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 / infectious disorders 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 eye, ocular surface, or surrounding area provides therapeutic benefit to patients with ocular surface disorders.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefits under U.S. Provisional Patent Application No. 62 / 835,975 filed April 18, 2019, and U.S. Provisional Patent Application No. 62 / 966,482 filed January 27, 2020, both of which are incorporated herein by reference in their entirety. [Background technology]

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

[0003] In some embodiments herein, compounds, pharmaceutical (e.g., ocular) compositions, and treatment methods are provided. In specific embodiments, the treatment methods provided herein include treatment of ocular and / or periorbital indications or disorders. In some embodiments, the ocular and / or periorbital indications or disorders treated with or using the compositions or compounds provided herein are indications or disorders with multifactorial etiologies and / or interactions. In some embodiments herein, compounds (and compositions containing such compounds) are provided that have a multifactorial effect when administered to the eye or its perior surface (e.g., the eyelid, such as the eye surface, eyelid margin, or eyelid inner surface).

[0004] In one embodiment, the method provided herein relates to a method for treating meibomian gland dysfunction (MGD). Currently, there are no approved pharmacological agents useful for treating MGD. The recognition that terminal duct obstruction resulting from hyperkeratosis of the ductal epithelium on the meibomian glands is the central mechanism behind meibomian gland (MGD) is consistent with clinical experience demonstrating that effective treatment of MGD requires restoration of duct obstruction and removal of glandular contents (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 attempts to raise the internal temperature of the meibomian glands above the normal melting point of meibomian glands (32°C–40°C) to restore terminal duct obstruction (Lane et al, 2012). Unfortunately, warm compresses cannot achieve such benefits for severely obstructed glands, where the melting point may be below 40°C. Current techniques for removing keratinized blockages of meibomian glands include physical removal methods (e.g., debridement and glandular probing) that cause significant pain to the patient.

[0005] Following the period of MGD, various stages of inflammatory or bacterial disease are observed on the ocular surface. This is because meibomian gland obstruction can trigger a series of events, including further glandular deterioration due to the stagnation of meibomian glands (Knop, IOVS, 2011), mechanical pressure and stress due to gland obstruction, and increased bacterial growth associated with the downstream release of bacterial lipases, toxic mediators, and / or inflammatory mediators. All of these factors can reduce the quality and / or quantity of meibomian glands that the glands can release, leading to chronic mechanical damage to conjunctival, corneal, and eyelid tissues, and subsequently causing tissue damage and the release of inflammatory mediators. For this reason, many MGD patients also have inflammatory diseases affecting the conjunctiva, cornea, lacrimal glands, eyelids, or goblet cells, leading to complications such as dry eye syndrome or blepharitis that do not meet medical needs.

[0006] For example, in the literature, the terms posterior blepharitis and MGD are used as if they had the same meaning, but these terms are not interchangeable. Posterior blepharitis describes an inflammatory condition of the posterior eyelid margin, and MGD is the only possible cause of this condition. In its earliest stages, MGD may not be associated with the clinically characteristic symptoms 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 eyelid marginal signs such as changes in the expression and quality of meibum and redness of the eyelid margin may become more visible. At this point, MGD-associated posterior blepharitis is said to be present.

[0007] In some embodiments herein, methods are provided for treating ocular (or dermatological) disorders associated with keratosis (e.g., blepharokeratosis, ocular surface keratosis, and / or glandular blockage in MGD, etc.), microbial infiltration / infection (e.g., bacterial infiltration / infection), and / or inflammation (inflammation associated with or unrelated to keratosis). In some cases, skin and / or eye (and / or surrounding tissue / skin) disorders are difficult to diagnose differentially and / or have multiple etiologies. For example, in some cases it may be difficult to differentiate between (1) inflammation alone, (2) inflammation associated with keratolytic activity, (3) inflammation associated with both keratolytic activity (e.g., inducing keratosis) and microbial infiltration, (4) inflammation with keratolytic activity but without inflammation and / or microbial infiltration, or various other combinations. In some cases, the compounds and compositions provided herein can be used for such ocular and / or dermatological indications without performing differential diagnosis (which may be difficult, e.g., due to similar symptom scores, etc.). Furthermore, many ocular and / or dermatological disorders involve multiple etiologies, such as inflammation, microbial infiltration, keratolytic activity, or various combinations thereof. Consequently, therapeutic agents targeting multiple etiologies, such as those described herein, are beneficial in providing therapeutic benefits by targeting both the underlying disease (e.g., keratolytic activity and / or microbial infiltration) and symptoms such as inflammation or dry eye.

[0008] Topical azithromycin is an anti-inflammatory cytokine that inhibits pro-inflammatory activity and is effective against Gram-negative microorganisms. It is believed that this topical azithromycin penetrates the ocular surface, remaining at therapeutic levels several days after treatment is discontinued.

[0009] Therefore, this specification provides compounds, compositions, methods, and formulations for treating ocular (e.g., periocular) or dermatological disorders, including those with multifactorial etiologies. In specific embodiments, non-limiting examples of eye disorders include surface disorders such as MGD, dry eye, and related inflammatory and bacterial diseases.

[0010] In some embodiments herein, compounds having the structure of formula (Ia), or pharmaceutically acceptable salts or solvates thereof are provided.

[0011] [ka] During the ceremony, Each R is independently H, R', a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl, and at least one R is R'. R' is DL-, D is a keratolytic agent (e.g., its radical), L stands for linker.

[0012] In some embodiments, each R is independently H, R', a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl, with one R being R'. In some embodiments, each R is independently H, R', a substituted alkyl, or an unsubstituted alkyl. In specific embodiments, at least one R is R'. In some embodiments, each R is independently H, R', or an unsubstituted alkyl, with one R being R'. In some embodiments, the unsubstituted alkyl is methyl, ethyl, or propyl. In some embodiments, each R is independently H, R', or an unsubstituted heteroalkyl, with one R being R'. In some embodiments, the unsubstituted heteroalkyl is selected from the group consisting of (C=O)alkyl, (C=O)O alkyl, (C=O)S alkyl, (C=O)S heteroalkyl, or (C=O)amino, where the alkyl or amino is optionally substituted. In some embodiments, each R is independently H, methyl, or R', with one R being R'.

[0013] In some embodiments, the alkyl is optionally substituted with one or more selected from the group consisting of -OH, -SH, substituted or unsubstituted alkyl(alkylene), unsubstituted or substituted aryl, substituted or unsubstituted heteroalkyl, -NHCOMe, -O(C=O)CH2OH, -O(C=O)CH(CH3)OH, -O(C=O)alkyl, and -(C=O)Oalkyl (for example, where alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl). In some embodiments, the alkyl is substituted with one or more selected from the group consisting of alkyl, heterocycloalkyl, -NHCOMe, -O(C=O)alkyl, and -(C=O)Oalkyl (for example, where alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl). In some embodiments, the heterocycloalkyl is dithiolane.

[0014] In some embodiments, R is H, methyl, ethyl, propyl, isopropyl, t-butyl, -(C=O)alkyl, -(C=O)CH2(OCH2CH2)4OH, -(C=O)CH2CH2(OCH2CH2)4OH

[0015] [ka] That is the case.

[0016] In some embodiments, R' is -(C=O)CH2(OCH2CH2)4OH, -(C=O)CH2CH2(OCH2CH2)4OH,

[0017] [ka] That is the case.

[0018] One embodiment provides a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof.

[0019] [ka] During the ceremony, R' is DL-, D is a keratolytic agent (e.g., its radical), L stands for linker.

[0020] In some embodiments, L comprises one or more linker groups, each linker group selected from the group consisting of single bonds, -O-, -S-, halo, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), disulfide, ester, and carbonyl (>C=O). In some embodiments, each linker group is selected from the group consisting of single bonds, -O-, -S-, halo, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), and ester. In some embodiments, each linker group is selected from alkyl (alkylene) and heteroalkyl (heteroalkylene), and the alkyl (alkylene) or heteroalkyl (heteroalkylene) is optionally substituted. In some embodiments, L is an alkyl (alkylene) substituted with one or more oxo, alkyl, and heteroalkyl groups. In some embodiments, the alkyl or heteroalkyl group is substituted with one or more halo, alkyl, or haloalkyl groups. In some embodiments, the alkyl or heteroalkyl group is substituted with one or more alkyl or haloalkyl groups. In some embodiments, L is a single bond, -O-, -S-, (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, each of which is optionally substituted with alkyl, heteroalkyl, alkylene, or heteroalkyl. 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.

[0021] In some embodiments, D is selected from alkyl and heteroalkyl groups, and the alkyl or heteroalkyl group is optionally substituted. In some embodiments, D is an alkyl group substituted with one or more groups selected from oxo and substituted alkyl and substituted heteroalkyl groups. In some embodiments, the alkyl group is substituted with one or more groups selected from -SH, -OH, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroalkyl groups, or substituted or unsubstituted heterocycloalkyl groups. In some embodiments, D is a heteroalkyl group substituted with one or more groups selected from oxo and substituted alkyl and substituted heteroalkyl groups. In some embodiments, the heteroalkyl group is substituted with one or more groups selected from -SH, -OH, alkyl, (C=O)alkyl, (C=O)heteroalkyl, and -NH(C=O)alkyl groups.

[0022] In some embodiments, the compound comprises one or more keratolytic agents. In some embodiments, the keratolytic agent is -(C=O)CH2(OCH2CH2)4OH, -O(C=O)CH2(OCH2CH2)4OH, -(C=O)CH2CH2(OCH2CH2)4OH, -O(C=O)CH2CH2(OCH2CH2)4OH, -CO2 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or t-butyl),

[0023] [ka] One or more elements are selected from the group consisting of the following.

[0024] In some embodiments, the keratolytic agent is -(C=O)CH2(OCH2CH2)4OH, -O(C=O)CH2(OCH2CH2)4OH, -(C=O)CH2CH2(OCH2CH2)4OH, -O(C=O)CH2CH2(OCH2CH2)4OH, -CO2 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or t-butyl),

[0025] [ka] That is the case.

[0026] In some embodiments, the keratolytic agent is -O(C=O)CH2(OCH2CH2)4OH, -O(C=O)CH2CH2(OCH2CH2)4OH, -CO2 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or t-butyl),

[0027] [ka] That is the case.

[0028] In some embodiments, the keratolytic agent is -C(O)CH2OH, -C(O)CH(CH3)OH, -C(O)CH2(OCH2CH2)4OH, -C(O)CH2CH2(OCH2CH2)4OH,

[0029] [ka] That is the case.

[0030] In some embodiments, D is a “keratolytic” radical that, upon release, hydrolysis, or other mechanisms, produces an active keratolytic agent (when administered to an individual or patient, for example, inside or around the eye, such as the eyelid margin) through metabolism or other means. In some examples, upon release (for example, by hydrolysis or other mechanisms), D produces multiple active keratolytic agents. In some examples, the active keratolytic agent comprises 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.

[0031] In some examples, a combination of an anti-inflammatory and / or antimicrobial moiety (e.g., having the structure of the formula provided herein with R' subtracted) and a keratolytic moiety (e.g., represented by and / or having the structure of D). In some embodiments, such a moiety is a radical linked by a single bond linker, and the keratolytic moiety is hydrolyzable to produce both (1) an anti-inflammatory and / or antimicrobial agent and (2) one or more active keratolytic agents. In some embodiments, such a moiety is a radical linked by a hydrolyzable linker, which is hydrolyzable, thereby releasing both (1) an anti-inflammatory and / or antimicrobial agent and (2) one or more active keratolytic agents (in vivo, e.g., after administration of a therapeutic agent (e.g., topically) to the eyes and / or skin).

[0032] In some embodiments, L is bonded to D by a single bond.

[0033] In some embodiments, R' is

[0034] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein, Z is -O-, -S-, or -(CR 8 R 9 ) m - and m is from 1 to 6, R 8 and R 9 are each independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R 10 is H, -OH, alkyl, or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted.

[0035] In some embodiments, Z is -O-, R 10 is alkyl or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted. In some embodiments, Z is -O-, R 10 is -CR 8 R 9 CO2 alkyl. In some embodiments, R 8 and R 9 are each independently H, halo, alkyl, or haloalkyl. In some embodiments, R 8 and R 9 are each independently H or alkyl. In some embodiments, R 8 is methyl and R 9 is H. In some embodiments, Z is -O- and R 10 is -CH(CH3)CO2 alkyl. In some embodiments, Z is -O- and R 10 is -CH(CH3)CO2CH3. In some embodiments, when Z is -O- or -S-, R 10 is not -OH.

[0036] In some embodiments, Z is -S- and R 10is an alkyl or heteroalkyl, and the alkyl or heteroalkyl is optionally substituted. In some embodiments, Z is -S- and R 10 -CR 8 R 9 It is CH(NHCOalkyl)(CO2alkyl). In some embodiments, R 8 and R 9 Each of these is independently H, halo, alkyl, or haloalkyl. In some embodiments, R 8 and R 9 Each is independently H or alkyl. In some embodiments, R 8 and R 9 These are H. In some embodiments, Z is -S- and R 10 is -CH2CH(NHCOalkyl)(CO2alkyl). In some embodiments, Z is -O- and R 10 It is -CH2CH(NHCOCH3)(CO2CH3).

[0037] In some embodiments, R' is

[0038] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, m is 1 to 6. R 8 and R 9 Each of these is independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R 10 The element is H, -OH, alkyl, heteroalkyl, -O(C=O) heteroalkyl, -O(C=O) alkyl, or aryl, and the alkyl, heteroalkyl, -O(C=O) heteroalkyl, -O(C=O) alkyl, or aryl can be optionally substituted.

[0039] In some embodiments, R 10The substituent is -OH, alkyl (e.g., methyl), heteroalkyl, -O(C=O)alkyl, or aryl, and the alkyl of the alkyl (e.g., methyl), heteroalkyl, aryl, or -O(C=O)alkyl is substituted with one or more substituents. In some embodiments, each substituent is independently selected from the group consisting of -OH, alkyl (e.g., alkylene), oxo, halo, alkoxy, alkylamide, thiol, and heterocycle, and the alkyl, alkoxy, alkylamide, or heterocycle is independently optionally substituted. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkylamide is methylamide. In some embodiments, the heterocycle includes a disulfide. In some embodiments, the heterocycle is dithiolane. In some embodiments, at least one substituent is oxo. In some embodiments, at least one substituent is alkyl (e.g., methyl). In some embodiments, at least one substituent is hydroxyl.

[0040] In some embodiments, R 10 is an -O(C=O)alkylene, and the alkylene is substituted with one or more substituents. In specific embodiments, each substituent is independently selected from the group consisting of methyl, -SH, -OH, and -NHCOCH3. In some embodiments, R 10 is an aryl, and the aryl is substituted with methoxy. In some embodiments, R 10 The substituent is an alkyl or heteroalkyl group, and the alkyl or heteroalkyl group is substituted with one or more substituents. In specific embodiments, each substituent is independently selected from the group consisting of -OH, heteroalkylenes (e.g., OCH2CH2), and heterocycloalkyl groups (e.g., dithiolanes).

[0041] In some embodiments, the R 10The alkyl or heteroalkyl of is substituted with one or more substituents, each substituent independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, seleno, sulfone, amide, ester, halo, oxo, heterocyclyl, and cycloalkyl, and the heterocyclyl and cycloalkyl are optionally substituted. In some embodiments, the heterocyclyl and cycloalkyl are substituted with one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, sulfone, amide, ester, halo, and oxo. In some embodiments, the R 10 The alkyl or heteroalkyl is -C(O)alkyl or -C(O)heteroalkyl, and the alkyl or heteroalkyl is optionally substituted with one or more substituents, each substituent independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, amide, halo, oxo, heterocyclyl, and cycloalkyl, and the heterocyclyl and cycloalkyl are optionally substituted.

[0042] In some embodiments, R 8 and R 9 Each of these is independently hydrogen, halo, or alkyl. In some embodiments, R 8 is alkyl, R 9 is hydrogen. In some embodiments, R 8 is a haloalkyl, and R 9 is hydrogen. In some embodiments, R 8 is methyl, and R 9 is hydrogen. In some embodiments, R 8 It is a halo, R 9 is hydrogen. In some embodiments, R 8 and R 9 Each of these is a halo. In some embodiments, R 8 and R 9 Each of these is an alkyl group. In some embodiments, R 8 and R9 Each of these is hydrogen. In some embodiments, m is 1 to 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1.

[0043] In some embodiments, R 10 R is selected from the group consisting of -OH, alkyl, aryl, or heteroalkyl, and the alkyl, aryl, or heteroalkyl is optionally substituted. In some embodiments, R 10 is -OH. In some embodiments, R 10 The alkyl is substituted with an oxo and one or more groups selected from the group consisting of substituted alkyls and substituted heteroalkyls. In some embodiments, the alkyl is substituted with one or more groups selected from -SH, -OH, substituted or unsubstituted heteroalkyls, and substituted or unsubstituted heterocycloalkyls. In some embodiments, the alkyl is substituted with one or more groups selected from halo, alkyl, alkoxy, or heteroalkyl. In some embodiments, the alkoxy is methoxy. In some embodiments, R 10 The heteroalkyl group is substituted with one or more groups selected from oxo, substituted alkyl, and substituted heteroalkyl groups. In some embodiments, the heteroalkyl group is substituted with one or more groups selected from -SH, -OH, and substituted or unsubstituted heteroalkyl groups. In some embodiments, the heteroalkyl group is substituted with one or more groups selected from -SH, -OH, alkyl, (C=O)alkyl, (C=O)heteroalkyl, and -NH(C=O)alkyl groups.

[0044] In some embodiments, R 10 This includes one or more groups selected from -O- (ether), -SH, -S- (thioether), -OH, COOH, esters (e.g., linear (in-line) esters such as -C(=O)O- or -OC(=O)-), carbonates, selenium, or disulfides. In some embodiments, R 10It comprises one or more groups selected from -SH, -OH, sulfides, and -COOH. In some embodiments, R 10 is a -SH, -OH, sulfide, or -COOH compound. In some embodiments, R 10 is -SH. In some embodiments, R 10 It contains -OH. In some embodiments, R 10 It contains sulfides.

[0045] In some embodiments, R 10 -OH, -(OCH2CH2)4OH, -CH2(OCH2CH2)4OH, -O(C=O)alkyl, -CHCH3, CO2alkyl,

[0046] [ka] Includes.

[0047] In some embodiments, R 10 -OH, -(OCH2CH2)4OH, -CH2(OCH2CH2)4OH, -O(C=O)alkyl, -CHCH3, CO2alkyl,

[0048] [ka] That is the case.

[0049] In some embodiments, R' is -OH, -C(O)CH2OH, -C(O)CH(CH3)OH, -C(O)CH2(OCH2CH2)4OH, -C(O)CH2CH2(OCH2CH2)4OH

[0050] [ka] That is the case.

[0051] One embodiment provides a compound having the structure of formula (I') or a pharmaceutically acceptable salt thereof,

[0052] [ka] During the ceremony, R is -C(O)CH(R 1 )(R 2 ) and R 1 This includes -OH, optionally substituted -OC(O)alkyl, optionally substituted phenyl, and -X(OCH2CH2). n Ure 3 ,or

[0053] [ka] And, R 2 It is selected from hydrogen or C1-C4 alkyl, X is a C1-C3 alkylene that is directly bonded or optionally substituted. R 3 is H, or a C1-C3 alkyl group optionally substituted. Furthermore, n is between 1 and 20.

[0054] In some embodiments, R 1 This is -OH, optionally substituted phenyl, -X(OCH2CH2) n Ure 3 , or alkyl-heterocycline. In some embodiments, R 1 is a substituted phenyl. In some embodiments, the phenyl is substituted with one or more selected from halo, alkyl, heteroalkyl, cyano, cycloalkyl, and heterocycloalkyl. In some embodiments, the phenyl is substituted with halo, alkyl, heteroalkyl, cyano, cycloalkyl, or heterocycloalkyl. In some embodiments, the heteroalkyl is an alkoxy. In some embodiments, the heteroalkyl is a methoxy.

[0055] In some embodiments, R 1is an alkyl-heterocyclyl. In some embodiments, the heterocyclyl contains a disulfide in its cyclic structure. In some embodiments, R 1 The heterocycline is an alkyl-heterocycline, and the heterocycline contains a disulfide in its cyclic structure. In some embodiments, the heterocycline is a dithiolane.

[0056] In some embodiments, R 1 is X(OCH2CH2) n Ure 3 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a substituted methylene, a substituted ethylene, or a substituted propylene. In some embodiments, R 3 X is methylene, ethylene, or propylene. In some embodiments, X is a single bond. In some embodiments, X is substituted methylene, substituted ethylene, or substituted propylene. In some embodiments, X is methylene, ethylene, or propylene.

[0057] In some embodiments, n is 1 to 15. In some embodiments, n is 1 to 10. In some embodiments, n is 1 to 5. In some embodiments, n is 1. In some embodiments, n is 2.

[0058] In some embodiments, R 1is optionally substituted -O-C(O)alkyl. In some embodiments, the optionally substituted alkyl of the optionally substituted -O-C(O)alkyl comprises one or more groups selected from -SH, -OH, alkyl (such as alkylene), and -NHCOalkyl. In some embodiments, the alkyl is methyl, ethyl, propyl, isopropyl, and tert-butyl. In some embodiments, the optionally substituted alkyl of the optionally substituted -O-C(O)alkyl is methyl, CH(-NHCOalkyl)(CH2SH), or CH(CH3)OH.

[0059] In some embodiments, R 2 is H. In some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, or t-butyl.

[0060] In some embodiments, R is -(C=O)CH2(OCH2CH2)4OH, -(C=O)CH2CH2(OCH2CH2)4OH, -CO2alkyl (such as methyl, ethyl, propyl, isopropyl, or t-butyl),

[0061]

Chemical formula

[0062] One embodiment provides a pharmaceutical composition comprising a compound provided herein, such as a compound of any one of formula (I), (Ia), (Ib), or (I’), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Another embodiment provides a pharmaceutical composition suitable for ophthalmic administration. Another embodiment provides a pharmaceutical composition suitable for topical ophthalmic administration. In some embodiments, topical ophthalmic administration is administration directed to the inside and / or around the eye, such as the eyelid margin. In some embodiments, topical ophthalmic administration is administration to the ocular surface and the inner surface of the eyelid.

[0063] In some embodiments, the compounds provided herein, such as any one of the compounds of formula (I), (Ia), (Ib), or (I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such compound, are substantially sensitive to hydrolysis. In some embodiments, the compound or pharmaceutical composition contains a nonpolar solvent. In some embodiments, the compound or pharmaceutical composition is formulated and stored in a nonpolar solvent.

[0064] In some embodiments, a compound provided herein, such as any one of the compounds of formula (I), (Ia), (Ib), or (I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such compound, when in or exposed to an aqueous composition (e.g., an aquatic biological environment (e.g., the eye) or a buffer (e.g., HEPES)), will be conditioned for an appropriate time such as less than 2 hours, less than 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 3 minutes, 2 minutes, 1 minute or less. 1 / 2 It has the following properties. In some examples, the rapid decomposition of the compound allows for the rapid release of an active agent (e.g., a free form of the radical in any one of the formulas provided herein, where R' is H) and one or more keratolytic agents into the local environment. In some embodiments, the compound (e.g., alone or in a pharmaceutical composition) is in or exposed to an aqueous composition (e.g., an aquatic biological environment (e.g., the eye) or a buffer (e.g., HEPES)) and has a T of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60 minutes or more 1 / 2 In some embodiments, the compound or pharmaceutical composition is subjected to a T-resistance of 1 to 60 minutes, 1 to 20 minutes, 1 to 20 minutes, or 1 to 5 minutes when in an aqueous buffer. 1 / 2 It has the following properties. In some embodiments, the compound (for example, alone or in a pharmaceutical composition) is present in or exposed to an aqueous composition and has a T of at most about 3 hours. 1 / 2 It has.

[0065] In some embodiments, a compound provided herein, such as any one of the compounds of formula (I), (Ia), (Ib), or (I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such compound, is hydrolyzed to an active pharmaceutical agent and a keratolytic agent. In some embodiments, the compound is hydrolyzed to an active pharmaceutical agent and a keratolytic agent in the ocular space. In some embodiments, the active pharmaceutical agent is an anti-inflammatory agent and / or an antimicrobial agent. In some embodiments, the anti-inflammatory agent and / or antimicrobial agent is azithromycin. In some embodiments, the keratolytic agent is a carboxylic acid. In some embodiments, the 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, the active keratolytic agent is a thiol.

[0066] Compounds provided herein, such as those of formula (I), (Ia), (Ib), (I'), (II), any one of the compounds in Table 1, Table 2, or Table 3, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing such compounds, are incorporated by reference into the summary and detailed description. The results in Table 3 are incorporated by reference into the summary and detailed description.

[0067] One embodiment provides a method for 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 (I), (Ia), (Ib), or (I'), or a pharmaceutically acceptable salt thereof. 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), contact lens discomfort, dry eye syndrome, evaporative dry eye syndrome, aqueous deficiency dry eye syndrome, blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland dysfunction, inflammation of the anterior surface of the eye, infection of the anterior surface of the eye, infection of the eyelid, demodex lid infestation, lid wiper epitheliopathy, and autoimmune disorders of the anterior surface of the eye.

[0068] In some embodiments herein, a method is provided for treating an eye (e.g., periocular) or dermatological indication (e.g., related to keratolytic activity, inflammation, and / or microbial infiltration), the method comprising the step of administering a therapeutically effective amount of a compound or composition provided herein. In some embodiments, a composition provided herein (e.g., used in a method provided herein) contains a therapeutically effective amount of a compound provided herein (e.g., a concentration effective for treating keratosis / keratolytic activity, inflammation, and / or microbial infiltration) targeting the eye, surrounding tissue, or skin. In some embodiments, a composition provided herein (e.g., pharmaceutical and / or ophthalmic) contains about 0.1% to about 10% by weight of a compound provided herein.

[0069] Ocular and / or dermatological disorders include inflammatory diseases of the eyelids (e.g., styes, blepharitis, and chalazion), the ocular surface (e.g., dry eye disease and anterior uveitis), and the posterior part of the eye (e.g., posterior and panuveitis), abnormalities of the periocular glands (e.g., meibomian gland dysfunction (MGD)), allergic diseases (e.g., eczema, atopic dermatitis, atopic keratoconjunctivitis resistant to topical steroids, and vernal keratoconjunctivitis), and surgical complications (e.g., corneal transplant rejection, post-corneal transplant glaucoma, etc.). Examples include cataracts associated with lens-corneal transplantation, fungal infections in corneal transplant patients, and dry eye after LASIK, and / or poor refractive outcomes; corneal abnormalities (e.g., inflammatory corneal ulcers, rheumatic corneal ulcers, and Thygeson's punctate superficial keratitis); conjunctival abnormalities (e.g., iridocyclitis, lignite conjunctivitis); ocular complications due to systemic therapy and / or autoimmune diseases (e.g., minor-joint juvenile rheumatoid arthritis, graft-versus-host disease, and Sjögren's syndrome); and / or infections of the anterior surface of the eye. This specification provides compositions and methods for treating ocular and periorbital abnormalities known to have multifactorial etiologies and interactions.

[0070] Citation by reference All published documents, patents, and patent applications referenced herein are incorporated herein by reference for the specific purposes identified herein. [Modes for carrying out the invention]

[0071] Specific definition As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the context makes it clear. Thus, for example, a reference to “drug” includes multiple such drugs, and a reference to “cell” includes one or more cells (or more cells), and equivalents known to those skilled in the art. Where ranges relating to physical properties such as molecular weight or chemical properties such as chemical formulas are used herein, all combinations of ranges and specific embodiments within them, and subcombinations, are intended to be inclusive. The term “about” when referring to a number or range of numbers means that the number or range of numbers referred to is an approximation within the range of experimental variation (or statistical experimental error), and therefore the number or range of numbers may vary by 1% to 15% of the expressed number or range of numbers. The term “comprising” (and related terms such as “comprise,” “comprises,” “having,” or “including”) is not intended to exclude, in other specific embodiments, for example, any embodiment of any compound, composition, method, or process described herein, which may consist of or substantially consist of the described features.

[0072] As used herein, the terms “treat,” “treating,” or “treatment” include reducing, weakening, mitigating, improving, alleviating, or decreasing symptoms associated with a disease, condition, or indication (e.g., MGD) in either a chronic or acute treatment scenario. In one embodiment, treatment includes reducing terminal duct obstruction. Furthermore, treatment of a disease or condition as described herein includes disclosure of the use of the aforementioned compounds or compositions for the treatment of such disease, condition, or indication.

[0073] The term "opening" refers to the removal (at least partially) of an obstructed meibomian duct or orifice and / or the maintenance of patency of the meibomian duct or orifice.

[0074] The terms “keratolytic agent” and / or “keratoplastic agent,” as used herein, refer to agents that soften, break down, dissolve, solubilize, or alleviate keratin occlusion, or prevent keratin occlusion formation. Specifically, “keratolytic agent” refers to agents used to promote the softening and dissolution of keratin, and “keratoplastic agent” refers to agents used to reduce keratin production.

[0075] "Amino" refers to the -NH2 radical.

[0076] "Cyano" refers to the -CN radical.

[0077] "Nitro" refers to the -NO2 radical.

[0078] "Oxa" refers to -O- (radical).

[0079] "Oxo" refers to the O radical.

[0080] "Thioxo" refers to the S radical.

[0081] "Imino" refers to the NH radical.

[0082] "Oxymo" refers to the N-OH radical.

[0083] "Hydrazino" refers to the N-NH2 radical.

[0084] "Alkyl" usually refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, such as having 1 to 15 carbon atoms (e.g., C1-C 15refers to (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 (in some cases 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 15In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 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), and 1-pentyl (n-pentyl). The alkyl group is bonded to the remainder of the molecule by a single bond. Typically, each alkyl group is independently substituted or unsubstituted. Unless otherwise specified, each detail of “alkyl” provided herein includes specific and explicit details of unsaturated “alkyl” groups. Similarly, unless otherwise specified herein, alkyl groups are defined as having the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -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 Ure 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) is arbitrarily replaced by one or more of these, and each R aThese are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0085] "Alkoxy" refers to a radical in which alkyl is an alkyl chain as defined above, with the alkyl being bonded via an oxygen atom of the formula -O-alkyl.

[0086] "Alkenyl" refers to a linear 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 some embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 4 carbon atoms. The alkenyl is optionally substituted as described for the "alkyl" group.

[0087] "Alkylene" or "alkylene chain" typically refers to a straight or branched divalent alkyl group having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, i-propylene, n-butylene, etc. Unless otherwise specified herein, alkylene chains are optionally substituted as described herein for alkyl groups.

[0088] The term "aryl" refers to a radical derived from monocyclic or polycyclic aromatic hydrocarbon ring systems by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems consist only of hydrogen and carbon atoms comprising 5 to 18 carbon atoms, where at least one of the rings in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Examples of ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indan, indene, tetralin, and naphthalene. Unless otherwise specified herein, the term “aryl” or the prefix “ar-” (as in “aralkyl”) is intended to include aryl radicals optionally substituted with one or more substituents, the one or more substituents being independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkyl, 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 , -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 -OR 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 Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R aEach R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b R is an independently directly bonded, or linear or branched alkylene or alkenylene chain, c is a linear or branched alkylene or alkenylene chain, and unless otherwise specified, the substituents are unsubstituted.

[0089] "Aralkyl" or "aryl-alkyl" is the formula -R c - Refers to the aryl radical, R c This refers to alkylene chains as defined above, such as methylene or ethylene. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl radical is optionally substituted as described above for aryl groups.

[0090] A "carbocyclyl" or "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including a system of fused or bridging rings, and having 3 to 15 carbon atoms. In some embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. The remainder of the molecule is bonded by single bonds. Carbocyclyls or cycloalkyls can be saturated (containing only CC 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 carbocyclyls are also called "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclyl radicals include adamantyl, norbornyl (bicyclo[2.2.1]heptanyl), norborneyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified herein, the term “carbocykrill” is intended to include a carbocykrill radical optionally substituted with one or more substituents, wherein the one or more substituents may independently be alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, optionally substituted carbocykrill, optionally substituted carbocykrillalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -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 -OR 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 Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2), each R is selected from 2. aR is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b R is an independently directly bonded, or linear or branched alkylene or alkenylene chain, c The substituents are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0091] "Carbocyclylalkyl" is formula -R c - Refers to the radical of carbocyclyl, R c This is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

[0092] "Carbocyclyl alkenyl" is represented by formula -R c - Refers to the radical of carbocyclyl, R c This is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0093] "Carbocyclylalkynyl" is represented by formula -R c - Refers to the radical of carbocyclyl, R c This is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0094] "Carbocyclylalkoxy" is formula -OR c - Refers to a radical bonded via the oxygen atom of a carbocyclyl, R c This is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

[0095] As used herein, “carboxylic acid biological equivalent” refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties as the carboxylic acid moiety. Examples of carboxylic acid biological equivalents include, but are not limited to, the following:

[0096] [ka]

[0097] "Halo" or "halogen" refers to a substituent of bromo, chloro, fluoro, or iodine.

[0098] "Fluoroalkyl" refers to an alkyl radical as defined above, which is substituted with one or more fluoro radicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, or 1-fluoromethyl-2-fluoroethyl. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted with alkyl as defined above.

[0099] The term "heteroalkyl" refers to an alkyl group as defined above, where one or more of the backbone carbon atoms of the alkyl are substituted with heteroatoms (by an appropriate number of substituents or valencies, e.g., -CH2- may be substituted with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, where the carbon is substituted with nitrogen, oxygen, selenium, or other suitable heteroatoms. In some examples, each substituted carbon atom is independently substituted with oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, -N(aryl)-, or having another substituent as intended herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-). In some embodiments, the heteroalkyl group is bonded to the rest of the molecule at the carbon atoms of the heteroalkyl group. In some embodiments, the heteroalkyl group is bonded to the rest of the molecule at the heteroatoms of the heteroalkyl group. In some embodiments, the heteroalkyl group is C1-C 18 It is a heteroalkyl. In some embodiments, the heteroalkyl is C1-C 12 The heteroalkyl group is a heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C6 heteroalkyl group. In some embodiments, the heteroalkyl group is a C1-C4 heteroalkyl group. Representative heteroalkyl groups include, but are not limited to, -OCH2OMe or -CH2CH2OMe. In some embodiments, the heteroalkyl group as defined herein includes alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl groups. Unless otherwise specified herein, the heteroalkyl group is optionally substituted with alkyl groups as defined above.

[0100] A "heteroalkylene" refers to a divalent heteroalkyl group, as defined above, which bonds one part of a molecule to another part of it. Unless otherwise specified, heteroalkylenes are optionally substituted with alkyl groups as defined above.

[0101] A "heterocyclyl" refers to a stable 3-18 member non-aromatic ring radical containing 2-12 carbon atoms selected from nitrogen, oxygen, and sulfur, and 1-6 heteroatoms. Unless otherwise specified herein, heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, optionally including fused or bridged ring systems. Heteroatoms in heterocyclyl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or completely saturated. Heterocyclyls are bonded to the remainder of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified herein, the term “heterocyclyl” is intended to include heterocyclyl radicals as defined above, which are optionally substituted by one or more substituents, such substituents are alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, 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 -OR 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 Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2), each R is selected from 2. aR is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b R is an independently directly bonded, or linear or branched alkylene or alkenylene chain, c The substituents are linear or branched alkylene or alkenylene chains, and each of the substituents is unsubstituted unless otherwise specified.

[0102] An "N-heterocyclyl" or "N-bonded heterocyclyl" refers to a heterocyclyl radical as defined above, which contains at least one nitrogen atom, and the bond site of the heterocyclyl radical to the rest of the molecule is via the nitrogen atom in the heterocyclyl radical. N-heterocyclyl radicals are optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0103] A "C-heterocyclyl" or "C-bonded heterocyclyl" refers to a heterocyclyl radical as defined above, which contains at least one heteroatom, and the bond site of the heterocyclyl radical to the rest of the molecule is via a carbon atom in the heterocyclyl radical. C-heterocyclyl radicals are optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl.

[0104] "Heterocyclylalkyl" is represented by formula -R c - Refers to the radical of a heterocycline, R c This is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, this heterocyclyl is optionally bonded to the alkyl radical at its nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for the heterocyclyl group.

[0105] "Heterocyclylalkoxy" is a formula -OR c - Refers to a radical bonded via the oxygen atom of a heterocycline, R c This is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, this heterocyclyl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for the heterocyclyl group.

[0106] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2- to 17 carbon atoms and 1- to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. 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 completely unsaturated, i.e., it contains a delocalized (4n+2)π-electron system of the ring according to Hückel's theory. Heteroaryls include fused or bridging ring systems. Heteroatoms in heteroaryl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryls are bonded to the remainder of the molecule via any atom of the ring. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinyl, carbazolyl, sinnolinyl, cyclopenta[d]pyrimidinyl, and 6,7-dihydro-5H-s Clopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]sinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexa Hydrocycloocta[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, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 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(p yrido)[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, 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]pyrimidinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,Examples include, but are not limited to, [3-d]pyridinyl and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term “heteroaryl” is intended to include heteroaryl radicals as defined above, which are optionally substituted by one or more substituents, such as alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkyl, 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 , -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 -OR 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), -Rb -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R a Each R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b R is an independently directly bonded, or linear or branched alkylene or alkenylene chain, c is a linear or branched alkylene or alkenylene chain, and unless otherwise specified, the substituents are unsubstituted.

[0107] An "N-heteroaryl" refers to a heteroaryl radical as defined above, which contains at least one nitrogen atom, and the bond of the heteroaryl radical to the rest of the molecule is via the nitrogen atom in the heteroaryl radical. N-heteroaryl radicals are optionally substituted as described above for heteroaryl radicals.

[0108] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the bond site of the heteroaryl radical to the rest of the molecule is via a carbon atom in the heteroaryl radical. The C-heteroaryl radical can be optionally substituted for the heteroaryl radical as described above.

[0109] "Heteroarylalkyl" is represented by formula -R c - Refers to a heteroaryl radical, R c This is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, this heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for the heteroaryl group.

[0110] "Heteroarylalkoxy" is a formula -OR c - Refers to a radical bonded via the oxygen atom of a heteroaryl group, R c This is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, this heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for the heteroaryl group.

[0111] In some embodiments, the compounds disclosed herein contain one or more chiral centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R) or (S) from an absolute stereochemical standpoint. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated in this disclosure. Where the compounds described herein contain an alkene double bond, and unless otherwise specified, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as 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 (e.g., cis or trans) of an alkene double bond. 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.

[0112] Typically, optionally substituted groups are either independently substituted or unsubstituted. Each detail of an optionally substituted group provided herein includes, unless otherwise specified, independent and explicit details of both the unsubstituted and substituted groups (e.g., substituted in one embodiment and unsubstituted in another). Unless otherwise specified, substituted groups include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -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 Urea (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) is arbitrarily replaced by one or more of these, and each R a These are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0113] In the compounds disclosed herein, any reference to an atom includes a reference to its isotope. For example, a reference to H is: 1 H, 2 H, 3 This includes references to any isotope of H, such as H or mixtures thereof. "Pharmacologically acceptable salt" includes both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the keratolytic conjugates described herein is intended to encompass all pharmaceutically acceptable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0114] "Pharmacologically acceptable acid addition salts" refer to salts that retain the biological effects and properties of a free base, and which are not biologically or otherwise unnecessary, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. Similarly, salts formed from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids are also included, such as 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, and salicylic acid. Therefore, typical salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Similarly, salts of amino acids such as alginates, glucons, and galacturonic acids have also been considered (e.g., Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0115] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effects and properties of a free acid and is not biologically or otherwise unnecessary. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from 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, and aluminum. Examples of salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and base 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, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. above.

[0116] Meibomian glands Meibomian glands are large oily glands located in the eyelids and, unlike skin, are not associated with hair. They produce the lipid layer of the tear film, which protects the tear film from evaporation of the aqueous phase. The meibomian gland orifices are located on the epithelial side of the eyelid margin, only a few hundred microns from the mucosal side. Meibomian glands are present in both the upper and lower eyelids, with a greater number in the upper eyelid. Each meibomian gland consists of a mass of secretory acini arranged in a ring around a long central canal, connected to the central canal by short ducts. The terminal end of the central canal is covered by endodermal growth, which covers the free eyelid margin and forms a short drainage duct that opens as an orifice at the posterior part of the eyelid margin, just anterior to the mucocutaneous junction near the inner eyelid boundary. The lipid-based oily secretion is synthesized within the secretory acini. The lipid secretions are a liquid close to body temperature and are delivered to the skin of the eyelid margin as a clear fluid called "meibomian gland." The lipid secretions form shallow storage areas at the margins of the upper and lower eyelids and consist of a complex mixture of cholesterol, wax, cholesterol esters, phospholipids, and small amounts of triglycerides, triacylglycerols, and hydrocarbons. The distinct meibomian glands are arranged in parallel and in a single row along the length of the tarsal plate in the upper and lower eyelids. The extent of the glands roughly corresponds to the dimensions of the tarsal plate.

[0117] As used herein, the term “keratin obstruction” refers to obstruction of the meibomian glands regardless of the location of the obstruction. In some embodiments, this obstruction is complete, and in other embodiments, it is partial. Regardless of the degree of obstruction, such keratin obstruction causes meibomian gland dysfunction. In some embodiments, keratin obstruction consists of keratinized material and lipids. In some embodiments, keratin obstruction is obstruction of the meibomian gland orifice and excretory duct. In some embodiments, keratin obstruction is caused by epithelial keratinization in the eyelid margin and meibomian glands. In some cases, keratin obstruction is affected by stem cell migration or abnormal differentiation. In some embodiments, keratin obstruction results in reduced delivery of oil to the eyelid margin and tear film, as well as stasis within the meibomian glands, which leads to increased blood pressure, resulting dilation, acinar atrophy, and decreased secretion. In some cases, keratinization of the meibomian glands causes degenerative gland dilation and atrophy.

[0118] Diseases or disorders of the eye surface Ocular surface diseases are a group of conditions including, but not limited to, dry eye syndrome (evaporative DES and / or dehydrative 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 chronic and widespread abnormalities of the meibomian glands characterized by terminal duct obstruction, 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 manifestations of MGD are obstruction of the meibomian gland orifices and terminal ducts, as well as changes in meibomian gland secretion.

[0119] In some cases, meibomian gland dysfunction (MGD) is a chronic and widespread abnormality of the meibomian glands, generally 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 meibomian glands can lead to ocular surface diseases such as lacrimal film changes, eye irritation symptoms, and evaporative dry eye. The primary clinical outcome of MGD is evaporative dry eye syndrome, and large-scale population studies (Bankok Study and Shihpai Eye Study) estimate that more than 60% of patients with dry eye symptoms also have MGD (Schaumberg et al, Investigative Ophthalmology and Visual Science.(2011).52(4):1994-2005).

[0120] Meibomian gland disease (MGD) is a major cause of dry eye syndrome. Dry eye syndrome is widespread, affecting approximately 20 million people in the United States alone. Dry eye syndrome is a disorder of the ocular surface caused by either inadequate tear production or excessive water evaporation from the ocular surface. The cornea has no blood vessels, and tears are essential for corneal health as they rely on the supply of oxygen and nutrients. Tear film and tear fluid are composed of lipids, water, and mucus, and damage to any of these can lead to dry eye. Excessive evaporation due to inadequate lipid outflow from the meibomian glands, such as caused by keratinization occlusion, can lead to dry eye syndrome.

[0121] 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 quality of the expressed lipid changes from an appearance of clear fluid to a viscous fluid containing particulate material and an opaque, thick toothpaste-like material. The meibomian gland orifice 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 lipid and keratinized material.

[0122] Obstructive MGD is characterized by all or some of the following: 1) chronic ocular discomfort, 2) anatomical abnormalities around the meibomian gland orifice (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 expression of meibum by moderate digital pressure).

[0123] 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.

[0124] In some embodiments, a patient's symptoms are assessed by asking the patient a series of questions. The questionnaire can assess the range of symptoms associated with ocular discomfort. In some embodiments, this questionnaire is a SPEED questionnaire. The SPEED questionnaire assesses the frequency and severity of a patient's dry eye symptoms. This questionnaire examines the occurrence of symptoms on the day, 72 hours later, and over the past three months. The SPEED score is compiled based on the patient's answers to the questions to provide a range of symptom severity for the patient. The SPEED questionnaire includes questions such as: 1) what dry eye symptoms occurred and when; 2) how often do you experience dryness, irritation, or itchiness of the eyes; 3) how often do you experience eye pain or irritation; 4) how often do you experience eye burns or tearing; 5) how often do you experience eye strain; and 6) how severe are your symptoms?

[0125] The degree of squeezing of the meibomian glands is optionally determined to assess meibomian gland function. In normal patients, meibomian fluid is a clear to pale yellow oil. When pressure is applied to the glands, meibomian fluid is secreted from them. Changes in the degree of squeezing of the meibomian glands are one possible indication for meibomian gland depressive disorder (MGD). In some embodiments, the quantification of the amount of physical force applied during squeezing is monitored in addition to the assessment of lipid volume and lipid quantity.

[0126] The tear breakup time (TBUT) is a surrogate marker for tear film 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 eye. The disruption is then analyzed with 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.

[0127] Other methods for evaluating other MGD symptoms include, but are not limited to, the 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 metrics.

[0128] 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.

[0129] Eyelid hygiene is considered the primary treatment for MGD and consists of three elements: 1) warming, 2) mechanical massage of the eyelids, and 3) eyelid cleansing. The eyelid warming procedure improves meibomian gland secretion by dissolving the lipids of the pathologically altered meibomian glands. Warming is achieved by warm compresses or devices. Mechanical eyelid hygiene includes the use of scrubs, mechanical compression, and cleansing of the eyelashes and eyelid margins with various solutions. The eyelid margins are further cleansed optionally with hypoallergenic bar soap, diluted infant shampoo, or commercially available eyelid scrubs. Physical compression of the meibomian glands is performed in the hospital or by the patient at home. This technique ranges from gentle eyelid massage of the eyeball to forcibly constricting the eyelids between them or between a rigid object on the inner eyelid surface and fingers, thumbs, or other rigid objects (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 force transmitted through the eyelid during compression and provides stable resistance to increase the amount of force applied to the glands.

[0130] Eyelid heating is limited because it dissolves lipids, but it does not address the movement of keratinized material. Furthermore, eyelid heating causes temporary vision loss due to corneal curvature. Mechanical eyelid sanitation is also limited because the force required to remove the obstruction is considerable and can cause severe pain to the patient. The effectiveness of mechanical eyelid sanitation is limited by the patient's ability to tolerate the associated pain during the procedure. Other treatments for MGD are limited.

[0131] Physical release of meibomian gland obstruction by meibomian gland compression is an acceptable method for improving meibomian gland secretion and dry eye symptoms. In addition, probing of the meibomian gland ducts is used to open obstructed ducts. However, both compression and probing methods are limited by the pain induced by the procedure, the physical irritation that can occur to the structure of the glands and ducts, and the temporary effects estimated to last for several days and weeks. Therefore, a method that improves patient comfort is needed, which would not harm the meibomian glands and ducts, reduce reliance on frequent hospital visits, and improve meibomian secretion.

[0132] U.S. Patent No. 9,463,201, entitled "Compositions and methods for the treatment of meibomian gland dysfunction," describes methods for treating meibomian gland dysfunction, comprising topical administration of at least one therapeutically effective amount of a keratolytic agent in an ocularly tolerable carrier. This patent includes keratolytic agents such as ebselen (2-phenyl-1,2-benzoserenazole-3-one, selenium disulfide (SeS2) or inorganic selenium (Se) compounds such as organoselen compounds). This agent addresses the underlying cause of MGD, rather than the "plus" inflammatory disease described in the DEWS report on MGD.

[0133] The role of inflammation in the pathogenesis of MGD is a subject of debate. The terms posterior blepharitis and MGD are not synonymous. Posterior blepharitis describes an inflammatory disease of the posterior eyelid margin, and while there are various causes, MGD is considered the sole possible cause (Nichols et al 2011). In its earliest stages, MGD is not associated with the clinically distinctive features of posterior blepharitis. As MGD progresses, MGD-associated posterior blepharitis is said to be present. MGD-associated posterior blepharitis affects the meibomian glands and meibomian gland orifices. MGD-associated posterior blepharitis is characterized by flora changes, esterase release, lipase release, lipid changes, and blepharoinflammation. Hyperkeratosis of the meibomian gland epithelium (thickening of the glandular endometrium) can lead to obstruction and a decrease in the quality of meibomian gland secretion, potentially causing MGD-associated posterior blepharitis. Diagnosis of MGD-associated posterior blepharitis includes evidence of altered quality of compressed secretion and / or meibomian gland compression due to loss of glandular function (decreased or lost squeezability). The TFOS report on meibomian gland diseases notes that anterior blepharitis and exacerbated inflammatory ocular surface disease are "plus" conditions associated with MGD managed with topical ocular steroids (Nichols et al 2011). Because these "plus" conditions can be present at varying degrees of severity from early to late stages of MGD, treatments and / or combined treatments are needed that can target both the underlying non-inflammatory pathophysiology of MGD and the inflammation associated with these co-occurring conditions.

[0134] MGD-related inflammatory eye diseases may involve different mechanisms than blepharitis-related MGD. MGD-related inflammatory eye diseases are characterized by an inflammatory cascade involving T lymphocyte activation and migration to inflamed tissue. T lymphocyte infiltration may lead to lacrimal gland stimulation and upregulation of cytokines. Typical 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-gamma, macrophage inflammatory protein 1α, and tumor necrosis factor α. Kinase pathways, including the mitogenic factor-activated protein kinase (MAPK) pathway, are also activated in the inflammatory cascade. This inflammatory process leads to loss of mucin-producing goblet cells and ocular surface damage that can cause further injury.

[0135] Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), is considered a self-sustaining disease progressively isolated from its initial causes. Dry eye syndrome is associated with inflammation of the ocular surface and periorbital tissues. The inflammation is characterized by the activation of T lymphocytes and their migration to inflammatory tissues, including those in the conjunctiva and lacrimal glands. Increased levels of inflammatory cytokines, chemokines, and matrix metalloproteinases have also been identified.

[0136] 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 exposure of normal mice to a low-humidity environment in a controlled environment 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 adequately represent the immune, endocrine, neuronal, and environmental factors that contribute to the pathogenesis of dry eye.

[0137] Anti-inflammatory agents can be used to treat ocular surface diseases or disorders, including dry eye syndrome. Corticosteroids are effective anti-inflammatory agents for dry eye conditions. For example, in a 4-week double-blind, randomized trial involving 64 patients with dry eye and delayed tear removal, four doses of 0.5% loteprednol etavonate ophthalmic suspension (Lotemax [Bausch and Lomb, Rochester, NY]) four times daily were found to be more effective than its solvent in improving some signs and symptoms (Pflugfelder et al, Am J Ophthalmol (2004). 138:444-57). The TFOS 2007 report on dry eye diseases concluded that, "Under U.S. federal regulations, ophthalmic corticosteroids that are 'classified and labeled' are indicated for 'steroid-responsive inflammatory diseases' such as allergic conjunctivitis, erythematous keratitis, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and selected infectious conjunctivitis of the eyelids and conjunctiva, cornea and anterior upper lobe of the eyeball, when the inherent risks of steroid use are acceptable to obtain the desired reduction of edema and inflammation. In some cases, 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)." The US FDA does not agree with this conclusion, but the steroid Lotemax is commonly used for short-term treatment of inflammation associated with dry eye disease.

[0138] Other anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the activity of cyclooxygenases, including cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), 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 diseases by treating inflammation of the ocular surface.

[0139] Treatment for dry eye can also be achieved with medications that enhance tear and mucin production. For example, P2Y2 receptor agonists have been shown to increase tear and mucin secretion. This mechanism is thought to be involved in P2Y2 signaling, which increases intracellular calcium and opens chloride channels in the apical cell membrane. The P2Y2 receptor belongs to the family of purine receptors, which are classified into P1 and P2 receptors based on their innate agonisms involving purine nucleosides and pyrimidine nucleotides, respectively. P2 receptors are further physiologically divided into two types: P2X receptors and P2Y receptors. P2Y receptors are involved in diver signaling, including platelet aggregation, immunology, 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 a major subtype of purine receptor located on the ocular surface. P2Y2 receptors have also been shown to be located in goblet cells and serous cells of the conjunctival epithelium in ocular tissue, as well as in acinar cells and ductal epithelial cells of the meibomian glands in rhesus monkeys.

[0140] Azithromycin Azithromycin is a macrolide antibiotic with a 15-membered ring. Its chemical name is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methylα-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl11-[[3,4,6-trideoxy-3-(dimethylamino)-bD-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one, with a molecular weight of 749, and its empirical formula is C 38 H 72 N2O 12 The structural formula is as follows:

[0141] [ka]

[0142] Azithromycin acts by binding to the 50S ribosome subunit of sensitive microorganisms and interfering with microbial protein synthesis. In the topical environment of the eye, azithromycin is formulated as a 1% solution at pH 6.3 containing benzalkonium chloride. Azithromycin is indicated for the treatment of bacterial conjunctivitis caused by sensitive isolates of Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis, or Streptococcus pneumoniae. Further information regarding azithromycin eye drops can be found in U.S. Patents 6,239,113, 6,569,443, or 7,056,893.

[0143] Drugs for meibomian gland dysfunction and dry eye disease Keratin-dissolving conjugate This specification describes a non-inflammatory keratolytic blocking component for meibomian gland dysfunction and a keratolytic conjugate that simultaneously addresses inflammatory-related dry eye diseases including the aqueous-deficient type. The keratolytic conjugates described herein are useful as either emergency treatment (e.g., by a trained professional or physician) or long-term treatment (e.g., under the management of the patient or alternatively by a trained professional or physician). In certain embodiments, the agent is tested using assays and methods described herein (such as those described in this example). The keratolytic conjugates described herein represent 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.

[0144] One embodiment provides a compound having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof,

[0145]

Chemical formula

[0146] One embodiment provides a compound having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof,

[0147]

Chemical formula

[0148] In some embodiments of the compounds of formula (Ia) or (Ib), L comprises one or more linker groups, each linker group selected from the group consisting of single bonds, -O-, -S-, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), disulfide, ester, and carbonyl (>C=O). Another embodiment provides a compound of formula (Ia) or (Ib), where the keratolytic agent comprises one or more of the aforementioned groups (e.g., keratolytic groups such as groups that impart keratolytic activity), each group (e.g., keratolytic groups) independently selected from the group consisting of thiols, disulfides, selenium (e.g., selenide, diselenide), carboxylic acids, or groups metabolizable to carboxylic acids.

[0149] Another embodiment provides a compound of formula (Ia) or (Ib), where R' is an alkyl or heteroalkyl substituted with at least one oxo, and further optionally substituted. Another embodiment provides a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, where R' is

[0150] [ka] And, During the ceremony, m is 1 to 6. R 8 and R 9 Each of these is independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R 10 is H, alkyl, aryl, or heteroalkyl, and the alkyl, aryl, or heteroalkyl is optionally substituted.

[0151] Another embodiment provides a compound of formula (Ia) or (Ib), wherein R 10The alkyl or heteroalkyl is substituted with one or more substituents, each substituent independently selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, seleno, sulfone, amide, halo, oxo, heterocyclyl, and cycloalkyl, and the heterocyclyl and cycloalkyl are optionally substituted (for example, by one or more substituents selected from the group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, sulfone, amide, halo, and oxo).

[0152] Another embodiment provides a compound of formula (Ia) or (Ib), where R' is -C(O)CH2OH, -C(O)CH(CH3)OH, -C(O)CH2(OCH2CH2)4OH, -C(O)CH2CH2(OCH2CH2)4OH

[0153] [ka] It is selected from the group consisting of the following.

[0154] Another embodiment provides compounds of formula (I) or (Ia), or pharmaceutically acceptable salts or solvates thereof, R' is -C(O)CH(R 1 )(R 2 ) and R 1 The elements are H, -OH, optionally substituted -OC(O)alkyl, optionally substituted phenyl, and -X(OCH2CH2). n Ure 3 , or optionally substituted alkyl-heterocyclines, R 2 is H or C1-C4 alkyl, X is a C1-C3 alkylene that is directly bonded or optionally substituted. R 3 is H, or a C1-C3 alkyl group optionally substituted, and n is between 1 and 20.

[0155] Another embodiment provides a compound of formula (I) or (Ia), R 1 is an alkyl-heterocyclyl, and the heterocyclyl contains a disulfide in its cyclic structure. In some embodiments, the heterocyclyl is a dithiolane. In some embodiments, R 1 teeth

[0156] [ka] That is the case.

[0157] Another embodiment provides a compound of formula (I) or (Ia), R 1 is -OH. Another embodiment provides a compound of formula (I) or (Ia), R 1 is optionally substituted phenyl. Another embodiment provides a compound of formula (I) or (Ia), and R 1 is -X(OCH2CH2) n Ure 3 In some embodiments, X is a direct bond. In some embodiments, X is an optionally substituted C1-C3 alkylene.

[0158] Another embodiment provides a compound of formula (I) or (Ia), R 3 is hydrogen. In some embodiments, R 3 This is a C1-C3 alkyl group that has been optionally substituted.

[0159] Another embodiment provides a compound of formula (I) or (Ia), where n is 20.

[0160] Another embodiment provides a compound of formula (I) or (Ia), R 2 is H. In some embodiments, R 2 is a C1-C4 alkyl group. In some embodiments, R 2 It is CH3.

[0161] One embodiment provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof,

[0162] [ka] During the ceremony, R is -C(O)CH(R 1 )(R 2 ) and R 1 This includes -OH, optionally substituted -OC(O)alkyl, optionally substituted -OC(O)hetalkyl, optionally substituted phenyl, and -X(OCH2CH2). n Ure 3 ,or

[0163] [ka] And, R 2 It is selected from hydrogen or C1-C4 alkyl, X is a C1-C3 alkylene that is directly bonded or optionally substituted. R 3 is H, or a C1-C3 alkyl group optionally substituted, and n is between 1 and 20.

[0164] One embodiment provides a compound having the structure of formula (Ia') or a pharmaceutically acceptable salt thereof,

[0165] [ka] During the ceremony, R is -CH(R 1 )(R 2 ) and R 1 is -OH, optionally substituted phenyl, or -X(OCH2CH2) n Ure 3 And, R 2 It is selected from hydrogen or C1-C4 alkyl, X is a C1-C3 alkylene that is directly bonded or optionally substituted. R 3 is H, or a C1-C3 alkyl group optionally substituted, and n is between 1 and 20.

[0166] Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 1 is -OH. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 1 is optionally substituted phenyl. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 1 is -X(OCH2CH2) n Ure 3 That is

[0167] Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, where X is a direct bond. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, where R 3 is hydrogen. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 3 is an optionally substituted C1-C3 alkyl group. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, where n is 20.

[0168] Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, where X is optionally substituted C1-C3 alkylene. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, where R 3 is hydrogen. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 3 is an optionally substituted C1-C3 alkyl group. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, where n is 20.

[0169] Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 2 is hydrogen. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 2 is a C1-C4 alkyl group. Another embodiment provides a compound of formula (I') or (Ia'), or a pharmaceutically acceptable salt thereof, R 2 It is CH3.

[0170] One embodiment provides a compound having the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof,

[0171] [ka] During the ceremony, Z is -O- or -(CR 8 R 9 ) m -and, m is 1 to 6. R 8 and R 9 Each of these is independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R 10 is H, -OH, alkyl, or heteroalkyl, and the alkyl or heteroalkyl can be optionally substituted.

[0172] In some embodiments, Z is -CR 8 R 9 - In some embodiments, R 8 is H or methyl, R 9 is H. In some embodiments, R 10 is -OH, -(OCH2CH2)4OH, -CH2(OCH2CH2)4OH, -O(C=O)CH3,

[0173] [ka] That is the case.

[0174] In some embodiments, Z is -O-. In some embodiments, R 10 teeth,

[0175] [ka] That is the case.

[0176] One embodiment provides a keratolytic conjugate having the structure shown in Table 1 or a pharmaceutically acceptable salt thereof.

[0177] [Table 1]

[0178] Additional examples with the structures shown in Table 2 were also prepared.

[0179] [Table 2]

[0180] The compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in the chemical literature, in accordance with organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), 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 It is obtained from standard commercial sources, including Co. Ltd. (Cornwall, UK), 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), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0181] Suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein, or provide references to papers describing such preparations, include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations”, 2nd Ed., Academic Press, New York, 1983; HOHouse, “Modern Synthetic Reactions”, 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Other suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein, or provide references to papers describing such preparations, 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, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5, Larock, RC "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.

[0182] Specific and similar reactants are optionally identified by indicators of known chemical products prepared by the American Chemical Society's Chemical Abstract Service, which is available through most public and university libraries as well as online databases (for details, please contact the American Chemical Society in Washington, D.C.). Chemicals that are known but not commercially available in catalogs are optionally prepared by specialized chemical synthesis facilities, many of which offer specialized chemical synthesis services, including those listed above as standard chemical supply facilities. A reference for the preparation and selection of pharmaceutical salts of the keratolytic conjugates described herein is PHStahl & CGWermuth, “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0183] Pharmaceutical composition In some embodiments, the keratolytic conjugates described herein have the structure provided for formula (I), formula (Ia), formula (I'), formula (Ia'), or formula (II). In some embodiments, the keratolytic conjugates described herein are administered as pure chemicals. In other embodiments, the keratolytic conjugates described herein are combined with a pharmaceutically appropriate or acceptable carrier (hereinafter also referred to as a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) based on a selected route of administration and standard pharmaceutical practices such as those described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0184] This specification provides pharmaceutical compositions comprising at least one keratolytic conjugate, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide, together with one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is not harmful to the recipient of the composition.

[0185] In some embodiments, keratolytic conjugates, such as those described by any one of formulas (I), (Ia), (I'), (Ia'), or (II), are substantially pure in that they contain less than about 5%, less than 1%, or less than 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts produced in one or more steps of the synthesis method.

[0186] Suitable oral dosage forms include, for example, tablets, pills, sachets, hard gelatin capsules, soft gelatin capsules, methylcellulose, or capsules of another suitable material that dissolves readily in the gastrointestinal tract. In some embodiments, a suitable non-toxic solid carrier is used, for example, containing pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005))).

[0187] One embodiment provides a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (I'), formula (Ia'), or formula (II) or a pharmaceutically acceptable salt thereof, and a 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 targeting the inside and / or periphery of 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.

[0188] In some embodiments, keratolytic conjugates such as those described in formula (I), formula (Ia), formula (I'), formula (Ia'), or formula (II) are formulated as solutions or suspensions for topical administration to the eye.

[0189] In some embodiments, keratolytic conjugates such as those described in formula (I), formula (Ia), formula (I'), formula (Ia'), or formula (II) are formulated for administration by injection. In some examples, the injectable formulation is an aqueous formulation. In some examples, the injectable formulation is a non-aqueous formulation. In some examples, the injectable formulation is an oil-based formulation, such as sesame oil.

[0190] The dosage of a composition containing at least one keratolytic conjugate as described herein varies depending on the patient's (e.g., human) condition, i.e., relative health status, age, and other factors.

[0191] Pharmaceutical compositions are administered in a manner appropriate to the disease being treated (or prevented). The appropriate dosage and duration and frequency of administration will be determined by factors such as the patient's condition, 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 provides a sufficient amount of the composition to produce therapeutic and / or preventive benefits (e.g., improved clinical outcomes such as more frequent complete or partial remission, longer disease-free survival and / or overall survival, or reduced symptom severity). The optimal dosage is generally determined using experimental models and / or clinical trials. The optimal dosage depends on the patient's body type, weight, or blood volume.

[0192] In other embodiments, the topical compositions described herein are combined with a pharmaceutically appropriate or acceptable carrier (e.g., a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (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)).

[0193] Treatment method using keratolytic conjugates One embodiment provides a method for treating an eye disease or disorder in a patient, the method comprising administering to the patient a composition comprising a compound of formula (I), formula (Ia), formula (I'), formula (Ia'), or formula (II) or a pharmaceutically acceptable salt thereof. Another embodiment provides a method in which the pharmaceutical composition is in the form of a solution or suspension suitable for topical ocular administration.

[0194] Another embodiment provides a method in which the eye disease or disorder is selected from dry eye, lid wiper corneal epithelial disease (LWE), contact lens discomfort (CLD), contact lens discomfort, dry eye syndrome, evaporative dry eye syndrome, tear-deficient dry eye syndrome, blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland dysfunction, inflammation of the anterior surface of the eye, infection of the anterior surface of the eye, infection of the eyelids, demodectic mange eyelid infection, lid wiper corneal epithelial disease, and autoimmune disorders of the anterior surface of the eye.

[0195] This specification describes a method for treating ocular surface disorders in a patient, including the administration of a keratolytic conjugate to the patient. There are two possible classifications of administration. One is performed with the assistance of a healthcare professional. This classification includes both acute and maintenance uses of the keratolytic conjugate. In one embodiment, acute use requires a more potent keratolytic conjugate (in terms of either the concentration or intrinsic activity of the drug). In one embodiment, maintenance use allows for the use of lower concentrations of the drug with less intrinsic activity. In one embodiment, maintenance use involves the patient during regular visits by a healthcare professional. Both acute and maintenance use optionally require the use of an eye protection device or apparatus. In one embodiment, acute use is performed by a healthcare professional, while maintenance use is performed by the patient or a non-healthcare professional. Another possible classification of administration is performed without the active assistance of a healthcare professional, with the patient administering the keratolytic conjugate to the eyelid margin themselves. In one embodiment, such administration is performed over a long period of time. This form of multiple administration by the patient is, in short, chronic administration. Typically, a different or second keratolytic conjugate formulation is recommended for chronic use or patient-administered use. 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 with lower activity than the first formulation.

[0196] It should be understood that the method of the present invention further comprises the physical removal of obstruction of the meibomian glands, followed by chronic and / or maintenance administration of the keratolytic conjugate described herein.

[0197] One embodiment provides a method for treating meibomian gland dysfunction in a patient, the method comprising topically administering to the patient a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier enhances meibum production.

[0198] In some embodiments, topical administration of a composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier is performed until keratinization occlusion is relieved. In some embodiments, topical administration of a composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier is performed periodically even after keratinization occlusion has been relieved. In some embodiments, topical administration of a composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier is a single dose. In some embodiments, topical administration of a composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier is a periodic administration. In some embodiments, topical administration of a composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier is performed once daily. In some embodiments, topical administration of a composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally tolerable carrier is performed twice daily. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ocularly tolerable carrier is performed more than twice daily.

[0199] In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is a solution. In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is a solution suitable for topical administration as eye drops. In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is a gel, an eyeball insert, a spray, or other method of topical ophthalmic administration. In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is semi-solid. In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is homogeneous. In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is a dispersion. In some embodiments, a topical administration composition containing a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally acceptable carrier is hydrophilic. In some embodiments, a topical administration composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmally 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 ophthalmally acceptable carrier has at least one ophthalmally acceptable excipient.

[0200] One embodiment provides a method for treating a patient's MGD, comprising topical administration of a composition containing a keratolytic conjugate. In some embodiments, topical administration of the composition containing the keratolytic conjugate is performed once a week. In some embodiments, topical administration of the composition containing the keratolytic conjugate is performed twice a week. In some embodiments, topical administration of the composition containing the keratolytic conjugate is performed every other day. In some embodiments, topical administration of the composition containing the keratolytic conjugate is performed daily. In some embodiments, topical administration of the composition containing the keratolytic conjugate is performed several times a day.

[0201] In some embodiments, the method includes treatment in an acute treatment scenario. In other embodiments, the method includes treatment of untreated patients. In other embodiments, the method includes treatment in a chronic treatment scenario. In other embodiments, the method includes treatment in a maintenance therapy scenario. The dose of keratolytic conjugate in an acute treatment scenario may be greater than that of keratolytic conjugate used in a chronic treatment scenario or maintenance therapy scenario. The keratolytic conjugate in an acute treatment scenario may be different from that used in a chronic treatment scenario. In some embodiments, the treatment period begins in the initial stage of treatment as an acute treatment scenario and then progresses to a chronic treatment scenario or maintenance therapy scenario. In some embodiments, the meibomian gland opening agent (pharmacological agent) administered in an acute treatment scenario is a keratolytic and / or keratolytic agent, and the agent administered in a chronic treatment scenario or maintenance therapy scenario is a keratolytic conjugate.

[0202] In certain clinical conditions, patients may require initial administration of therapeutic agents by a physician or healthcare professional to open the meibomian glands, such as by administering a highly concentrated formulation consisting of one of the keratolytic conjugates described herein. If a higher concentration formulation is required, its administration may necessitate eye shielding or other activities to minimize the impact of irritation or damage to the ocular surface or surrounding tissues. Following such procedures, patients may be administered different keratolytic conjugate formulations at home, regularly applied to the eyelid margins, to maintain meibomian gland patency. This administration may be twice daily, once daily, weekly, or monthly, depending on the formulation activity and the desired therapeutic profile.

[0203] One aspect of the treatment method described herein is the site of topical administration of the composition. In one embodiment, the composition containing the keratolytic conjugate is administered in a manner that does not irritate the eye. In one embodiment, the composition containing the keratolytic conjugate is administered to the eyelid margin.

[0204] Another embodiment of the treatment method described herein is the use of protective elements provided on the eye to avoid eye irritation. While the formulations described herein are generally non-irritating, in some embodiments (e.g., when used with high concentrations of the drug or on sensitive eyes), protective elements provide an additional layer for patient safety and comfort. In one embodiment, an eye shield is provided on the eye to reduce contact of the drug with the cornea and / or conjunctiva while the composition containing the keratolytic conjugate is administered, thereby reducing eye irritation. In some embodiments, this eye shield is a contact lens or an eye cover. In some embodiments, this eye cover is self-adhesive. In one embodiment, the eyelid is separated from the eyeball to reduce contact of the drug with the cornea and / or conjunctiva while the composition containing the keratolytic conjugate is administered, thereby reducing eye irritation. [Examples]

[0205] I. Chemical synthesis Solvents, reagents, and starting materials were purchased from commercial suppliers and used as is unless otherwise specified. Unless otherwise specified, all reactions were carried out at room temperature. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using procedures found in the literature.

[0206] Abbreviation The following abbreviations are used in the examples and other parts of this specification. CD2Cl2: Deuterodichloromethane CDCl3: Deuterochloroform COMU: (1-Cyano-2-Ethoxy-2-Oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DCC:N,N'-Dicyclohexylcarbodiimide DCM: Dichloromethane DMF: N,N-dimethylformamide Et2O: Diethyl ether æ:ethyl acetate H2O: Water HPLC: High-performance liquid chromatography MeCN: Acetonitrile MeOH: methanol MgSO4: Magnesium sulfate mins: minutes NaHCO3: Sodium bicarbonate RT: retention time was: saturated TBDPS: tert-butyldiphenylsilyl TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran

[0207] Analysis method Method A: Phenomenex Luna C18(2)3μm, 50×4.6mm, A=water+0.1% formic acid, B=MeCN+0.1% formic acid, 50℃, %B:0.0min 10% 1.2mL / min, 3.0min 95% 1.3mL / min, 3.5min 97% 1.3mL / min, 3.51min 10% 1.5mL / min, 4.45 min 10% 1.5mL / min, 4.5 min 10% 1.2mL / min.

[0208] Method B: Waters Sunfire C18 3.5 μm 50 x 4.6 mm, A = water + 0.1% formic acid, B = MeCN, 45 °C, %B: 0.0 min 5% 2.25 mL / min, 1.0 min 37.5% 2.2 mL / min, 3.0 min 95% 2.2 mL / min 3.5 min, 95% 2.3mL / min, 3.51 min 0% 2.3mL / min, 4.0 min 0% 2.25mL / min.

[0209] Method C: Waters Sunfire C18 5μm 100×4.6mm, A=water + 0.1% formic acid, B=MeCN + 0.1% formic acid, 45℃, %B: 0.0 min 5%, 0.50 min 5%, 7.5 min 95%, 10.0 min 95%, 10.1 min 5%, 13.0 min 5%, 1.5 mL / min.

[0210] Method D: Phenomenex Luna C18(2)3μm, 50×4.6mm, A=water+0.1% formic acid, B=MeOH+0.1% formic acid, 45℃, %B:0.0min 5% 2.25mL / min, 1.0min 37.5% 2.2mL / min, 3.0min 95% 2.2mL / min, 3.5min 95% 2.3mL / min, 3.51 min 5% 2.3mL / min, 4.0 min 5% 2.25mL / min.

[0211] Method E: AnalpH2_MeCN_AZ_25cm: Phenomenex Luna C18(2)5μm 250×4.6mm, A=water+0.1% formic acid, B=MeCN, 40℃, %B:0.0min 5% 1.20mL / min, 0.5min 5% 1.2mL / min, 13.0min 60% 1.2mL / min, 15min 95% 1.2mL / min, 18 minutes 95% 1.2mL / min, 18.10 minutes 5% 1.20mL / min, 24.0 minutes 5% 1.2mL / min.

[0212] Method F:AnalpH2_JD2MECN_4MIN:Waters Sunfire C18 3.5μm 50×4.6mm, A=water+0.1% formic acid, B=MeCN, 45℃, %B:0.0min 5% 2.25mL / min, 1.0min 20% 2.2mL / min, 3.0min 50% 2.2mL / min, 3.25min 95% 2.2mL / min, 3.50 min 95% 2.3mL / min, 3.51 min 100% 2.30mL / min, 4.0 min 100% 2.25mL / min.

[0213] Chemical synthesis example 1: Step 1: Methyl 2-((tert-butyldiphenylsilyl)oxy)acetate

[0214] [ka]

[0215] Methyl glycolate (0.77 mL, 10.0 mmol) was dissolved in anhydrous DMF (14 mL) and a stirred solution was prepared. Imidazole (803 mg, 11.8 mmol) and tert-butylchlorodiphenylsilane (3.12 mL, 12.0 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum, the residue was diluted with DCM, and washed with ice water. The organic layer was dried (MgSO4), and the solvent was evaporated under vacuum to obtain the crude product. This was purified by flash chromatography (Biotage SP1, 100 g SNAP cartridge), and the title compound was obtained as a colorless oil (3.26 g, 99%) by elution with isohexane → 10% siRNA. LCMS (Method B): Rt = 3.50 min; [M + Na] + = 351.2. 1 H-NMR(400MHz,CDCl3) δ 7.67-7.69(m,4H),7.37-7.43(m,6H),4.24(s,2H),3.68(s,3H),1.09(t,J=3.0Hz,9H)

[0216] Step 2: 2-((tert-butyldiphenylsilyl)oxy)acetic acid

[0217] [ka]

[0218] A 0.75M lithium hydroxide solution was prepared by dissolving methyl 2-((tert-butyldiphenylsilyl)oxy (1.00 g, 3.04 mmol) in THF (2.75 mL) and water (0.92 mL) and stirring it. (aq)(4.06 mL, 3.05 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with water (10 mL) and extracted with Et2O (3 × 20 mL). The aqueous phase was acidified with 5 M HCl (aq) to pH 3, and this solution was extracted with Depositphotos (3 × 20 mL). The combined organic matter was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 25 g SNAP cartridge), and the title compound was obtained as a colorless oil (0.65 g, 68%) by elution with isohexane → Depositphotos. LCMS (Method B): Rt = 2.77 min; [MH]- = 313.3. 1 H-NMR(400MHz,CDCl3) δ 7.61-7.66(m,4H),7.39-7.47(m,6H),4.22(s,2H),1.08-1.12(m,9H)

[0219] Step 3: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-((tert-butyldiphenylsilyl)oxy)acetate

[0220] [ka]

[0221] To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (97 mg, 0.308 mmol) and azithromycin dihydrate (291 mg, 0.370 mmol) dissolved in toluene (15 mL) at room temperature, TEA (155 μL, 1.11 mmol), 4-(dimethylamino)pyridine (286 mg, 2.34 mmol), and 2,4,6-trichlorobenzoyl chloride (162 μL, 1.05 mmol) were added. The mixture was stirred at room temperature for 121 hours. The resulting mixture was then mixed with DCM (10 mL), saturated NaHCO3. 3(aq) The mixture was diluted with (10 mL) and H2O (10 mL), and the layers were separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic matter was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. This crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), eluted with 4:1 isohexane-acetone (1% TEA) → acetone (1% TEA), and further purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge) and eluted with isohexane → acetone (1% TEA). The crude product was then purified by reverse-phase preparative HPLC. The fractions containing the product were combined, diluted with DCM, and neutralized with saturated NaHCO3 (aq). The organic layer was separated, and the aqueous phase was extracted with DCM. The combined organic compounds were washed with saturated brine, dried (MgSO4), and evaporated under vacuum to obtain the title compound as a colorless gum (40 mg, 12%). LC-MS (Method B): Rt = 1.72 mins; [M+H]+= 1046.0

[0222] Step 4: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl 2-hydroxyacetate

[0223] [ka]

[0224] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxy To a stirred solution of so-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-((tert-butyldiphenylsilyl)oxy)acetate (40 mg, 0.0383 mmol) dissolved in anhydrous THF (1 mL) under N2, 115 μL, 0.115 mmol, tetrabutylammonium fluoride hydrate dissolved in THF was added. The reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated NaHCO3 (aq), and extracted with ELISA. The organic layer was washed with saturated brine, and the layers were separated. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10g SNAP cartridge), and the title compound was obtained as a white solid (12mg, 39%) by elution with isohexane (2% TEA) followed by acetone (2% TEA). LC-MS (Method C): Rt = 3.04 mins; [M+H]+ = 807.9

[0225] Chemical synthesis example 2: The following components were prepared for 2-((tert-butyldiphenylsilyl)oxy)acetic acid using the same method as described above.

[0226] [Table 3]

[0227] Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-((tert-butyldiphenylsilyl)oxy)propanoate

[0228] [ka]

[0229] (R)-2-((tert-butyldiphenylsilyl)oxy)propanoic acid (361 mg, 1.10 mmol) was dissolved in DCM (10.7 mL) at 0°C and stirred. DCC (227 mg, 1.10 mmol) was added to the stirred solution, and the mixture was warmed to room temperature and stirred for 2 hours. Azithromycin dihydrate (393 mg, 0.500 mmol) was added, and the mixture was stirred at room temperature for 112 hours. The resulting mixture was diluted with DCM and saturated NaHCO3 (aq), and the layers were separated. The organic phase was washed with saturated NaHCO3 (aq). The combined aqueous layer was extracted with DCM, the combined organic matter was washed with saturated brine, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 25 g), and the title compound was obtained as a white gum (149 mg, 28%) that solidified over time by elution with isohexane (1% TEA) followed by acetone (1% TEA). LC-MS (Method B): Rt = 1.93 min; [M+H]+ = 1059.8

[0230] Step 2: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-hydroxypropanoate

[0231] [ka]

[0232] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-ox 145 mg, 0.135 mmol of sa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-((tert-butyldiphenylsilyl)oxy)propanoate (145 mg, 0.135 mmol) was dissolved in anhydrous THF (3.4 mL) under N2 at room temperature. To this stirred solution, 411 μL, 0.411 mmol, of 1 M tetrabutylammonium fluoride hydrate (0.411 mmol) dissolved in THF was added. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with saturated NaHCO3 (aq) and ethylacetin, and the layers were separated. The organic phase was washed with saturated brine, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by reverse-phase preparative HPLC. The fractions containing the product were combined, diluted with ethylacetin, and neutralized with saturated NaHCO3 (aq). The organic phase was washed with saturated brine, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The title compound was obtained as a white solid (12 mg, 11%). LC-MS (Method B): Rt = 3.18 mins; [M+H]+= 821.9

[0233] Alternatively, synthesis example 2 can also be prepared by the following method.

[0234] Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-(benzyloxy)propanoate

[0235] [ka]

[0236] (R)-(+)-2-benzyloxypropionic acid (115 mg, 0.640 mmol) was dissolved in anhydrous DCM (25 mL) and stirred. DIPEA (0.83 mL, 4.78 mmol), COMU (1.36 g, 3.18 mmol), and azithromycin dihydrate (500 mg, 0.640 mmol) were added to this stirred solution. The mixture was stirred at room temperature for 19 hours. The resulting mixture was diluted with DCM (50 mL), and this solution was saturated with NaHCO3. 3(aq)The mixture was washed with (2 × 20 mL) and then with water (2 × 20 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 50 g SNAP cartridge) and eluted with isohexane (1% TEA) → acetone (1% TEA). Further purification by flash chromatography (Biotage SP1, 25 g SNAP cartridge) and elution with isohexane (1% TEA) → 40% acetone-isohexane (1% TEA) yielded the title compound as a yellow gum (424 mg, 73%). LC-MS (Method B): Rt = 1.55 min; [M + H] + = 911.5. Nearly half of this material was further purified by flash chromatography (Biotage SP1, 50g SNAP cartridge), and the title compound was obtained as a yellow gum (192mg, 33%) by elution with isohexane (1% TEA) → 25% acetone-isohexane (1% TEA). LC-MS (Method B): Rt = 1.55 min; [M+H]+ = 911.6

[0237] Step 2: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-hydroxypropanoate

[0238] [ka]

[0239] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-ol A solution of xo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-(benzyloxy)propanoate (50 mg, 0.060 mmol) dissolved in ethyl acetate (2 mL) was added to a stirred suspension of 20 wt% palladium carbon hydroxide (11.6 μm, 0.0200 mmol) dissolved in ethyl acetate (0.5 mL) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere and stirred for 44 hours. The resulting mixture was diluted with ethyl acetate, passed through a Celite cartridge (2.5 g), washed with ethyl acetate, and the filtrate was evaporated under vacuum.

[0240] In another flask, (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptameth A solution of 106 mg, 0.120 mmol of ru-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-(benzyloxy)propanoate dissolved in 4 mL of ethyl acetate was added to a stirred suspension of 10 wt% palladium carbon (37.1 mg, 0.0300 mmol) dissolved in ethyl acetate (1 mL) under a nitrogen atmosphere. The reaction mixture was placed under a hydrogen atmosphere and stirred for 76 hours. The resulting mixture was diluted with ethyl acetate, passed through a Celite cartridge, washed with ethyl acetate, and the filtrate was evaporated under vacuum.

[0241] These two reaction mixtures were combined, and the product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge). The title compound was obtained as a white solid (58 mg, 41%) by elution with isohexane (1% TEA) followed by acetone (1% TEA). LC-MS (Method C): Rt = 3.21 min; [M+H] = 821.9. 1 H-NMR(400MHz,CDCl3) δ 5.06(d,J=4.8Hz,1H),4.59-4.75(m,3H),4.21-4.27(m,2H),4.02(m, 1H),3.49-3.68(m,3H),3.21-3.37(m,3H),3.00-3.08(m,1H),2.87(s, 1H),2.59-2.73(m,3H),2.30-2.33(m,4H),2.14-2.24(m,7H),1.82-2 .07(m,4H),1.66-1.74(m,2H),1.01-1.59(m,31H),0.83-0.91(m,10H)

[0242] Chemical synthesis example 3: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2-(4-methoxyphenyl)acetate

[0243] [ka]

[0244] Azithromycin dihydrate (250 mg, 0.3200 mmol) was dissolved in dry DCM (5 mL). 4-methoxyphenylacetyl chloride (65 μL, 0.425 mmol) and pyridine (50 μL, 0.618 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The resulting mixture was diluted with DCM (30 mL), and this solution was saturated with NaHCO3. 3(aq) The mixture was washed with (40 mL) and then with saturated brine solution (40 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and the title compound was obtained as a colorless gum by elution with isohexane → 3:1 isohexane-acetone (1% TEA). Scratching of this gum yielded a colorless solid (97 mg, 34%). LC-MS (Method A): Rt = 2.04 min; [M + H] + = 897.50. 1 H-NMR(400MHz,CD2Cl2) δ 7.12-7.15(m,2H),6.78-6.83(m,2H),4.96(d,J=4.6Hz,1H),4.63-4.69(m,2H),4 .53(d,J=7.3Hz,1H),4.17-4.27(m,1H),3.92-4.01(m,1H),3.74(s,3H),3.42-3.5 9(m,4H),3.22-3.36(m,3H),2.95-3.00(m,1H),2.47-2.83(m,5H),2.29-2.34(m, 4H),1.79-2.16(m,9H),1.41-1.69(m,4H),1.00-1.37(m,26H),0.80-0.90(m,11H)

[0245] Chemical synthesis example 4: Step 1: 2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silapentadecane-15-ol

[0246] [ka]

[0247] Tetraethylene glycol (889 μL, 5.15 mmol) and imidazole (425 mg, 6.24 mmol) were dissolved in dry DMF (15 mL). Tert-butylchlorodiphenylsilane (1.0 mL, 3.85 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum, and the residue was dissolved in DCM (50 mL). This solution was washed with saturated brine (2 × 40 mL), and the organic phase was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 50 g SNAP cartridge), and the title compound was obtained as a colorless oil (767 mg, 46%) by elution with isohexane → ethyl. 1 H-NMR(400MHz,CD2Cl2) δ 7.65-7.68(m,4H),7.34-7.41(m,6H),3.78(t,J=5.3Hz,2H),3.51-3.64(m,14H),1.02(s,9H)

[0248] Step 2: Methyl 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-silaoctadecane-18-oate

[0249] [ka]

[0250] 2,2-dimethyl-3,3-diphenyl-4,7,10,13-tetraoxa-3-silapentadecane-15-ol (755 mg, 1.75 mmol) was dissolved in dry THF (10 mL). Sodium hydride (60% dispersed in oil, 90 mg, 2.25 mmol) was added at room temperature, and the mixture was stirred at room temperature for 20 minutes. Methyl bromoacetate (250 μL, 2.64 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with MeOH (10 mL), and the solvent was evaporated under vacuum. The residue was dissolved in DCM, and this solution was washed with saturated brine (40 mL). The aqueous phase was back-extracted with DCM (30 mL), the combined organic matter was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography, and the title compound was obtained as a colorless oil (327 mg, 37%) by elution with isohexane followed by 60% siRNA-isohexane. 1 H-NMR(400MHz,CD2Cl2) δ 7.65-7.67(m,4H),7.34-7.40(m,6H),4.08(d,J=8.7Hz,2H),3.78(t,J=5.3Hz,2H),3.68(s,2H),3.54-3.64(m,15H),1.02(s,9H)

[0251] Step 3: 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-silaoctadecane-18-oic acid

[0252] [ka]

[0253] Methyl 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-silaoctadecane-18-oate (312 mg, 0.620 mmol) was dissolved in 3:1 THF-H2O (8 mL), and the mixture was stirred at room temperature for 64 hours. The mixture was acidified to pH 3 (2N HCl), and the solution was extracted with DCM (4 × 30 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and the title compound was identified as a colorless oil (101 mg, 34%) by elution with isohexane → DCM → 10% MeOH-DCM. LCMS (Method D): Rt = 3.72 min (98.3%) [MH] - = 489.3

[0254] Step 4: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-silaoctadecane-18-oate

[0255] [ka]

[0256] 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-silaoctadecane-18-oic acid (101 mg, 0.210 mmol) and DCC (45 mg, 0.220 mmol) were dissolved in dry DCM (5 mL). The mixture was stirred at room temperature for 2 hours. Azithromycin dihydrate (120 mg, 0.150 mmol) was added, and the mixture was stirred at room temperature for 40 hours. The solvent was evaporated under vacuum, and the residue was dissolved in siRNA (30 mL). This solution was stored in a freezer for 16 hours, and the resulting solution was filtered. The solvent was evaporated under vacuum, and the residue was dissolved in DCM (30 mL). This solution was saturated with NaHCO3 3(aq) The mixture was washed with (20 mL), then dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and the title compound was identified as a colorless gum (143 mg, 57%) by elution with isohexane → 3:1 isohexane-acetone (1% TEA). LC-MS (Method D): Rt = 2.74 min; [M+H]+ = 1222.1

[0257] Step 5: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl-hydroxy-3,6,9,12-tetraoxatetradecanoate

[0258] [ka]

[0259] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10, 12,14-Heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-silaoctadecane-18-oate (130 mg, 0.110 mmol) was dissolved in anhydrous THF (5 mL). Tetrabutylammonium fluoride hydrate (1 M, 350 μL, 0.350 mmol in THF) was added, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was saturated with NaHCO3. 3(aq) The solution was diluted with (10 mL) and DCM (20 mL), and the layers were separated. The aqueous phase was extracted with DCM (2 x 20 mL), the combined organic matter was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and the title compound was obtained as a colorless gum (23 mg, 22%) by elution with isohexane → 3:1 isohexane-acetone (1% TEA) → acetone (1% TEA). LCMS (Method C): Rt = 3.29 min; [M + H] + = 984.0

[0260] Chemical synthesis example 5: Step 1: tert-butyl1-hydroxy-3,6,9,12-tetraoxapentadecane-15-oate

[0261] [ka]

[0262] Tetraethylene glycol (5.0 g, 25.7 mmol) was dissolved in anhydrous THF (60 mL). Sodium hydride (60% dispersed in oil, 52 mg, 1.30 mmol) was added and the mixture was stirred until gas generation ceased. Tert-butyl acrylate (1.5 mL, 10.2 mmol) was added in small amounts over 2 hours, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated brine solution (20 mL) and THF, and evaporated under vacuum. The residue was dissolved in DCM (60 mL), and this solution was washed with saturated brine solution (30 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography, and the title compound was obtained as a pale yellow oil (2.48 g, 75%) by elution with DCM → 10% MeOH-DCM. 1 H-NMR(400MHz,CDCl3) δ 3.56-3.70(m,18H),2.67(s,1H),2.47(t,J=6.6Hz,2H),1.41(s,9H)

[0263] Step 2: tert-butyl 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-cyranonadecane-19-oate

[0264] [ka]

[0265] 1.20 g, 3.72 mmol of tert-butyl 1-hydroxy-3,6,9,12-tetraoxapentadecane-15-oate and 305 mg, 4.48 mmol of imidazole were dissolved in 15 mL of dry DMF. 1.15 mL, 4.42 mmol of tert-butyl chlorodiphenylsilane was added dropwise, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under vacuum, and the residue was separated into 60 mL of DCM and 40 mL of saturated brine. The layers were separated, the organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 50 g SNAP cartridge), and the title compound was obtained as a colorless solution (1.96 g, 94%) by elution with DCM → 5% MeOH-DCM. 1 H-NMR(400MHz,CD2Cl2) δ 7.66-7.68(m,4H),7.35-7.41(m,6H),3.78(t,J=5.0Hz,2H),3.64(t,J=6.4 Hz,2H),3.54-3.59(m,14H),2.43(t,J=6.4Hz,2H),1.41(s,9H),1.02(s,9H)

[0266] Step 3: 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-cyranonadecane-19-oic acid

[0267] [ka]

[0268] 1.96 g, 3.5 mmol of tert-butyl 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-cyranonadecane-19-oate was dissolved in 15 mL of DCM-TFA in a 2:1 ratio, and the solution was stirred at room temperature for 1 hour. The resulting mixture was diluted with 10 mL of H2O and 30 mL of DCM. The solution was vigorously stirred to mix the layers, and the solution was based with 2 M NaOH to pH 3. The layers were separated, and the aqueous phase was extracted with 30 mL of DCM. The combined organic compounds were evaporated under vacuum, and the crude product was purified by flash chromatography (Biotage SP1, 50 g SNAP cartridge). The title compound was obtained as a colorless oil (0.926 g, 52%) by elution with DCM → 10% MeOH-DCM. 1 H-NMR(400MHz,CD2Cl2) δ 7.63-7.69(m,4H),7.34-7.40(m,6H),3.78(t,J=5.0Hz,2H),3.70(t,J= 6.0Hz,2H),3.54-3.62(m,14H),2.54(t,J=6.0Hz,2H),0.99-1.04(m,9H)

[0269] Step 4: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-cyrannonadecane-19-oate

[0270] [ka]

[0271] 2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-cyranonadecane-19-oic acid (82 mg, 0.160 mmol), azithromycin dihydrate (105 mg, 0.130 mmol), and COMU (280 mg, 0.650 mmol) were dissolved in anhydrous DCM (5 mL). DIPEA (175 μL, 1.00 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The resulting mixture was diluted with DCM (50 mL), and this solution was saturated with NaHCO3. 3(aq) The mixture was washed with (2 × 50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and the title compound was obtained as a pale yellow gum (119 mg, 59%) by elution with isohexane → 3:1 isohexane-acetone (1% TEA). LC-MS (Method D): Rt = 2.72 mins; [M + H] + = 1236.1

[0272] Step 5: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl1-hydroxy-3,6,9,12-tetraoxapentadecane-15-oate

[0273] [ka]

[0274] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10 12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl2,2-dimethyl-3,3-diphenyl-4,7,10,13,16-pentaoxa-3-cyranonadecane-19-oate (57 mg, 0.050 mmol) was dissolved in anhydrous THF (5 mL). Tetrabutylammonium fluoride hydrate (1 M, 155 μL, 0.155 mmol in THF) was added, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was saturated with NaHCO₃⁻. 3(aq) The solution was quenched with (10 mL) and extracted with DCM (2 × 25 mL). The combined organic matter was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and the title compound was obtained as an off-white gum (36 mg, 78%) that solidifies when scratched by elution with isohexane → 3:1 isohexane-acetone (1% TEA) → acetone (1% TEA). LCMS (Method D): Rt = 1.87 min; [M + H] + = 998.0

[0275] Chemical synthesis example 6: Step 1: (R)-1-(tert-butoxy)-1-oxopropan-2-yl N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinate

[0276] [ka]

[0277] N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteine ​​(800 mg, 1.72 mmol), tert-butyl(2S)-2-hydroxypropanoate (260 mg, 1.78 mmol), and triphenylphosphine (680 mg, 2.59 mmol) were dissolved in anhydrous DCM (20 mL). Diisopropyl azodicarboxylate (500 μL, 2.55 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under vacuum, and the crude product was purified by flash chromatography. (R)-1-(tert-butoxy)-1-oxopropan-2-yl N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinate (1.06 g, 104%) was obtained as an off-white solid by elution with isohexane → 1:1 SiO-isohexane. LCMS (Method D): Rt=3.59 min; [M+Na]+=616.2.

[0278] Step 2: (R)-2-((acetyl-L-cysteinyl)oxy)propanoic acid

[0279] [ka]

[0280] (R)-1-(tert-butoxy)-1-oxopropan-2-yl N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinate (1.06 g, 1.79 mmol) was dissolved in DCM (10 mL) and TFA (10 mL). Triethylsilane (1000 μL, 6.26 mmol) was added, and the mixture was stirred at room temperature for 3 hours. TFA (2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under vacuum. The residue was dissolved in DCM (30 mL), and the solvent was evaporated under vacuum. Approximately 10% of the crude residue was purified by reverse-phase HPLC. The fractions containing the desired product were combined, and the solutions were frozen (-78°C). The solvent was then evaporated by freeze-drying to obtain (R)-2-((acetyl-L-cysteinyl)oxy)propanoic acid (13 mg, 31%) as a white solid. 1H-NMR(400MHz,MeOD) δ 5.18-4.98(m,1H),4.77-4.62(m,1H),3.08-2.75(m,2H),2.15-1.89(m,3H),1.62-1.38(m,3H)

[0281] Step 3: (R)-2-((N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinyl)oxy)propanoic acid

[0282] [ka]

[0283] (R)-2-((acetyl-L-cysteinyl)oxy)propanoic acid (900 mg, 0.910 mmol) and 4,4'-dimethoxytrityl chloride (280 mg, 0.826 mmol) were dissolved in anhydrous DCM (20 mL). TEA (0.50 μL, 3.59 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (40 mL), and this solution was saturated with NH4Cl (aq) Washed with (40 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 25 g SNAP cartridge), and (R)-2-((N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinyl)oxy)propanoic acid (403 mg, 82%) was obtained as a pale pink solid by elution with ethyl → 20% MeOH-ethyl. LCMS (Method D): Rt = 3.52 mins; [MH]- = 536.2

[0284] Step 4: (R)-1-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-1-oxopropan-2-yl N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinate

[0285] [ka]

[0286] Azithromycin dihydrate (280 mg, 0.357 mmol), (R)-2-((N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinyl)oxy)propanoic acid (200 mg, 0.372 mmol), and TCFH (350 mg, 1.25 mmol) were dissolved in anhydrous DCE (10 mL). DIPEA (400 μL, 2.30 mmol) was added, and the mixture was stirred at 40°C for 3 hours. The mixture was diluted with DCM (30 mL), and the solution was saturated with NH4Cl (aq)The mixture was washed sequentially with (2 × 30 mL), H₂O (20 mL), and saturated brine solution (20 mL). The organic phase was dried (MgSO₄), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge) and eluted with isohexane → 3:1 isohexane-acetone (1% TEA) to obtain (R)-1-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethylamino Tyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-1-oxopropan-2-yl N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinate (220 mg, 49%) was obtained as an off-white solid. LCMS (Method D): Rt = 2.62 mins; [M+H]+ = 1269.2

[0287] Step 5: (R)-1-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-1-oxopropane-2-ylacetyl-L-cysteinate

[0288] [ka]

[0289] (R)-1-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10, 12,14-Heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-1-oxopropan-2-yl N-acetyl-S-(bis(4-methoxyphenyl)(phenyl)methyl)-L-cysteinate (75 mg, 0.0591 mmol) was dissolved in anhydrous DCM (8 mL). Formic acid (900 μL) and triethylsilane (40 μL, 0.250 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Formic acid (100 μL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with isohexane (50 mL) and water (30 mL), and the layers were separated. The aqueous phase was successively washed with a 9:1 isohexane-DCM (50 mL) and DCM (3 × 30 mL). The aqueous phase was based to pH 4, then the solution was extracted with DCM (3 × 30 mL), the combined organic matter was dried and filtered, and the solvent was evaporated under vacuum to obtain (R)-1-(((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5 -Hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-1-oxopropan-2-ylacetyl-L-cysteinate (14 mg, 25%) was obtained as a pale yellow solid. LC-MS (Method D): Rt = 1.98 min; [M + H] + = 967.0

[0290] Chemical synthesis example 7: Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-(((R)-2-(benzyloxy)propanoyl)oxy)propanoate

[0291] [ka]

[0292] (R)-(+)-2-benzyloxypropionic acid (72.1 mg, 0.400 mmol) and DIPEA (70 μL, 0.400 mmol) were dissolved in anhydrous DCM (4 mL) and COMU (171 mg, 0.400 mmol) was added to the stirred solution. The resulting mixture was stirred at room temperature for 5 minutes, followed by the addition of L-(+)-lactic acid (30 μL, 0.400 mmol). The mixture was stirred at room temperature for 30 minutes. DIPEA (120 μL, 0.700 mmol), COMU (214 mg, 0.500 mmol), and azithromycin dihydrate (157 mg, 0.200 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM and saturated NaHCO3 solution, and the layers were separated. The organic phase was sequentially washed with H2O and saturated brine solution, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was separated into Et2O / ELISA and H2O, and the layers were separated. The organic phase was washed with saturated brine solution, dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10g SNAP cartridge) and eluted with isohexane → 20% acetone-isohexane (1% TEA) to obtain (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-meth Xy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-(((R)-2-(benzyloxy)propanoyl)oxy)propanoate was obtained as a colorless gum (125 mg, 64%). LCMS (Method F): Rt = 2.48 mins; [M + H] + = 983.8

[0293] Step 2: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-(((R)-2-hydroxypropanoyl)oxy)propanoate

[0294] [ka]

[0295] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azasik A stirred mixture of lopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-(((R)-2-(benzyloxy)propanoyl)oxy)propanoate (125 mg, 0.130 mmol), palladium carbon 10 wt% (67.7 mg, 0.0600 mmol), and ammonium formate (80.2 mg, 1.27 mmol) dissolved in ethyl acetate (3.5 mL) was heated at 50°C for 1 hour. The reaction mixture was diluted with ethyl acetate, filtered through Celite, washed with ethyl acetate, and the resulting filtrate was evaporated under vacuum. The crude product was flash-chromatographed (Biotage). The solution was purified using SP1 (10g SNAP cartridge) and eluted with isohexane → acetone (1% TEA), resulting in (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy -4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(S)-2-(((R)-2-hydroxypropanoyl)oxy)propanoate (38 mg, 33%) was obtained as a colorless gum. LCMS (Method E): Rt = 7.95 min; [M+H] + = 894.0

[0296] Chemical synthesis example 8: Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-acetoxypropanoate

[0297] [ka]

[0298] (R)-(+)-2-acetoxypropionic acid (45 μL, 0.401 mmol) was dissolved in anhydrous DCE (8 mL) and stirred. DIPEA (240 μL, 1.40 mmol), azithromycin dihydrate (315 mg, 0.401 mmol), and COMU (430 mg, 1.00 mmol) were added to this solution. The solution was stirred at 60°C for 1 hour. The solvent was evaporated under vacuum, and the resulting residue was dissolved in DCM. The solution was then saturated with NaHCO3. 3(aq)The mixture was washed sequentially with (20 mL), H2O (20 mL), and saturated brine solution (20 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude reaction mixture was dissolved in HCl, diluted with Et2O (60 mL), and washed sequentially with saturated NaHCO3 (aq), H2O, and saturated brine solution. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography, and eluted with isohexane → acetone (1% TEA) to obtain (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-acetoxypropanoate (140 mg, 40%) as a pale yellow solid. LCMS (Method E): Rt=8.32 min; [M+H]+=863.8

[0299] Chemical synthesis example 9: Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl5-((R)-1,2-dithiolan-3-yl)pentanoate

[0300] [ka]

[0301] Azithromycin dihydrate (120 mg, 0.153 mmol), lipoic acid (40 mg, 0.194 mmol), and COMU (230 mg, 0.537 mmol) were dissolved in anhydrous DCE (5 mL). DIPEA (150 μL, 0.861 mmol) was added, and the mixture was stirred at 40°C for 18 hours. The mixture was diluted with DCM (50 mL), and the solution was saturated with NH4Cl (aq) Washed with (3 × 40 mL), H2O (30 mL), and saturated brine solution (30 mL). The solution was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The sample flask was purged with N2, sealed, and stored in a freezer for 60 hours. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge) and eluted with isohexane → 1:1 isohexane-ELISA to obtain [(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3, 5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadeca-11-yl]oxy]-6-methyltetrahydropyran-3-yl]5-[(3R)-dithiolan-3-yl]pentanoate (39 mg, 27%) was obtained as a yellow viscous solid. LCM (DMX133_A021219-144_): Rt=2.31 min (>95%) [M+H]+=937.8. LCMS (Method B): Rt=2.31 min; [M+H]+=937.8

[0302] Chemical synthesis example 10: Step 1: Methyl(R)-2-(((((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)carbonyl)oxy)propanoate

[0303] [ka]

[0304] Azithromycin dihydrate (200 mg, 0.255 mmol) was dissolved in anhydrous DMF (2 mL) under an N2 atmosphere at 0°C and stirred. DIPEA (270 μL, 1.53 mmol) and 1-chloroethyl chloroformate (330 μL, 0.306 mmol) were added to this stirred solution. The mixture was stirred at 0°C for 5 minutes. (R)-methyl 2-hydroxypropanoate (240 μL, 0.255 mmol) was added, and the reaction mixture was heated at 55°C for 1 hour. The reaction mixture was allowed to stand at room temperature for 64 hours. The mixture was diluted with DCM and saturated with NH4Cl (aq)The layers were separated by washing with (2 × 10 mL). The aqueous phase was extracted with DCM (10 mL), and the combined organic matter was successively washed with a 1:1 H2O / saturated brine solution (40 mL) and saturated brine solution (10 mL), dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The residue was dissolved in DCM and purified by flash column chromatography (Biotage SP1, 10 g SNAP cartridge), and eluted with isohexane → acetone (1% TEA). The crude product was further purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and eluted with isohexane → 6:4 acetone-isohexane (1% TEA). The crude product was further purified by reverse-phase HPLC, and the fractions containing the desired product were combined and extracted with DCM. The combined organic materials are continuously washed with H2O and saturated brine solution, dried (MgSO4), filtered, and the solvent is evaporated in a vacuum to obtain methyl(R)-2-(((((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S, 6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)carbonyl)oxy)propanoate was obtained as a white solid (2 mg, 1%). LCMS (Method B): Rt = 1.49 min; [M + H] + = 879.7

[0305] Chemical synthesis example 11: Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate

[0306] [ka]

[0307] A solution of acetic anhydride (260 μL, 2.75 mmol) dissolved in anhydrous DCM (5 mL) was added dropwise to a stirred solution of azithromycin dihydrate (2.00 g, 2.55 mmol) and pyridine (210 μL, 2.60 mmol) dissolved in anhydrous DCM (20 mL). The mixture was stirred at room temperature for 3 hours. Acetic anhydride (80 μL, 0.846 mmol) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with DCM (40 mL) and saturated with NH4Cl (aq) (2 x 40 mL), H2O (2 x 20 mL), saturated NaHCO 3(aq)The samples were then washed sequentially with (40 mL) and saturated brine solution (40 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate (1.15 g, 57%) as a pale yellow solid. LCMS (Method D): Rt=1.93 min; [M+H]+=791.9.

[0308] Step 2: (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl2-(benzyloxy)acetate

[0309] [ka]

[0310] Benzyloxyacetic acid (65 mg, 0.390 mmol) was dissolved in anhydrous DCM (5 mL). Oxalyl chloride (140 μL, 1.63 mmol), followed by anhydrous DMF (100 μL), was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under vacuum, and the residue was dissolved in DCM (10 mL). The solvent was evaporated under vacuum, and the residue was dissolved in anhydrous DCM (5 mL). (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate (200 mg, 0.250 mmol) and pyridine (10 μL, 0.120 mmol) were added, and the mixture was stirred at room temperature for 1 hour, followed by reflux for 1 hour. Benzyloxyacetic acid (42 mg, 0.253 mmol) was dissolved in anhydrous DCM (5 mL). Oxalyl chloride (90 μL, 1.05 mmol), followed by anhydrous DMF (100 μL), was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under vacuum, and the residue was dissolved in DCM (10 mL). The solvent was evaporated under vacuum. Anhydrous DCM (2 mL) and anhydrous pyridine (100 μL, 0.120 mmol) were added, and this solution was added to the reaction mixture and stirred under reflux for 1.5 hours. TEA (90 μL, 0.650 mmol) was added, and the mixture was stirred under reflux for 1.5 hours. Benzyloxyacetic acid (42 mg, 0.253 mmol) was dissolved in anhydrous DCM (5 mL). Oxalyl chloride (90 μL, 1.05 mmol), followed by anhydrous DMF (100 μL), was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under vacuum, and the residue was dissolved in DCM (10 mL). The solvent was evaporated under vacuum. DCM (2 mL), anhydrous pyridine (100 μL, 0.120 mmol), and TEA (90 μL, 0.650 mmol) were added, and the solution was added dropwise to the reaction mixture. The reaction mixture was stirred under reflux for 6 hours. The mixture was diluted with DCM (10 mL), and the solution was saturated with NaHCO₃⁻. 3(aq)Washed with (20 mL), dried, filtered, and the solvent evaporated under vacuum. The crude product was purified by flash chromatography and eluted with isohexane → 3:1 isohexane-acetone (1% TEA) to obtain (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-yl Tyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl 2-(benzyloxy)acetate (47 mg, 20%) was obtained as a pale yellow solid. LCMS (Method D): Rt = 2.18 mins; [M + H] + = 939.9.

[0311] Step 3: (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl2-(benzyloxy)acetate

[0312] [ka]

[0313] (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl2-(benzyloxy)acetate (36 mg, 0.0400 mmol) was dissolved in MeOH (5 mL), and the mixture was stirred at 60°C for 5 hours. The solvent was evaporated under vacuum, and the crude product was purified by flash chromatography (Biotage SP1, 10g SNAP cartridge). Elution was performed with isohexane → 3:1 isohexane-acetone (1% TEA) to obtain (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-yl Tyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-4-yl 2-(benzyloxy)acetate (17 mg, 49%) was obtained as a pale yellow gum. LCMS (Method D): Rt = 2.13 mins; [M + H] + = 897.9

[0314] Step 4: (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl2-hydroxyacetate

[0315] [ka]

[0316] (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl 2-(benzyloxy)acetate (15 mg, 0.0200 mmol) was dissolved in ELISA (5 mL). 10 wt% palladium-carbon (9.00 mg, 0.0100 mmol) was added, and the mixture was stirred at 70°C for 1 minute. Ammonium formate (15.0 mg, 0.240 mmol) was added all at once, and the mixture was stirred at 70°C for 16 hours. 10 wt% palladium-carbon (18 mg, 0.169 mmol) and ammonium formate (50 mg, 0.786 mmol) were added, and the mixture was stirred at 70°C for 98 hours. The mixture was filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was saturated with NaHCO3. 3(aq)The samples were then washed sequentially with (20 mL) and saturated brine solution (20 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl 2-hydroxyacetate (10.0 mg, 74%) as a white solid. LCMS (Method D): Rt=1.69 min; [M+H]+=807.8.

[0317] Chemical synthesis example 12: Step 1: (2S,3R,4S,6R)-2-(((2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-4-acetoxy-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate

[0318] [ka]

[0319] Azithromycin dihydrate (300 mg, 0.382 mmol) was dissolved in anhydrous DCM (10 mL). Acetic anhydride (90 μL, 0.952 mmol) and pyridine (90 μL, 1.11 mmol) were added, and the mixture was stirred at 40°C for 108 hours. The mixture was diluted with DCM (40 mL), and the solution was saturated with NH4Cl (aq)The samples were washed sequentially with (3 × 25 mL), water (25 mL), and saturated brine solution (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum to obtain (2S,3R,4S,6R)-2-(((2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-4-acetoxy-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate (201 mg, 63%) as a colorless gum. LCMS (Method D): Rt=1.86 min; [M+H]+=833.8.

[0320] Step 2: (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl acetate

[0321] [ka]

[0322] (2S,3R,4S,6R)-2-(((2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-4-acetoxy-2-ethyl-3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate (201 mg, 0.241 mmol) was dissolved in anhydrous MeOH (10 mL), and the mixture was stirred at 50°C for 4 hours. The solvent was evaporated under vacuum. The crude product was purified by flash chromatography and eluted with isohexane → 3:1 isohexane-acetone (1% TEA). The crude product was re-purified by flash chromatography and eluted with isohexane → 3:1 isohexane-acetone (1% TEA) to obtain (2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl -3,10-dihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-4-yl acetate (25 mg, 13%) was obtained as a colorless gum that solidified into a white solid when scratched. LCMS (Method D): Rt = 1.77 min; [M + H] + = 791.9.

[0323] Chemical synthesis example 13: Step 1: (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3aR,4R,7R,8S,9S,10R,11R,13R,16R,16aS)-4-ethyl-11-hydroxy-8-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-isopropyl-3a,7,9,11,13,15,16-heptamethyl-6-oxotetradecahydro-[1,3,2]dioxazolo[4,5-c][1]oxa[6]azacyclopentadecine-10-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate

[0324] [ka]

[0325] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(R)-2-acetoxypropanoate (500 mg, 0.632 mmol) was dissolved in chloroform (5 mL). N,N-dimethylformamide dimethylacetal (600 μL, 4.52 mmol) was added, and the mixture was stirred at 55°C for 16 hours. The solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), and eluted with isohexane → 7:1 isohexane-acetone (1% TEA) to obtain (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3aR,4R,7R,8S,9S,10R,11R,13R,16R,16aS)-4-ethyl-11-hydroxy-8-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4 ,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-isopropyl-3a,7,9,11,13,15,16-heptamethyl-6-oxotetradecahydro-[1,3,2]dioxazolo[4,5-c][1]oxa[6]azacyclopentadecine-10-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate (421 mg, 79%) was obtained as a white solid. LCMS (Method D): Rt = 2.03 mins; [M + H] + = 846.8.

[0326] Step 2: (2S,3S,4R,6R)-6-(((3aR,4R,7R,8S,9S,10R,11R,13R,16R,16aS)-10-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-11-hydroxy-2-isopropyl-3a,7,9,11,13,15,16-heptamethyl-6-oxotetradecahydro-[1,3,2]dioxazolo[4,5-c][1]oxa[6]azacyclopentadecine-8-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate

[0327] [ka]

[0328] (2S,3R,4S,6R)-4-(dimethylamino)-2-(((3aR,4R,7R,8S,9S,10R,11R,13R,16R,16aS)-4-ethyl-11-hydroxy-8-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-isopropyl-3a,7,9,11,13,15,1 6-Heptamethyl-6-oxotetradecahydro-[1,3,2]dioxazolo[4,5-c][1]oxa[6]azacyclopentadecine-10-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate (150 mg, 0.177 mmol) and 4-(dimethylamino)pyridine (5.0 mg, 0.0409 mmol) were dissolved in anhydrous DCM (10 mL). TEA (150 μL, 1.08 mmol) and acetic anhydride (100 μL, 1.06 mmol) were added, and the mixture was stirred at room temperature for 48 hours. This mixture was diluted with DCM (40 mL) and saturated with NH4Cl (aq)The samples were washed sequentially with (3 × 25 mL), water (2 × 25 mL), and saturated brine solution (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. (2S,3S,4R,6R)-6-(((3aR,4R,7R,8S,9S,10R,11R,13R,16R,16aS)-10-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-11-hydroxy-2-isopropyl-3a,7,9,11,13,15,16-heptamethyl-6-oxotetradecahydro-[1,3,2]dioxazolo[4,5-c][1]oxa[6]azacyclopentadecine-8-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate (129 mg, 82%) was obtained as a white solid. LCMS (Method D): Rt=2.10 min; [M+H]+=888.9

[0329] Step 3: (2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-13-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate

[0330] [ka]

[0331] (2S,3S,4R,6R)-6-(((3aR,4R,7R,8S,9S,10R,11R,13R,16R,16aS)-10-(((2S,3R,4S,6R)-3-acetoxy-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-11-hydroxy-2-isopropyl-3a,7,9,11,13,15,16-heptamethyl-6-oxotetradecahydro-[1,3,2]dioxazolo[4,5-c][1]oxa[6]azacyclopentadecine-8-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate (129 mg, 0.145 mmol) was dissolved in anhydrous MeOH (5 mL). Formic acid (50 μL, 1.33 mmol) was added, and the mixture was stirred at 55°C for 16 hours. This mixture was diluted with DCM (40 mL) and saturated with NH4Cl. (aq) The mixture was washed sequentially with (3 × 25 mL), water (2 × 25 mL), and saturated brine solution (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge) and eluted with isohexane → 3:1 isohexane-acetone (1% TEA) to obtain (2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H- Pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-13-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate (58 mg, 51%) was obtained as a colorless gum that solidified into a white solid when scratched. LCMS (Method D): Rt = 1.76 min; [M+H]+ = 791.8

[0332] Chemical synthesis example 14: Step 1. Methyl N-acetyl-S-((((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)carbonyl)-L-cysteinate

[0333] [ka]

[0334] Azithromycin dihydrate (100 mg, 0.127 mmol) was dissolved in anhydrous DCM (5 mL). MgSO4 was added and the mixture was stirred for 1 minute. This solution was then filtered. TEA (100 μL, 0.717 mmol) and triphosgene (23 mg, 0.0775 mmol) were added to the filtrate and the mixture was stirred at room temperature for 1 hour. N-acetyl-L-cysteine ​​methyl ester (45 mg, 0.254 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Triphosgene (23 μL, 0.0775 mmol) was added and the mixture was stirred at room temperature for 16.5 hours. The mixture was diluted with DCM (40 mL) and this solution was saturated with NaHCO3. 3(aq)The mixture was washed sequentially with (20 mL) and saturated brine solution (20 mL). The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge) and eluted with isohexane → 3:1 isohexane-acetone (1% TEA) to obtain methyl N-acetyl-S-((((2S,3R,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5 S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)carbonyl)-L-cysteinate (49 mg, 40%) was obtained as a colorless gum. LC-MS (Method D): Rt = 1.83 mins; [M+H]+ = 952.8

[0335] II. Biological Evaluation Example 1: Rabbit corneal homogenate stability assay The stability of rabbit corneal homogenate in the test compound was determined using HPLC-MS. This assay was performed on two concentrations of rabbit corneal homogenate (0.15 mg / mL and 0.45 mg / mL of total protein) to allow for the assignment of observed hydrolysis to esterase-dependent or not.

[0336] Homogenization of rabbit corneas Five rabbit corneas (e.g., New Zealand Whites), each approximately 50 mg in size, were sliced ​​and scraped with a scalpel and forceps until they were small (1-3 mm) thin pieces. These were transferred to tare-weighted vials, accurately weighed, and then diluted in 10 volumes of PBS aqueous solution at pH 7.4.

[0337] The sample was intermittently cooled on ice, sheared and homogenized for 3 minutes, and then centrifuged at 3000 rpm for 3 minutes. The supernatant was pipetteed and transferred to a vial, and the total protein concentration was determined at 280 nm. The sample was stored at -78°C.

[0338] Rabbit corneal esterase assay Preparation of stock solution: 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 pH 7.5 buffer. The compound was further diluted to 10 μM. 100 μl of the 100 μM compound was added to 900 μl of 50 mM HEPES pH 7.5 buffer. Esterase homogenate was diluted to 300 ng / μl and 900 ng / μl. Assay conditions: The heater shaker was set to 37°C. 75 μl of 300 or 900 ng / μl esterase homogenate was dispensed into each of the required wells (2 min, 5 min, 10 min, 20 min, and 45 min) of a suitable 96-well plate (Run Plate). 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, and labeled for 0, 2, 5, 10, 20, and 45 minutes. The plate was covered to minimize evaporation. For T=0 samples 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. For the remaining time intervals, 75 μl of 10 μM compound solution was added to the Run Plate, starting with the row at T=45 minutes and ending with the row at T=2 minutes. At the appropriate time, 100 μl of the assay mixture was added to the wells of a matching kill plate containing 100 μl of cold MeCN. Once the sample became available using LCMS (Waters Xevo TQ-S or Micromass Ultima), it was analyzed promptly. The parent conjugate and parent concentration are determined for an appropriate standard response curve, and the half-life (T) of the parent conjugate is calculated using the peak area of ​​the parent conjugate in the linear region of the log-linear plot at each time point. 1 / 2 ) was calculated. Hydrolysis rate of the compound in the example

[0339] [Table 4-1]

[0340] [Table 4-2]

[0341] Example 2: Stability assay of aqueous hydrolysis 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 pH 7.5 buffer or in a 1:1 (v / v) acetonitrile:water ratio to prepare a 100 μM solution. The final DMSO concentration was 1%. This solution was kept at room temperature and injected into LC-MS (Waters Xevo TQ-S or Micromass Ultima) without delay. Additional injections were performed at appropriate time points. At each time point, the peak area of ​​the parent conjugate in the linear region of the log-linear plot was used to determine the half-life (T) of the parent conjugate. 1 / 2 ) was calculated.

[0342] Example 3: Experimental mouse model of dry eye disease Female C57BL / 6 mice (6-8 weeks old) or female HEL BCR Tg mice (6-8 weeks old) were obtained through commercial channels. 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). In short, the mice were exposed to desiccation stress in a perforated cage with a constant airflow from fans positioned on both sides and the room humidity maintained at 30-35%. The mice were subcutaneously injected with scopolamine hydrobromide (0.5 mg / 0.2 mL; Sigma-Aldrich, St. Louis, MO) three times a day (8:00 AM, 12:00 PM, and 5:00 PM) into the alternating hind-flanks to exacerbate the disease. The mice were then exposed to dehydration stress for three weeks. Untreated control mice were maintained in a stress-free environment with a relative humidity of 50% to 75% without forced air supply. The test animals were exposed to the test compound, followed by the collection of tear samples to determine the stability of the test compound, and tissue samples were taken to determine the presence of pro-inflammatory biomarkers.

[0343] II. Preparation of Pharmaceutical Dosage Forms Example 1: Solution for topical ophthalmic use The active ingredients were the compounds listed in Table 1 or their pharmaceutically acceptable salts, which were formulated as solutions with concentrations of 0.1–1.5% w / v.

Claims

1. Structure selected from the following: 【Chemistry 1】 A pharmaceutical composition for ophthalmic or dermatological use comprising a compound having or a pharmaceutically acceptable salt or solvate thereof.

2. The following structure: 【Chemistry 2】 A pharmaceutical composition for ophthalmic or dermatological use comprising a compound having or a pharmaceutically acceptable salt or solvate thereof.

3. The following structure: 【Transformation 3】 A pharmaceutical composition for ophthalmic or dermatological use comprising a compound having or a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition for eye drops or dermatology comprising a compound having the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof, 【Chemistry 4】 During the ceremony, Z is -O- or -(CR ８ R ９ ) ｍ - and m is 1 to 6, R ８ and R ９ Each of these is independently H, halo, alkoxy, alkyl, heteroalkyl, or haloalkyl, R １０ is -OH, alkyl, heteroalkyl, -O(C=O) heteroalkyl, -O(C=O) alkyl, or aryl, and the alkyl, heteroalkyl, -O(C=O) heteroalkyl, -O(C=O) alkyl, or aryl may be optionally substituted. Pharmaceutical composition.

5. Z is -CR ８ R ９ - The ophthalmic or dermatological pharmaceutical composition according to claim 4.

6. R ８ is H or methyl, and R ９ is H. The ophthalmic or dermatological pharmaceutical composition according to claim 4.

7. R １０ The pharmaceutical composition for eye drops or dermatology according to claim 4, wherein is -OH, alkyl, heteroalkyl, -O(C=O)alkyl, or aryl, and the alkyl of the alkyl, heteroalkyl, aryl, or -O(C=O)alkyl is substituted with one or more substituents, each substituent independently selected from the group consisting of -OH, alkyl, oxo, halo, alkoxy, alkylamide, thiol, and heterocycle, and each alkyl, alkoxy, alkylamide, or heterocycle is independently optionally substituted.

8. R １０ is an -O(C=O)alkylene, where the alkylene is substituted with one or more substituents, each substituent independently being methyl, -SH, -OH, and -NHCOCH ３ A pharmaceutical composition for eye drops or dermatology according to claim 4, selected from the group consisting of the following.

9. R １０ The pharmaceutical composition for eye drops or dermatology according to claim 4, wherein is an aryl, and the aryl is substituted with methoxy.

10. R １０ The pharmaceutical composition for eye drops or dermatology according to claim 4, wherein is an alkyl or heteroalkyl, and the alkyl or heteroalkyl is substituted with one or more substituents, each substituent independently selected from the group consisting of -OH, alkoxy, and heterocycloalkyl.

11. R １０ Yes, -OH, -(OCH ２ CH ２ ) ４ OH、-H ２ (OCH) ２ CH ２ ) ４ OH、-(C=O)CH ３ 、 【Transformation 5】 The ophthalmic or dermatological pharmaceutical composition according to claim 4.

12. The ophthalmic or dermatological pharmaceutical composition according to claim 4, wherein Z is -O-.

13. R １０ teeth, 【Transformation 6】 The ophthalmic or dermatological pharmaceutical composition according to claim 12.

14. Z is - (CR ８ R ９ ) ｍ - and R １０ teeth 【Transformation 7】 The ophthalmic or dermatological pharmaceutical composition according to claim 4.

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