synthesis facilities, where many of the standard chemical substance supply facilities (e.g., those listed above) offer special chemical synthesis services. A reference for the preparation and selection of pharmaceutical salts of the dual-action drugs for myotonic dystrophy described herein is P.H. Stahl & C.G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0213] Pharmaceutical composition In some embodiments, the keratolytic conjugate described herein has a structure provided in any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (I), or formula (I'). In some embodiments, the keratolytic conjugate described herein has a structure provided in formula (II). In some embodiments, the keratolytic conjugate described herein has a structure provided in formula (III). In certain embodiments, the keratolytic conjugate as described herein is administered as a pure chemical substance. In other embodiments, the keratolytic conjugate described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) based on the selected route of administration and standard pharmacy practices such as those described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0214] The present specification provides a pharmaceutical composition comprising at least one keratolytic conjugate, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or appropriate when it is compatible with the other components of the composition and not harmful to the recipient (subject) of the composition.

[0215] One embodiment provides a pharmaceutical composition comprising a compound provided herein, such as a compound of any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (I), or formula (I'), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound provided herein, such as a compound of formula (II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Another embodiment provides a pharmaceutical composition suitable for ocular administration. Another embodiment provides a pharmaceutical composition suitable for topical ocular administration. In some embodiments, topical ocular administration is administration directed to the inside and / or around the eye, such as the eyelid margin. In some embodiments, topical ocular administration is administration to the ocular surface and the inner surface of the eyelid.

[0216] One embodiment provides a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Another embodiment provides a pharmaceutical composition suitable for ocular administration. Another embodiment provides a pharmaceutical composition suitable for topical ocular administration. In some embodiments, topical ocular administration is administration directed to the inside and / or around the eye, such as the eyelid margin. In some embodiments, topical ocular administration is administration to the ocular surface and the inner surface of the eyelid.

[0217] In certain embodiments, a compound (or a pharmaceutically acceptable salt thereof) provided herein, such as a keratolytic conjugate as described in any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (I), or formula (I’), is substantially pure in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthesis method.

[0218] Suitable oral dosage forms include, for example, tablets, pills, sachets, hard gelatin capsules, soft gelatin capsules, methylcellulose, or capsules of another suitable material that readily dissolves in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0219] In some embodiments, a keratolytic conjugate as described in any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (I), formula (I’), formula (II), or formula (III) is formulated as a solution or suspension for topical administration to the eye.

[0220] In some embodiments, a keratolytic conjugate as described in any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (I), formula (I’), formula (II), or formula (III) is formulated for administration by injection. In some examples, the injection formulation is an aqueous formulation. In some examples, the injection formulation is a non-aqueous formulation. In some examples, the injection formulation is an oil-based formulation, such as sesame oil.

[0221] The dosage of a composition comprising at least one keratolytic conjugate as described herein will vary depending on the condition of the patient (e.g., human), i.e., the relative state of health, age, and other factors.

[0222] The pharmaceutical composition is administered in a manner appropriate for the disease being treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment regimen will provide the composition in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improvement in clinical outcomes such as more frequent complete or partial remission, longer disease-free survival and / or overall survival, or reduction in the severity of symptoms). The optimal dosage is generally determined using experimental models and / or clinical trials. The optimal dosage depends on the body size, weight, or blood volume of the patient.

[0223] In other embodiments, the topical compositions described herein are combined with a pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier). Typical excipients are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0224] Methods of treatment utilizing keratolytic conjugates One embodiment provides a method of treating an eye disease or disorder in a patient, the method comprising administering to the patient a compound provided herein, such as a compound of any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (I), formula (I’), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, or a composition (e.g., a pharmaceutical) comprising the compound. Other embodiments provide a method in which the pharmaceutical composition is in the form of a solution or suspension suitable for topical ocular administration. In some embodiments, the topical ocular administration is administration to the interior and / or surrounding of the eye, such as to the eyelid margin. In some embodiments, the topical ocular administration is administration to the ocular surface and the inner surface of the eyelid.

[0225] Another embodiment provides a method in which the eye disease or disorder is selected from dry eye, lid wiper epitheliopathy (LWE), contact lens discomfort (CLD), dry eye syndrome, evaporative dry eye syndrome, aqueous tear-deficient dry eye syndrome, blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland disorders, diseases and inflammation of the anterior surface of the eye related to contact lenses, infectious diseases of the anterior surface of the eye, and autoimmune disorders of the anterior surface of the eye.

[0226] This specification describes methods of treating ocular surface disorders of a patient, including administration of a keratolytic conjugate to the patient. There are two possible classifications of administration. One is performed with the assistance of a healthcare provider. This classification includes both acute and maintenance uses of the keratolytic conjugate. In one embodiment, more potent keratolytic conjugates (in terms of either the concentration or the intrinsic activity of the agent) are required for acute use. In one embodiment, maintenance use allows for the use of a lower concentration agent with less intrinsic activity. In one embodiment, maintenance use is associated with the patient during regular visits by a healthcare provider. Both acute and maintenance use optionally require the use of a device or apparatus for protecting the eye. In one embodiment, acute use is performed by a healthcare provider and maintenance use is performed by the patient or a non-healthcare provider. The other possible classification of administration is not performed with the active assistance of a healthcare provider, but rather the patient administers the keratolytic conjugate to the lid margin of their own eye. In one embodiment, such administration is performed over a long period of time. The mode of multiple administrations performed by the patient in this way is, in a word, chronic administration. Usually, a different or second keratolytic conjugate formulation is recommended for chronic use or self-use by the patient. In one embodiment, the different or second formulation utilizes a lower concentration of the keratolytic conjugate. In another embodiment, the different or second formulation utilizes a keratolytic conjugate that is less active than the first formulation.

[0227] It should be understood that the methods of the invention further include physical removal of blockages of the meibomian glands, followed by chronic and / or maintenance administration of a keratolytic conjugate as described herein.

[0228] One embodiment provides a method of treating a patient's meibomian gland dysfunction, the method comprising topically administering to the patient a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier enhances meibum production.

[0229] In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is performed until the keratosis obturans is reduced. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is performed periodically even after the reduction of the keratosis obturans. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is a single administration. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is a regular administration. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is performed once a day. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is performed twice a day. In some embodiments, the topical administration of the composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is performed more than twice a day.

[0230] In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is a solution. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is a solution suitable for topical administration as eye drops. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is a gel, an ocular insert, a spray, or other topical eye administration method. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is semi-solid. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is homogeneous. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is a dispersion. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier is hydrophilic. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier has an oily base. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmologically acceptable carrier has at least one ophthalmologically acceptable excipient.

[0231] One embodiment provides a method of treating MGD in a patient, comprising topical administration of a composition comprising a keratolytic conjugate. In some embodiments, the topical administration of the composition comprising a keratolytic conjugate is performed once a week. In some embodiments, the topical administration of the composition comprising a keratolytic conjugate is performed twice a week. In some embodiments, the topical administration of the composition comprising a keratolytic conjugate is performed every other day. In some embodiments, the topical administration of the composition comprising a keratolytic conjugate is performed daily. In some embodiments, the topical administration of the composition comprising a keratolytic conjugate is performed several times a day.

[0232] In some embodiments, the method includes treatment in an acute treatment scenario. In another embodiment, the method includes treatment of a patient who has not received treatment. In another embodiment, the method includes treatment in a chronic treatment scenario. In another embodiment, the method includes treatment in a maintenance therapy scenario. The dosage of the keratolytic conjugate in an acute treatment scenario may be more than the keratolytic conjugate utilized in a chronic treatment scenario or a maintenance therapy scenario. The keratolytic conjugate in an acute treatment scenario may be different from the keratolytic conjugate utilized in a chronic treatment scenario. In some embodiments, the treatment period begins as an acute treatment scenario at the initial stage of treatment and then transitions to a chronic treatment scenario or a maintenance therapy scenario. In some embodiments, the meibomian gland opening drug administered in an acute treatment scenario is a keratolytic agent and / or a keratoplastic agent, and the drug administered in a chronic treatment scenario or a maintenance therapy scenario is a keratolytic conjugate.

[0233] In certain clinical situations, the patient may first require administration of a therapeutic agent by a physician or healthcare professional in order to initially open the blockage of the meibomian gland, such as by dispensing a high-concentration formulation consisting of one of the keratolytic conjugates described herein. If a higher concentration formulation is required, the administration may require eye shielding or other activities to minimize the effects of irritation or disruption to the eye surface or surrounding tissues. After such a procedure, the patient may be administered a different keratolytic conjugate formulation that is regularly administered to the eyelid margin at home to maintain the patency of the meibomian gland. This administration can be performed twice daily, once daily, weekly, or monthly depending on the formulation activity and the desired therapeutic profile.

[0234] One aspect of the treatment method described herein is the location of local administration of the composition. In one embodiment, the composition comprising the keratolytic conjugate is administered so as not to cause irritation to the eye. In one embodiment, the composition comprising the keratolytic conjugate is administered to the eyelid margin.

[0235] Another embodiment of the treatment method described herein is the use of a protective element provided on the eye to avoid eye irritation. The formulations described herein are usually non-irritating, but in some embodiments (e.g., when using high concentrations of the drug or when using it on sensitive eyes), the protective element provides an additional layer for patient safety and comfort. In one embodiment, an eye shield is applied to the eye to reduce contact of the drug with the cornea and / or conjunctiva while a composition containing a keratolytic conjugate is being administered, thereby reducing irritation to the eye. In some embodiments, this eye shield is a contact lens or an eye cover. In some embodiments, this eye cover includes self-adhesion. In one embodiment, the eyelids are pulled away from the eyeball to reduce contact of the drug with the cornea and / or conjunctiva while a composition containing a keratolytic conjugate is being administered, thereby reducing irritation to the eye.

Examples

[0236] I. Chemical Synthesis Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were carried out at room temperature unless otherwise specified. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures.

[0237] Abbreviations In the examples and other parts of this specification, the following abbreviations were used. AcOH: Acetic acid CD2Cl2: Deuterated dichloromethane CDCl3: Deuterated chloroform COMU: (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DCC: Dicyclohexylcarbodiimide DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformamide DMSO-d6: Dimethyl sulfoxide-d6 EtOAc: Ethyl acetate EtOH: Ethanol HCl: Hydrochloric acid H2O: Water HPLC: High-performance liquid chromatography KHSO4: Potassium hydrogen sulfate MeCN: Acetonitrile MeOH: Methanol MgSO4: Magnesium sulfate mins: Minutes N2: Nitrogen NaHCO3: Sodium bicarbonate NH4Cl: Ammonium chloride RT: Retention time r.t: Room temperature sat.: Saturated TFA: Trifluoroacetic acid THF: Tetrahydrofuran

[0238] Analysis method Method A: Phenomenex Gemini C18 5μm 150×4.6mm, A = water + 0.1% formic acid, B = MeOH, 40°C, %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1 min 5%, 13.0 min 5%, 1.5 mL / min.

[0239] Method B: Phenomenex Luna C18(2) 3μm, 50×4.6mm, A = water + 0.1% formic acid, B = MeOH + 0.1% formic acid, 45°C, %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5 min 95%, 3.51 min 5%, 4.0 min 5%, 2.25 mL / min.

[0240] Method C: Phenomenex Luna C18(2) 5μm 150×4.6mm, A = water + 0.1% formic acid, B = MeCN, 40°C, %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1 min 5%, 13.0 min 5%, 1.50 mL / min.

[0241] Method D: Phenomenex Luna C18(2) 3μm, 50×4.6mm, A = water pH9 (ammonium bicarbonate 10mM), B = MeOH, 45°C, %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5 min 95%, 3.51 min 5%, 4.0 min 5%, 2.25 mL / min.

[0242] Method E: Waters Sunfire C18 3.5μm 50×4.6mm, A = water + 0.1% formic acid, B = MeCN, 40°C, %B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5 min 95%, 3.51 min 5%, 4.0 min 5%, 2.25 mL / min.

[0243] Method F: Phenomenex Gemini NX C18 5μm 150×4.6mm, A = water + 0.1% formic acid, B = MeOH + 0.1% formic acid, 40°C, %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1 min 5%, 13.0 min 5%, 1.5 mL / min.

[0244] Chemical Synthesis Example 1: 1 - ((Isopropoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0245]

Chem.

[0246] To a stirred solution of lifitegrast (250 mg, 0.410 mmol) in anhydrous DMF (5 mL) was added 1-chloroethyl isopropyl carbonate (81.2 mg, 0.490 mmol), followed by potassium carbonate (73.0 mg, 0.530 mmol), and the mixture was stirred at 55 °C for 2 h. The mixture was diluted with EtOAc and washed successively with water and then saturated brine solution. The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was dissolved in DMSO and the product was purified by reverse phase preparative HPLC. Fractions containing the product were combined and concentrated in vacuo to a volume of approximately 1 / 5. The mixture was diluted with EtOAc and washed successively with water and then saturated brine solution. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O and the solution was frozen. The solvent was evaporated by lyophilization to afford the title compound as an off-white solid (72 mg, 24%). LCMS (Method A): Rt = 7.87 min; [M+H]+ = 745.3. 1 1H-NMR (400 MHz, CD2Cl2) δ 7.78 - 7.91 (m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.57 - 7.64 (m, 2H), 7.49 - 7.56 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.83 - 6.93 (m, 1H), 6.77 (td, J = 11.1, 5.5 Hz, 1H), 6.32 (dd, J = 20.4, 8.5 Hz, 1H), 5.17 - 5.28 (m, 1H), 4.51 - 4.99 (m, 3H), 3.78 (s, 2H), 3.17 - 3.49 (m, 2H), 2.98 - 3.07 (m, 3H), 2.87 (s, 2H), 1.49 - 1.56 (m, 3H), 1.25 - 1.34 (m, 6H).

[0247] Chemical Synthesis Example 2: 4-((2S)-3-(1-((Isopropoxycarbonyl)oxy)ethoxy)-2-((S)-4-methyl-2-(2-(o-tolyloxy)acetamido)pentaamido)-3-oxopropyl)phenyl 4-carbamoylpiperidine-1-carboxylate

[0248] [Chem.]

[0249] 3-[4-(4-Carbamoylpiperidine-1-carbonyl)oxy-phenyl]-2-[[(2S)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]propionic acid (80 mg, 0.134 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.0 mL). 1-Chloroethyl isopropyl carbonate (50 mL, 0.327 mmol) was added and the mixture was stirred at 60 °C for 24 h. N,N-Diisopropylethylamine (80 mL, 0.459 mmol) and 1-chloroethyl isopropyl carbonate (50 mL, 0.327 mmol) were added and the mixture was stirred at 60 °C for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc (40 mL) and saturated NaHCO 3(aq) (20 mL). The layers were separated, the organic phase was washed with saturated brine solution (20 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), eluting with EtOAc → 20% acetone-EtOAc to give [4-[3-(1-Isopropoxycarbonyloxyethoxy)-2-[[(2S)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]-3-oxo-propyl]phenyl] 4-carbamoylpiperidine-1-carboxylate (58 mg, 60%) as an off-white solid. LCMS (method F): Rt = 8.36 min (98.1%) [M+H]+ = 727.6.

[0250] Chemical Synthesis Example 3: 1-((tert-Butoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0251] [Chemical]

[0252] Method A: To a mixture of Lifitegrast (20 mg, 0.0300 mmol), DIPEA (11 mL, 0.0650 mmol), and DMF (1 mL) under a N2 atmosphere, tert-butyl 1-chloroethyl carbonate (7.04 mg, 0.0400 mmol) was added. The reaction mixture was stirred at 60 °C for 48 h. tert-Butyl 1-chloroethyl carbonate (5.9 mg, 0.033 mmol) and DIPEA (8.9 μL, 0.065 mmol) were added, and the reaction mixture was stirred at 60 °C for 4 h. Potassium iodide (5.4 mg, 0.0325 mmol) was added, and the reaction mixture was stirred at 60 °C for 72 h. The reaction mixture was diluted with EtOAc (10 mL), and this solution was successively washed with H2O (2 × 5 mL) and saturated brine solution (5 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was then purified by preparative reverse-phase HPLC.

[0253] Method B: A mixture of Lifitegrast (15 mg, 0.0244 mmol), tert-butyl 1-chloroethyl carbonate (8.8 mg, 0.0487 mmol), and cesium carbonate (8.0 mg, 0.0244 mmol) was dissolved in DMF (1 mL), and this mixture was stirred at room temperature for 72 h. The reaction mixture was passed through a syringe filter, and the crude product was purified by preparative reverse-phase HPLC.

[0254] Method C: A mixture of Lifitegrast (15 mg, 0.0244 mmol), tert-butyl 1-chloroethyl carbonate (8.8 mg, 0.0487 mmol), cesium carbonate (8.0 mg, 0.0244 mmol), and potassium iodide (2.0 mg, 0.0122 mmol) was dissolved in DMF (1 mL), and this mixture was stirred at room temperature for 72 h. The reaction mixture was passed through a syringe filter, and the crude product was purified by preparative reverse-phase HPLC.

[0255] Method D: Three samples obtained from Methods A, B, and C were combined (as solutions in MeOH), and the solvent was evaporated in vacuo. The crude product was purified by preparative reverse-phase HPLC, the desired fractions were combined, and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (2 mL), and the solution was frozen. By evaporating the solvent in vacuo (lyophilization), 1-((tert-butoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (10.2 mg, 16% (combined yield)) was obtained as a white solid. LCMS (Method F): Rt = 7.87 min; [M+H]+ = 759.5 1 1H-NMR (400 MHz, DMSO-d6) δ 9.15 - 9.20 (1H, m), 8.12 (1H, d, J = 2.3 Hz), 7.87 (1H, br s), 7.66 - 7.78 (4H, m), 7.53 - 7.58 (1H, m), 7.10 - 7.50 (2H, br m), 7.03 - 7.04 (1H, m), 6.62 - 6.69 (1H, m), 4.85 - 4.93 (1H, m), 4.60 - 4.84 (2H, br s), 3.52 - 3.94 (2H, m), 3.25 - 3.30 (1H, m, partially obscured by H2O peak), 3.13 - 3.15 (3H, m), 2.98 - 3.05 (1H, m), 2.76 (2H, br s), 1.39 - 1.46 (12H, m).

[0256] Chemical Synthesis Example 4: 1-chloroethyl ((2,2-dimethyl-1,3-dioxan-5-yl)methyl carbonate

[0257]

Chemical Structure

[0258] (2,2-Dimethyl-1,3-dioxan-5-yl)methanol (0.40 mL, 2.78 mmol) and pyridine (0.45 mL, 5.56 mmol) were added dropwise over 1 minute to an ice-cooled solution of 1-chloroethyl chloroformate (0.30 mL, 2.78 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between DCM (10 mL) and H2O (10 mL), and the organic phase was separated (phase separator). The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography, eluting with isohexane → EtOAc, to give 1-chloroethyl ((2,2-dimethyl-1,3-dioxan-5-yl)methyl carbonate as a yellow / green oil (508 mg, 72%). 1 1H-NMR (400 MHz, DMSO-d6) δ 6.47 (1H, q, J = 5.8 Hz), 4.21 (2H, d, J = 7.3 Hz), 3.88 (2H, dd, J = 11.7, 3.9 Hz), 3.60 (2H, J = 5.8 Hz, 2H), 1.89 - 1.95 (1H, m), 1.73 (3H, d, J = 6.0 Hz), 1.30 (3H, s), 1.26 (3H, s).

[0259] Chemical Synthesis Example 5: 1-((((2,2-Dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0260]

Chemical Structure

[0261] Lifitegrast (100 mg, 0.162 mmol), 1-chloroethyl (2,2-dimethyl-1,3-dioxan-5-yl) methyl carbonate (123 mg, 0.487 mmol), and DIPEA (110 mL, 0.650 mmol) were dissolved in DMF (1 mL). The mixture was stirred at 60 °C for 18 h under N2. The reaction mixture was diluted with EtOAc (25 mL) and successively washed with H2O (10 mL), saturated NaHCO 3(aq) (10 mL), and saturated brine solution (10 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. Three purification strategies were then attempted.

[0262] Purification method A: Approximately one-fourth of the crude material was dissolved in MeCN (2 mL) and purified by preparative reverse-phase HPLC. The desired fractions were combined and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (2 mL) and the solution was frozen. The solvent was evaporated in vacuo (lyophilized).

[0263] Purification method B: Approximately one-fourth of the crude material was dissolved in MeCN (2 mL) and purified by preparative reverse-phase HPLC. The desired fractions were combined and extracted with EtOAc (2 × 50 mL). The combined organic matter was successively washed with H2O (50 mL) and saturated brine solution (50 mL), dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (2 mL) and the solution was frozen. By evaporating the solvent in vacuo (lyophilization), 1-((((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (10.3 mg, 8%) was obtained as a white solid.

[0264] Purification method C: The remaining crude material was combined with the material isolated from Purification Method A in a solution of MeCN (2 mL) to form a solution, which was then purified by preparative reverse-phase HPLC. The desired fractions were combined and extracted with EtOAc (2 × 50 mL). The combined organic matter was washed with a saturated brine solution (50 mL), dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (2 mL), and the solution was frozen. By evaporating the solvent in vacuo (lyophilization), 1-((((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate was obtained as an off-white viscous solid (39.1 mg, 29%). LCMS (Method F): Rt = 7.78 min; [M+H]+ = 831.6. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.18 (1H, d, J = 7.8 Hz), 8.12 (1H, d, J = 2.3 Hz), 7.88 (1H, br s), 7.65 - 7.78 (4H, m), 7.55 (1H, td, J = 7.8, 1.8 Hz), 7.10 - 7.50 (2H, br m), 7.03 - 7.04 (1H, m), 6.68 - 6.73 (1H, m), 4.87 - 4.95 (1H, m), 4.61 - 4.81 (2H, br s), 4.19 (2H, d, J = 7.3 Hz), 3.50 - 4.00 (6H, br m), 3.27 - 3.31 (1H, m, partially obscured by H2O peak), 3.13 - 3.14 (3H, m), 3.00 - 3.06 (1H, m), 2.76 (2H, br s), 1.89 - 1.96 (1H, br m), 1.48 (1.5H, d, J = 5.5 Hz), 1.44 (1.5H, d, J = 5.5 Hz), 1.31 (3H, s), 1.27 (3H, s).

[0265] Chemical Synthesis Example 6: 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diylbis(2,2-dimethylpropanoate

[0266] [Chemistry]

[0267] A solution of 1-chloroethyl chloroformate (56 mL, 0.519 mmol) in DCM (2 mL) was placed under a nitrogen atmosphere and cooled to 0 °C. Pyridine (56 mL, 0.693 mmol) was added, followed by [2-(2,2-dimethylpropanoyloxymethyl)-3-hydroxy-propyl] 2,2-dimethylpropanoate (200 mL, 0.346 mmol), and the mixture was stirred at room temperature for 3 hours. 1-Chloroethyl chloroformate (56 mL, 0.519 mmol) and pyridine (56 mL, 0.693 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between DCM (10 mL) and H2O (10 mL), and the layers were separated (phase separator). The solvent was evaporated in vacuo, and the residue was purified by flash chromatography (Biotage SP1, 10 g cartridge), eluting with isohexane → 40% EtOAc-isohexane, to give 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl bis(2,2-dimethylpropanoate) (91 mg, 69%) as a colorless oil. 1 1H-NMR (400 MHz, CDCl3) δ 6.40 (1H, q, J = 5.8 Hz), 4.24 - 4.31 (2H, m), 4.06 - 4.18 (4H, m), 2.43 - 2.52 (1H, m), 1.82 (3H, d, J = 5.5 Hz), 1.19 (18H, s).

[0268] Chemical Synthesis Example 7: 2-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl bis(2,2-dimethylpropanoate)

[0269] [Chemistry]

[0270] A mixture of Lifitegrast (145 mg, 0.236 mmol), [2-(1-chloroethoxycarbonyloxymethyl)-3-(2,2-dimethylpropanoyloxy)propyl] 2,2-dimethylpropanoate (90 mg, 0.236 mmol), DIPEA (82 mL, 0.473 mmol), and DMF (1 mL) was heated in a sealed tube at 60 °C. The crude product was purified by preparative reverse-phase HPLC. The desired fractions were combined and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (3 mL) and the solution was frozen. The solvent was evaporated in vacuo (lyophilized) to give 2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl bis(2,2-dimethylpropanoate) (81.1 mg, 36%) as a white solid. LCMS (Method F): Rt = 8.54 min; [M+H]+ = 960.1. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.16 (1H, d, J = 7.8 Hz), 8.11 (1H, d, J = 2.3 Hz), 7.87 (1H, br s), 7.66 - 7.77 (4H, m), 7.53 - 7.57 (1H, m), 7.10 - 7.50 (2H, br m), 7.03 - 7.04 (1H, m), 6.68 - 6.74 (1H, m), 4.86 - 4.94 (1H, m), 4.72 (2H, br s), 4.15 - 4.26 (2H, m), 4.02 - 4.11 (4H, m), 3.50 - 3.90 (2H, br s), 3.26 - 3.29 (1H, m, partially obscured by H2O peak), 3.13 - 3.14 (3H, m), 2.98 - 3.07 (1H, m), 2.76 (2H, br s), 2.40 - 2.47 (1H, m), 1.48 (1.5H, d, J = 5.3 Hz), 1.44 (1.5H, d, J = 5.3 Hz), 1.10 - 1.11 (18H, m).

[0271] Chemical Synthesis Example 8: 1-(((3-Hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)ethyl (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0272]

Chem.

[0273] To a solution of 1-((((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (36 mg, 0.0433 mmol) in THF (1 mL) was added 2M HCl (aq) (0.50 mL, 1.00 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (10 mL), and the solution was extracted with EtOAc (2 × 10 mL). The combined organics were washed with saturated NaHCO 3(aq)(10 mL), water (10 mL), and saturated brine solution (10 mL) were washed successively. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by preparative reverse-phase HPLC. The desired fractions were combined and extracted with EtOAc (2 × 50 mL). The combined organic matter was washed with saturated brine solution (50 mL), dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (2 mL), and the solution was frozen. The solvent was evaporated in vacuo (lyophilized) to give 1-(((3-hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)ethyl (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (9.5 mg, 28%) as a white solid. LCMS (Method F): Rt = 7.14 min; [M+H]+ = 791.5. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.16 - 9.21 (1H, m), 8.11 - 8.12 (1H, m), 7.88 (1H, br s), 7.66 - 7.78 (4H, m), 7.53 - 7.58 (1H, m), 7.10 - 7.50 (2H, br m), 7.03 - 7.04 (1H, m), 6.67 - 6.73 (1H, m), 4.87 - 4.93 (1H, m), 4.73 (2H, br s), 4.54 - 4.57 (2H, m), 4.09 - 4.18 (2H, m), 3.54 - 3.94 (2H, br m), 3.36 - 3.47 (4H, m), 3.27 - 3.31 (1H, m, partially obscured by H2O peak), 3.13 - 3.15 (3H, m), 2.99 - 3.06 (1H, m), 2.76 (2H, br s), 1.82 - 1.89 (1H, m), 1.48 (1.5H, d, J = 5.3 Hz), 1.44 (1.5H, d, J = 5.3 Hz).

[0274] Chemical Synthesis Example 9: 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl diacetate

[0275]

Chem.

[0276] A solution of 1-chloroethyl chloroformate (53 mL, 0.494 mmol) in DCM (2 mL) was placed under a nitrogen atmosphere and cooled to 0 °C. Pyridine (60 mL, 0.741 mmol) was added, followed by [2-(acetoxymethyl)-3-hydroxy-propyl] acetate (200 mL, 0.247 mmol). The mixture was stirred at 0 °C for 6.5 h. Pyridine (20 ml, 0.250 mmol) and 1-chloroethyl chloroformate (26 mL, 0.250 mmol) were added, and the mixture was stirred at 0 °C for 90 min. 1-chloroethyl chloroformate (26 mL, 0.250 mmol) was added, and the mixture was stirred at 0 °C for 90 min. The mixture was diluted with DCM (10 mL) and H2O (10 mL). The layers were separated (phase separator), and the organic phase was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage SP1, 10 g cartridge), eluting with isohexane → 40% EtOAc isohexane, to give 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl diacetate (34 mg, 46%) as a colorless oil. 1 1H-NMR (400 MHz, CDCl3) δ 6.39 (1H, q, J = 5.8 Hz), 4.27 (2H, d, J = 6.0 Hz), 4.09 - 4.17 (4H, m), 2.38 - 2.47 (1H, m), 2.05 (6H, s), 1.81 (3H, d, J = 5.5 Hz).

[0277] Chemical Synthesis Example 10: 2-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl diacetate

[0278]

Chemical Structure

[0279] [2-(Acetoxymethyl)-3-(1-chloroethoxycarbonyloxy)propyl] acetate (34 mg, 0.115 mmol), Lifitegrast (71 mg, 0.115 mmol), and DIPEA (40 mL, 0.229 mmol) were dissolved in DMF (1 mL), and the mixture was stirred at 60 °C for 72 h. The crude product was purified by preparative reverse-phase HPLC. The desired fractions were combined and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (3 mL), and the solution was frozen. The solvent was evaporated in vacuo (lyophilized) to give 2-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl) propane-1,3-diacetate (34.4 mg, 34%) as an off-white solid. LCMS (Method F): Rt = 7.66 min; [M+H]+ = 875.5. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.18 (1H, d, J = 7.8 Hz), 8.12 (1H, d, J = 2.3 Hz), 7.88 (1H, br s), 7.66 - 7.77 (4H, m), 7.53 - 7.58 (1H, m), 7.15 - 7.50 (2H, br m), 7.03 - 7.04 (1H, m), 6.67 - 6.73 (1H, m), 4.87 - 4.94 (1H, m), 4.73 (2H, br s), 4.14 - 4.23 (2H, m), 4.05 (4H, d, J = 6.0 Hz), 3.55 - 3.90 (2H, br m), 3.27 - 3.31 (1H, m, partially obscured by H2O peak), 3.13 - 3.14 (3H, m), 2.99 - 3.06 (1H, m), 2.76 (2H, br s), 2.35 - 2.41 (1H, m), 1.98 - 2.00 (6H, m), 1.48 (1.5H, d, J = 5.5 Hz), 1.44 (1.5H, d, J = 5.5 Hz).

[0280] Chemical Synthesis Example 11: 1-Acetoxyethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0281]

Chem.

[0282] A solution of Lifitegrast (60 mg, 0.0975 mmol), 1-chloroethyl acetate (18 mg, 0.147 mmol), and DIPEA (34 mL, 0.195 mmol) in DMF (0.90 mL) was heated in a sealed tube at 60 °C for 16 h. The crude product was purified by preparative reverse-phase HPLC to give 1-acetoxyethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (28 mg, 39%) as an off-white solid. LCMS (Method F): Rt = 7.45 min; [M+H]+ = 701.5. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.13 - 9.16 (1H, m), 8.09 (1H, d, J = 2.3 Hz), 7.84 (1H, s), 7.63 - 7.74 (4H, m), 7.51 - 7.55 (1H, m), 7.28 (2H, s), 7.00 - 7.01 (1H, m), 6.74 - 6.79 (1H, m), 4.82 - 4.88 (1H, m), 4.70 (2H, br s), 3.61 (2H, br s), 3.23 - 3.29 (1H, m, partially obscured by H2O peak), 3.11 (3H, m), 2.94 - 3.03 (1H, m), 2.73 (2H, br s), 2.01 (3H, s), 1.39 (3H, dd, J = 17.9, 5.5 Hz).

[0283] Chemical Synthesis Example 12: 1-(Isobutyryloxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0284]

Chem.

[0285] Lifitegrast (60 mg, 0.0975 mmol), 1-chloroethyl 2-methylpropanoate (22 mg, 0.146 mmol), and DIPEA (34 mL, 0.195 mmol) were dissolved in DMF (0.90 mL) and heated in a sealed tube at 60 °C for 16 h. The crude product was purified by preparative reverse-phase HPLC to give 1-(isobutyryloxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (46 mg, 61%) as a brown solid. LCMS (Method F): Rt = 7.88 min; [M+H]+ = 729.5. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.13 - 9.17 (1H, m), 8.09 (1H, d, J = 2.3 Hz), 7.84 (1H, s), 7.63 - 7.75 (4H, m), 7.50 - 7.55 (1H, m), 7.27 - 7.29 (2H, m), 7.01 (1H, m), 6.72 - 6.79 (1H, m), 4.80 - 4.89 (1H, m), 4.70 (2H, br s), 3.62 (2H, br s), 3.21 - 3.26 (1H, m), 3.11 (3H, d, J = 3.4 Hz), 2.94 - 3.03 (1H, m), 2.73 (2H, br s), 2.48 - 2.53 (1H, m), 1.39 (3H, dd, J = 22.9, 5.5 Hz), 1.04 (6H, dd, J = 7.1, 2.1 Hz).

[0286] Chemical Synthesis Example 13: Methyl (2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate

[0287] [Chem.]

[0288] A solution of 1-chloroethyl chloroformate (339 μL, 3.14 mmol) and pyridine (381 μL, 4.71 mmol) in DCM (2 mL) under N2 at 0 °C was added dropwise over 5 minutes with a solution of (R)-methyl 2-hydroxypropanoate (150 μL, 1.57 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 h. * The mixture was diluted with DCM (30 mL) and the solution was washed with H2O (30 mL). The organic phase was separated (phase separator) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography, eluting with isohexane → 15% EtOAc-isohexane to give methyl (2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate (275 mg, 75%) as a colorless oil. 1 1H-NMR (400 MHz, CDCl3) δ 6.38 - 6.43 (1H, m), 5.04 - 5.10 (1H, m), 3.77 (3H, m), 1.84 (3H, dd, J = 6.0, 4.1 Hz), 1.54 - 1.56 (3H, m).

[0289] * Alternatively, to ensure near-complete conversion of the starting materials, additional equivalents of chloroformate (up to 0.54) may be added in small portions regularly during the reaction period and the reaction mixture may be stirred at 0 °C → room temperature for up to 40 h.

[0290] Chemical Synthesis Example 14: 1-((((R)-1-methoxy-1-oxopropan-2-yl)oxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0291] [Chemical]

[0292] A solution of Lifitegrast (60 mg, 0.0975 mmol), methyl (2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate (34 mg, 0.146 mmol) and DIPEA (34 mL, 0.195 mmol) in DMF (0.90 mL) was heated at 60 °C for 16 h in a sealed tube. * The crude product was purified by preparative reverse-phase HPLC to give ** 1-(((((R)-1-methoxy-1-oxopropan-2-yl)oxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (30 mg, 37%) as an off-white solid. LCMS (Method F): Rt = 7.62 min; [M+H]+ = 789.5. 1 1H-NMR (400 MHz, DMSO-d6) δ 9.14 - 9.21 (1H, m), 8.08 (1H, d, J = 1.8 Hz), 7.85 - 7.89 (1H, m), 7.63 - 7.74 (4H, m), 7.50 - 7.55 (1H, m), 7.28 (2H, br s), 7.00 - 7.01 (1H, m), 6.64 - 6.70 (1H, m), 4.97 - 5.04 (1H, m), 4.82 - 4.90 (1H, m), 4.64 (2H, br s), 3.64 - 3.66 (5H, m), 3.21 - 3.26 (1H, m), 3.11 (3H, m), 2.96 - 3.07 (1H, m), 2.73 (2H, br s), 1.39 - 1.48 (6H, m).

[0293] * Alternatively, the mixture may be stirred at 60 °C for up to 18 h under N2.

[0294] ** In addition, fractions containing the desired product may be combined and the solution frozen. The solvent may be evaporated in vacuo (lyophilization).

[0295] Chemical Synthesis Example 15: The following compound was synthesized in the same manner as described for 1 - ((((R)-1 - methoxy - 1 - oxopropan - 2 - yl)oxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran - 6 - carbonyl)-5,7 - dichloro - 1,2,3,4 - tetrahydroisoquinoline - 6 - carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate).

[0296] [Table 2]

[0297] Chemical Synthesis Example 16: (R)-2 - ((allyloxy)carbonyl)oxy)propionic acid

[0298] [Chemical Formula]

[0299] A solution of methyl (R)-2-(((allyloxy)carbonyl)oxy)propanoate (1.00 g, 5.05 mmol) in THF (1 mL) and H2O (1 mL) was cooled to 0 °C. Lithium hydroxide monohydrate (254 mg, 6.06 mmol) was added, and the reaction mixture was stirred at 0 °C for 3 hours. Lithium hydroxide monohydrate (254 mg, 6.06 mmol) was added, and the reaction mixture was stirred at room temperature for 23 hours. Lithium hydroxide monohydrate (254 mg, 6.06 mmol) and methanol (2 mL) were added, and the mixture was stirred at room temperature for 90 minutes. Lithium hydroxide monohydrate (254 mg, 6.06 mmol) was added, and the reaction mixture was heated at 40 °C for 90 minutes. The solvent was evaporated in vacuo to a maximum volume of 2 mL and cooled to 0 °C. This solution was acidified to pH 1 with 1 M HCl, diluted with H2O (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organics were washed with saturated brine solution (10 mL), dried (MgSO4), and the solvent was evaporated in vacuo to give (R)-2-(((allyloxy)carbonyl)oxy)propionic acid (412 mg, 47%). 1 1H-NMR (400 MHz, CDCl3) δ 5.88 - 5.97 (1H, m), 5.34 - 5.40 (1H, m), 5.25 - 5.30 (1H, m), 5.05 (1H, q, J = 7.2 Hz), 4.66 (2H, td, J = 3.4, 1.8 Hz), 1.58 (3H, d, J = 6.9 Hz).

[0300] Chemical Synthesis Example 17: 2-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl (2R,2R’)-bis(2-(((allyloxy)carbonyl)oxy)propanoate)

[0301]

Chemical Structure

[0302] (R)-2-(((allyloxy)carbonyl)oxy)propanoic acid (81 mg, 0.467 mmol), COMU (200 mg, 0.467 mmol), and DIPEA (110 mL, 0.654 mmol) were dissolved in DCM (3 ml), and the solution was stirred at room temperature for 10 minutes. A solution of 1-(((3-hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (74 mg, 0.0935 mmol) in DCM (2 mL) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo, and the residue was dissolved in EtOAc (30 mL). The solution was successively washed with saturated NH4Cl (aq) (30 mL), H2O (30 mL), and saturated brine solution (30 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by preparative reverse-phase HPLC to give 2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl (2R,2’R)-bis(2-(((allyloxy)carbonyl)oxy)propanoate) (10 mg, 10%) as a white solid. LCMS (Method D): Rt = 3.34 min; [M+H]+ = 1103.8.

[0303] Chemical Synthesis Example 18: (3R)-1-hydroxy-7-((((R)-2-hydroxypropanoyl)oxy)methyl)-3-methyl-1,4,10-trioxo-2,5,9,11-tetraoxatridecan-12-yl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0304] [Chem.]

[0305] A solution of 2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl (2R,2’R)-bis(2-(((allyloxy)carbonyl)oxy)propanoate) (13 mg, 0.0113 mmol) in DCM (2 mL) was stirred under N2. Phenylsilane (5.6 mL, 0.0453 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.3 mg, 0.00113 mmol) were added and the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated in vacuo. The crude product was purified by preparative reverse phase HPLC, the desired fractions were combined, and the solvent was evaporated in vacuo. The residue was dissolved in 1:1 MeCN-H2O (2 mL) and the solution was frozen. The solvent was then evaporated in vacuo (lyophilized) to give (3R)-1-hydroxy-7-((((R)-2-hydroxypropanoyl)oxy)methyl)-3-methyl-1,4,10-trioxo-2,5,9,11-tetraoxatridecan-12-yl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate (3.5 mg, 33%) as a white solid. LCMS (Method F): Rt = 7.31 min; [M+H]+ = 935.7. 11H-NMR (400 MHz, CDCl3) δ 7.90 - 7.91 (1H, m), 7.81 - 7.85 (1H, m), 7.72 (1H, m), 7.61 - 7.67 (3H, m), 7.44 - 7.55 (1H, m), 7.32 (1H, d, J = 7.8 Hz), 7.13 (1H, br s), 6.74 - 6.83 (2.5H, m), 6.64 (0.5H, d, J = 8.2 Hz), 5.26 - 5.32 (1H, m), 4.77 (2H, br s), 4.36 - 4.46 (1H, m), 4.12 - 4.32 (7H, m), 3.78 (2H, m), 3.44 - 3.51 (1H, m), 3.26 (1H, dt, J = 14.3, 7.6 Hz), 3.05 (3H, d, J = 1.4 Hz), 2.70 - 2.96 (4H, br m), 2.48 - 2.55 (1H, m), 1.57 (3H, t, J = 5.5 Hz, partially obscured by H2O peak), 1.37 - 1.41 (6H, m).

[0306] Chemical Synthesis Example 19: 1-Chloroethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate

[0307] [Chemical Structure Diagram]

[0308] Sodium hydrogen carbonate (122 mg, 1.60 mmol), tetrabutylammonium hydrogensulfate (14 mg, 0.0400 mmol), and lipoic acid (83 mg, 0.400 mmol) were added to a stirred mixture dissolved in DCM (3 mL) under a N2 atmosphere. H2O (3 mL) was followed by a solution of 1-chloroethyl sulfochloridate (100 mg, 0.560 mmol) dissolved in DCM (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The organic phase was separated (phase separator), and the solvent was evaporated in vacuo to obtain 1-chloroethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate as a pale yellow gum (130 mg), which was not further purified.

[0309] Chemical Synthesis Example 20: 1-(((S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate

[0310]

Chem.

[0311] Crude 1-chloroethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate (74 mg, 0.275 mmol) was dissolved in DMF (2.5 mL). Lifitegrast (178 mg, 0.275 mmol) and DIPEA (96 mL, 0.549 mmol) were added and the mixture was stirred at 60 °C for 16 h. The crude product was purified by preparative reverse-phase HPLC, the desired fractions were combined and the volume of the solvent was reduced to 40 mL. The mixture was diluted with MeCN to produce a homogeneous mixture. The solution was frozen and the solvent was evaporated in vacuo (lyophilized) to give 1-(((S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate (9.1 mg, 4%) as a white solid. LCMS (Method C): Rt = 7.97 min; [M+H]+ = 847.1. 1H-NMR (400 MHz, CDCl3) δ 7.81 - 7.89 (2H, m), 7.71 - 7.72 (1H, m), 7.57 - 7.65 (3H, m), 7.47 - 7.52 (1H, m), 7.28 - 7.31 (1H, m), 6.88 (1H, td, J = 10.8, 5.3 Hz), 6.81 (1H, m), 6.27 (1H, dd, J = 10.8, 8.0 Hz), 5.19 - 5.27 (1H, m), 4.75 (1H, br s), 3.81 (1H, br s), 3.39 - 3.58 (2H, m), 3.05 - 3.29 (3H, m), 3.03 (3H, d, J = 4.1 Hz), 2.87 (2H, br s), 2.31 - 2.48 (3H, m), 1.82 - 1.92 (1H, m), 1.38 - 1.74 (11H, m).

[0312] Chemical Synthesis Example 21: Methyl (R)-2-(trityloxy)propanoate

[0313]

Chem.

[0314] To a stirred solution of methyl (R)-2-hydroxypropanoate (0.91 mL, 11.1 mmol), 4-(dimethylamino)pyridine (210 mg, 1.74 mmol), and pyridine (0.70 mL) in MeCN (12 mL) was added triphenylmethyl chloride (2.38 g, 8.55 mmol), and the mixture was stirred at reflux for 16 h. The reaction mixture was cooled and allowed to stand at room temperature for 24 h and then partitioned between EtOAc and H2O. The organic phase was washed successively with 1 M NaHCO 3(aq) , saturated NaHCO 3(aq) , saturated Na2CO 3(aq) , and saturated brine solution. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo to give methyl (R)-2-(trityloxy)propanoate (2.98 g, 77%) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7.41 - 7.52 (6H, m), 7.18 - 7.35 (13H, m), 4.20 (1H, q, J = 6.7 Hz), 3.22 (3H, s), 1.37 (3H, d, J = 6.9 Hz).

[0315] Chemical Synthesis Example 22: (R)-2-(Trityloxy)propionic acid

[0316] [Chemical Structure]

[0317] Methyl (2R)-2-trityloxypropanoate (2.98 g, 8.60 mmol) and sodium hydroxide (3.08 g, 77.0 mmol) were dissolved in MeOH (28 mL), and the mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered, and the filtrate was diluted with H2O (40 mL). MeOH was evaporated in vacuo, and the solution was washed with tert-butyl methyl ether. The aqueous phase was acidified to pH 3 by adding 5M HCl (aq) and extracted with tert-butyl methyl ether. The organic phase was washed with saturated brine solution, dried (MgSO4), and the solution was filtered. Evaporation of the solvent in vacuo gave (R)-2-(trityloxy)propionic acid (1.53 g, 54%) as a pale yellow gum. LCMS (Method E): Rt = 2.87 min, [M - H]- = 331.2.

[0318] Chemical Synthesis Example 23: 1-Chloroethyl (2R)-2-(trityloxy)propanoate

[0319] [Chemical Structure]

[0320] (R)-2-(Trityloxy)propanoic acid (100 mg, 0.301 mmol), tetrabutylammonium hydrogensulfate (10 mg, 0.0301 mmol), and NaHCO3 (101 mg, 1.20 mmol) were added to a stirred mixture of DCM (1.5 mL) and water (1.5 mL) under N2. A solution of 1-chloroethyl sulfochloridate (75 mg, 0.421 mmol) in DCM (0.5 mL) was added, and the mixture was stirred at room temperature for 2 h. The solution was passed through a phase separator, and the filtrate was evaporated in vacuo to give crude 1-chloroethyl (2R)-2-(trityloxy)propanoate (130 mg) as a pale yellow solid. LCMS (Method E): Rt = 3.53 min (no ionization).

[0321] Chemical Synthesis Example 24: 1-(((R)-2-(Trityloxy)propanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0322]

Chem.

[0323] A stirred solution of 1-chloroethyl (2R)-2-(trityloxy)propanoate (100 mg, 0.253 mmol) in anhydrous DMF (2 mL) was added to DIPEA (88 mL, 0.506 mmol) and Lifitegrast (125 mg, 0.193 mmol), and the mixture was stirred at 55 °C for 16 h under N2. The mixture was partitioned between EtOAc (50 mL) and saturated NaHCO 3(aq)(20 mL) was diluted and the layers were separated. The organic phase was washed with saturated brine solution (20 mL), dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (Biotage SP1, 10 g cartridge), eluting with isohexane → EtOAc to give 1-(((R)-2-(trityloxy)propanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (61 mg, 25%) as a white solid. LCMS (method E): Rt = 3.37 min; [M+H]+ = 973.2 (weak ionization).

[0324] Chemical Synthesis Example 25: 1-(((R)-2-hydroxypropanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0325]

Chemical Structure

[0326] Method A 1-(((R)-2-(trityloxy)propanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (14 mg, 0.0144 mmol) was added to a stirred solution of anhydrous DCM (0.5 mL) dissolved at room temperature under N2, followed by the addition of triethylsilane (110 μL, 0.0719 mmol), and then TFA (50 μL) was added dropwise. The reaction was stirred at room temperature for 73 hours. Anhydrous DCM (1 mL), triethylsilane (110 μL, 0.0719 mmol), and TFA (50 μL) were added, and the reaction was stirred at room temperature for 1 hour.

[0327] Method B 1-(((R)-2-(Trityloxy)propanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (48 mg, 0.0493 mmol) was added to a stirred solution of anhydrous DCM (1.5 mL) dissolved at room temperature under N2, followed by triethylsilane (79 μL, 0.493 mmol), and then TFA (150 μL) was added dropwise. The mixture was stirred at room temperature for 75 minutes.

[0328] Method C The two reaction mixtures obtained from Methods A and B were combined, diluted with DCM (30 mL) and saturated NaHCO 3(aq) (30 mL), and the layers were separated. The aqueous phase was extracted with DCM (20 mL), the combined organics were washed with saturated brine solution (10 mL), dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The crude product was purified by preparative reverse-phase HPLC. The desired fractions were combined and the solution was frozen. The solvent was evaporated in vacuo (lyophilized), the residue was dissolved in 1:1 MeCN-H2O, frozen, and evaporated in vacuo (lyophilized) to obtain 1-(((R)-2-hydroxypropanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (15 mg, 42%) as a white solid. LCMS (Method C): Rt = 6.49 min; [M+H]+ = 731.2. 1H-NMR (400 MHz, CDCl3) δ 7.79 - 7.88 (2H, m), 7.72 (1H, d, J = 2.3 Hz), 7.57 - 7.68 (3H, m), 7.51 (1H, td, J = 7.9, 3.5 Hz), 7.31 (1H, d, J = 7.8 Hz), 6.90 - 6.98 (1H, m), 6.80 - 6.86 (1H, m), 6.22 - 6.40 (1H, m), 5.24 (1H, dd, J = 14.0, 6.2 Hz), 4.79 (2H, s), 4.24 - 4.37 (1H, m), 3.87 (2H, br s), 3.38 - 3.44 (1H, m), 3.21 - 3.32 (1H, m), 3.06 (3H, d, J = 10.5 Hz), 2.88 (2H, s), 1.55 (3H, dd, J = 12.4, 5.5 Hz), 1.42 (3H, dd, J = 7.1, 5.7 Hz).

[0329] Chemical Synthesis Example 26: The following compound was prepared in the same manner as described above for 1 - (((R)-2-hydroxypropanoyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate.

[0330] [Table 3]

[0331] Chemical Synthesis Example 27: 1 - (((S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl pivalate

[0332] [Chemical Structure]

[0333] A stirred solution of 1-chloroethyl pivalate (40 mg, 0.243 mmol) in anhydrous DMF (1.6 mL) was added to DIPEA (85 mL, 0.486 mmol) and Lifitegrast (130 mg, 0.201 mmol). The mixture was stirred at 40 °C for 72 h under N2. The crude product was purified by preparative reverse-phase HPLC, the desired fractions were combined, and approximately half of the solvent was evaporated in vacuo. The solution was frozen and the solvent was evaporated in vacuo (lyophilized) to give 1-(((S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl pivalate (40 mg, 22%) as an off-white solid. LCMS (Method C): Rt = 7.66 min; [M+H]+ = 743.1. 1 1H-NMR (400 MHz, CDCl3) δ 7.80 - 7.91 (2H, m), 7.71 (1H, d, J = 1.8 Hz), 7.56 - 7.64 (3H, m), 7.49 (1H, td, J = 7.7, 5.3 Hz), 7.29 (1H, d, J = 6.4 Hz), 6.81 - 6.89 (2H, m), 6.32 (1H, q, J = 7.8 Hz), 5.19 - 5.27 (1H, m), 4.74 (2H, br s), 3.78 (2H, br s), 3.41 (1H, dd, J = 14.4, 5.7 Hz), 3.11 - 3.27 (1H, m), 3.03 (3H, d, J = 6.9 Hz), 2.85 - 2.94 (2H, m), 1.50 (3H, dd, J = 15.8, 5.3 Hz), 1.15 - 1.19 (9H, m).

[0334] Chemical Synthesis Example 28: 1-((methoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0335]

Chemical Structure

[0336] Lifitegrast (205 mg, 0.333 mmol) and DIPEA (90 mL, 0.517 mmol) were dissolved in anhydrous DMF (5 mL). 1-Chloroethyl methyl carbonate (40 mg, 0.289 mmol) was added, and the mixture was stirred at room temperature for 16 h, followed by stirring at 40 °C for 2 h. DIPEA (50 μ, 0.287 mmol) was added, and the mixture was stirred at 50 °C for 20 h. The solvent was evaporated in vacuo, and the residue was dissolved in DCM (20 mL). The solution was washed with saturated NaHCO 3(aq) (20 mL), and the layers were separated. The organic phase was evaporated in vacuo, and the crude product was purified by flash chromatography, eluting with isohexane → 8:2 EtOAc-isohexane, to give 1-((methoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (88 mg, 42%) as a white solid. LCMS (Method C): Rt = 6.94 min; [M+H]+ = 717.1. 1 1H-NMR (400 MHz, CDCl3) δ 7.79 - 7.86 (2H, m), 7.70 (1H, d, J = 1.8 Hz), 7.57 - 7.64 (3H, m), 7.45 - 7.51 (1H, m), 7.28 (1H, d, J = 7.8 Hz), 6.75 - 6.80 (2H, m), 6.43 (1H, t, J = 8.5 Hz), 5.24 (1H, s), 4.72 (2H, br s), 3.59 - 4.00 (5H, m), 3.41 (1H, dd, J = 14.7, 5.5 Hz), 3.21 - 3.29 (1H, m), 3.01 (3H, d, J = 3.7 Hz), 2.85 (2H, s), 1.51 - 1.64 (4H, m).

[0337] Chemical Synthesis Example 29: 1-((Ethoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0338] [Chem.]

[0339] A stirred solution of 1-chloroethyl ethyl carbonate (37 mg, 0.243 mmol) in DMF (1.6 mL) was added to DIPEA (85 mL, 0.486 mmol) and Lifitegrast (120 mg, 0.185 mmol), and the mixture was stirred at 40 °C for 16 h under N2. DIPEA (85 mL, 0.486 mmol) and 1-chloroethyl ethyl carbonate (37 mg, 0.243 mmol) were added, and the mixture was stirred at 40 °C for 4 h. The crude product was purified by preparative reverse-phase HPLC. Fractions containing the desired product were combined, frozen, and the solvent was evaporated in vacuo (lyophilized) to give 1-((ethoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (6.0 mg, 3%) as an off-white solid. LCMS (Method C): Rt = 7.15 min; [M+H]+ = 731.1.

[0340] Chemical Synthesis Example 30: 1-chloroethyl propionate

[0341] [Chem.]

[0342] Propionyl chloride (7.0 mL, 80.1 mmol) was placed under an N2 atmosphere and cooled to 0 °C. Zinc chloride (0.7 M in THF, 1.10 mL, 0.801 mmol) was added, followed by chilled acetaldehyde (5.40 mL, 96.1 mmol). The reaction mixture was stirred at 0 °C for 2 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in isohexane (10 mL) and the solution was saturated with NaHCO 3(aq)(10 mL), washed successively with H2O (10 mL) and saturated brine solution (10 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated in vacuo to afford 1-chloroethyl propionate (4.54 g, 41%) as an orange oil. * .

[0343] * This product contained a mixture of impurities and was used in the crude state without further purification.

[0344] Chemical Synthesis Example 31: 1-((Ethoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate

[0345]

Chemical Structure

[0346] A mixture of Lifitegrast (100 mg, 0.162 mmol) and 1-chloroethyl propionate (111 mg, 0.812 mmol) was dissolved in DMF (1 mL). DIPEA (170 μL, 0.975 mmol) was added and the mixture was stirred at 60 °C under N2 for 18 h. The crude product was purified by preparative reverse-phase HPLC, the desired fractions were combined, frozen, and the solvent was evaporated in vacuo (lyophilized) to afford 1-((ethoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamide)-3-(3-(methylsulfonyl)phenyl)propanoate (41.1 mg, 35%) as an off-white solid. LCMS (Method B): Rt = 3.08 min; [M+H]+ = 715.3. 11H-NMR (400 MHz, CDCl3) δ 7.83 - 7.90 (2H, m), 7.73 (1H, d, J = 2.7 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.59 - 7.61 (2H, m), 7.48 - 7.53 (1H, m), 7.31 - 7.33 (1H, m), 7.14 (1H, br s), 6.87 - 6.93 (1H, m), 6.82 - 6.83 (1H, m), 6.22 - 6.28 (1H, m), 5.21 - 5.28 (1H, m), 4.78 (2H, br s), 3.84 (2H, br s), 3.40 - 3.46 (1H, m), 3.20 - 3.31 (1H, m), 3.05 (1.5H, s), 3.04 (1.5H, s) 2.88 (2H, br s), 2.32 - 2.41 (2H, m), 1.53 (1.5H, d, J = 5.2 Hz, partially obscured by H2O peak), 1.50 (1.5H, d, J = 5.6 Hz), 1.11 - 1.17 (3H, m).

[0347] II. Biological Evaluation Example 1: Rabbit Corneal Homogenate Stability Assay The stability of the test compound in rabbit corneal homogenate was determined using HPLC - MS. This assay was performed on two concentrations of rabbit corneal homogenate (total protein of 0.15 mg / mL and 0.45 mg / mL) so as to be able to assign the observed hydrolysis as either esterase - dependent or not.

[0348] Homogenization of Rabbit Corneas Five rabbit corneas (e.g., New Zealand Whites), each approximately 50 mg, were sliced and rubbed with a scalpel and forceps until small (1 - 3 mm) thin pieces were obtained. These were transferred to tared vials, accurately weighed, and then diluted with 10 volumes of PBS aqueous solution at pH 7.4.

[0349] The samples were intermittently cooled on ice, subjected to shear homogenization for 3 minutes, and then centrifuged at 3000 rpm for 3 minutes. The supernatant was removed with a pipette and transferred to a vial, and the total protein concentration was determined at 280 nm. The samples were stored at - 78 °C.

[0350] Rabbit Corneal Esterase Assay Preparation of Stock Solutions: A 10 mM compound stock was diluted to 100 μM in a 96 - deep well plate. 10 μl of the 10 mM compound stock was added to 990 μl of 50 mM HEPES buffer at pH 7.5. The compound was further diluted to 10 μM. 100 μl of the 100 μM compound was added to 900 μl of 50 mM HEPES buffer at pH 7.5. The esterase homogenate was diluted to 300 ng / μl and 900 ng / μl. Assay Conditions: A heater shaker was set to 37 °C. 75 μl of 300 or 900 ng / μl esterase homogenate was dispensed into the required wells of an appropriate 96 - well plate (Run Plate) at each of 2 minutes, 5 minutes, 10 minutes, 20 minutes, and 45 minutes. After sealing the plate, it was warmed at 37 °C for 5 minutes. Another 96 - well PCR plate was placed on ice (Kill Plate). 100 μl of MeCN was added to each well of this plate, and it was labeled at 0 minutes, 2 minutes, 5 minutes, 10 minutes, 20 minutes, and 45 minutes. The plate was covered to minimize evaporation. For the T = 0 sample only, 50 μl of 300 or 900 ng / μl esterase homogenate was added to 100 μl of cold MeCN stop solution, followed by 50 μl of 10 μM compound solution. At the remaining time points, 75 μl of 10 μM compound solution was added to the Run Plate starting from the row at T = 45 minutes and ending at the row at T = 2 minutes. At the appropriate time points, 100 μl of the assay mixture was added to the wells of the matching kill plate containing 100 μl of cold MeCN. The samples were analyzed promptly by LCMS (Waters Xevo TQ - S or Micromass Ultima) as soon as they were ready for analysis.

[0351] The parent conjugate and parent concentration were determined for an appropriate standard response curve, and the half-life (T 1 / 2 ) of the parent conjugate was calculated using the peak area of the parent conjugate in the linear region of the log-linear plot at each time point.

[0352]

Table 4-1

[0353]

Table 4-2

[0354] Example 2: Aqueous Hydrolysis Stability Assay The aqueous stability of the test compound was determined using HPLC-MS. A 10 mM stock solution of the test compound was prepared in DMSO. 10 μl of the DMSO stock solution was dissolved in 990 μl of 50 mM HEPES buffer at pH 7.5 or 1:1 (v / v) acetonitrile:water to make a 100 μM solution. The final DMSO concentration was 1%. This solution was kept at room temperature and injected into an LCMS (Waters Xevo TQ-S or Micromass Ultima) without delay. Additional injections were made at appropriate time points. The half-life (T 1 / 2 ) of the parent conjugate was calculated using the peak area of the parent conjugate in the linear region of the log-linear plot at each time point.

[0355]

Table 4-3

[0356]

Table 4-4

[0357] Example 3: Experimental Dry Eye Disease Mouse Model Female C57BL / 6 mice (6 - 8 weeks old) or female HEL BCR Tg mice (6 - 8 weeks old) were obtained through commercial routes. Experimental dry eye was induced as described by Niederkorn, et al. (J. Immunol. 2006, 176: 3950 - 3957) and Dursun et al. (Invest. Ophthalmol. Vis. Sci. 2002, 43: 632 - 638). Briefly, the mice were exposed to dry stress in a perforated cage with a constant airflow from fans positioned on both sides and the room humidity maintained at 30% - 35%. Scopolamine hydrobromide (0.5 mg / 0.2 mL; Sigma - Aldrich, St. Louis, MO) was subcutaneously injected into the alternating hind - flanks three times a day (8:00 am, 12:00 noon, 5:00 pm) to exacerbate the disease. The mice were exposed to dry stress for 3 weeks. Untreated control mice were maintained in a non - stressed environment with a relative humidity of 50% - 75% without forced air injection. The test animals were exposed to the test compound, followed by obtaining tear samples to determine the stability of the test compound and collecting tissue samples to determine the presence of pro - inflammatory biomarkers.

[0358] III. Preparations of Pharmaceutical Dosage Forms Example 1: Solution for Topical Ophthalmic Use The active ingredient is the compound of Table 1 or its pharmaceutically acceptable salt, formulated as a solution with a concentration of 0.1 - 1.5% w / v.

Claims

1. A compound having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein 【Chemical 1】 R is and 【Chemical 2】 either R ８ is hydrogen, alkyl, heteroalkyl, or haloalkyl, and (a) X is -O-, R9 is C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with alkyl, heteroalkyl, alkoxy, hydroxyl, heterocyclyl, or heterocyclylalkyl, or (b) X is a single bond and R9 is heteroalkyl. The compound, or a pharmaceutically acceptable salt or solvate thereof.

2. R ８ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl.

3. R ９ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

4. R ９ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH ２ OH, -CH(CH ３ )OH, -CH ２ (OCH ２ CH ２ ) ４ OH, -CH ２ CH ２ (OCH ２ CH ２ ) ４ OH, 【Chemical 3】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein

5. The compound according to claim 1 having the following structure [Chemical Formula 4]

6. R ８ is C １ -C ４ alkyl, the compound according to claim 5.

7. R ８ The compound according to claim 5, wherein R is methyl.

8. The compound according to claim 5 having the structure of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof. 【Chemical Formula 5】

9. The compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a single bond.

10. R ９ is C １ -C ４ alkyl, a compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof.

11. R ９ is alkyl optionally substituted with one or more substituents, each substituent independently being selected from the group consisting of -OH and optionally substituted alkyl, a compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof.

12. R ９ The compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R is alkyl or heterocycloalkyl, and the heterocycloalkyl is further optionally substituted with alkyl which is further optionally substituted.

13. R ９ The compound according to claim 12, wherein R is alkyl substituted with dithiolane.

14. R ９ is C １ -C ４ alkyl, -CH(CH ３ )OH, -CH ２ OH, or ​ The compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein

15. The compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

16. R ９ is C １ -C ６ alkyl, the compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof.

17. R ９ is C １ -C ４ alkyl, 【Chemical Formula 7】 The compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof, wherein

18. Said C １ -C ４ The alkyl is methyl, ethyl, propyl, isopropyl, or tert-butyl, the compound according to claim 17, or a pharmaceutically acceptable salt or solvate thereof.

19. X is -O-, and R ９ is C １ -C 6 alkyl, and the C １ -C 6 alkyl is substituted with alkyl, heteroalkyl, alkoxy, hydroxyl, heterocyclyl, or heterocyclylalkyl, the compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof.

20. X is a single bond, R ９ is heteroalkyl, a compound according to claim 5 or 8, or a pharmaceutically acceptable salt or solvate thereof.

21. A compound having the following structure, or a pharmaceutically acceptable salt or solvate thereof. 【Chemical Formula 8-1】 【Chemical Figure 8-2】

22. A compound having the following structure, or a pharmaceutically acceptable salt or solvate thereof. 【Chemical Formula 9】

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

24. The pharmaceutical composition according to claim 23, which is suitable for ocular administration.

25. Use of a compound according to any one of claims 1 to 22 for the manufacture of a medicament for treating a disease or disorder of the eye or skin of an individual.

26. The use according to claim 25, wherein the eye disease or disorder is selected from disorders including inflammatory diseases of the eyelid, ocular surface, and / or posterior segment of the eye, abnormalities of the periorbital glands, allergic diseases, parasitosis, surgical complications, corneal abnormalities, conjunctival abnormalities, ocular complications due to systemic therapy and / or autoimmune diseases, and / or infections of the anterior surface of the eye.

27. The use according to claim 25, wherein the skin disease or disorder is selected from disorders including inflammatory diseases of the skin, hyperkeratosis of the skin, parasitosis, allergy, injury, and / or autoimmune diseases.

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