JP2023546453A - Compounds and methods for treating eye disorders - Google Patents

Abstract

Described herein are compositions and methods for treating or preventing ocular surface disorders including meibomian gland dysfunction, blepharitis, dry eye disease, and other inflammatory diseases and/or infections in the anterior surface of the eye. is described. The compositions and methods include keratolytic activity and keratolytic conjugates that exhibit anti-inflammatory or other desirable activities. Topical administration of the composition to the eyelid margin or surrounding area provides therapeutic benefit to patients suffering from ocular surface disorders. [Selection diagram] None

Description

CROSS REFERENCES TO RELATED APPLICATIONS This application is based on U.S. Provisional Application No. 63/094,793, filed October 21, 2020, and U.S. Provisional Application No. 63/170,988, filed April 5, 2021. each of which is incorporated by reference in its entirety.

Restasis (0.05% cyclosporine A, Allergan) has been approved by the U.S. 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. ) was approved. Xiidra® (lifitegrast ophthalmic solution) 5% is indicated for the signs and symptoms of dry eye disease (DED).

Certain embodiments herein provide compounds, pharmaceutical (eg, ophthalmic) compositions, and methods of treatment. In specific embodiments, the methods of treatment provided herein include treatment of ocular and/or periocular indications or abnormalities. In some embodiments, the ocular and/or periocular indication or disorder treated by or with the compositions or compounds provided herein has a multifactorial etiology and and/or are indications or abnormalities that have an interaction. Certain embodiments herein provide compounds (and compositions) are provided.

Some embodiments provided herein provide methods of treating inflammation or hyperkeratosis (eg, of the eye or skin).

In certain embodiments, the methods provided herein relate to methods of treating meibomian gland dysfunction (MGD).

Currently, there are no approved pharmacological agents useful for the treatment of MGD. The recognition that terminal ductal obstruction resulting from hyperkeratosis of the ductal epithelium over the meibomian glands is a central mechanism behind meibomian gland dysfunction (MGD) suggests that effective treatment of MGD may result in restoration of ductal obstruction and removal of glandular contents. consistent with clinical experience demonstrating the need for removal (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 meibum (32°C to 40°C) to reverse terminal duct obstruction. (Lane et al., 2012). Unfortunately, warm compresses are unable to achieve such benefits for severely obstructed glands, which may have melting points above 40°C. Current techniques for removing meibomian gland keratosis occlusions include physical removal methods (eg, debridement and gland probing), but they are associated with significant pain for the patient.

Following the period of MGD, various stages of inflammatory or bacterial diseases are observed on the ocular surface, the reason being that meibomian gland obstruction is due to further deterioration of the glands due to meibum stasis in the secretory glands (Knop, IOVS, 2011 ), which can trigger a cascade of events including increased bacterial growth associated with mechanical pressure and stress due to glandular obstruction and downstream release of bacterial lipases, toxic mediators, and/or inflammatory mediators. be. All of these factors can reduce the quality and/or quantity of meibum that the glands can release, resulting in chronic mechanical damage to conjunctival, corneal, and eyelid tissues, as well as tissue damage and inflammation. This will lead to the release of sex mediators. Because of this, many MGD patients also have inflammatory diseases that affect the conjunctiva, cornea, lacrimal glands, eyelids, or goblet cells, leading to comorbid conditions such as dry eye syndrome or blepharitis that have unmet medical needs. have.

For example, in the literature, the terms posterior blepharitis and MGD are used as if they were synonymous, but these terms are not interchangeable. Posterior blepharitis describes an inflammatory condition of the posterior eyelid margin, for which one possible cause is MGD. In its earliest stages, MGD may not be associated with the clinical sign features of posterior blepharitis. At this stage, the affected individual may be symptomatic or asymptomatic, and the condition is considered subclinical. As MGD progresses, symptoms develop and lid margin signs such as changes in meibum expression and quality and lid margin redness may become more visible. At this point, MGD-related posterior blepharitis is said to be present.

Certain embodiments herein include keratosis (e.g., blepharokeratosis, ocular surface keratosis, and/or gland plugging, such as in MGD), microbial infiltration/infection (e.g., bacterial infiltration/infection, Methods are provided for treating ophthalmological (or dermatological) disorders associated with hyperkeratosis) and/or inflammation (inflammation associated with or unrelated to keratosis). In some instances, disorders of the skin and/or eye (and/or surrounding tissue/skin) are differentially difficult to diagnose and/or have multiple etiologies. For example, in some instances, (1) inflammation alone, (2) inflammation associated with keratolytic activity, (3) inflammation associated with both keratolytic activity (e.g., inducing keratosis) and microbial infiltration. (4) Keratolytic activity but no inflammation and/or microbial infiltration, or various other combinations, can be difficult to differentiate. In some instances, the compounds and compositions provided herein can be used to treat such ophthalmic and / or can be used for dermatological indications. Furthermore, many ophthalmological and/or dermatological disorders involve multiple etiologies such as inflammation, microbial infiltration, keratolytic activity, or various combinations thereof. As a result, therapeutics that target multiple etiologies, such as those described herein, are designed to address both the underlying disease (e.g., keratolytic activity and/or microbial infiltration) and symptoms such as inflammation and dry eye. Targeting both would be beneficial in providing therapeutic benefit.

Thus, provided herein are compounds, compositions, methods, and formulations for treating ophthalmic (e.g., periocular) or dermatological disorders, including those in which disorders have a multifactorial etiology. In specific embodiments, non-limiting examples of ophthalmic disorders include surface disorders such as MGD, dry eye, and related inflammatory and bacterial diseases.

In some embodiments herein, formula (I):

or a pharmaceutically acceptable salt or solvate thereof is provided.

In some embodiments, each R ^Q is independently H, R ^N , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, and at least one R ^Q is R ^N. In some embodiments, R ^N is DL ^a -. In some embodiments, D is a keratolytic agent. In some embodiments, L ^a is a linker.

In some embodiments, each R ^Q is independently H, R ^N , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, and one R ^Q is R ^N. In some embodiments, each R ^Q is independently H, R ^N , substituted alkyl, or unsubstituted alkyl. In specific embodiments, at least one R ^Q is R ^N. In some embodiments, each R ^Q is independently H, R ^N , or unsubstituted alkyl, and one R ^Q is R ^N. In some embodiments, unsubstituted alkyl is methyl, ethyl, or propyl. In some embodiments, each R ^Q is independently H, R ^N , or unsubstituted heteroalkyl, and one R ^Q is R ^N. In some embodiments, each R ^Q is independently H, methyl, or R ^N , and one R ^Q is R ^N.

In some embodiments, alkyl is -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, optionally by one or more selected from the group consisting of Optionally substituted (eg, alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl). In some embodiments, alkyl is substituted with one or more selected from the group consisting of alkyl, heterocycloalkyl, -NHCOMe, -O(C=O)alkyl, and -(C=O)Oalkyl. (eg, alkyl is methyl, ethyl, propyl, isopropyl, or t-butyl). In some embodiments, heterocycloalkyl is dithiolane oxide.

In some embodiments herein, formula (IA):

or a pharmaceutically acceptable salt or solvate thereof is provided.

In some embodiments, R' is DL ^a -. In some embodiments, D is a keratolytic agent. In some embodiments, L ^a is a linker.

In some embodiments, L ^a includes one or more linker groups, each linker group including a bond, -O-, -S-, halo, alkyl (alkylenyl), heteroalkyl (heteroalkyl enyl) , disulfide, ester, and carbonyl (>C=O). In some embodiments, each linker group is selected from the group consisting of a bond, -O-, -S-, halo, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), and ester. In some embodiments, L ^a includes one or more linker groups, each linker group including a bond, an alkyl (alkylenyl), a heteroalkyl (heteroalkylenyl), an ester, and a carbonyl (>C=O ) selected from the group consisting of In some embodiments, each linker group is selected from the group consisting of a bond, halo, alkyl (alkylenyl), heteroalkyl (heteroalkyl enyl), and ester. In some embodiments, each linker group is selected from alkyl (alkylene) and heteroalkyl (heteroalkylene), where alkyl (alkylene) and heteroalkyl (heteroalkylene) are optionally substituted.

In some embodiments, L ^a is alkyl (alkylene) substituted with one or more of oxo and alkyl and heteroalkyl. In some embodiments, an alkyl or heteroalkyl is substituted with one or more halo, alkyl, or haloalkyl. In some embodiments, the alkyl or heteroalkyl is substituted with one or more alkyl or haloalkyl. In some embodiments, L ^a includes one or more linker groups, each linker group independently including a bond, -O-, -S-, halo, (C=O), -(C= O) alkyl-, -(C=O)heteroalkyl-, -(C=O)O-, -(C=O)Oalkyl-, -(C=O)Oheteroalkyl-, -(C=O )S-, -(C=O)S alkyl-, -(C=O)S heteroalkyl-, alkylene, or heteroalkylene, where each alkyl, heteroalkyl, alkylene, or heteroalkyl is independently Optionally replaced. In some embodiments, L ^a is (C=O), -(C=O)alkyl-, -(C=O)heteroalkyl-, -(C=O)O-, -(C=O )Oalkyl-, -(C=O)Oheteroalkyl-, -(C=O)OalkylO-, -(C=O)OheteroalkylO-, -(C=O)S-, -( Includes C=O)S alkyl-, -(C=O)S heteroalkyl-, alkylene, and heteroalkylene. In some embodiments, L ^a includes one or more linker groups, each linker group being independently a bond, (C=O), -(C=O)alkyl-, -(C=O ) heteroalkyl-, -(C=O)O-, -(C=O)Oalkyl-, -(C=O)Oheteroalkyl-, -(C=O)S-, -(C=O) selected from S alkyl-, -(C=O)S heteroalkyl-, alkylene, or heteroalkylene, where each alkyl, heteroalkyl, alkylene, or heteroalkyl is independently optionally substituted. In some embodiments, L ^a is (C=O), -(C=O)alkyl-, -(C=O)heteroalkyl-, -(C=O)O-, -(C=O )Oalkyl-, -(C=O)Oheteroalkyl-, -(C=O)OalkylO-, -(C=O)OheteroalkylO-, -(C=O)S-, -( Includes C=O)S alkyl-, -(C=O)S heteroalkyl-, alkylene, and heteroalkylene. In some embodiments, L' is -O-, (C=O), -(C=O)alkyl-, -(C=O)O-, -(C=O)Oalkyl-, and /or -(C=O)OalkylO-. In some embodiments, L' is a bond.

In some embodiments, the linker has the formula (A):

contains the structure of
During the ceremony,
Q is a bond, -O-, -S-, or an optionally substituted amino;
G ¹ and G ² are each independently hydrogen, halo, alkyl, heteroalkyl, or cycloalkyl, where the alkyl or cycloalkyl is optionally substituted;
g is 1 to 20.

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

In some embodiments, g is 1-20. In some embodiments, g is 1-10. In some embodiments, g is 1-5. In some embodiments, g is 2. In some embodiments, g is 1.

In some embodiments, g is 1 or 2, Q is a bond, each G ¹ is hydrogen, and each G ² is methyl. In some embodiments, g is 1 or 2, Q is a bond, and G ¹ and G ² are each hydrogen. In some embodiments, g is 1 or 2, Q is -O-, each G ¹ is hydrogen, and each G ² is methyl. In some embodiments, g is 1 or 2, Q is -O-, and G ¹ and G ² are hydrogen.

In some embodiments, the linker includes one or more bonds, oxo, -O-, methylene,

including.

In some embodiments, g is 1-20. In some embodiments, g is 1-10. In some embodiments, g is 1-8. In some embodiments, g is 1, 2, 3, 4, 5, 6, 7, or 8.

In some embodiments, the linker is

including one or more of the following.

In some embodiments, the linker is one or more of -O-, oxo, methylene,

including.

In some embodiments, the linker includes one or more oxo, one or more -O-, and

including.

In some embodiments, the linker includes one or more oxo, one or more -O-, and

including.

In some embodiments, L is a bond.

In some embodiments, any linker or L provided herein is attached to the remainder of the molecule provided herein to form a ketal. In some embodiments, any linker or L provided herein is attached to the remainder of the molecule provided herein to form an ester.

In some embodiments, D comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA), Thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N - a radical of acetylcysteine (NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, D comprises one or more radicals of keratolytic groups, each independently a radical of glycolic acid (GA), a radical of thioglycol Acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N-acetyl The radical is selected from the group consisting of cysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical.

In some embodiments, D comprises a thiol radical of one or more keratolytic groups, and each thiol radical of one or more keratolytic groups is independently a thiol of thioglycolic acid (TGA). Radical, thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetyl cysteine (NAC), thiol radical of cysteine (Cys), thiol radical of glutathione (GSH), captopril (Cap) ), and the thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap -Cap]・, [diHLip-Cap]・, [diHLip-Cys-Cys]・, [diHLip-Cys]・, [diHLip-Lipox-Lipox]・, and [diHLip-Lipox]・Ru.

In some embodiments, D is substituted (e.g., straight or branched) alkyl, substituted (e.g., straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (e.g., with oxo and thiol) further substituted) with (N-)alkyl). In some embodiments, a substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -OH, -SH, -COOH, substituted unsaturated cycloalkyls (e.g., substituted with one or more C ₁ -C ₄ alkyls), and substituted or unsubstituted (disulfide-containing) heterocycloalkyls (e.g., dithiolanyl, dithiolanyl sulfone, and dithio ranyl oxide). In some embodiments, the substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -SH, substituted unsaturated cycloalkyl ( for example, substituted or _{unsubstituted} disulfide-containing heterocycloalkyl (eg _, dithiolane oxide). In some embodiments, the substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -SH, substituted unsaturated cycloalkyl ( for example, substituted with one or more C ₁ -C ₄ alkyl), and dithiolanyl oxide. In some embodiments, a substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents, and at least one (heteroalkyl) substituent is independently -SH, -COOH, and thioalkyl. selected from the group consisting of. In some embodiments, a substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl is further optionally substituted.

In some embodiments, D is substituted (e.g., straight or branched) alkyl, substituted (e.g., straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (e.g., with oxo and thiol) further substituted) with (N-)alkyl). In some embodiments, the substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently from the group consisting of -SH and dithiolanyl oxide. selected. In some embodiments, a substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents, and at least one (heteroalkyl) substituent is independently -SH, -COOH, and thioalkyl. selected from the group consisting of. In some embodiments, a substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl is further optionally substituted.

In some embodiments, D is a substituted (e.g., straight or branched) alkyl, wherein the (e.g., straight or branched) alkyl is substituted with one or more (alkyl) substituents; alkyl) substituents are each independently hydroxyl, thiol, amino, acetamido, -COOH, substituted unsaturated cycloalkyl (e.g., substituted with one or more C ₁ -C ₄ alkyl), substituted (saturated) heterocycloalkyl (eg, dithiolanyl), and substituted (saturated) heterocycloalkyl (eg, dithiolanyl oxide or dithiolanyl sulfone).

In some embodiments, D is a substituted (e.g., straight or branched) alkyl, and the (e.g., straight or branched) alkyl is substituted with one or more substituents, and the substituents are each independently thiol, amino, acetamido, substituted unsaturated cycloalkyl, e.g. substituted with one or more C ₁ -C ₄ alkyl), and substituted (e.g. saturated) heterocycloalkyl (e.g. dithiolanyl oxide).

In some embodiments, the substituted heterocycloalkyl is saturated (eg, dithiolanyl, dithiolanyl sulfone, or dithiolanyl oxide).

In some embodiments, D is a substituted alkyl, and the alkyl is substituted with a substituted heterocycloalkyl (eg, dithiolanyl oxide). In some embodiments, a substituted heterocycloalkyl is substituted with one or more substituents, each substituent being independently C ₁ -C ₃ alkyl, oxo (e.g., or -O-), and -COOH.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D-L ^a - is

It is.

In some embodiments, D-L ^a - is

It is.

In some embodiments, D is substituted heterocycloalkyl (eg, N-substituted with alkyl (eg, further substituted with oxo and thiol)).

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D-L ^a - is

It is.

In some embodiments, D is one or more esters, one or more amides, and/or one or more Substituted (e.g., straight or branched) heteroalkyl containing disulfide.

In some embodiments, D is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with one or more (heteroalkyl) substituents. , (heteroalkyl) substituents are each independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted (saturated) heterocycloalkyl (e.g. dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide, or N-linked heterocycloalkyl substituted with a carboxylic acid).

In some embodiments, D is a substituted (eg, straight or branched) heteroalkyl that includes one ester (eg, within the (eg, straight or branched) heteroalkyl chain).

In some embodiments, D is a substituted or unsubstituted (e.g., linear or branched) heterozygous compound containing one or two amides (e.g., in the (e.g., linear or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, D is a substituted or unsubstituted (e.g., straight or branched) heterozygote containing one or two disulfides (e.g., in the (e.g., straight or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, D is a substituted or unsubstituted (e.g., straight or branched) heteroalkyl containing one disulfide (e.g., within the (e.g., straight or branched) heteroalkyl chain) It is.

In some embodiments, D is a substituted or unsubstituted (e.g., linear or branched chain) heteroalkyl.

In some embodiments, D is a substituted (e.g., straight or branched) heteroalkyl, the (e.g., straight or branched) heteroalkyl is substituted with one or more substituents, and the substituents are , each independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., carboxylic acid) ).

In some embodiments, D is a substituted branched heteroalkyl.

In some embodiments, D is

including.

In some embodiments, D is

It is.

In some embodiments, D is

including.

In some embodiments, D is

It is.

In some embodiments, D is

It is.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

It is.

In some embodiments, D is

including.

In some embodiments, D is

It is.

In some embodiments, D is

including.

In some embodiments, D is

It is.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some embodiments, D is

including.

In some _embodiments , D is _HOCH2- , _HOCH ( _CH3 )-, HO _{( CH2CH2O ) 4CH2-} , HO( _CH2CH2O ) _4CH2CH2- , _{HOCH 2} (C=O)-, HOCH(CH ₃ )(C=O)-, HO(CH ₂ CH ₂ O) ₄ CH ₂ (C=O)-, HO(CH ₂ CH ₂ O) ₄ CH ₂ CH ₂ (C=O)-, CH ₃ O(C=O)-, CH ₃ CH ₂ O(C=O)-, (CH ₃ ) ₂ CO(C=O)-, (CH ₃ ) ₃ CO( C=O)-, CH ₃ (C=O)-, CH ₃ CH ₂ (C=O)-, (CH ₃ ) ₂ C(C=O)-, (CH ₃ ) ₃ C(C=O) -, HOCH ₂ (C=O)-, HO(CH ₃ )CH(C=O)-, HO(CH ₃ )CH(C=O)O(CH ₃ )CH(C=O)-, CH ₃ (C=O)O( _CH3 )CH(C=O)-, _CH3O (C=O)O( _CH3 )CH(C=O)-, _CH3O (C=O)( _CH3 ) CHO(C=O)-, CH ₃ CH ₂ O(C=O) (CH ₃ )CHO(C=O)-, HOCH ₂ (HOCH ₂ )CHCH ₂ O(C=O)-, CH ₃ ( C=O)OCH ₂ (CH ₃ (C=O)OCH ₂ )CHCH ₂ O(C=O)-, (CH ₃ ) ₃ C(C=O)OCH ₂ ((CH ₃ ) ₃ C(C= O) _OCH2 ) _CHCH2O (C=O)-, HO( _CH3 )CH(C=O) _OCH2 (HO( _CH3 )CH(C=O) _OCH2 ) _CHCH2O (C=O )-, HSCH ₂ (C=O)-, HS(CH ₃ )CH(C=O)-, HSCH ₂ (NH ₂ )CH(C=O)-, HSCH ₂ (CH ₃ (C=O)NH )CH(C=O)-, HOOC(NH ₂ )CHCH ₂ CH ₂ (C=O)NH(HSCH ₂ )CH(C=O)NHCH ₂ (C=O)-, -(C=O)CH ( _NH2 ) _CH2CH2 (C=O)NHCH( _CH2SH )(C=O) _NHCH2COOH , HS( _CH3 ) _2C (C=O)NH( _SHCH2 )CH(C= _O )-, HOOC(NH ₂ )CHCH ₂ SSCH ₂ CH(NH ₂ )(C=O)-, HSCH ₂ (CH ₃ (C=O)NH)CH(C=O)OCH(CH ₃ )(C= O)-,

including.

In some embodiments, D is HSCH ₂ (C=O)-, HS(CH ₃ )CH(C=O)-, HSCH ₂ (NH ₂ )CH(C=O)-, HSCH ₂ (CH ₃ (C=O)NH) _CH (C=O)-, HOOC( _NH2 ) _CHCH2CH2 (C=O)NH( _HSCH2 )CH(C=O) _NHCH2 (C=O)-, -( _C =O)CH( _NH2 ) _CH2CH2 (C=O)NHCH( _CH2SH )(C=O)NHCH2COOH, HS( _CH3 ) _2C (C ₌ O)NH(SHCH ₂ ) CH(C=O)-, HOOC(NH ₂ ) CHCH ₂ SSCH ₂ CH(NH ₂ )(C=O)-, HSCH ₂ (CH ₃ (C=O)NH) CH(C=O)OCH (CH ₃ )(C=O)-,

including.

In some embodiments, D-L ^a is

It is.

In some embodiments, D-L ^a is

It is.

In some embodiments, D is a "keratolytic" radical that, upon release, hydrolysis, or other mechanism, is capable of being absorbed into an individual or metabolize or otherwise produce active keratolytic agents (eg, carboxylic acids and/or thiols) when administered to a patient). In some instances, upon release (eg, by hydrolysis or other mechanisms), D produces more than one active keratolytic agent. In some examples, the active keratolytic agent includes one or more of -SH, -OH, COOH (or COO-), or a 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. In some embodiments, the active keratolytic agent is a carboxylic acid.

In some embodiments, one or more groups (e.g., thiol, hydroxy, carboxylic acid, amide, or amine) of the keratolytic agent (e.g., optionally substituted with (e.g., oxo) optionally substituted C ₁ -C ₆ alkyl) or masked. In some embodiments, one or more thiols of the keratolytic agent are acetyl protected or masked. In some embodiments, one or more amines of the keratolytic agent are acetyl protected or masked. In some embodiments, one or more carboxylic acids of the keratolytic agent are protected or masked with methyl, ethyl, propyl, isopropyl, or t-butyl. In some embodiments, one or more carboxylic acids of the keratolytic agent are ethyl protected or masked.

In some embodiments, L ^a is attached to D by a bond.

In some embodiments, any L or linker provided herein includes one or more substituted or unsubstituted alkoxys (eg, polyethylene glycol (PEG)).

In some embodiments, any L or linker provided herein has the formula (B):
-X(C=O)-
Contains compounds with the structure.

In some embodiments, X is a bond or O. In some embodiments, X is a bond. In some embodiments, X is O.

In some embodiments, any L or linker provided herein is attached to a compound having the structure of Formula (B). In some embodiments, the linker is -(C=O)(OCR ⁸ R ⁹ ) _z -.

In some embodiments, the linker is -(C=O)OCH( _CH3 )-. In some embodiments, the linker is -(C=O)(OCH ₂ CH ₂ ) _z and is attached to a compound having the structure of Formula (B).

In some embodiments, z is an integer from 1 to 20. In some embodiments, z is an integer from 1 to 10. In some embodiments, z is an integer from 1 to 5. In some embodiments, z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, z is 4. In some embodiments, z is 8.

In some embodiments, the linker is -(C=O)(OCH ₂ CH ₂ ) _z , attached to -O(C=O)-. In some embodiments, the linker is -(C=O)(OCH ₂ CH ₂ ) ₄ and is attached to -O(C=O)-. In some embodiments, the linker is -(C=O)(OCH ₂ CH ₂ ) ₈ and is attached to -O(C=O)-.

In some embodiments, a compound having the structure of Formula (B) is coupled to a keratolytic agent provided herein (eg, as described elsewhere herein). In some embodiments, a compound having the structure of formula (B) is conjugated to at least a portion of a keratolytic agent provided herein (e.g., as described elsewhere herein), and includes at least a portion thereof.

In some embodiments, a compound having the structure of Formula (B) is attached to R or R' as provided herein (eg, as otherwise provided herein).

Certain examples herein include an anti-inflammatory and/or antimicrobial moiety (e.g., having the structure of the formula provided herein minus R') and a keratolytic moiety ( For example, combinations with D and/or having the structure D are provided. In certain embodiments, such a moiety is a radical connected by a linker that is a bond, and the keratolytic moiety is associated with (1) an anti-inflammatory and/or antimicrobial agent and (2) one or more can be hydrolyzed to produce both active keratolytic agents. In some embodiments, such a moiety is a radical connected by a hydrolyzable linker, where the hydrolyzable linker connects (1) an anti-inflammatory and/or antimicrobial agent and (2) Both of the one or more active keratolytic agents are hydrolyzable to be released (eg, in vivo, such as after delivery of a therapeutic agent (eg, topically) to the eye and/or skin).

In some embodiments, the compounds provided herein can be used in conjunction with a second radical (e.g., a second radical of Formula I (or any other formula provided herein)). quantified first radical (e.g., a first radical of Formula I (or any other formula provided herein). In some embodiments, a first radical of Formula I (or any other formula provided herein) is quantified. Each radical of any other formula provided in ) is dimerized (eg, forming an S--S bond) via its --SH group.

In some embodiments herein, formula (Ia):

or a pharmaceutically acceptable salt or solvate (eg, or stereoisomer) thereof is provided.

In some embodiments, L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, L is a bond, -(C=O)O(CR ⁸ R ⁹ ) _z -, or -(C=O)O(CR ⁸ R ⁹ ) _z O-. In some embodiments, R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cyclo alkyl, or R ⁸ and R ⁹ together with the atoms to which they are attached form a C ₃ -C ₅ cycloalkyl. In some embodiments, z is 1-6. In some embodiments, X is absent or -O-. In some embodiments, R is substituted (e.g., straight or branched) alkyl, substituted (e.g., straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., with oxo and thiol). further substituted) with (N-)alkyl). In some embodiments, a substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -SH, substituted or unsubstituted (e.g., unsubstituted). cycloalkyl (saturated), and substituted heteroalkyl (eg, dithiolanyl oxide). In some embodiments, a substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -SH, substituted or unsubstituted (e.g., unsubstituted). (saturated) cycloalkyl, and dithiolanyl oxide. In some embodiments, the substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently from the group consisting of -SH and dithiolanyl oxide. selected. In some embodiments, a substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents, and at least one (heteroalkyl) substituent is independently -SH, -COOH, and thioalkyl. selected from the group consisting of. In some embodiments, a substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl is further optionally substituted.

In some embodiments, L is a bond. In some embodiments, L is -(C=O)(OCR ⁸ R ⁹ ) _z - or -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, L is -(C=O)(OCR ⁸ R ⁹ ) _z -. In some embodiments, L is -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, z is 1-3. In some embodiments, z is 1. In some embodiments, R ⁸ and R ⁹ are each independently H or C ₁ -C ₃ alkyl. In some embodiments, each R ⁸ is H and each R ⁹ is C ₁ -C ₃ alkyl. In some embodiments, each R ⁸ is H and each R ⁹ is CH ₃ . In some embodiments, R ⁸ and R ⁹ are H. In some embodiments, L is -(C=O)OCH(CH ₃ )-. In some embodiments, L is -(C=O)OCH( _CH3 )O-.

In some embodiments, X is absent. In some embodiments, X is -O-.

In some embodiments, L is -(C=O)OCH( _CH3 )- or -(C=O)OCH( _CH3 )O- and X is absent or -O- be.

In some embodiments, L is -(C=O)OCH( _CH3 )- and X is absent. In some embodiments, L is -(C=O)OCH( _CH3 )O- and X is absent.

In some embodiments, L is -(C=O)OCH( _CH3 )- and X is -O-. In some embodiments, L is -(C=O)OCH( _CH3 )O- and X is -O-.

In some embodiments, L is a bond and X is absent.

In some embodiments, R is substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl.

In some embodiments, R is a substituted (e.g., straight or branched) alkyl, wherein the (e.g., straight or branched) alkyl is substituted with one or more (alkyl) substituents; alkyl) substituents are each independently hydroxyl, thiol, amino, acetamido, -COOH, substituted unsaturated cycloalkyl (e.g., substituted with one or more C ₁ -C ₄ alkyl), non- selected from the group consisting of substituted (saturated) heterocycloalkyl (eg, dithiolanyl), and substituted (saturated) heterocycloalkyl (eg, dithiolanyl oxide or dithiolanyl sulfone). In some embodiments, R is a substituted (e.g., straight or branched) alkyl, wherein the (e.g., straight or branched) alkyl is substituted with one or more (alkyl) substituents; alkyl) substituents are each independently thiol, amino, acetamido, substituted unsaturated cycloalkyl (e.g., substituted with one or more C ₁ -C ₄ alkyl), and substituted (saturated) hetero selected from the group consisting of cycloalkyl (eg dithiolanyl oxide); In some embodiments, R is a substituted (eg, straight or branched) alkyl, and the (eg, straight or branched) alkyl is substituted with a thiol. In some embodiments, R is a substituted (eg, straight or branched) alkyl, and the (eg, straight or branched) alkyl is substituted with a thiol and an amide. In some embodiments, R is a substituted (e.g., straight or branched) alkyl, where the (e.g., straight or branched) alkyl is a thiol and acetamide (e.g., -N(C=O)CH ₎ will be replaced with In some embodiments, R is a substituted (eg, straight or branched) alkyl, and the (eg, straight or branched) alkyl is substituted with 1,2-dithiolanyl oxide. In some embodiments, R is a substituted (e.g., straight or branched) alkyl, and the (e.g., straight or branched) alkyl is (e.g., one or more C ₁ -C ₄ alkyl) substituted) with substituted unsaturated cycloalkyl.

In some embodiments, R is substituted alkyl. In some embodiments, R is substituted alkyl, substituted alkyl is substituted with one or more alkyl substituents, and at least one alkyl substituent is substituted or unsubstituted cycloalkyl and substituted heterocycloalkyl. selected from the group consisting of. In some embodiments, R is a substituted alkyl, and the alkyl is substituted with a substituted (saturated) heterocycloalkyl. In some embodiments, R is substituted alkyl and the alkyl is substituted with 1,2-dithiolanyl oxide. In some embodiments, R is substituted alkyl, and alkyl is substituted heterocycloalkyl (e.g., _C5 - _{C15heterocycloalkyl} (e.g., one or more disulfides and one or C12 heterocycloalkyl with amide)), the substituted heterocycloalkyl is substituted with one or more substituents, and at least one substituent is independently _C1 - _C3 alkyl, oxo, and -COOH. In some embodiments, substituted alkyls are further optionally substituted.

In some embodiments, L is a bond, X is absent, and R is a substituted (e.g., straight or branched) alkyl, and the (e.g., straight or branched) alkyl is one or Substituted with multiple (alkyl) substituents, each (alkyl) substituent being independently thiol, amino, acetamido, substituted unsaturated cycloalkyl (e.g., one or more C ₁ -C ₄ alkyl) and substituted (saturated) heterocycloalkyl (e.g., dithiolanyl oxide).

In some embodiments, L is a bond, X is absent, R is a substituted alkyl, the substituted alkyl is substituted with one or more alkyl substituents, and at least one alkyl substituent is independently selected from the group consisting of substituted or unsubstituted cycloalkyl and substituted heterocycloalkyl. In some embodiments, substituted alkyls are further optionally substituted.

In some embodiments, R is

and
During the ceremony,
R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl,
p is an integer from 1 to 10,
q is an integer from 1 to 3.

In some embodiments, q is 1 and p is an integer from 3 to 5.

In some embodiments, R ^4a and R ^4b are each H.

In some embodiments, R is

and
During the ceremony,
R ⁵ is -SR ^1c ,
R ^1c is substituted alkyl or substituted heteroalkyl,
Alkyl is substituted with one or more alkyl substituents, each independently from carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted heterocycloalkyl. the heteroalkyl is substituted with one or more heteroalkyl substituents, each heteroalkyl substituent being independently selected from the group consisting of oxo, carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl;
R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,
R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ¹⁰ and R ¹¹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl,
s is an integer from 1 to 10.

In some embodiments, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are each H and s is 1-3.

In some embodiments, R ^1c is heteroalkyl substituted with carboxylic acid. In some embodiments, R ^1c is alkyl substituted with one or more alkyl substituents, and each alkyl substituent is independently selected from the group consisting of carboxylic acid and acetamide.

In some embodiments, R ⁵ is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is one or more esters (e.g., in a heteroalkyl chain (e.g., linear or branched)), one or more amides, and/or one or more Substituted (e.g., straight or branched) heteroalkyl containing disulfide.

In some embodiments, R is a substituted (eg, straight or branched) heteroalkyl that includes one ester (eg, within the (eg, straight or branched) heteroalkyl chain).

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched) heterozygote containing one or two amides (e.g., in the (e.g., linear or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., straight or branched) heterozygote containing one or two disulfides (e.g., in the (e.g., straight or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., straight or branched) heteroalkyl containing one disulfide (e.g., within the (e.g., straight or branched) heteroalkyl chain) It is.

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched chain) heteroalkyl.

In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with one or more heteroalkyl substituents; Heteroalkyl) substituents are each independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide, or N-linked heterocycloalkyl substituted with carboxylic acid). In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with one or more (heteroalkyl) substituents. , (heteroalkyl) substituents are each independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, thiol, oxo, and optionally substituted (e.g., N-attached) heterocycloalkyl (e.g. , optionally substituted with a carboxylic acid). In some embodiments, R is a substituted straight chain heteroalkyl, and the straight chain heteroalkyl is substituted with thioalkyl, amino, and carboxylic acid. In some embodiments, R is a substituted straight chain heteroalkyl, and the straight chain heteroalkyl is substituted with thioalkyl, thiol, and C ₁ -C ₄ alkyl. In some embodiments, R is a substituted branched heteroalkyl, and the branched heteroalkyl is substituted with one or more carboxylic acids. In some embodiments, R is a substituted branched heteroalkyl, wherein the branched heteroalkyl is substituted with one or more C ₁ -C ₄ alkyl, one or more oxo, and a carboxylic acid. substituted with one or more N-linked pyrrolidines. In some embodiments, R is a substituted straight chain heteroalkyl, and the straight chain heteroalkyl is substituted with an amino and a carboxylic acid. In some embodiments, R is a substituted straight chain heteroalkyl, and the straight chain heteroalkyl is substituted with thioalkyl. In some embodiments, R is a substituted straight chain heteroalkyl, and the straight chain heteroalkyl is substituted with an acetamide and a carboxylic acid.

In some embodiments, R is substituted heteroalkyl, the substituted heteroalkyl is substituted with one or more heteroalkyl substituents, and each heteroalkyl substituent is independently -COOH, substituted heterocyclo selected from the group consisting of alkyl, acetamido, alkoxy, oxo, thiol, C ₁ -C ₃ alkyl, and thioalkyl. In some embodiments, R is a substituted heteroalkyl, and the heteroalkyl is substituted with -COOH, -CH ₂ SH, and/or an optionally substituted N-linked heterocycloalkyl. In some embodiments, substituted heteroalkyl is further optionally substituted. In some embodiments, the substituted heteroalkyl is substituted with one or more substituents, each substituent being independently a group consisting of acetamido, amino, C ₁ -C ₆ alkyl, thiol, and oxo. selected from.

In some embodiments, R is substituted heteroalkyl, and the heteroalkyl is substituted with one or more substituents, each substituent independently selected from the group consisting of -COOH and acetamide.

In some embodiments, R is a substituted heteroalkyl, and the heteroalkyl is substituted with one or more substituents, each substituent being independently selected from the group consisting of oxo and acetamido (e.g. , the heteroalkyl chain contains a disulfide bond and -O-).

In some embodiments, R is substituted heteroalkyl, and the heteroalkyl is substituted with one or more substituents, each substituent being independently C ₁ -C ₃ alkyl, oxo, and substituted N-linked heterocycloalkyl (eg, optionally substituted with -COOH).

In some embodiments, R is substituted heteroalkyl, and the heteroalkyl is substituted with one or more substituents, each substituent being independently C ₁ -C ₃ alkyl, oxo, -COOH, and thiols (eg, a branched heteroalkyl chain contains two disulfide bonds and two -NH-).

In some embodiments, R is a substituted heteroalkyl that includes one or more ester, amide, or disulfide linkages within the heteroalkyl chain.

In some embodiments, R is a substituted heteroalkyl, wherein the heteroalkyl is substituted with -COOH, _-CH SH, and/or an optionally substituted N-linked heterocycloalkyl, and one or more with other substituents, each substituent being independently selected from the group consisting of acetamido, amino, C ₁ -C ₆ alkyl, thiol, and oxo.

In some embodiments, R is a substituted heteroalkyl containing two disulfide bonds within the heteroalkyl chain, and the heteroalkyl is substituted with -COOH or a substituted N-linked heterocycloalkyl. In some embodiments, the heteroalkyl is further substituted with one or more substituents, each substituent independently selected from the group consisting of acetamido and C ₁ -C ₆ alkyl.

In some embodiments, R is a substituted heteroalkyl containing one disulfide bond within the heteroalkyl chain, and the heteroalkyl is substituted with acetamide, -COOH, and -SH.

In some embodiments, R is heterocycloalkyl N-substituted with alkyl, where the alkyl is further substituted with oxo and/or thiol.

In some embodiments, L is a bond, X is absent, R is a substituted (e.g., straight or branched) heteroalkyl, and one (e.g., straight or branched) heteroalkyl or substituted with multiple (heteroalkyl) substituents, each (heteroalkyl) substituent being independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted (eg, N-attached) heterocycloalkyl (eg, optionally substituted with a carboxylic acid);

In some embodiments, L is a bond, X is absent, R is substituted heteroalkyl, and the substituted heteroalkyl is substituted with one or more heteroalkyl substituents, and at least one Substituents are independently selected from the group consisting of -COOH, substituted heterocycloalkyl, and thioalkyl. In some embodiments, substituted heteroalkyl is further optionally substituted.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is a substituted branched heteroalkyl.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R is substituted heterocycloalkyl (eg, N-substituted with alkyl (eg, further substituted with oxo and/or thiol)).

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA), Thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, lipoic acid (Lip) radical, From the group consisting of acid sulfonyl (Lipsulf) radical, N-acetylcysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical selected).

In some embodiments, R comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA), Thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N - a radical of acetylcysteine (NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R comprises one or more radicals of keratolytic groups, each independently a radical of glycolic acid (GA), a radical of thioglycol Acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N-acetyl The radical is selected from the group consisting of cysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical.

In some embodiments, R comprises a thiol radical of one or more keratolytic groups, and each thiol radical of one or more keratolytic groups is independently a thiol of thioglycolic acid (TGA). Radical, thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetyl cysteine (NAC), thiol radical of cysteine (Cys), thiol radical of glutathione (GSH), captopril (Cap) ), and the thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, diHLip-Cap-Cap]・, [diHLip- Cap]·, [diHLip-Cys-Cys]·, [diHLip-Cys]·, [diHLip-Lipox-Lipox]·, and [diHLip-Lipox]·.

In some embodiments, R is

It is.

In some embodiments, R-X-L- is

It is.

In some embodiments, R-X-L- is

It is.

In some embodiments, the compound has the structure:

It is other than a compound having

In some embodiments herein, formula (Ib):

or a pharmaceutically acceptable salt or solvate (eg, or stereoisomer) thereof is provided.

In some embodiments, L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cyclo alkyl, or R ⁸ and R ⁹ together with the atoms to which they are attached form a C ₃ -C ₅ cycloalkyl. In some embodiments, z is 1-6. In some embodiments, X is absent or -O-.

In some embodiments, R ^x is

It is.

In some embodiments, R ^1a and R ^1b are each independently -H or -SR ^1c . In some embodiments, each R ^1c is independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino , oxo, optionally substituted heterocycloalkyl (e.g., N-linked pyrrolidinyl substituted with -COOH), or substituted with one or more (alkyl) substituents selected from the group consisting of or an unsubstituted (e.g., straight or branched) heteroalkyl (e.g., one selected from the group consisting of, each independently, carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) or substituted with multiple (heteroalkyl) substituents). In some embodiments, R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or two of R ^2a and R ^2b , R ^2c and R ^2d , or R ^2e and R ^2f are integral with the atoms to which they are bonded; to form C ₃ -C ₅ cycloalkyl. In some embodiments, m is an integer from 1 to 10. In some embodiments, n and o are each independently an integer from 0 to 3. In some embodiments, n and o are each independently an integer from 1 to 3.

In some embodiments, L, R ⁸ , R ⁹ , X, and z are each specified separately herein.

In some embodiments, n and o are each independently 0, 1, or 2. In some embodiments, n is 1 or 1. In some embodiments, n is 2. In some embodiments, o is 0 or 1. In some embodiments, o is 0. In some embodiments, o is 0 and n is 2.

In some embodiments, n and o are each independently 0 or 1. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, o is 0 or 1. In some embodiments, o is 0. In some embodiments, o is 0 and n is 1.

In some embodiments, m is 3-5. In some embodiments, m is 4. In some embodiments, o is 0 and m is 4. In some embodiments, n is 2 and m is 4. In some embodiments, o is 0, n is 2, and m is 4.

In some embodiments, m is 3-5. In some embodiments, m is 4. In some embodiments, n is 0 and m is 4. In some embodiments, n is 1 and m is 4. In some embodiments, o is 0, n is 1, and m is 4.

In some embodiments, R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl It is. In some embodiments, R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl and at least one of R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f is halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl. In some embodiments, R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each H.

In some embodiments, R ^x is

It is.

In some embodiments, R ^x is

It is.

In some embodiments, R ^1a and R ^1b are each independently -H or -SR ^1c . In some embodiments, each R ^1c is independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino , oxo, optionally substituted heterocycloalkyl (e.g., N-linked pyrrolidinyl substituted with -COOH), or substituted with one or more (alkyl) substituents selected from the group consisting of or an unsubstituted (e.g., straight or branched) heteroalkyl (e.g., one selected from the group consisting of, each independently, carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) or substituted with multiple (heteroalkyl) substituents).

In some embodiments, R ^1a is -H or -SR ^1c , R ^1b is -SR ^1c , or R ^1a is -SR ^1c and R ^1b is -H or -SR ^1c . . In some embodiments, R ^1a is -H or -SR ^1c and R ^1b is -SR ^1c . In some embodiments, R ^1a is -H and R ^1b is -SR ^1c . In some embodiments, R ^1a is -SR ^1c and R ^1b is -H or -SR ^1c . In some embodiments, R ^1a is -SR ^1c and R ^1b is -SR ^1c . In some embodiments, R ^1a and R ^1b are each -SR ^1c .

In some embodiments, R ^1a and R ^1b each independently comprise a radical of one or more keratolytic groups (e.g., a radical of one or more keratolytic groups each independently , glycolic acid (GA) radical, thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, From the group consisting of dihydrolipoic acid (diHLip) radical, N-acetylcysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical selected).

In some embodiments, R ^1a and R ^1b are each independently a radical of one or more keratolytic groups, and the one or more radicals of keratolytic groups are each independently a glycol Acid (GA) radical, thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N-acetylcysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical. Ru.

In some embodiments, R ^1a and R ^1b each independently include one or more keratolytic (thiol) radicals, and the one or more keratolytic (thiol) radicals are: Each independently, the (thiol) radical of thioglycolic acid (TGA), the (thiol) radical of thiolactic acid (TLac), the (thiol) radical of dihydrolipoic acid (diHLip), and the (thiol) radical of N-acetylcysteine (NAC). The radical is selected from the group consisting of the (thiol) radical of cysteine (Cys), the (thiol) radical of glutathione (GSH), the (thiol) radical of captopril (Cap), and the (thiol) radical of bucillamine (Buc).

In some embodiments, R ^1a and R ^1b are each independently a thiol radical of one or more keratolytic groups, and the thiol radicals of one or more keratolytic groups are each independently , thiol radical of thioglycolic acid (TGA), thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetylcysteine (NAC), thiol radical of cysteine (Cys), glutathione ( The thiol radical is selected from the group consisting of the thiol radical of GSH), the thiol radical of captopril (Cap), and the thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap -Cap]・, [diHLip-Cap]・, [diHLip-Cys-Cys]・, [diHLip-Cys]・, [diHLip-Lipox-Lipox]・, and [diHLip-Lipox]・Ru.

In some embodiments, the thiol radical of the keratolytic group is the point at which R ^1a and/or R ^1b attach to the remainder of the molecule. In some embodiments, R ^1a and/or R ^1b (thiol radicals) are each independently attached to the remainder of the molecule to form a disulfide bond.

In some embodiments, R ^1a and R ^1b are each independently -H, or

It is.

In some embodiments, R ^1a and R ^1b are the same. In some embodiments, R ^1a and R ^1b are each -SR ^1c and the same. In some embodiments, R ^1a and R ^1b are different. In some embodiments, R ^1a and R ^1b are each SR ^1c and different.

In some embodiments, L is a bond, X is absent, and R ^x is

It is.

In some embodiments, L is -(C=O)OCH( _CH3 )-, X is absent, and R ^x is

It is.

In some embodiments, L is -(C=O)OCH( _CH3 )-, X is absent, and R ^x is

It is.

In some embodiments, each R ^1c is independently substituted or unsubstituted (e.g., straight or branched) alkyl or substituted or unsubstituted (e.g., straight or branched) heteroalkyl. . In some embodiments, each R ^1c is independently substituted (e.g., straight or branched) alkyl, or substituted (e.g., straight or branched) heteroalkyl. In some embodiments, each R ^1c is independently substituted (eg, straight or branched) alkyl. In some embodiments, each R ^1c is (the same) substituted (eg, straight or branched) alkyl. In some embodiments, each R ^1c is a (differently) substituted (eg, straight or branched) alkyl.

In some embodiments, each R ^1c is independently substituted (eg, straight or branched) heteroalkyl. In some embodiments, each R ^1c is an (identical) substituted (eg, straight or branched) heteroalkyl. In some embodiments, each R ^1c is a (differently) substituted (eg, straight or branched) heteroalkyl.

In some embodiments, one of R ^1c is substituted (eg, straight or branched) alkyl and the other is substituted (eg, straight or branched) heteroalkyl.

In some embodiments, each R ^1c is the same. In some embodiments, each R ^1c is different.

In some embodiments, each R ^1c is independently a substituted (e.g., straight or branched) alkyl, and the substituted alkyl is substituted with one or more (alkyl) substituents; Substituents are each independently carboxylic acid, -SH, thioalkyl (e.g., _-CH2SH ), acetamido (e.g., -NH(C=O) _CH3 ), amino, oxo, and optionally substituted (eg, N-linked pyrrolidinyl substituted with -COOH).

In some embodiments, the optionally substituted heterocycloalkyl is

It is.

In some embodiments, each R ^1c is independently a substituted (e.g., straight or branched) heteroalkyl, and the substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents; (Heteroalkyl) substituents are each independently carboxylic acid, amino, thioalkyl (e.g., -CH ₂ SH), thiol, acetamido (e.g., -NH(C=O)CH ₃ ), and C ₁ -C ₃ alkyl.

In some embodiments, R ^1c is

It is.

In some embodiments, R ^1a , R ^1b , and each R ^1c each independently includes one or more substituents that are carboxylic acids or esters. In some embodiments, R ^1a , R ^1b , and each R ^1c each independently include one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ^1a includes one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ^1b includes one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ^1b includes one or more substituents that are each independently a carboxylic acid (eg, -(C=O)OH). In some embodiments, R ^1a , R ^1b , and each R ^1c each independently include one or more substituents that are esters (e.g., -(C=O)O-C ₁ - _C4 alkyl). In some embodiments, R ^1a includes one or more substituents that are esters (eg, -(C=O)O-C ₁ -C ₄ alkyl). In some embodiments, R ^1b includes one or more substituents that are esters (eg, -(C=O)O-C ₁ -C ₄ alkyl). In some embodiments, R ^1b includes one or more substituents that are each independently an ester (eg, -(C=O)O-C ₁ -C ₄ alkyl).

In some embodiments, -(C=O)OH of R ^1a , R ^1b , and/or R ^1c is optionally esterified (e.g., -(C=O)OH or -(C= O) O-C ₁ -C ₄ alkyl). In some embodiments, C ₁ -C ₄ alkyl is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

In some embodiments herein, formula (Ic):

or a pharmaceutically acceptable salt or solvate (eg, or stereoisomer) thereof is provided.

In some embodiments, L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cyclo alkyl, or R ⁸ and R ⁹ together with the atoms to which they are attached form a C ₃ -C ₅ cycloalkyl. In some embodiments, z is 1-6. In some embodiments, X is absent or -O-.

In some embodiments, R ^y is

It is.

In some embodiments, R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl. In some embodiments, p is an integer from 1 to 10. In some embodiments, q is an integer from 1 to 3.

In some embodiments, L, R ⁸ , R ⁹ , z, and X are each specified separately herein.

In some embodiments, R ^y is

It is.

In some embodiments, R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl. In some embodiments, p is an integer from 1 to 10. In some embodiments, q is an integer from 1 to 3.

In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some embodiments, p is an integer from 3 to 5. In some embodiments, p is 4. In some embodiments, q is 1 and p is 4.

In some embodiments, R ^4a and R ^4b are each independently H or substituted or unsubstituted alkyl. In some embodiments, R ^4a and R ^4b are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl. In some embodiments, R ^4a and R ^4b are each H.

In some embodiments, q is 1, p is an integer from 3 to 5, and R ^4a and R ^4b are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ - _C3 haloalkyl. In some embodiments, q is 1, p is 4, and R ^4a and R ^4b are each H.

In some embodiments, L is -(C=O)OCH( _CH3 )-, X is absent, and R ^y is

It is.

In some embodiments herein, formula (Id):

or a pharmaceutically acceptable salt or solvate (eg, or stereoisomer) thereof is provided.

In some embodiments, L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cyclo alkyl, or R ⁸ and R ⁹ together with the atoms to which they are attached form a C ₃ -C ₅ cycloalkyl. In some embodiments, z is 1-6. In some embodiments, X is absent or -O-.

In some embodiments, R ^z is

It is.

In some embodiments, R ⁵ is -SR ^1c . In some embodiments, R ^1c is a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally heterocycloalkyl substituted with (e.g. N-linked pyrrolidinyl substituted with -COOH), or substituted or unsubstituted (e.g. , straight chain or branched chain ₎ , such as _one or more (hetero (alkyl) substituent). In some embodiments, R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cyclo alkyl, or both R ¹⁰ and R ¹¹ together with the atoms to which they are attached form a C ₃ -C ₅ cycloalkyl. In some embodiments, s is an integer from 1 to 10.

In some embodiments, L, R ⁸ , R ⁹ , X, and z are each specified separately herein.

In some embodiments, R ⁵ is -SR ^1c . In some embodiments, R ^1c is a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally heterocycloalkyl substituted with (e.g. N-linked pyrrolidinyl substituted with -COOH), or substituted or unsubstituted (e.g. , straight chain or branched chain ₎ , such as _one or more (hetero (alkyl) substituent). In some embodiments, R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cyclo is alkyl, or two or more of R ¹⁰ and R ¹¹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl. In some embodiments, s is an integer from 1 to 10.

In some embodiments, R ^1c is substituted alkyl or substituted heteroalkyl.

In some embodiments, R ^1c is substituted alkyl, and the alkyl is substituted with one or more alkyl substituents, each alkyl substituent being independently carboxylic acid, -SH, thioalkyl, acetamido, selected from the group consisting of amino, oxo, and optionally substituted heterocycloalkyl. In some embodiments, R ^1c is alkyl substituted with one or more alkyl substituents, each alkyl substituent being independently selected from the group consisting of carboxylic acid and acetamide.

In some embodiments, R ^1c is a substituted heteroalkyl, the heteroalkyl is substituted with one or more heteroalkyl substituents, and each heteroalkyl substituent is independently oxo, carboxylic acid, amino , thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl. In some embodiments, R ^1c is heteroalkyl substituted with carboxylic acid.

In some embodiments, R ^1c is substituted heteroalkyl, and the heteroalkyl is substituted with -COOH and oxo. In some embodiments, R ^1c is substituted heteroalkyl, and the heteroalkyl is substituted with oxo and acetamide. In some embodiments, R ^1c is substituted heteroalkyl, and heteroalkyl is substituted with C ₁ -C ₃ alkyl, oxo, and substituted N-linked heterocycloalkyl. In some embodiments, R ^1c is a substituted heteroalkyl, and the heteroalkyl is substituted with -COOH, C ₁ -C ₃ alkyl, oxo, and thiol.

In some embodiments, R ⁶ and R ⁷ are each independently H or substituted or unsubstituted alkyl (eg, C ₁ -C ₃ alkyl optionally substituted with oxo). In some embodiments, R ⁶ and R ⁷ are each independently H or C ₁ -C ₃ alkyl optionally substituted with oxo. In some embodiments, R ⁶ and R ⁷ are each independently H or -(C=O)CH ₃ . In some embodiments, R ⁶ is H and R ⁷ is H or -(C=O)CH ₃ . In some embodiments, R ⁶ is H and R ⁷ is -(C=O)CH ₃ . In some embodiments, R ⁶ and R ⁷ are H.

In some embodiments, R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl. In some embodiments, R ¹⁰ and R ¹¹ are each H.

In some embodiments, s is 1-3. In some embodiments, s is 1. In some embodiments, s is 1 and R ¹⁰ and R ¹¹ are H.

In some embodiments, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are each H and s is 1-3.

In some embodiments, R ⁵ comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA) , thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, a radical of N-acetylcysteine (NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R ⁵ is a radical of one or more keratolytic groups, and the one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA), a radical of thiolytic acid, Glycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N- The radical is selected from the group consisting of an acetylcysteine (NAC) radical, a cysteine (Cys) radical, a glutathione (GSH) radical, a captopril (Cap) radical, and a bucillamine (Buc) radical.

In some embodiments, each R ⁵ independently comprises one or more keratolytic (thiol) radicals, and the one or more keratolytic (thiol) radicals are each independently (thiol) radical of thioglycolic acid (TGA), (thiol) radical of thiolactic acid (TLac), (thiol) radical of dihydrolipoic acid (diHLip), (thiol) radical of N-acetylcysteine (NAC), cysteine. (Cys) (thiol) radical, glutathione (GSH) (thiol) radical, captopril (Cap) (thiol) radical, and bucillamine (Buc) (thiol) radical.

In some embodiments, R ⁵ is a thiol radical of one or more keratolytic groups, and each thiol radical of one or more keratolytic groups is independently a thiol radical of thioglycolic acid (TGA). Thiol radical, thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetylcysteine (NAC), thiol radical of cysteine (Cys), thiol radical of glutathione (GSH), captopril ( The thiol radical is selected from the group consisting of the thiol radical of Bucillamine (Buc), and the thiol radical of Bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap -Cap]・, [diHLip-Cap]・, [diHLip-Cys-Cys]・, [diHLip-Cys]・, [diHLip-Lipox-Lipox]・, and [diHLip-Lipox]・Ru.

In some embodiments, the thiol radical of the keratolytic group is the point at which R ⁵ is attached to the remainder of the molecule. In some embodiments, R ⁵ is attached to the remainder of the molecule to form a disulfide bond.

In some embodiments, R ⁵ is

It is.

In some embodiments, R ⁵ includes one or more substituents that are carboxylic acids or esters. In some embodiments, R ⁵ includes one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ⁵ includes one or more substituents that are esters (eg, -(C=O)O-C ₁ -C ₄ alkyl).

In some embodiments, -(C=O)OH at R ⁵ is optionally esterified (e.g., -(C=O)OH or -(C=O)O-C ₁ -C ₄ alkyl). In some embodiments, C ₁ -C ₄ alkyl is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

In some embodiments, R ^z is

It is.

In some embodiments, R ⁷ is H or -(C=O)CH ₃ . In some embodiments, ^R7 is H. In some embodiments, R ⁷ is -(C=O)CH ₃ .

In some embodiments, R ^1c is specified elsewhere herein.

In some embodiments herein, formula (I), formula (IA), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), any compound provided herein, such as a compound represented by any one of Table 1, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. A pharmaceutical composition comprising: In some embodiments, the pharmaceutical composition is suitable for ocular administration. In some embodiments, the pharmaceutical composition is suitable for topical ocular administration. In some embodiments, topical ocular administration is into and/or around the eye, such as at the lid margin. In some embodiments, topical ocular administration is to the ocular surface and inner surface of the eyelid.

In some embodiments, any of Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), Table 1 A compound or pharmaceutical composition comprising any compound provided herein, such as a compound, or a pharmaceutically acceptable salt thereof, is substantially hydrolytically stable (e.g., in a buffered solution). or stable in aqueous compositions (e.g. solutions), such as ophthalmically acceptable aqueous compositions). In some embodiments, the compound or pharmaceutical composition is formulated in an aqueous solvent. In some embodiments, the compound or pharmaceutical composition is formulated and stored in an aqueous solvent. In some examples, compositions or formulations provided herein are chemically and/or physically stable in aqueous compositions.

In some embodiments, any of Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), Table 1 A compound provided herein, such as a compound, or a pharmaceutically acceptable salt thereof, may contain one or more keratolytic agents (e.g., R is negatively charged or H, , formula (IA), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), or the free form of the radical of Table 1), and/ or an active pharmaceutical agent (e.g., where R is negatively charged or H, formula (I), formula (IA), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), or the free form of the radical in Table 1). In some embodiments, the compound or pharmaceutical composition is reduced to one or more keratolytic agents in the ocular space. In some embodiments, the compound or pharmaceutical composition is reduced to one or more keratolytic agents by a reductase in the ocular space.

In some embodiments, any of Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), Table 1 A compound provided herein, such as a compound, or a pharmaceutically acceptable salt thereof, is an active pharmaceutical agent (e.g., R is negatively charged or H, formula (I), formula (I-A ), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), or the free form of the radical of Table 1) and keratolytic agents. In some embodiments, the compound or pharmaceutical composition is hydrolyzed into the active pharmaceutical agent and keratolytic agent in the ocular space. In some embodiments, the compound or pharmaceutical composition is hydrolyzed by esterases into the active pharmaceutical agent and keratolytic agent in the ocular space. In some embodiments, the active pharmaceutical agent is an antibacterial agent. In some embodiments, the antibacterial 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.

In some embodiments, any of Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), Table 1 A compound or pharmaceutical composition comprising any compound provided herein, such as a compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition comprises Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), Table 1 (eg, the free form is a radical and R is a negative charge or H). In some embodiments, the compositions provided herein include a compound provided herein and a compound of formula (I), formula (IA), formula (Ia), formula (Ia') , the free form of the radical of formula (Ib), formula (Ic), formula (Id), Table 1, or a pharmaceutically acceptable salt thereof (e.g., R is a negative charge or H) with a certain ( (e.g., by weight or molar) and from about 1:99 to about 100:0 (e.g., the amount of the free form of the radical to the total amount of the free form of the radical plus the conjugate is 0% ( weight or mole) to 99%). In some embodiments, the relative amount of the free form of the radical is 0% to about 20%, 0% to about 10%, about 0.1% to about 10%, about 0.1% to about 5%, 0% to about 50%, such as less than 5%, less than 2.5%, less than 2% (percentages are weight/weight or mole/mole ratios). In some instances, such aqueous compositions are prepared in advance or at the time of application to maintain a high concentration of the compound relative to its radical free form. In some embodiments, such compound concentrations are present in an aqueous composition (such as an aqueous composition under the conditions described herein, such as in Table 2, such as a HEPES buffer) for at least 45 minutes in the composition. exist. Table 2 of the Examples illustrates the good stability of the compositions provided herein, and such listing is incorporated into the disclosure. Additionally, in some instances, the compounds provided herein are administered to an individual (e.g., ocularly (e.g., periocularly)) or cutaneously, such as by formula (I), formula (I- A), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), or the free form of a radical of a compound of Table 1 (e.g., R is a negative charge or H ) is emitted. In a more specific example, when administered to an individual in the presence of an esterase and/or reductase, formula (I), formula (IA), formula (Ia), formula (Ia'), formula (Ib ), formula (Ic), formula (Id), or the active (free) form of the radical of Table 1 (e.g., R is negatively charged or H) (as well as keratolytic agents and/or (e.g., further hydration thereof) Upon degradation and/or reduction) the agent) which further produces the active keratolytic agent is rapidly released.

In some embodiments herein, formula (I), formula (IA), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), Provided is a compound or pharmaceutical composition comprising any compound provided herein, such as any one compound of Table 1, or a pharmaceutically acceptable salt thereof, having a keratolytic effect. (eg, reducing disulfide (SS) bonds) (eg, in any environment provided herein).

Some embodiments herein provide a method of treating inflammation and/or hyperkeratosis, comprising: treating an individual (e.g., in need of treatment) with any of the methods provided herein. Methods are provided that include administering (eg, in a therapeutically effective amount) a compound (eg, of any formula or table provided herein). In specific embodiments, the inflammation and/or hyperkeratosis is inflammation and/or hyperkeratosis of the eye, periocular structures (eg, eyelids), and/or skin.

Some embodiments herein provide a method of treating a skin or eye disease or disorder in an individual, comprising: formula (I), formula (IA), formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), any compound provided herein, such as a compound represented by any one of Table 1; or a pharmaceutically acceptable salt thereof. In some embodiments, the skin or eye disease or disorder is associated with keratosis, microbial infiltration, microbial infection, inflammation, or any combination thereof.

Some embodiments herein provide a method of treating a dermatological or ophthalmological disease or disorder in an individual, comprising: formula (I), formula (IA), Any compound provided herein, such as a compound represented by any one of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), Table 1 , or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, the dermatological or ophthalmological disease or disorder is inflammation or hyperkeratosis of the eye or skin (eg, ocular surface). In some embodiments, the dermatological or ophthalmological disease or disorder is meibomian gland dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft-versus-host disease, vernal keratoconjunctivitis, atopic keratoconjunctivitis. , Corneliya de Lange syndrome, evaporative eye disease, aqueous dry eye, blepharitis, and seborrheic blepharitis. In some embodiments, the dermatological or ophthalmological disease or disorder is, for example, meibomian gland dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft-versus-host disease, vernal keratoconjunctivitis, atopic cornea. Inflammation or hyperkeratosis (of the eye or skin, for example), such as conjunctivitis, Cornelilla de Lange syndrome, evaporative eye disease, tear-deficient dry eye, blepharitis, seborrheic blepharitis, or any combination thereof It is a disease.

In some embodiments, the ophthalmic disease or disorder is dry eye, lid wiper corneal epitheliopathy (LWE), contact lens discomfort (CLD), contact lens discomfort, dry eye syndrome, evaporative dry eye syndrome, lacrimal fluid Deficiency dry eye syndrome, blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland disorder, inflammation of the front of the eye, infection of the front of the eye, eyelid infection, Demodex eyelid infection, lid wiper corneal epitheliopathy, and autoimmune disorders of the anterior aspect of the eye.

Some embodiments herein provide a method of treating an ocular (e.g., periocular) or dermatological indication (e.g., related to keratolytic activity, inflammation, and/or microbial infiltration), comprising: Methods are provided comprising 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) is directed to the eye, surrounding tissue, or skin of a compound provided herein. in a therapeutically effective amount (eg, a concentration effective to treat keratosis/keratolytic activity, inflammation, and/or microbial infiltration). In some embodiments, a composition provided herein (eg, pharmaceutical and/or ophthalmic) comprises from about 0.1% to about 10% by weight of a compound provided herein.

In some embodiments, ocular and/or dermatological disorders include, for example, eyelids (e.g., stye, blepharitis, and chalazion), ocular surface (e.g., dry eye disease and anterior uveitis). ), and inflammatory diseases of the back of the eye (e.g., posterior and bilateral (pan) uveitis), abnormalities of the periocular glands (e.g., meibomian gland dysfunction (MGD)), diseases of the allergic type (e.g., eczema, atopy). surgical complications (e.g., corneal transplant rejection, post-keratotransplant glaucoma, cataract associated with phakic keratoplasty, corneal transplantation); Fungal infections in surgical patients and post-LASIK dry eyes and/or poor refractive outcomes), corneal abnormalities (e.g., inflammatory corneal ulcers, rheumatic corneal ulcers, and Thygeson superficial punctate keratitis) , conjunctival abnormalities (e.g., iridocyclitis, ligneous conjunctivitis), ocular complications due to systemic treatment and/or autoimmune diseases (e.g., oligoarticular juvenile rheumatoid arthritis, graft-versus-host disease, and Sjögren's disease). sjogren's syndrome) and/or infections of the front of the eye. Some embodiments herein provide compositions and methods for treating ocular and periocular abnormalities that have multifactorial etiologies and interactions.

INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned herein are herein incorporated by reference for the specific purpose identified herein.

Specific Definitions As used in this specification and the appended claims, the singular forms "a,""an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes one or more cells (or cells) and equivalents thereof. Contains references to objects, etc. When ranges are used herein that relate to a physical property, such as molecular weight, or a chemical property, such as a chemical formula, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be encompassed. intended. When referring to a number or range of numbers, the term "about" means that the number or range of numbers referred to is an approximation within experimental variation (or within statistical experimental error). As such, numbers or ranges of numbers may vary from 1% to 15% of the stated number or range of numbers. The term "comprising" (and related words such as "comprise,""comprises,""having," or "including") In certain embodiments, for example, any composition, composition, method, or process described herein "consists of" or "consists substantially of" the recited feature. is not intended to exclude that it may become.

As used herein, the terms "treat", "treating", or "treatment" refer to the treatment of a disease, disease state, in either chronic or acute treatment scenarios. sate) or symptoms associated with an indication (e.g., addiction, such as opioid addiction, or pain). Furthermore, treatment of diseases or conditions described herein includes disclosure of the use of the aforementioned compounds or compositions for the treatment of such diseases, conditions, or indications.

"Amino" refers to the _-NH2 radical.

"Cyano" refers to the -CN radical.

"Nitro" refers to the _-NO2 radical.

"Oxo" refers to the =O radical.

"Alkyl" generally refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, such as having from 1 to 15 carbon atoms (eg, C ₁ -C ₁₅ alkyl). Unless otherwise specified, alkyl is saturated or unsaturated (eg, alkenyl containing at least one carbon-carbon double bond). The disclosure of "alkyl" provided herein is intended to include independent recitation of saturated "alkyl" unless otherwise specified. The alkyl groups described herein are generally monovalent, but may also be divalent (sometimes also described herein as "alkylene" or "alkylenyl" groups). In certain embodiments, alkyl contains 1-13 carbon atoms (eg, C ₁ -C ₁₃ alkyl). In certain embodiments, alkyl contains 1-8 carbon atoms (eg, C ₁ -C ₈ alkyl). In other embodiments, alkyl contains 1-5 carbon atoms (eg, C ₁ -C ₅ alkyl). In other embodiments, alkyl contains 1-4 carbon atoms (eg, C ₁ -C ₄ alkyl). In other embodiments, alkyl contains 1-3 carbon atoms (eg, C ₁ -C ₃ alkyl). In other embodiments, alkyl contains 1-2 carbon atoms (eg, C ₁ -C ₂ alkyl). In other embodiments, alkyl contains 1 carbon atom (eg, C ₁ alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (eg, C ₅ -C ₁₅ alkyl). In other embodiments, alkyl contains 5 to 8 carbon atoms (eg, C ₅ -C ₈ alkyl). In other embodiments, alkyl contains 2-5 carbon atoms (eg, C ₂ -C ₅ alkyl). In other embodiments, alkyl contains 3 to 5 carbon atoms (eg, C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl). ), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Typically, each alkyl group is independently substituted or unsubstituted. Each listing of "alkyl" provided herein includes a specific and explicit listing of unsaturated "alkyl" groups, unless otherwise specified. Similarly, unless otherwise specified herein, an alkyl group includes the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 OR ^a (t is 1 or 2), -S(O) _t R ^a (t is 1 or 2), and -S(O) _t optionally substituted with one or more of N(R ^a ) ₂ (t is 1 or 2), each R ^a independently hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl); ), fluoroalkyl, carbocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted by 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).

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

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

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

"Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removal of a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems can contain hydrogen and carbon consisting of 5 to 18 carbon atoms, and at least one of the plurality of rings in the ring system It is completely unsaturated, ie it contains a cyclic delocalized (4n+2) π-electron system according to Huckel's theory. Ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indane, indene, tetralin, naphthalene, and other groups. Unless specifically stated otherwise herein, the term "aryl" or the prefix "ar-" (as in "aralkyl") is optionally substituted with one or more substituents. substituents are independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, any optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl , optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (t is 1 or 2), -R ^b -S(O ) _t R ^a (t is 1 or 2), -R ^b -S(O) _t OR ^a (t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (t is 1 or 2), and each R ^a 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 is independently a direct bond or a straight or branched alkylene or alkenylene chain. and R ^c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

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

"Carbocyclyl" or "cycloalkyl" means a non-aromatic monocyclic or polycyclic ring consisting exclusively of carbon and hydrogen atoms, containing fused or bridged ring systems, and having from 3 to 15 carbon atoms. refers to hydrocarbon radicals. In certain embodiments, carbocyclyl contains 3-10 carbon atoms. In other embodiments, the carbocyclyl contains 5-7 carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl can be saturated (contains only C-C bonds and no double or triple bonds between two carbons), or unsaturated (contains 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 referred to as "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), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. It will be done. Unless specifically stated otherwise herein, the term "carbocyclyl" is intended to include carbocyclyl radicals optionally substituted with one or more substituents, where the substituents are independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted Heteroarylalkyl substituted with, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N( R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C( O) R ^a , -R ^b -N(R ^a )S(O) _t R ^a (t is 1 or 2), -R ^b -S(O) _t R ^a (t is 1 or 2) ), -R ^b -S(O) _t OR ^a (t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (t is 1 or 2) and R ^a is each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (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 by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (halogen, hydroxy , methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or optionally substituted by trifluoromethyl), R ^b is each independently a direct bond, or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain; An alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

"Carboxylic acid,""COOH," or "(C=O)OH" refers to a radical of the formula -COOH. A recitation of "carboxylic acid,""COOH," or "(C=O)OH" provided herein each refers to an esterified "carboxylic acid,""COOH," or "(C=O)OH," unless otherwise specified. (C=O)OH" groups (eg, or radicals thereof). In some embodiments, the esterified carboxylic acid group (or radical thereof) is (C=O)O-C ₁ -C ₄ alkyl, where alkyl is as defined herein above. . In some embodiments, "carboxylic acid,""COOH," or "(C=O)OH" is COOH. In some embodiments, "carboxylic acid,""COOH," or "(C=O)OH" is (C=O)O-C ₁ -C ₄ alkyl.

"Carbocyclylalkyl" refers to a radical of the formula -R ^c -carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

"Carbocyclylalkenyl" refers to a radical of the formula -R ^c -carbocyclyl, where R ^c is an alkenylene chain as defined above. The alkenylene chain and carbocyclyl radical are optionally substituted as defined above.

"Carbocyclylalkoxy" refers to a radical attached through an oxygen atom of the formula -O-R ^c -carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

"Halo" or "halogen" refers to a fluoro, bromo, chloro, or iodo substituent.

"Haloalkyl" refers to an alkyl radical as defined above, substituted with one or more halogens as defined above, such as trihalomethyl, dihalomethyl, halomethyl, and the like. In some embodiments, haloalkyl is fluoroalkyl, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

The term "heteroalkyl" refers to an alkyl group, as defined above, in which one or more backbone carbon atoms of the alkyl are substituted with a heteroatom (with appropriate number of substituents or valences). For example, -CH ₂ - may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently replaced with a heteroatom, such as carbon being replaced with nitrogen, oxygen, sulfur, or other suitable heteroatom. In some examples, each substituted carbon atom is independently oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -NS(aryl)-, or as contemplated herein with another substituent), or with sulfur (eg, -S-, -S(=O)-, or -S(=O) ₂ -). In some embodiments, the heteroalkyl is attached to the remainder of the molecule at the heteroalkyl carbon atom. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at the heteroatom of the heteroalkyl. In some embodiments, heteroalkyl is C ₁ -C ₁₈ heteroalkyl. In some embodiments, heteroalkyl is C ₁ -C ₁₂ heteroalkyl. In some embodiments, heteroalkyl is C ₁ -C ₆ heteroalkyl. In some embodiments, heteroalkyl is C ₁ -C ₄ heteroalkyl. Representative heteroalkyl groups include, but are not limited to, -OCH ₂ OMe or -CH ₂ CH ₂ OMe. In some embodiments, heteroalkyl, as defined herein, includes alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl. include. Unless stated otherwise specifically herein, a heteroalkyl group is optionally substituted as defined above for an alkyl group.

"Heteroalkylene" refers to a divalent heteroalkyl group, as defined above, linking one part of the molecule to another part of the molecule. Unless otherwise specified, a heteroalkylene is optionally substituted as defined above for an alkyl group.

"Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, "heterocyclyl" and "heterocycloalkyl" are used interchangeably herein. Unless otherwise specified herein, heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, optionally fused or bridged ring systems. include. Heteroatoms in heterocyclyl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or fully saturated. Heterocyclyl radicals are saturated (ie, contain only C--C bonds) or unsaturated (eg, contain one or more double or triple bonds within the ring system). In some examples, the heterocyclyl radical is saturated (eg, dithiolanyl, dithiolanyl, or dithiolanyl oxide). In some examples, the heterocyclyl radical is saturated or partially saturated (eg, dithiolanyl oxide). In some instances, the heterocyclyl radical is unsaturated. Heterocyclyl is attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclyl radicals include dithiolanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, imithiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, Octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, Examples include, but are not limited to, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified herein, the term "heterocyclyl" is intended to include a heterocyclyl radical as defined above, optionally substituted with one or more substituents, and is alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted Heteroarylalkyl substituted with, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N( R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C( O) R ^a , -R ^b -N(R ^a )S(O) _t R ^a (t is 1 or 2), -R ^b -S(O) _t R ^a (t is 1 or 2) ), -R ^b -S(O) _t OR ^a (t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (t is 1 or 2) and R ^a is each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (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 by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (halogen, hydroxy , methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or optionally substituted by trifluoromethyl), R ^b is each independently a direct bond, or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain; An alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

"N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, where the point of attachment of the heterocyclyl radical to the remainder of the molecule is the nitrogen in the heterocyclyl radical. via atoms. 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.

"C-heterocyclyl" or "C-bonded heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, wherein the point of attachment of the heterocyclyl radical to the remainder of the molecule is Via a carbon atom.
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-, 3-, or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

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

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

"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 in which at least one ring in the ring system is completely unsaturated. That is, it contains a cyclic delocalized (4n+2) π-electron system according to Huckel's theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in heteroaryl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any ring atom. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1 , 4] dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl , benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[ d] pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 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-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1- Phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyrrolyl Lysinyl, pyrido [3 ,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl , 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3- d] pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2- d]pyrimidinyl, thieno[2,3-d]pyridinyl, and thiophenyl (ie, thienyl). Unless stated otherwise specifically herein, the term "heteroaryl" includes heteroaryl radicals as defined above, optionally substituted with one or more substituents. Substituents are intended to include alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally aralkenyl substituted with, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , - R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (t is 1 or 2), -R ^b -S(O) _t R ^a (t is 1 or 2), -R ^b -S(O) _t OR ^a (t is 1 or 2), and -R ^b -S(O) _t N(R ^a ) ₂ (t is 1 or 2), and each R ^a is independently selected from 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), , or optionally substituted with 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 is independently a direct bond or a straight or branched alkylene or alkenylene chain. , Rc is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

"N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, where the point of attachment of the heteroaryl radical to the remainder of the molecule is through the nitrogen atom in the heteroaryl radical. N-heteroaryl radicals are optionally substituted as described above for heteroaryl radicals.

"C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the remainder of the molecule is through a carbon atom in the heteroaryl radical. C-heteroaryl radicals are optionally substituted as described above for heteroaryl radicals.

"Heteroarylalkyl" refers to a radical of the formula -R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for alkylene chains. The heteroaryl portion of a heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

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

In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, such that enantiomers defined as (R) or (S) in terms of absolute stereochemistry, give rise to stereomers, and other stereoisomeric forms. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by this disclosure. If the compounds described herein contain an alkene double bond, and unless otherwise specified, the disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). . Similarly, all possible isomers, as well as racemic and optically pure forms, and all tautomers thereof are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer (eg, cis or trans) of an alkene double bond. The term "regioisomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

Typically, each optionally substituted group is independently substituted or unsubstituted. Each listing of optionally substituted groups provided herein refers to unsubstituted groups and substituted groups (e.g., substituted in certain embodiments, but not in others), unless otherwise specified. (not substituted in embodiments). Unless otherwise specified, substituted groups include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 OR ^a (t is 1 or 2), -S(O) _t R ^a (t is 1 or 2), and -S(O) _t N(R ^a ) ₂ (t is 1 or 2), and R ^a is each independently optionally substituted with hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl); ), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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 (halogen, hydroxy, methoxy) , or trifluoromethyl), heterocyclylalkyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any one of the pharmaceutical agents described herein is intended to encompass any and all pharmaceutically suitable salt forms. Exemplary pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effects and properties of the free base, are not biologically or otherwise unnecessary, and are salts containing hydrochloric, hydrobromic, sulfuric, or nitric acids. , formed by inorganic acids such as phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. They are also formed by organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids. salts 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, etc. Acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, Metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate Salts, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoates, phthalate, benzenesulfonate, toluene Examples include sulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Additionally, salts of amino acids such as alginate, gluconate, galacturonate, etc. are contemplated (e.g., "Pharmaceutical Salts" by Berge S.M. et al., Journal of Pharmaceutical Science, 66:1-19 (1997)). ). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art. be done.

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

Composition Meibomian glands are large sebaceous glands located in the eyelids that are distinct from the skin and are not associated with hair. The meibomian glands produce the lipid layer of the tear film, which protects the tear film from evaporation of the aqueous phase. The meibomian gland orifice is located on the epithelial side of the eyelid margin and can be several hundred microns from the mucosal side. Meibomian glands are found in both the upper and lower eyelids, and the amount of meibomian glands is greater in the upper eyelid. A meibomian gland is composed of a cluster of secretory acini arranged in a ring around a long central canal and connected to the central canal by short ducts. The distal end of the central canal is covered by an inwardly extending epidermis that covers the free lid margin and forms an orifice at the posterior part of the lid margin just anterior to the mucocutaneous transition near the inner lid border. Form a short discharge tube that opens. Oily secretions composed of lipids are synthesized within the secretory acini. Lipid secretions are liquid at near body temperature and are delivered to the skin at the eyelid margin as a clear fluid called "meibum." Lipid secretions form shallow reservoirs at the margins of the upper and lower eyelids and consist of mixed complexes of cholesterol, waxes, cholesterol esters, phospholipids, and small amounts of triglycerides, triacylglycerols, and hydrocarbons. The separate meibomian glands are arranged in parallel and in a line across the length of the tarsal plate in the upper and lower eyelids. The extent of the gland corresponds approximately to the dimensions of the tarsal plate.

As used herein, the term "keratotic occlusion" refers to blockage of the meibomian glands regardless of the location of the blockage. In some embodiments, the blockage is complete, while in other embodiments it is partial. Regardless of the degree of blockage, such keratotic occlusion causes meibomian gland dysfunction. In some embodiments, the keratotic occlusion is composed of keratinized material and lipid. In some embodiments, the keratotic occlusion is a blockage in the meibomian gland orifice and drainage canal. In some embodiments, the keratinization occlusion results from keratinization of the epithelium at the lid margin and meibomian glands. In certain instances, keratin obstruction is affected by stem cell migration or aberrant differentiation. In some embodiments, keratotic occlusion causes decreased delivery of oil to the lid margin and tear film, as well as increased blood pressure, resulting dilatation, atrophy of the acini, and decreased secretion within the meibomian glands. resulting in stasis. In certain instances, meibomian gland keratinization results in degenerative gland enlargement and atrophy.

Ocular surface diseases include dry eye syndrome (evaporative DES and/or tear-deficient DES), blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland disorders, contact lens-related diseases, and inflammation of the front surface of the eye. A group of diseases including, but not limited to, sexual, infectious, or autoimmune diseases or disorders. The term "meibomian gland dysfunction" as used herein refers to a chronic and widespread abnormality of the meibomian glands characterized by terminal duct obstruction, qualitative or quantitative changes in glandular secretion, or both. Point. MGD may result in tear film changes, ocular irritation, inflammation, or ocular surface disease. The most prominent aspects of MGD are obstruction of the meibomian gland orifices and terminal ducts and changes in meibomian gland secretion.

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

MGD is the main cause of dry eye syndrome. The occurrence of dry eye syndrome is widespread, affecting approximately 20 million patients in the United States alone. Dry eye syndrome is a disorder of the ocular surface due to either inadequate tear production or excessive evaporation of water from the ocular surface. Lacrimal fluid is important for corneal health because the cornea has no blood vessels and relies on lachrymal fluid for its oxygen and nutrient supply. Tears and the tear film are made up of lipids, water, and mucus, and destruction of any of these can result in dry eye. Inadequate amounts of lipid efflux from the meibomian glands, as occurs with keratinous occlusion, can result in excessive evaporation, thereby resulting in dry eye syndrome.

In some embodiments, alterations in meibomian gland secretion are detected by physically squeezing the meibomian glands by applying finger pressure to the tarsal plate. In subjects without MGD, meibum is a collection of clear oils. In MGD, both the quality and the expressibility of the squeezed material are altered. Meibum alterations, also known as meibomian gland excreta, consist of a mixture of altered secretions and keratinized epithelial material. In MGD, the quality of expressed lipids varies in appearance from a clear fluid to a viscous fluid containing particulate matter and thick, opaque, toothpaste-like materials. The meibomian gland orifice may exhibit a protuberance that exceeds the surface level of the eyelid; this protuberance is termed a plugging or pouting, leading to obstruction of the terminal canal and removal of meibomian gland lipids and keratinized material. This is due to extrusion of the mixture.

Obstructive MGD is characterized by: 1) chronic ocular discomfort; 2) anatomical abnormalities around the meibomian gland orifice (vascular hyperemia, anterior or posterior displacement of the mucocutaneous junction, or irregularity of the lid margin). 3) meibomian gland occlusion (slit-lamp biomicroscopy showing obstructed gland orifices (bulges, blockages, or bumps); moderate acupressure to reduce meibum squeezing); characterized in whole or in part.

Current methods for assessing and monitoring MGD symptoms include patient questionnaires, meibomian gland expression, tear stability breakdown time, and determination of the patient's gland count as determined by acupressure. but not limited to.

In some embodiments, a patient's symptoms are assessed by asking the patient a series of questions. Questionnaires allow assessment of the range of symptoms associated with ocular discomfort. In some embodiments, the survey is a SPEED survey. The SPEED questionnaire evaluates the frequency and severity of dry eye symptoms in patients. This questionnaire examines the occurrence of symptoms on the day, 72 hours later, and in the past 3 months. SPEED scores are aggregated based on the patient's responses to questions to provide a range of severity of the patient's symptoms. The SPEED questionnaire asks: 1) What dry eye symptoms occur and when? 2) How often do you experience dry, rough, or itchy eyes? 3) How often do you experience eye pain or irritation? 4) Questions include: how often do you have eye burns or watering, 5) how often do you have eye strain, and 6) how severe are your symptoms?

Meibomian gland aperture is optionally determined to assess meibomian gland function. Meibum in normal patients is a clear to pale yellow oil. When acupressure is applied to the glands, meibum is secreted from the glands. Changes in meibomian gland aperture are one of the possible MGD indications. In some embodiments, quantification of the amount of physical force applied during squeezing is monitored in addition to assessing lipid volume and lipid content.

Tear stability breakdown time (TBUT) is a surrogate marker of tear stability. Tear film instability is a central mechanism of dry eye and MGD. A short TBUT hints at lipid layer compromise and possible MGD. TBUT is optionally measured by examining the fluorescein breakdown time, defined as the time to the first breakdown that occurs in the tear film after blinking. Fluorescein is optionally applied by moistening a commercially available fluorescein-soaked strip with saline and applied to the inferior fornix or bulbar conjunctiva. The patient is then asked to blink several times and move their eyes. The fracture is then analyzed with a slit lamp, a cobalt blue filter, and a beam width of 4 mm. The patient is asked to blink and the time from the last blink upward movement to the first tear film breakdown or dry spot formation is recorded as a measurement.

Other methods for evaluating MGD symptoms include Schirmer test, ocular surface staining, eyelid morphology analysis, meibography, meibometry, interferometry, evaporimetry, tear lipid composition analysis, fluorescence analysis, and meniscometry ( meiscometry), osmolality analysis, tear film dynamics, evaporation, and tear turnover indicators.

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

Eyelid hygiene is considered the main treatment for MGD and consists of three components: 1) warm compresses, 2) mechanical massage of the eyelids, and 3) eyelid cleansing. Eyelid warming procedures improve meibomian gland secretion by melting the lipids of pathologically altered meibomian glands. Warming is accomplished with a hot compress or device. Mechanical lid hygiene methods include the use of scrubs, mechanical compression, and cleaning of the eyelashes and lid margins with various solutions. The lid margin is further optionally cleaned with a hypoallergenic bar soap, diluted infant shampoo, or a commercially available lid scrub. Physical expression of the meibomian glands can be performed in the hospital or by the patient at home. The technique ranges from light massage of the eyelids against the eyeballs, either against each other or with a rigid object on the inner eyelid surface and a finger, thumb, or rigid object (such as a glass rod, cotton swab, or metal paddle) on the outer eyelid surface. The symptoms range from one that forcibly tightens the eyelids. A rigid object on the inner eyelid surface protects the eyeball from the forces transmitted through the eyelid during squeezing and provides a stable resistance to increase the amount of force applied to the gland.

Lid warming is limited because heating melts the lipids, but does not address the movement of keratinized material. Additionally, eyelid warming causes temporary visual loss due to corneal distortion. Mechanical eyelid hygiene methods are also limited because the force required to dislodge the obstruction is considerable and can cause severe pain to the patient. The effectiveness of mechanical eyelid hygiene methods is limited by the patient's ability to tolerate associated pain during the procedure. Other treatments for MGD are limited.

Physical release of meibomian gland obstruction by meibomian gland expression is an acceptable method to improve meibomian gland secretion and dry eye symptoms. Additionally, meibomian duct probing has been used to open occluded ducts. However, both squeezing and probing methods are limited by the pain induced by the procedure, the possible physical invasion to the glandular and ductal structures, and the temporary effects estimated at days and weeks. . Therefore, there is a need for a method to improve patient comfort, which would not harm the meibomian glands and ducts, reduce dependence on frequent office visits, and improve meibum secretion.

U.S. Pat. No. 9,463,201, entitled "Compositions and methods for the treatment of meibomian grand dysfunction," discloses the use of a therapeutically effective amount of at least one keratolytic agent in an ophthalmically acceptable carrier. Methods for treating meibomian gland dysfunction are described, including topical administration. The patent describes keratolytic drugs that are inorganic selenium (Se) compounds, such as selenium disulfide (SeS ₂ ) or organic selenium compounds, such as ebselen (2-phenyl-1,2-benzoselenazol-3-one). is included. This drug would treat the underlying cause of MGD rather than the "plus" inflammatory disease as described by the DEWS report on MGD.

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 has a variety of causes, but one possible cause may be MGD (Nichols et al., 2011). In its earliest stages, MGD is not associated with the clinical features of posterior blepharitis. As MGD progresses, MGD-related posterior blepharitis is said to exist. MGD-related 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 eyelid inflammation. Hyperkeratosis of the meibomian gland epithelium (thickening of the lining of the gland) can lead to obstruction and reduced quality of meibomian gland secretion, and can also contribute to MGD-related posterior blepharitis. Diagnosis of MGD-associated posterior blepharitis includes meibomian gland squeezing due to demonstration of altered quality of expressed secretions and/or loss of glandular function (decreased squeezing or loss). The TFOS report on meibomian gland disease specifically notes that anterior blepharitis and exacerbated inflammatory ocular surface disease are "plus" diseases to MGD that are managed with topical ocular steroids. (Nichols et al., 2011). These "plus" diseases can be present in varying degrees of severity from early to late stages of MGD, and thus may target both the underlying non-inflammatory pathophysiology of MGD and the inflammation associated with these comorbidities. Treatment and/or combination treatment is required.

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 into inflamed tissues. T lymphocyte infiltration may result in lacrimal gland stimulation and cytokine upregulation. Exemplary cytokines that may be involved in MGD-related inflammatory eye diseases include interleukin 1, interleukin 4, interleukin 6, interleukin 8, interferon gamma, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha. , but not limited to. Kinase pathways, including the mitogen-activated protein kinase (MAPK) pathway, are also activated in the inflammatory cascade. This inflammatory process results in loss of mucin-producing goblet cells and destruction of the ocular surface that can cause further damage.

Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), is considered a self-sustaining disease that gradually separates from its initial cause. Dry eye syndrome is associated with inflammation of the ocular surface and periocular tissues. Inflammation is characterized by activation of T lymphocytes and migration into inflamed tissues, including tissues in the conjunctiva and lacrimal glands. Inflammatory cytokines, chemokines, and matrix metalloproteinases have also been identified as increased.

Animal models of dry eye disease have been established and investigated (Barabino et al. (Invest. Ophthalmol. Vis. Sci. 2004, 45:1641-1646)). Barabino et al. (Invest. Ophthalmol. Vis. Sci. 2005, 46:2766-2771) found that exposing normal mice to a low-humidity environment in a controlled environmental chamber reduced tear secretion, goblet cell density, and dry eye-related It has been described that significant changes in the acquisition of ocular surface signs are induced. However, no single animal model adequately represents the immune, endocrine, neuronal, and environmental factors that contribute to dry eye pathogenesis.

Anti-inflammatory agents can be used to treat ocular surface diseases or disorders, including dry eye syndrome. Corticosteroids are effective anti-inflammatory treatments for dry eye disease. For example, in a 4-week, double-blind, randomized trial of 64 patients with dry eyes and delayed tear clearance, loteprednol etabonate 0.5% ophthalmic suspension (Lotemax [Bausch and Lomb, Rochester, NY]) administered four times daily was found to be more effective than its vehicle in improving some signs and symptoms (Pflugfelder et al., Am J Ophthalmol (2004) ;138:444-57). The TFOS 2007 report on Dry Eye Disease has previously stated that ``under U.S. federal regulations, ophthalmic corticosteroids that receive 'classification labeling' are not suitable for obtaining the desired reduction in edema and inflammation, although the inherent risks of steroid use allergic conjunctivitis, erythema, superficial punctate keratitis, herpes zoster keratitis, iritis, cystitis, in the eyelids and bulbar conjunctiva, cornea and anterior superior segment of the eyeball, if accepted It is indicated for ``steroid-responsive inflammatory diseases'' such as infectious conjunctivitis. 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 Internat ional Dry Eye WorkShop (2007). 2007; 5:163-178). Although the US FDA disagrees with this conclusion, in the short term steroids, specifically Lotemax, may be used to treat the inflammation associated with dry eye disease.

Other anti-inflammatory agents include non-steroidal 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 regulation of inflammation and immunity. NSAIDs are sometimes used to treat dry eye disease by treating inflammation of the ocular surface.

Treatment of dry eye is also accomplished with drugs that enhance tear and mucin production. For example, agonists of _P2Y2 receptors have been shown to increase tear and mucin secretion. This mechanism is thought to involve _P2Y2 signaling that raises intracellular calcium and opens chloride channels in the apical cell membrane. _P2Y2 receptors belong to the family of purinergic receptors, which are classified into P1 and P2 receptors based on their innate agonism with purine nucleosides and purine and pyrimidine nucleotides, respectively. P2 receptors are further physiologically differentiated into two types: P2X receptors and P2Y receptors. P2Y receptors are involved in diver signaling, including platelet aggregation, immunity, lipid metabolism, and bone activity. Some studies have also demonstrated the presence of P2X and P2Y receptors in ocular tissues including the retina, ciliary body, and lens. These studies suggest that _P2Y2 receptors are the major subtype of purinergic receptors located on the ocular surface. _P2Y2 receptors have further been demonstrated to be located on goblet cells and serous cells of the conjunctival epithelium in ocular tissues, as well as on meibomian gland acinar cells and ductal epithelial cells of rhesus monkeys.

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 -Methyl α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl11-[[3,4,6 -trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecane-15-one, with the empirical formula C ₃₈ H ₇₂ N ₂ O ₁₂ . The structural formula is

It is.

Azithromycin acts by binding to the 50S ribosomal subunit of sensitive microorganisms and preventing microbial protein synthesis. In the topical ophthalmic environment, 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 group, or Streptococcus pneumoniae. Detailed information regarding azithromycin eye drops can be found, for example, in US Pat. No. 6,239,113, No. 6,569,443, or No. 7,056,893.

Included herein are non-inflammatory, keratolytic blocking components of meibomian gland dysfunction, and compounds (e.g., keratolytic conjugates and/or heavy-acting drugs) are described. In some embodiments, the compounds provided herein are administered for short-term treatment (e.g., by a trained professional or physician) or for administration (e.g., under the supervision of a patient, or alternatively, a trained Useful as either long-term treatment (by a specialist or physician). Compounds provided herein, in some embodiments, are tested using the assays and methods described herein (eg, those described in the Examples). In some embodiments, the compounds provided herein are useful in the art because the primary metabolism resulting from the metabolism of the drug acts against both the keratolytic and inflammatory components of dry eye disease. represents a major advance in

In some embodiments herein, formula (I):

A compound having the structure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate,
During the ceremony,
R ^Q is each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; at least one R ^Q is R ^N ;
R ^N is D-L ^a -;
D is a keratolytic drug;
L ^a is a linker,
A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate is provided.

In some embodiments, the compound is

It has the structure represented by .

In some embodiments herein, formula (IA):

A compound having the structure, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate,
During the ceremony,
R' is DL ^a -,
D is a keratolytic drug;
L ^a is a linker,
A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate is provided.

In some embodiments, L ^a includes one or more linker groups, each independently a bond, -O-, -S-, alkyl (alkylenyl), heteroalkyl (heteroalkyl (enyl), disulfide, ester, and carbonyl (>C=O). In some embodiments, the keratolytic agent comprises one or more of the groups described above (e.g., a keratolytic group, such as a group that confers keratolytic activity); are each independently selected from the group consisting of thiol, disulfide, selenium (eg, selenide, diselenide), carboxylic acid, or a group metabolizable to carboxylic acid.

In some embodiments, R' is alkyl or heteroalkyl substituted with at least one oxo and is further optionally substituted.

In some embodiments, R' is

or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate;
During the ceremony,
z is 1 to 6,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
R ¹² is H, alkyl, aryl, or heteroalkyl, and the alkyl, aryl, or heteroalkyl is optionally substituted.

In some embodiments, the alkyl or heteroalkyl of R ¹² is substituted with one or more substituents, each substituent being independently alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno. , selenol, sulfone, amide, halo, oxo, heterocyclyl, and cycloalkyl, where heterocyclyl and cycloalkyl are selected from the group consisting of (e.g., alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, sulfone, amide) , halo, and oxo).

In some embodiments, z is specified elsewhere herein.

In some embodiments, R ⁸ and R ⁹ are each specified separately herein.

In some embodiments herein, formula (Ia'):

or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R is substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl, where substituted alkyl is substituted with one or more alkyl substituents, and at least one alkyl substituent is independently substituted or unsubstituted. cycloalkyl and substituted heterocycloalkyl, the substituted heteroalkyl is substituted with one or more heteroalkyl substituents, and at least one heteroalkyl substituent is independently -COOH, substituted selected from the group consisting of heterocycloalkyl, and thioalkyl, wherein the substituted alkyl or substituted heteroalkyl is further optionally substituted;
A compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

In some embodiments herein, formula (Ia):

or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R is substituted (e.g., straight-chain or branched) alkyl, substituted (e.g., straight-chain or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., alkyl (further substituted with, e.g., oxo and thiol) (N-)substituted), substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -SH, substituted or unsubstituted (e.g., unsaturated) cycloalkyl, and dithiolanyl oxide, or substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents, and at least one (heteroalkyl) The substituents are independently selected from the group consisting of -SH, -COOH, and thioalkyl, wherein the substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl is further optionally substituted.
A compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

In some embodiments, L is a bond. In some embodiments, L is -(C=O)(OCR ⁸ R ⁹ ) _z - or -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, L is -(C=O)(OCR ⁸ R ⁹ ) _z -. In some embodiments, L is -(C=O)(OCR ⁸ R ⁹ ) _z O-. In some embodiments, z is 1-3. In some embodiments, z is 1. In some embodiments, R ⁸ and R ⁹ are each independently H or C ₁ -C ₃ alkyl. In some embodiments, each R ⁸ is H and each R ⁹ is C ₁ -C ₃ alkyl. In some embodiments, each R ⁸ is H and each R ⁹ is CH ₃ . In some embodiments, R ⁸ and R ⁹ are H. In some embodiments, L is -(C=O)OCH(CH ₃ )-. In some embodiments, L is -(C=O)OCH( _CH3 )O-.

In some embodiments, X is absent. In some embodiments, X is -O-.

In some embodiments, L is -(C=O)OCH( _CH3 )- or -(C=O)OCH( _CH3 )O- and X is absent or -O- be.

In some embodiments, L is -(C=O)OCH( _CH3 )- and X is absent.

In some embodiments, L is -(C=O)OCH( _CH3 )- and X is -O-.

In some embodiments, L is a bond and X is absent.

In some embodiments, R is a substituted (e.g., straight or branched) alkyl, and the (e.g., straight or branched) alkyl is substituted with one or more (alkyl) substituents; The substituents (alkyl) are each independently hydroxy, optionally substituted alkoxy (e.g., optionally substituted with oxo and hydroxy, or oxo and C ₁ -C ₃ alkoxy), oxo, optionally substituted with Substituted alkyl (e.g., optionally substituted by alkoxy optionally further substituted by oxo, C ₁ -C ₄ alkyl, and/or hydroxy), optionally substituted heterocycloalkyl (e.g., optionally substituted dioxane (e.g. 1,3-dioxanyl optionally substituted with methyl, dithiolanyl, or dithiolanyl oxide), hydroxyalkyl, thiol, acetamido, substituted unsaturated cycloalkyl (e.g. , substituted with one or more C ₁ -C ₄ alkyl), and amino.

In some embodiments, R is a substituted (e.g., straight or branched) alkyl, wherein the (e.g., straight or branched) alkyl is substituted with one or more (alkyl) substituents; alkyl) substituents are each independently thiol, amino, acetamido, substituted unsaturated cycloalkyl (e.g., substituted with one or more C ₁ -C ₄ alkyl), and substituted heterocycloalkyl ( for example, dithiolanyl oxide).

In some embodiments, R is a substituted alkyl, and the alkyl is substituted with a substituted heterocycloalkyl.

In some embodiments, R is substituted alkyl. In some embodiments, R is substituted alkyl, substituted alkyl is substituted with one or more alkyl substituents, and at least one alkyl substituent is substituted or unsubstituted cycloalkyl and substituted heterocycloalkyl. selected from the group consisting of. In some embodiments, R is a substituted alkyl, and the alkyl is substituted with a substituted heterocycloalkyl. In some embodiments, R is substituted alkyl and the alkyl is substituted with 1,2-dithiolanyl oxide. In some embodiments, R is a substituted alkyl, and the alkyl is a substituted C ₅ -C ₁₅ heterocycloalkyl (e.g., a C ₁₂ with one or more disulfides and one or amide within the heterocycloalkyl ring). C ₅ -C ₁₅ heterocycloalkyl is substituted with one or more substituents, and at least one substituent is independently C ₁ -C ₃ alkyl, oxo, and -COOH. In some embodiments, substituted alkyls are further optionally substituted.

In some embodiments, L is a bond, X is absent, and R is a substituted (e.g., straight or branched) alkyl, and the (e.g., straight or branched) alkyl is one or Substituted with multiple (alkyl) substituents, each (alkyl) substituent being independently thiol, amino, acetamido, substituted unsaturated cycloalkyl (e.g., one or more C ₁ -C ₄ alkyl) ), and substituted heterocycloalkyl (e.g., dithiolanyl oxide).

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is

and
During the ceremony,
R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl,
p is an integer from 1 to 10,
q is an integer from 1 to 3.

In some embodiments, q is 1 and p is an integer from 3 to 5.

In some embodiments, R ^4a and R ^4b are each H.

In some embodiments, R is

It is.

In some embodiments, R is substituted or unsubstituted (e.g., straight) containing one or more -C-O-C- (e.g., in the (e.g., straight or branched) heteroalkyl chain). heteroalkyl (chain or branched).

In some embodiments, R is one or more esters, one or more carbonates, one or more amides (e.g., in a heteroalkyl chain (e.g., linear or branched)), and and/or a substituted or unsubstituted (eg, straight or branched) heteroalkyl containing one or more disulfides.

In some embodiments, R is one or more esters (e.g., in a heteroalkyl chain (e.g., linear or branched)), one or more amides, and/or one or more Substituted (e.g., straight or branched) heteroalkyl containing disulfide.

In some embodiments, R is a substituted or unsubstituted (e.g., straight or branched) heteroalkyl containing one carbonate (e.g., within the (e.g., straight or branched) heteroalkyl chain). be.

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched) heterozygote containing one or two esters (e.g., in the (e.g., linear or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., straight or branched) heteroalkyl comprising one ester (e.g., within the (e.g., straight or branched) heteroalkyl chain). be.

In some embodiments, R is substituted or unsubstituted (e.g., straight or branched), including one ester and one carbonate (e.g., in the (e.g., straight or branched) heteroalkyl chain). ) is a heteroalkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched chain) heteroalkyl.

In some embodiments, R is substituted or unsubstituted (e.g., straight or branched), including one ester and one amide (e.g., in the (e.g., straight or branched) heteroalkyl chain). ) is a heteroalkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched) heterozygote containing one or two amides (e.g., in the (e.g., linear or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., straight or branched) heterozygote containing one or two disulfides (e.g., in the (e.g., straight or branched) heteroalkyl chain). It is an alkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., straight or branched) heteroalkyl containing one disulfide (e.g., within the (e.g., straight or branched) heteroalkyl chain) It is.

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched chain) heteroalkyl.

In some embodiments, R is a substituted or unsubstituted (e.g., linear or branched chain) heteroalkyl.

In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with one or more (heteroalkyl) substituents. and each (heteroalkyl) substituent is independently selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, acetamido, hydroxy, heterocycloalkyl, thiol, thioalkyl, amino, and carboxylic acid. be done.

In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with one or more (heteroalkyl) substituents. , (heteroalkyl) substituents are each independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., optionally substituted with a carboxylic acid).

In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with a substituted C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl is substituted with heteroalkyl optionally further substituted with one or more additional substituents, each additional substituent being independently hydroxy, carboxylic acid, optionally selected from the group consisting of substituted N-substituted pyrrolidinyl (eg, optionally substituted with a carboxylic acid);

In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with heterocycloalkyl. In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is 1,2-dithiolane, 1,2-dithiolane oxide, optionally substituted dioxane (e.g., optionally substituted with one or more C ₁ -C ₆ alkyl), (e.g., N-substituted) pyrrolidine (e.g., (e.g., oxo, thiol, and C _{1 )} -C ₃ alkyl, further substituted with alkyl), or substituted (eg, N-attached) pyrrolidine (eg, substituted with a carboxylic acid).

In some embodiments, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is substituted with acetamide and carboxylic acid.

In some embodiments, R is a substituted heteroalkyl, wherein the heteroalkyl is substituted with -COOH, _-CH SH, and/or an optionally substituted N-linked heterocycloalkyl, and one or more with other substituents, each substituent being independently selected from the group consisting of acetamido, amino, C ₁ -C ₆ alkyl, thiol, and oxo.

In some embodiments, R is a substituted heteroalkyl containing two disulfide bonds within the heteroalkyl chain, and the heteroalkyl is substituted with -COOH or a substituted N-linked heterocycloalkyl, and one or Further substituted with a plurality of other substituents, each substituent being independently selected from the group consisting of acetamido and C ₁ -C ₆ alkyl.

In some embodiments, R is a substituted heteroalkyl containing one disulfide bond within the heteroalkyl chain, and the heteroalkyl is substituted with acetamide, -COOH, and -SH.

In some embodiments, L is a bond, X is absent, R is a substituted (e.g., straight or branched) heteroalkyl, and one (e.g., straight or branched) heteroalkyl or substituted with multiple (heteroalkyl) substituents, each (heteroalkyl) substituent being independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted (eg, N-attached) heterocycloalkyl (eg, optionally substituted with a carboxylic acid);

In some embodiments, R is

and
During the ceremony,
R ⁵ is -SR ^1c ,
R ^1c is substituted alkyl or substituted heteroalkyl,
Alkyl is substituted with one or more alkyl substituents, each independently from carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted heterocycloalkyl. the heteroalkyl is substituted with one or more heteroalkyl substituents, each heteroalkyl substituent being independently selected from the group consisting of oxo, carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl;
R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,
R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ¹⁰ and R ¹¹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl,
s is an integer from 1 to 10.

In some embodiments, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are each H and s is 1-3.

In some embodiments, R ^1c is heteroalkyl substituted with carboxylic acid.

In some embodiments, R ^1c is alkyl substituted with one or more alkyl substituents, and each alkyl substituent is independently selected from the group consisting of carboxylic acid and acetamide.

In some embodiments, R ⁵ is

It is.

In some embodiments, R is

It is.

In some embodiments, R is a substituted branched heteroalkyl.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R-X-L is

It is.

In some embodiments, R is substituted heterocycloalkyl (eg, N-substituted with alkyl (eg, further substituted with oxo and thiol)).

In some embodiments, R is heterocycloalkyl N-substituted with alkyl, where the alkyl is further substituted with oxo and/or thiol.

In some embodiments, R is

It is.

In some embodiments, R comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA), Thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N - a radical of acetylcysteine (NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R comprises one or more radicals of keratolytic groups, each independently a radical of glycolic acid (GA), a radical of thioglycol Acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N-acetyl The radical is selected from the group consisting of cysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical.

In some embodiments, R comprises a thiol radical of one or more keratolytic groups, and each thiol radical of one or more keratolytic groups is independently a thiol of thioglycolic acid (TGA). Radical, thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetyl cysteine (NAC), thiol radical of cysteine (Cys), thiol radical of glutathione (GSH), captopril (Cap) ), and the thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap -Cap]・, [diHLip-Cap]・, [diHLip-Cys-Cys]・, [diHLip-Cys]・, [diHLip-Lipox-Lipox]・, and [diHLip-Lipox]・Ru.

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, diHLip-Cap-Cap]・, [diHLip- Cap]·, [diHLip-Cys-Cys]·, [diHLip-Cys]·, [diHLip-Lipox-Lipox]·, and [diHLip-Lipox]·.

Unless otherwise specified, a radical (or .) is a molecule with an unpaired electron. In some embodiments, the radical is a radical of a heteroatom (eg, -O., -N., or -S.). In some embodiments, radicals (eg, molecules with unpaired electrons) pair with other unpaired electrons of other molecules to form electron pairs. In some embodiments, a keratolytic agent radical provided herein is paired with any compound provided herein. In some embodiments, a first radical of a keratolytic agent provided herein is paired with a second radical of a keratolytic agent provided herein.

In some embodiments, the radical of the keratolytic group is the point at which R is attached to the remainder of the molecule. In some embodiments, each R (thiol radical) is independently attached to the remainder of the molecule to form a disulfide bond.

In some embodiments, R is

It is.

In some embodiments, R is

It is.

In some embodiments, R is a radical listed in Compound 1.

In some embodiments, R is a radical listed in Compound 2.

In some embodiments, R is a radical listed in Compound 3.

In some embodiments, R is a radical listed in Compound 4.

In some embodiments, R is a radical listed in compound 5.

In some embodiments, R is a radical listed in compound 6.

In some embodiments, R is a radical listed in compound 7.

In some embodiments, R is a radical listed in Compound 8.

In some embodiments, R is a radical listed in Compound 9.

In some embodiments, R is a radical listed in Compound 10.

In some embodiments, R is a radical listed in Compound 11.

In some embodiments, R is a radical listed in compound 12.

In some embodiments, R is a radical listed in compound 13.

In some embodiments, R is a radical listed in compound 14.

In some embodiments, R is a radical listed in compound 15.

In some embodiments, R is a radical listed in compound 16.

In some embodiments, R is a radical listed in compound 17.

In some embodiments, R is a radical listed in compound 18.

In some embodiments, R is a radical listed in compound 19.

In some embodiments, R is a radical listed in compound 20.

In some embodiments, R is a radical listed in compound 24.

In some embodiments, R is a radical listed in compound 25.

In some embodiments, R is a radical listed in compound 26.

In some embodiments, R is a radical listed in compound 28.

In some embodiments, R is a radical listed in compound 29.

In some embodiments, R is a radical listed in compound 31.

In some embodiments, R is a radical listed in compound 32.

In some embodiments, R is a radical listed in compound 33.

In some embodiments, R is a radical listed in compound 34.

In some embodiments, R is a radical listed in compound 35.

In some embodiments, R is a radical listed in compound 36.

In some embodiments, R is a radical listed in compound 37.

In some embodiments, R is a radical listed in compound 38.

In some embodiments, R is a radical listed in compound 40.

In some embodiments, R is a radical listed in compound 41.

In some embodiments, R is a radical listed in compound 42.

In some embodiments, R is a radical listed in compound 43.

In some embodiments, R is a radical listed in compound 44.

In some embodiments, R is a radical listed in compound 45.

In some embodiments, R is a radical listed in compound 46.

In some embodiments, R is a radical listed in compound 47.

In some embodiments, R is a radical listed in compound 48.

In some embodiments, R is a radical listed in compound 49.

In some embodiments, R is a radical listed in compound 50.

In some embodiments, R is a radical listed in compound 51.

In some embodiments, the compound has the structure:

It is other than a compound having

In some embodiments herein, formula (Ib):

or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
^Rx is

and
R ^1a and R ^1b are each independently -H or -SR ^1c ,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g. directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., one or more (heteroalkyl) each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) substituted with a substituent),
R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f each independently represent H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or two of R ^2a and R ^2b , R ^2c and R ^2d , or R ^2e and R ^2f together with the atoms to which they are bonded are C ₃ - forming _C5 cycloalkyl,
m is an integer from 1 to 10,
n and o are each independently an integer from 0 to 3,
A compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

In some embodiments herein, formula (Ib):

or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
^Rx is

and
R ^1a and R ^1b are each independently -H or -SR ^1c ,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g. directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., one or more (heteroalkyl) each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) substituted with a substituent),
R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f each independently represent H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or two of R ^2a and R ^2b , R ^2c and R ^2d , or R ^2e and R ^2f together with the atoms to which they are bonded are C ₃ - forming _C5 cycloalkyl,
m is an integer from 1 to 10,
n and o are each independently an integer of 1 to 3,
A compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

In some embodiments, o is 0.

In some embodiments, o is 0 and R ^x is

It is.

In some embodiments, o is 0 and n is 2.

In some embodiments, o is 0, n is 2, and R ^x is

It is.

In some embodiments, o is 0 and n is 1.

In some embodiments, o is 0, n is 1, and R ^x is

It is.

In some embodiments, m is an integer from 3 to 5.

In some embodiments, R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl It is. In some embodiments, R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each H.

In some embodiments, R ^x is

and
During the ceremony,
R ^1a and R ^1b are each independently -H or -SR ^1c ,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g., directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituents selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) ).

In some embodiments, R ^x is

and
During the ceremony,
R ^1a and R ^1b are each independently -H or -SR ^1c ,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g., directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituents selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) ).

In some embodiments, R ^1a is -H or -SR ^1c , R ^1b is -SR ^1c , or R ^1a is -SR ^1c and R ^1b is -H or -SR ^1c . . In some embodiments, R ^1a and R ^1b are each -SR ^1c .

In some embodiments, R ^1a and R ^1b each independently comprise a radical of one or more keratolytic groups (e.g., a radical of one or more keratolytic groups each independently , glycolic acid (GA) radical, thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, From the group consisting of dihydrolipoic acid (diHLip) radical, N-acetylcysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical selected).

In some embodiments, R ^1a and R ^1b are each independently a radical of one or more keratolytic groups, and the one or more radicals of keratolytic groups are each independently a glycol Acid (GA) radical, thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N-acetylcysteine (NAC) radical, cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical. Ru.

In some embodiments, R ^1a and R ^1b each independently include one or more keratolytic (thiol) radicals, and the one or more keratolytic (thiol) radicals are: Each independently, the (thiol) radical of thioglycolic acid (TGA), the (thiol) radical of thiolactic acid (TLac), the (thiol) radical of dihydrolipoic acid (diHLip), and the (thiol) radical of N-acetylcysteine (NAC). The radical is selected from the group consisting of the (thiol) radical of cysteine (Cys), the (thiol) radical of glutathione (GSH), the (thiol) radical of captopril (Cap), and the (thiol) radical of bucillamine (Buc).

In some embodiments, R ^1a and R ^1b are each independently a thiol radical of one or more keratolytic groups, and the thiol radicals of one or more keratolytic groups are each independently , thiol radical of thioglycolic acid (TGA), thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetylcysteine (NAC), thiol radical of cysteine (Cys), glutathione ( The thiol radical is selected from the group consisting of the thiol radical of GSH), the thiol radical of captopril (Cap), and the thiol radical of bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap -Cap]・, [diHLip-Cap]・, [diHLip-Cys-Cys]・, [diHLip-Cys]・, [diHLip-Lipox-Lipox]・, and [diHLip-Lipox]・Ru.

Unless otherwise specified, a radical (or .) is a molecule with an unpaired electron. In some embodiments, the radical is a radical of a heteroatom (eg, -O., -N., or -S.). In some embodiments, radicals (eg, molecules with unpaired electrons) pair with other unpaired electrons of other molecules to form electron pairs. In some embodiments, a keratolytic agent radical provided herein is paired with any compound provided herein. In some embodiments, a first radical of a keratolytic agent provided herein is paired with a second radical of a keratolytic agent provided herein.

In some embodiments, the thiol radical of the keratolytic group is the point at which R ^1a and/or R ^1b attach to the remainder of the molecule. In some embodiments, R ^1a and/or R ^1b are attached to the remainder of the molecule to form a disulfide bond.

In some embodiments, R ^1a and R ^1b are each independently -H, or

It is.

In some embodiments, R ^1a and R ^1b are the same. In some embodiments, R ^1a and R ^1b are different.

In some embodiments, R ^x is

and
During the ceremony,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g., directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituents selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) ).

In some embodiments, R ^x is

and
During the ceremony,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g., directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituents selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) ).

In some embodiments, each R ^1c is independently substituted or unsubstituted (e.g., straight or branched) alkyl or substituted or unsubstituted (e.g., straight or branched) heteroalkyl. . In some embodiments, each R ^1c is independently substituted (e.g., straight or branched) alkyl, or substituted (e.g., straight or branched) heteroalkyl.

In some embodiments, each R ^1c is independently a substituted (e.g., straight or branched) alkyl, and the substituted alkyl is substituted with one or more (alkyl) substituents; The substituents are each independently from the group consisting of carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted heterocycloalkyl (e.g., N-linked pyrrolidinyl substituted with -COOH) selected.

In some embodiments, each R ^1c is independently a substituted (e.g., straight or branched) heteroalkyl, and the substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents; (Heteroalkyl) substituents are each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl.

In some embodiments, R ^1a , R ^1b , and each R ^1c each independently includes one or more substituents that are carboxylic acids or esters. In some embodiments, R ^1a , R ^1b , and each R ^1c each independently include one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ^1a includes one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ^1b includes one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ^1b includes one or more substituents that are each independently a carboxylic acid (eg, -(C=O)OH). In some embodiments, R ^1a , R ^1b , and each R ^1c each independently include one or more substituents that are esters (e.g., -(C=O)O-C ₁ - _C4 alkyl). In some embodiments, R ^1a includes one or more substituents that are esters (eg, -(C=O)O-C ₁ -C ₄ alkyl). In some embodiments, R ^1b includes one or more substituents that are esters (eg, -(C=O)O-C ₁ -C ₄ alkyl). In some embodiments, R ^1b includes one or more substituents that are each independently an ester (eg, -(C=O)O-C ₁ -C ₄ alkyl).

In some embodiments, -(C=O)OH of R ^1a , R ^1b , and/or R ^1c is optionally esterified (e.g., -(C=O)OH or -(C= O) O-C ₁ -C ₄ alkyl). In some embodiments, C ₁ -C ₄ alkyl is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

In some embodiments herein, formula (Ic):

or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R ^y is

and
R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl,
p is an integer from 1 to 10,
q is an integer from 1 to 3;
A compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

In some embodiments, q is 1.

In some embodiments, p is an integer from 3 to 5. In some embodiments, p is 4. In some embodiments, q is 1 and p is 4.

In some embodiments, q is 1 and p is an integer from 3 to 5.

In some embodiments, R ^4a and R ^4b are each independently H or substituted or unsubstituted alkyl. In some embodiments, R ^4a and R ^4b are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl. In some embodiments, R ^4a and R ^4b are each H.

In some embodiments, R ^y is

It is.

In some embodiments, the sulfoxide of any compound provided herein is racemic. In some embodiments, the sulfoxides of any compounds provided herein are enantiomers. In some embodiments, the sulfoxide of any compound provided herein has a stereochemistry that is (R) or (S).

In some embodiments herein, formula (Id):

or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
^Rz is

and
R ⁵ is -SR ^1c ,
R ^1c is substituted or unsubstituted (e.g., straight chain or branched) alkyl (e.g., each independently carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted heterocycloalkyl) (e.g., N-linked pyrrolidinyl substituted with -COOH), or substituted or unsubstituted (e.g., straight-chain or branched) heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituents each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) ) and
R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,
R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ¹⁰ and R ¹¹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl,
s is an integer from 1 to 10,
A compound, or a pharmaceutically acceptable salt or solvate thereof, is provided.

In some embodiments, R ⁶ and R ⁷ are each independently H or substituted or unsubstituted alkyl (eg, C ₁ -C ₃ alkyl optionally substituted with oxo). In some embodiments, R ⁶ and R ⁷ are each independently H or C ₁ -C ₃ alkyl optionally substituted with oxo. In some embodiments, R ⁶ and R ⁷ are each independently H or -(C=O)CH ₃ . In some embodiments, R ⁶ is H and R ⁷ is H or -(C=O)CH ₃ . In some embodiments, R ⁶ is H and R ⁷ is -(C=O)CH ₃ . In some embodiments, R ⁶ and R ⁷ are H.

In some embodiments, R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl. In some embodiments, R ¹⁰ and R ¹¹ are each H.

In some embodiments, s is 1-3. In some embodiments, s is 1. In some embodiments, s is 1 and R ¹⁰ and R ¹¹ are H.

In some embodiments, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are each H and s is 1-3.

In some embodiments, R ^1c is substituted alkyl or substituted heteroalkyl.

In some embodiments, R ^1c is heteroalkyl substituted with carboxylic acid.

In some embodiments, R ^1c is alkyl substituted with one or more alkyl substituents, and each alkyl substituent is independently selected from the group consisting of carboxylic acid and acetamide.

In some embodiments, R ^1c is a substituted heteroalkyl, the heteroalkyl is substituted with one or more heteroalkyl substituents, and each heteroalkyl substituent is independently oxo, carboxylic acid, amino , thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl. In some embodiments, R ^1c is heteroalkyl substituted with carboxylic acid.

In some embodiments, R ^1c is substituted heteroalkyl, and the heteroalkyl is substituted with -COOH and oxo. In some embodiments, R ^1c is substituted heteroalkyl, and the heteroalkyl is substituted with oxo and acetamide. In some embodiments, R ^1c is substituted heteroalkyl, and heteroalkyl is substituted with C ₁ -C ₃ alkyl, oxo, and substituted N-linked heterocycloalkyl. In some embodiments, R ^1c is a substituted heteroalkyl, and the heteroalkyl is substituted with -COOH, C ₁ -C ₃ alkyl, oxo, and thiol.

In some embodiments, R ⁵ comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA) , thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, a radical of N-acetylcysteine (NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).

In some embodiments, R ⁵ is a radical of one or more keratolytic groups, and the one or more radicals of keratolytic groups are each independently a radical of glycolic acid (GA), a radical of thiolytic acid, Glycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N- The radical is selected from the group consisting of an acetylcysteine (NAC) radical, a cysteine (Cys) radical, a glutathione (GSH) radical, a captopril (Cap) radical, and a bucillamine (Buc) radical.

In some embodiments, each R ⁵ independently comprises one or more keratolytic (thiol) radicals, and the one or more keratolytic (thiol) radicals are each independently (thiol) radical of thioglycolic acid (TGA), (thiol) radical of thiolactic acid (TLac), (thiol) radical of dihydrolipoic acid (diHLip), (thiol) radical of N-acetylcysteine (NAC), cysteine. (Cys) (thiol) radical, glutathione (GSH) (thiol) radical, captopril (Cap) (thiol) radical, and bucillamine (Buc) (thiol) radical.

In some embodiments, R ⁵ is a thiol radical of one or more keratolytic groups, and each thiol radical of one or more keratolytic groups is independently a thiol radical of thioglycolic acid (TGA). Thiol radical, thiol radical of thiolactic acid (TLac), thiol radical of dihydrolipoic acid (diHLip), thiol radical of N-acetyl cysteine (NAC), thiol radical of cysteine (Cys), thiol radical of glutathione (GSH), captopril ( The thiol radical is selected from the group consisting of the thiol radical of Bucillamine (Buc), and the thiol radical of Bucillamine (Buc).

In some embodiments, the (e.g., thiol) radical of the keratolytic agent comprises a (e.g., thiol) radical of one or more keratolytic groups; ) radicals are each independently [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap -Cap]・, [diHLip-Cap]・, [diHLip-Cys-Cys]・, [diHLip-Cys]・, [diHLip-Lipox-Lipox]・, and [diHLip-Lipox]・Ru.

In some embodiments, the thiol radical of the keratolytic group is the point at which R ⁵ is attached to the remainder of the molecule. In some embodiments, R ⁵ is attached to the remainder of the molecule to form a disulfide bond.

In some embodiments, R ⁵ is

It is.

In some embodiments, R ^z is

It is.

In some embodiments, R ⁷ is H or -(C=O)CH ₃ . In some embodiments, ^R7 is H. In some embodiments, R ⁷ is -(C=O)CH ₃ .

In some embodiments, each R ^1c is independently substituted or unsubstituted (e.g., straight or branched) alkyl or substituted or unsubstituted (e.g., straight or branched) heteroalkyl. . In some embodiments, each R ^1c is independently substituted (e.g., straight or branched) alkyl, or substituted (e.g., straight or branched) heteroalkyl.

In some embodiments, each R ^1c is independently a substituted (e.g., straight or branched) alkyl, and the substituted alkyl is substituted with one or more (alkyl) substituents; The substituents are each independently from the group consisting of carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted heterocycloalkyl (e.g., N-linked pyrrolidinyl substituted with -COOH) selected.

In some embodiments, each R ^1c is independently a substituted (e.g., straight or branched) heteroalkyl, and the substituted heteroalkyl is substituted with one or more (heteroalkyl) substituents; (Heteroalkyl) substituents are each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl.

In some embodiments, R ⁵ and each R ^1c each independently include one or more substituents that are carboxylic acids or esters. In some embodiments, R ⁵ and each R ^1c each independently include one or more substituents that are carboxylic acids (eg, -(C=O)OH). In some embodiments, R ⁵ and each R ^1c each independently include one or more substituents that are esters (e.g., -(C=O)O-C ₁ -C ₄ alkyl) .

In some embodiments, -(C=O)OH of R ⁵ and/or R ^1c is optionally esterified (e.g., -(C=O)OH or -(C=O)O- C ₁ -C ₄ alkyl). In some embodiments, C ₁ -C ₄ alkyl is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

In some embodiments herein, a compound having the structure provided in Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer is provided.

Provided herein,

Unless otherwise specified, each listing is

Contains a specific and explicit listing of

The compounds used in the reactions described herein are made according to organic synthesis techniques starting from commercially available chemicals and/or from compounds described in the chemical literature or this disclosure. "Commercially available chemicals" are commercially available from Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, 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.S.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA) from standard commercial sources.

Suitable reference books and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing this preparation include, for example, "Synthetic Organic Chemistry"; John Wiley & Sons, Inc. , New York, S. R. "Organic Functional Group Preparations" by Sandler et al., 2nd Ed. , Academic Press, New York, 1983, H. O. "Modern Synthetic Reactions" by House, 2nd Ed. , W. A. Benjamin, Inc. Menlo Park, Calif. 1972, T. L. "Heterocyclic Chemistry" by Gilchrist, 2nd Ed. , John Wiley & Sons, New York, 1992, J. "Advanced Organic Chemistry: Reactions, Mechanisms and Structure" by John March, 4th Ed. , Wiley-Interscience, New York, 1992. Other suitable reference books and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing the preparation include, for example, Fuhrhop, J.; and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials" by John Wiley & Sons, Second, Revised and Enlarged Edition (1994) ISBN: 3-527-29074-5, Hoffman, R. V. "Organic Chemistry, An Intermediate Text" (1996) by Oxford University Press, ISBN 0-19-509618-5, Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19 031-4, March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) by 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) by 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: Sta. ting 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 Grou John Wiley & Sons, in 73 volumes.

Specific and similar reactants are optionally identified through indexes of chemical products prepared by the American Chemical Society's Chemical Abstracts Service, available through most public and university libraries as well as online databases (for more information) (Please contact the American Chemical Society, Washington, DC.) Chemicals that are not commercially available in the catalog are optionally prepared by special chemical synthesis facilities, so many of the standard chemical supply facilities (such as those listed above) offer specialized chemical synthesis services. providing. References for the preparation and selection of pharmaceutical salts of the keratolytic conjugates described herein include P. H. Stahl & C. G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

In some embodiments, the compounds provided herein have formula (I), formula (IA), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), A compound represented by formula (Id) or any one of Table 1. In some embodiments, compounds provided herein are administered as pure chemicals. In other embodiments, the compounds provided herein can be administered by a selected route of administration and as described, for example, in Remington: The Science and Practice of Pharmacy, Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005). A pharmaceutically suitable or acceptable carrier (herein referred to as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) carrier, selected on the basis of standard pharmaceutical practice as described in ) excipients or physiologically suitable (or acceptable) carriers).

Some embodiments herein provide pharmaceutical compositions comprising at least one keratolytic conjugate along with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is not deleterious to the recipient (ie, subject) of the composition.

In some embodiments, a compound provided herein (e.g., Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic) . Substantially pure in that it contains less than about 5%, less than about 1%, or less than about 0.1% small molecules.

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

In some embodiments herein, compounds provided herein (e.g., Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib) , formula (Ic), formula (Id), or any one of Table 1) and at least one pharmaceutically acceptable excipient. Ru. In some embodiments, the pharmaceutical composition is suitable for ocular administration. In some embodiments, the pharmaceutical composition is suitable for topical ocular administration. In some embodiments, topical ocular administration is into and/or around the eye, such as at the lid margin. In some embodiments, topical ocular administration is to the ocular surface and inner surface of the eyelid.

In some embodiments, the keratolytic conjugates provided herein (e.g., Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), or any one of Table 1) is formulated as a solution or suspension for topical administration to the eye.

In some embodiments, the keratolytic conjugates provided herein (e.g., Formula (I), Formula (IA), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id), or any one of Table 1) are formulated for administration by injection. In some instances, injectable formulations are aqueous formulations. In some instances, injectable formulations are non-aqueous formulations. In some examples, the injectable formulation is an oil-based formulation, such as sesame oil.

In some embodiments, the dosage of a composition comprising at least one keratolytic conjugate provided herein depends on the condition of the patient (e.g., human), i.e., general health, age, and other factors. Varies depending on.

The pharmaceutical compositions provided in some embodiments herein are administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose, and appropriate duration and frequency of administration, will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, appropriate doses and treatment regimens will determine clinical benefits such as therapeutic and/or preventive benefits, such as more frequent complete or partial remissions, longer disease-free survival and/or overall survival, or decreased severity of symptoms providing the composition in an amount sufficient to provide (improved outcome). Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends on the patient's body type, weight, or blood volume.

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

Methods of Treatment Utilizing Keratolytic Conjugates Some embodiments herein provide methods of treating a dermatological or ophthalmological disease or disorder in a patient in need thereof, comprising: (IA), formula (Ia), formula (Ia'), formula (Ib), formula (Ic), formula (Id), or any one of Table 1 herein. or a (e.g., pharmaceutical) composition comprising any compound provided herein or a pharmaceutically acceptable salt thereof. A method is provided that includes administering to a patient. In some embodiments provided herein, the pharmaceutical composition is in the form of a solution or suspension suitable for topical ocular administration. In some embodiments, topical ocular administration is into and/or around the eye, such as at the lid margin. In some embodiments, topical ocular administration is to the ocular surface and inner surface of the eyelid.

In some embodiments, the dermatological or ophthalmological disease or disorder is inflammation (eg, of the eye or skin) or hyperkeratosis. In some embodiments, the dermatological or ophthalmological disease or disorder is inflammation or hyperkeratosis of the eye or skin (eg, ocular surface). In some embodiments, the dermatological or ophthalmological disease or disorder is meibomian gland dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft-versus-host disease, vernal keratoconjunctivitis, atopic keratoconjunctivitis. , Corneliya de Lange syndrome, evaporative eye disease, aqueous dry eye, blepharitis, and seborrheic blepharitis. In some embodiments, the dermatological or ophthalmological disease or disorder is, for example, meibomian gland dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft-versus-host disease, vernal keratoconjunctivitis, atopic cornea. Inflammation or hyperkeratosis (of the eye or skin, for example), such as conjunctivitis, Cornelilla de Lange syndrome, evaporative eye disease, tear-deficient dry eye, blepharitis, seborrheic blepharitis, or any combination thereof It is a disease.

In some embodiments, the ophthalmic disease or disorder is dry eye, lid wiper corneal epitheliopathy (LWE), contact lens discomfort (CLD), dry eye syndrome, evaporative dry eye syndrome, tear deficiency dry eye syndrome selected from the group consisting of: blepharitis, keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland disorders, contact lens related diseases and inflammation of the front of the eye, infections of the front of the eye, and autoimmune disorders of the front of the eye be done.

Provided herein is a method of treating an ocular surface disorder in an individual in need thereof, the method comprising topical administration of a keratolytic conjugate to the individual in need of treatment. Ru. In some embodiments, administration is with the assistance of a health care professional (eg, this category includes both short-term and maintenance use of keratolytic conjugates). In some embodiments, short-term use requires a more potent keratolytic conjugate (either in terms of concentration or intrinsic activity of the drug). In some embodiments, sustained use allows for the use of lower concentrations of drugs with less intrinsic activity. In some embodiments, maintenance use requires the patient to visit a health care professional on a regular basis. Both short-term and maintenance use optionally require the use of eye protection devices or equipment. In some embodiments, short-term use is performed by a health care professional and maintenance use is performed by a patient or non-health care professional. In some embodiments, administration is not performed with the active assistance of a health care professional (eg, requires the patient to administer the keratolytic conjugate to his or her eyelid margin). In some embodiments, such administration is over an extended period of time (eg, chronic use is one way to describe the multiple dosage form administered to the patient). In some embodiments, a different or second keratolytic conjugate formulation is used for chronic or patient-administered use. In some embodiments, a different or second formulation utilizes a lower concentration of keratolytic conjugate. In some embodiments, a different or second formulation utilizes a less active keratolytic conjugate than the first formulation.

It is to be understood that the methods of the invention further include physical removal of meibomian gland obstruction (eg, following chronic and/or maintenance administration of a keratolytic conjugate provided herein).

Some embodiments herein provide a method of treating meibomian gland dysfunction in a patient in need thereof, comprising: administering a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier. A method is provided comprising locally administering to a patient a composition comprising: In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier enhances meibum production.

In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier is performed until keratotic occlusion is alleviated. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier is performed periodically after reduction of keratotic occlusion. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier is a single administration. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier is periodic administration. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier is performed once daily. In some embodiments, topical administration of a composition comprising a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable 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 ophthalmically acceptable carrier is more than twice daily.

In some embodiments, the composition for topical administration comprises a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and is a solution. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and are solutions suitable for topical administration as eye drops. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier, such as a gel, ocular insert, spray, or other topical ocular delivery. It's a method. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and are semisolid. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and are homogeneous. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and are a dispersion. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and are hydrophilic. In some embodiments, a composition for topical administration comprises a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and includes an oleaginous base. In some embodiments, compositions for topical administration include a therapeutically effective amount of at least one keratolytic conjugate in an ophthalmically acceptable carrier and at least one ophthalmically acceptable excipient. include.

In some embodiments herein, a method of treating MGD in a patient in need thereof, the method comprising topical administration of a composition comprising a keratolytic conjugate. A method is provided. In some embodiments, topical administration of a composition comprising a keratolytic conjugate is performed once a week. In some embodiments, topical administration of a composition comprising a keratolytic conjugate is twice weekly. In some embodiments, topical administration of a composition comprising a keratolytic conjugate is performed every other day. In some embodiments, topical administration of the composition includes a keratolytic conjugate and is done daily. In some embodiments, topical administration of the composition includes a keratolytic conjugate and is performed several times a day.

In some embodiments, the methods include administering a compound or formulation provided herein in a short-term treatment scenario. In some embodiments, the method includes treatment of a treatment-naïve patient. In some embodiments, the methods include administering a compound or formulation provided herein in a chronic treatment scenario. In some embodiments, the methods include administering a compound or formulation provided herein in a maintenance therapy scenario. In short-term treatment scenarios, the dosage of keratolytic conjugate may be higher than the keratolytic conjugate utilized in long-term treatment or maintenance therapy scenarios. In short-term treatment scenarios, the keratolytic conjugate may be different from the keratolytic conjugate utilized in long-term treatment scenarios. In some embodiments, the treatment period begins early in the treatment as a short-term treatment scenario and then transitions to a long-term treatment scenario or maintenance therapy scenario. In some embodiments, the meibomian gland opening drug administered in a short-term treatment scenario is a keratolytic and/or keratoplastic agent, and the drug administered in a long-term treatment scenario or maintenance therapy scenario. is a keratolytic conjugate.

In some embodiments, the initial treatment first unblocks the meibomian glands, such as by placing a higher concentration formulation of one of the keratolytic conjugates provided herein. administered to an individual (e.g., by a physician or health care worker) for purposes of treatment. If higher concentration formulations are required, their administration may require ocular shielding or other actions to minimize irritating or destructive effects on the ocular surface or surrounding tissue. After such a procedure, the patient may receive different keratolytic conjugate formulations to take home and administer periodically to the lid margin to maintain meibomian gland patency. Such administration may occur twice daily, once daily, weekly, or monthly, depending on the formulation activity and therapeutic product profile of the formulation.

Some embodiments of the treatment methods described herein provide a site for topical administration of the composition. In some embodiments, compositions comprising keratolytic conjugates are administered in a manner that does not cause eye irritation. In some embodiments, a composition comprising a keratolytic conjugate is administered to the eyelid margin.

Another embodiment of the treatment methods provided herein is the use of protective elements placed on the eye to avoid eye irritation. Although the formulations described herein are generally non-irritating, in some embodiments (e.g., with high drug concentrations, or during sensitive ophthalmic use), protective elements are important for patient safety. Provides an extra layer for comfort and comfort. In some embodiments, an eye shield is placed on the eye to reduce contact of the pharmaceutical agent to the cornea and/or conjunctiva to reduce eye irritation while the composition comprising the keratolytic conjugate is administered. will be arranged. In some embodiments, the eye shield is a contact lens or an eye cover. In some embodiments, the eye cover includes a self-adhesive. In some embodiments, while a composition comprising a keratolytic conjugate is administered, the eyelid is pulled away from the eyeball so that the medicament contacts the cornea and/or conjunctiva to reduce irritation to the eye.

While exemplary embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be available in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

I. Chemical Synthesis Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise stated. All reactions were performed at room temperature unless otherwise specified. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures or the present disclosure.

Abbreviations The following abbreviations are used in the examples and elsewhere herein.
AcOH: Acetic acid CDCl ₃ : Deuterated chloroform COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate CV: Column volume DBU: 1,8-diazabicyclo[ 5,4,0]undec-7-ene DCM: dichloromethane DIPEA: N,N-diisopropylethylamine D ₂ O: deuterium oxide DMF: N,N-dimethylformamide DMSO-d6: deuterated dimethyl sulfoxide DPBS: Dulbeccoline Acid-buffered saline EtOAc: ethyl acetate h: time HCl: hydrochloric acid LCMS: liquid chromatography mass spectrometry MS: moles MeCN; acetonitrile MeOH: methanol MgSO ₄ : magnesium sulfate mins: minutes N ₂ : nitrogen Na ₂ SO ₄ : sodium sulfate NH ₄ Cl: ammonium chloride r. t: Room temperature RT: Holding time s: Second sat. : Saturated TEA: Triethylamine THF: Tetrahydrofuran vac: Vacuum

analysis method:
Method A: 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% 2.3 mL/min, 3.51 min 0% 2.3 mL/min, 4.0 min 0% 2.25mL/min.

Method B: Waters Sunfire C18 5 μm 100 x 4.6 mm, A = water + 0.1% formic acid, B = MeCN + 0.1% formic acid, 45°C, %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.

Method C: Phenomenex Luna C18 (2) 3 μm, 50 x 4.6 mm, A = water + 0.1% formic acid, B = MeOH + 0.1% formic acid, 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% 2.3 mL/min, 3.51 min 5% 2.3 mL/min min, 4.0 min 5% 2.25 mL/min.

Method D: 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 20% 2.2 mL/min, 3.0 min 50% 2.2 mL/min, 3.25 min 95% 2.2 mL/min, 3.50 min 95% 2.3 mL/min, 3.51 min 100% 2.30 mL/min, 4.0 min 100% 2.25 mL/min.

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

Method F: Waters CSH C18 1.7 μm 100 x 2.1 mm, A = water + 0.1% formic acid, B = MeCN, 45 °C, %B: 0.05 min 5% 0.35 mL/min, 5.00 min 95% 0.35 mL/min, 6.60 min 5% 0.35 mL/min. 8.00 minutes finished.

Chemical substance synthesis example 1:
Method 1:

Step 1: Methyl 2-((tert-butyldiphenylsilyl)oxy)acetate

To a stirred solution of methyl glycolate (0.77 mL, 10.0 mmol) in anhydrous DMF (14 mL) was added imidazole (803 mg, 11.8 mmol) and tert-butylchlorodiphenylsilane (3.12 mL, 12.0 mmol), The mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was diluted with DCM and washed with ice water. The organic layer was dried (MgSO ₄ ) and the solvent was evaporated under vacuum to give the crude product, which was purified by flash chromatography (Biotage SP1, 100 g SNAP cartridge) and purified with isohexane → 10% EtOAc- Elution with isohexane gave the title compound as a colorless oil (3.26g, 99%). LCMS (Method A): Rt = 3.50 min; [M+Na]+ = 351.2. ¹ H-NMR (400 MHz, CDCl ₃ ) 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)

Step 2: 2-((tert-butyldiphenylsilyl)oxy)acetic acid

0.75 M lithium hydroxide (aq. ) (4.06 mL, 3.05 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water (10 mL) and extracted with Et2O (3 x 20 mL). The aqueous phase was diluted with 5M HCl Acidified with _(aq) to pH 3 and the solution extracted with EtOAc (3 x 20 mL). The combined organics were dried ( _MgSO4 ), filtered and the solvent was evaporated under vacuum.The crude product was Purification by flash chromatography (Biotage SP1, 25g SNAP cartridge), eluting with isohexane→EtOAc, afforded the title compound as a colorless oil (0.65g, 68%). LCMS (Method A): Rt= 2.77 minutes, [MH] ⁻ = 313.3. ¹ H-NMR (400 MHz, CDCl ₃ ) δ7.61-7.66 (m, 4H), 7.39-7.47 (m, 6H ), 4.22 (s, 2H), 1.08-1.12 (m, 9H).

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

To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (97 mg, 0.308 mmol) and azithromycin dihydrate (291 mg, 0.370 mmol) in toluene (15 mL) was added TEA (155 μL, 1.11 mmol) at room temperature. ), 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 diluted with DCM (10 mL), saturated NaHCO _{3 (aq)} , and H ₂ O (10 mL) and the layers were separated. The aqueous phase was extracted with DCM (3 x 10 mL). The combined organics were dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge), eluting with 4:1 isohexane-acetone (1% TEA) → acetone (1% TEA), which was 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. Fractions containing the desired product were combined, diluted with DCM, and neutralized with saturated NaHCO _(aq) . The organic layer was separated and the aqueous phase was extracted with DCM. The combined organics were washed with saturated brine solution, dried ( _MgSO4 ) and evaporated under vacuum to give the title compound as a colorless gum (40mg, 12%). LCMS (Method A): Rt = 1.72 min; [M+H] ⁺ = 1046.0

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- hydroxy acetate

(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-((tert To a stirred solution of -butyldiphenylsilyl)oxy)acetate (40 mg, 0.0383 mmol) in anhydrous THF (1.0 mL) was added a THF solution of 1M tetrabutylammonium fluoride hydrate (115 μL, 0.115 mmol) under _N2 . was added. The reaction was stirred at room temperature for 2 hours, then quenched with saturated NaHCO _(aq) and extracted with EtOAc. The organic layer was washed with saturated brine solution and the layers were separated. The organic phase was dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage SP1, 10 g SNAP cartridge) and the title compound was obtained as a white solid (12 mg, 39% ) was obtained. LCMS (Method B): Rt = 3.04 min; [M+H] ⁺ =807.9.

Method 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 -Hydroxypropanoate

This reaction was performed using the following flow settings. A solution of L-(+)-lactic acid (0.24 mL, 3.18 mmol) and DIPEA (0.67 mL, 3.82 mmol) in DCM (10 mL) (flow rate: 2.0 mL/min), and triphosgene (0.5 mL/min). A solution of 15 g, 0.510 mmol) in DCM (6 mL) (flow rate: 1.2 mL/min) was introduced into T-mixer 1 at room temperature using a syringe pump. The resulting mixture was passed through reaction tube 1 (inner diameter: 0.8 mm, length: 54 mm, volume: 27 mL, reaction time: 0.5 seconds) at room temperature. The resulting mixture and a solution of azithromycin dihydrate (1.00 g, 1.27 mmol) in DCM (10 mL) (flow rate: 2.0 mL/min) were introduced into T-mixer 2 at room temperature. The resulting mixture was passed through reaction tube 2 (inner diameter: 0.8 mm, length: 742 mm, volume: 373 mL, reaction time: 4.3 seconds) at room temperature. After 55 seconds, the resulting mixture was collected, diluted with DCM (25 mL), and washed with saturated NH ₄ Cl _(aq) (8 x 30 mL). The combined organics were washed with saturated brine solution (20 mL), dried (MgSO ₄ ), filtered and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 25 g Sfar cartridge), eluting with 8:2 isohexane-acetone (1% TEA) → acetone (1% TEA) to give (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-hydroxypropanoate (227 mg, 22%) was obtained as a white solid. LCMS (Method D): Rt = 1.73 min; [M+H] ⁺ =821.6.

Chemical substance synthesis example 2:
Method A:
(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 5-((3R )-2-oxide-1,2-dithiolan-3-yl)pentanoate and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate

(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 5-((R )-1,2-dithioran-3-yl)pentanoate (1.50 g, 1.60 mmol) was stored under vacuum in the dark (vacuum oven) at 30° C. for 2 weeks. Over this time approximately 10% of the various sulfoxide isomers were generated. The crude material was purified by flash chromatography (Biotage SP1, 25 g SNAP cartridge), eluting with 3:1 isohexane-acetone (1% TEA) → acetone to give (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 5-((3R)-2-oxide-1,2-dithiolane -3-yl)pentanoate, and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate (103 mg, 3%) was obtained as a white solid. LCMS (Method A): Rt = 1.60 min; [M+H] ⁺ =953.7.

Method B:
(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 5-((3R )-2-oxide-1,2-dithiolan-3-yl)pentanoate and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate

5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoic acid and 5-((3R)-2-oxide-1,2-dithiolan-3-yl)pentanoic acid (0. 73 g, 3.27 mmol), azithromycin (1.87 g, 2.50 mmol), and 1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (3.74 g, 8 .74 mmol) was dissolved in anhydrous DCM (25 mL). DIPEA (2.5 mL, 14.3 mmol) was added and the mixture was stirred at 30° C. for 20 hours. The mixture was diluted with DCM (40 mL) and the solution was washed successively with saturated NH ₄ Cl _(aq) (2 x 60 mL) and saturated brine solution (50 mL). The organic phase was dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography, eluting with isohexane (1% TEA) → 3:1 isohexane-acetone (1% TEA) to give the title product (1.45 g, 58%) as a viscous Obtained as an orange oil. LCMS (Method A): Rt = 2.14 min; [M+H] ⁺ =953.6.

Chemical substance synthesis example 3:
Step 1: (R)-2,2-dimethylthiazolidine-4-carboxylic acid

A suspension of L-cysteine (2.00 g, 16.0 mmol) in anhydrous acetone (50 mL) was stirred at reflux under nitrogen atmosphere for 18 hours. The reaction mixture was cooled to room temperature, filtered through a Celite cartridge, concentrated to about 50% of its original volume, and then allowed to stand at room temperature. After 4 hours, the mother liquor was decanted. The solid was further washed with acetone (10 mL) and then dried under vacuum to yield (R)-2,2-dimethylthiazolidine-4-carboxylic acid (2.29 g, 89%) as a white solid. Ta. LCMS (Method A): Rt = 0.53 min; [M+H] ⁺ = 162.1. ¹ H-NMR (400MHz, D2O) δ4.47 (dd, J=8.0, 7.3Hz, 1H), 3.50 (dd, J=12.1, 8.0Hz, 1H), 3.35 (dd, J=12.4, 7.3Hz, 1H), 1.70 (s, 3H), 1.69 (3s, 3H).

Step 2: (R)-3-acetyl-2,2-dimethylthiazolidine-4-carboxylic acid

(R)-2,2-dimethylthiazolidine-4-carboxylic acid (500 mg, 3.10 mmol) was dissolved in acetone (30 mL). Acetic anhydride (0.60 mL, 6.20 mmol) was added in one portion and the mixture was stirred at room temperature for 10 minutes. DBU (0.93 mL, 6.20 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NH ₄ Cl _(aq) (50 mL) and EtOAc (30 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 30 mL), the combined organics were dried ( _MgSO4 ), filtered and the solvent was evaporated under vacuum. The aqueous phase was acidified with 2M HCl and the solution was extracted with EtOAc (3x30 mL). The combined organics were dried (MgSO ₄ ), filtered and the solvent was evaporated under vacuum. (R)-3-acetyl-2,2-dimethylthiazolidine-4-carboxylic acid (350 mg, 56%) was obtained as a white solid. LCMS (Method E): Rt = 5.70 min; [MH] ^- = 204.3. ^1H -NMR (400MHz, acetone-D6) δ11.52 (br s, 1H), 5.09 (dd, J=6.0, 0.9Hz, 1H), 3.41 (dd, J=11. 9, 6.0Hz, 1H), 3.30 (dd, J=11.9, 1.4Hz, 1H), 2.02 (s, 3H), 1.83 (s, 3H), 1.79 ( s, 3H).

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-yl(R )-3-acetyl-2,2-dimethylthiazolidine-4-carboxylate

(R)-3-acetyl-2,2-dimethylthiazolidine-4-carboxylic acid (100 mg, 0.490 mmol), azithromycin (380 mg, 0.490 mmol), and COMU (737 mg, 1.72 mmol) were dissolved in anhydrous THF ( 10 mL). DIPEA (0.50 mL, 2.95 mmol) was added and the mixture was stirred at room temperature under _N2 for 18 h. The mixture was diluted with EtOAc (50 mL) and the solution was washed with saturated NH ₄ Cl _(aq) (3 x 20 mL), dried (MgSO ₄ ), filtered and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage SP1, 25 g Sfar cartridge), eluting with isohexane→3:1 isohexane-acetone (1% TEA). (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)-3 -Acetyl-2,2-dimethylthiazolidine-4-carboxylate (250 mg, 54%) was obtained as a white solid. LCMS (Method E): Rt = 5.43 min; [M+H] ⁺ =934.9. ¹ H-NMR (400 MHz, CDCl ₃ ) δ5.07 (d, J = 4.8 Hz, 1H), 4.74 (dd, J = 10.5, 7.3 Hz, 1H), 4.68 (td, J=6.2, 2.4Hz, 1H), 4.58 (d, J=7.3Hz, 1H), 4.26 (q, J=2.3Hz, 1H), 4.11-4.21 (m, 1H), 4.00-4.07 (m, 1H), 3.63-3.70 (m, 2H), 3.49-3.54 (m, 1H), 3.30-3 .38 (m, 3H), 3.22-3.26 (m, 1H), 3.05 (t, J=9.8Hz, 1H), 2.84 (s, 1H), 2.62-2 .79 (m, 2H), 2.48-2.57 (m, 1H), 2.33 (d, J = 15.6Hz, 3H), 2.23-2.29 (m, 1H), 2 .20 (d, J=10.1Hz, 4H), 2.12 (d, J=10.1Hz, 1H), 1.87-2.06 (m, 6H), 1.85 (d, J= 6.9Hz, 2H), 1.35-1.75 (m, 4H), 1.29-1.34 (m, 4H), 1.25 (t, J=5.7Hz, 4H), 1. 21 (d, J = 6.9Hz, 3H), 1.13-1.16 (m, 1H), 1.06-1.10 (m, 4H), 0.85-0.94 (m, 6H ).

Chemical substance synthesis example 4:
Step 1: 3-acetyl-2-methylthiazolidine-4-carboxylic acid

To a solution of 2-methyl-1,3-thiazolidine-4-carboxylic acid (300 mg, 2.04 mmol) in anhydrous acetone (30 mL) under an atmosphere _of N was added acetic anhydride (0.39 mL, 4.08 mmol) followed by DBU. (0.61 mL, 4.08 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. Water (30 mL) was added and the mixture was stirred for 10 minutes. The mixture was extracted with EtOAc (2 x 30 mL) and the combined organics were washed with saturated brine solution (30 mL), dried (MgSO ₄ ), filtered and the solvent was evaporated under vacuum to obtain 3-acetyl -2-Methylthiazolidine-4-carboxylic acid (212 mg, 55%) was obtained as a yellow oil. LCMS (Method C): Rt = 1.271.31 min; [M+H] ⁺ = no ions of apparent mass. ¹ H-NMR (400 MHz, CDCl ₃ ) δ8.48 (br s, 2H), 5.08-5.41 (m, 1H), 4.70-4.90 (m, 1H), 3.02- 3.49 (m, 2H), 2.00-2.18 (m, 3H), 1.48-1.69 (m, 3H).

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 3- Acetyl-2-methylthiazolidine-4-carboxylate

3-Acetyl-2-methyl-thiazolidine-4-carboxylic acid (50 mg, 0.264 mmol), azithromycin (204 mg, 0.264 mmol), and COMU (396 mg, 0.925 mmol) were dissolved in anhydrous THF (20 mL). . DIPEA (0.28 mL, 1.59 mmol) was added and the mixture was stirred at room temperature under _N2 for 18 hours. The mixture was diluted with _EtOAc (50 mL _{) ,} washed with sat. (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 3-acetyl-2-methylthiazolidine-4-carboxylate (104 mg, 43%) was obtained as an off-white solid. LCMS (Method C): Rt = 1.96 min; [M+H] ⁺ =920.7.

Chemical substance synthesis example 5:
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-ylN- (((9H-fluoren-9-yl)methoxy)carbonyl)-S-(tert-butyl)-L-cysteinate

Azithromycin (1.88 g, 2.50 mmol), COMU (3.75 g, 8.76 mmol), and DIPEA (2.60 mL, 15.0 mmol) were dissolved in anhydrous DCM (50 mL). N-Fmoc-(R)-2-amino-3-(S-tert-butyl)propanoic acid (1.00 g, 2.50 mmol) was added and the mixture was stirred at 30° C. for 2 hours. The solution was diluted with DCM (50 mL) and the solution was washed with saturated NH ₄ Cl _(aq) (2 x 30 mL). The organic phase was dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage Isolera four, 50 g Sfar cartridge), eluting with 95:5 isohexane-acetone (1% TEA) → 65:35 isohexane-acetone (1% TEA). and (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-ylN-( ((9H-fluoren-9-yl)methoxy)carbonyl)-S-(tert-butyl)-L-cysteinate (1.35 g, 45%) was obtained as a yellow oil. LCMS (Method A): Rt = 2.02 min; [M+H] ⁺ = 1131.3.

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-ylS- (tert-butyl)-L-cysteinate

(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-ylN-((( 9H-fluoren-9-yl)methoxy)carbonyl)-S-(tert-butyl)-L-cysteinate (1.35 g, 1.19 mmol) was dissolved in DMF (20 mL). Piperidine (5.00 mL, 50.6 mmol) was added and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated under vacuum and then dried in a vacuum oven at 40° C. for 16 hours. Crude (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-ylS-( tert-butyl)-L-cysteinate (3.14 g) was obtained as a yellow solid without further purification. LCMS (Method A): Rt = 1.57 min; [M+H] ⁺ =909.0.

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-ylN- Acetyl-S-(tert-butyl)-L-cysteinate

Crude (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-ylS-( tert-Butyl)-L-cysteinate (1.00 g) was dissolved in anhydrous acetone (18 mL). DBU (0.160 mL, 1.10 mmol) was added in one portion and the mixture was stirred at room temperature for 10 minutes. Acetic anhydride (0.100 mL, 1.10 mmol) was added dropwise over 2 minutes. The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue was diluted with EtOAc (25 mL) and saturated NH ₄ Cl _(aq) (25 mL). The mixture was stirred at room temperature for 10 minutes and the layers were separated. The organic phase was dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage Isolera four, 50 g Sfar cartridge), eluting with 9:1 isohexane-acetone (1% TEA) → 6:4 isohexane-acetone (1% TEA). (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 N-acetyl- S-(tert-butyl)-L-cysteinate (650 mg, 56%) was obtained as a white solid. LCMS (Method A): Rt = 1.60 min; [M+H] ⁺ =950.8.

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-ylN- Acetyl-S-((2-nitrophenyl)thio)-L-cysteinate

2-Nitrobenzenesulfenyl chloride (40.5 mg, 0.210 mmol) was suspended in acetic anhydride (4.20 mL), and (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 N-acetyl-S-(tert-butyl)-L-cysteinate (200-400 mg, 0.210 ~0.420 mmol) was added. The mixture was stirred at room temperature for 30 minutes. Evaporation of the solvent under vacuum yielded the crude (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 N-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate (180-375 mg) was obtained as an orange oil. Purification was not attempted. LCMS (Method A): Rt = 1.62 min; [M+H] ⁺ = 1047.7.

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-ylacetyl-L - Cysteinate

Method 1: In a solution of thioglycolic acid (10.0 μL, 0.0900 mmol) in acetone (1 mL), crude (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 N-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate (180 mg, 0.0300 mmol), and DIPEA (10 μL, 0.0573 mmol) was added. The resulting suspension was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage Isolera four, 10 g SNAP cartridge), eluting with 9:1 isohexane-acetone (1% TEA) → 6:4 isohexane-acetone (1% TEA). and (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-ylacetyl-L- Cysteinate (5.0 mg, 2%) was obtained as a yellow solid. LCMS (Method A): Rt = 1.53 min; [M+H] ⁺ =894.7.

Method 2: Add (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 N-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate (375 mg, 0.358 mmol), and TEA (110 μL, 0.789 mmol) was added. The solvent was evaporated under vacuum and the resulting orange oil was purified by reverse phase preparative HPLC. To each fraction containing purified, pure target material, water (10 mL), DCM (10 mL), and potassium acetate (0.300 g) were immediately added and the layers were separated. The organic phase was dried (Na ₂ SO ₄ ), filtered and the filtrates were combined. By evaporating the solvent under vacuum, (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-ylacetyl-L-cysteinate (79 mg, 21%) was obtained as a white solid. LCMS (Method A): Rt = 1.54 min; [M+H] ⁺ =894.6.

Chemical substance synthesis example 6:
Step 1: ((R)-2-methyl-3-(tris(4-methoxyphenyl)-l4-sulfaneyl)propanoyl)-L-proline

Captopril (0.500 g, 2.30 mmol) was dissolved in DCM (8 mL) and 4,4',4''-trimethoxytrityl chloride (0.850 g, 2.30 mmol) was added under _N2 . TEA (0.430 mL, 3.06 mmol) was added dropwise and the solution was stirred at room temperature for 1.5 hours. Water (5 mL) was added and the layers were separated (phase separator). The aqueous phase was diluted with saturated NH ₄ Cl _(aq) (15 mL) and extracted with DCM (15 mL). The combined organics were dried (MgSO ₄ ), filtered and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage Isolera Four, 25 g Sfar cartridge), eluting with DCM→95:5 DCM-MeOH to give ((R)-2-methyl-3-(Tris). (4-Methoxyphenyl)-l4-sulfanayl)propanoyl)-L-proline (1.03 g, 88%) was obtained as an orange solid. LCMS (Method A): Rt = 2.95 min; [MH] ^- = 548.7.

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-Methyl-3-(tris(4-methoxyphenyl))-l4-sulfanayl)propanoyl)-L-prolinate

Azithromycin (681 mg, 0.910 mmol), COMU (1.36 g, 3.18 mmol), and DIPEA (0.950 mL, 5.46 mmol) were dissolved in anhydrous DCM (45 mL). ((R)-2-Methyl-3-(tris(4-methoxyphenyl)-l4-sulfanayl)propanoyl)-L-proline (500 mg, 0.910 mmol) was added and the mixture was stirred at room temperature for 5 days. The mixture was diluted with DCM (25 mL) and the solution was washed with saturated NH ₄ Cl _(aq) (2 x 30 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage Isolera Four, 25 g Sfar cartridge), eluting with 95:5 isohexane-acetone (1% TEA) → 60:40 isohexane-acetone (1% TEA). and (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-Methyl-3-(tris(4-methoxyphenyl))-l4-sulfanayl)propanoyl)-L-prolinate (960 mg, 60%) was obtained as an orange solid. LCMS (Method A): Rt = 2.06 min; [M+H] ⁺ = 1280.9.

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-yl(( R)-3-mercapto-2-methylpropanoyl)-L-prolinate

(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-Methyl-3-(tris(4-methoxyphenyl))-l4-sulfanayl)propanoyl)-L-prolinate (960 mg, 0.570 mmol) and triethylsilane (0.270 mL, 1.71 mmol) were dissolved in anhydrous DCM ( 25 mL). Chloroacetic acid (3.95 g, 41.8 mmol) was added and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with DCM (20 mL), water (25 mL), and triethylamine (5 mL) at 0°C. The organic phase was washed with triethylamine diluted with water (25 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage Isolera Four, 25 g SFar cartridge), eluting with 95:5 isohexane-acetone (1% TEA) → 60:40 isohexane-acetone (1% TEA). and (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 )-3-Mercapto-2-methylpropanoyl)-L-prolinate (31 mg, 6%) was obtained as a white solid. LCMS (Method A): Rt = 2.30 min; [M+H] ⁺ =948.8. ¹ H-NMR (400 MHz, CDCl ₃ ) δ5.06 (d, J = 4.8 Hz, 1H), 4.55-4.75 (m, 1H), 4.43 (d, J = 7.3 Hz, 1H), 3.95-4.36 (m, 3H), 3.66 (t, J=6.6Hz, 2H), 3.51 (dd, J=15.3, 6.2Hz, 1H), 3.28-3.37 (m, 4H), 3.15-3.28 (m, 1H), 3.02 (t, J=10.1Hz, 1H), 2.53-2.85 (m , 4H), 2.38-2.53 (m, 2H), 2.24-2.38 (m, 9H), 1.40-2.23 (m, 13H), 1.01-1.39 (m, 33H), 0.79-0.95 (m, 9H).

Chemical substance synthesis example 7:
[(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-azacyclopentadec-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl](2E,4E,6E,8E )-3,7-dimethyl-9-(2,6,6-trimethylcyclohexan-1-yl)nona-2,4,6,8-tetraenoate

Azithromycin (500 mg, 0.668 mmol), COMU (1.00 g, 2.34 mmol), and DIPEA (0.700 mL, 4.02 mmol) were dissolved in anhydrous DCM (15 mL). Retinoic acid (all-trans) (201 mg, 0.668 mmol) was added and the mixture was stirred at 30° C. for 20 hours. The mixture was diluted with DCM (15 mL) and washed with saturated NH ₄ Cl _(aq) (2 x 15 mL). The organic phase was dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (Biotage Isolera Four, 25 g Sfar cartridge), eluting with 95:5 isohexane-acetone (1% TEA) → 60:40 isohexane-acetone (1% TEA); It was further purified by flash chromatography (Biotage Isolera Four, 10 g Sfar cartridge), eluting with 95:5 isohexane-acetone (1% TEA) → 70:30 isohexane-acetone (1% TEA). (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-azacyclopentadec-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl] (2E, 4E, 6E, 8E) -3,7-dimethyl-9-(2,6,6-trimethylcyclohexan-1-yl)nona-2,4,6,8-tetraenoate (25 mg, 4%) was obtained as a yellow solid. LCMS (Method A): Rt = 2.30 min; [M+H] ⁺ = 1032.0.

Chemical substance synthesis example 8:
Step 1: N-acetyl-S-(pyridin-2-ylthio)-L-cysteine

2,2'-Dipyridyl disulfide (1.10 g, 4.90 mmol) and N-acetyl L-cysteine (400 mg, 2.45 mmol) were dissolved in 1:1 H ₂ O-MeOH (6.8 mL). The solution was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum and the crude product was purified by flash chromatography, eluting with DCM→75:25 DCM-MeOH to give N-acetyl-S-(pyridin-2-ylthio)-L- Cysteine (386 mg, 55%) was obtained as a yellow oil. LCMS (Method A): Rt = 1.60 min; [M+H] ⁺ =273.2.

Step 2: S-(((R)-2-acetamido-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-yl)oxy)-3-oxopropyl)thio)-N-acetyl-L-cysteine

To a solution of N-acetyl-S-(pyridin-2-ylthio)-L-cysteine (15.2 mg, 0.0600 mmol) in chloroform (2.0 mL), TEA (10 μL, 0.060 mmol) and (2S,3R ,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-tri Hydroxy-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-ylacetyl-L-cysteinate (25.0 mg, 0.030 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under vacuum and the crude product was purified by reverse phase preparative HPLC. Fractions containing the product are frozen (-78°C) and the solvent is evaporated under vacuum (lyophilization) to produce S-(((R)-2-acetamido-3-(((2S,3R) ,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-tri Hydroxy-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)-3-oxopropyl) Thio)-N-acetyl-L-cysteine (10 mg, 34%) was obtained as a white solid. LCMS (Method A): Rt = 2.20 min; [M+H] ⁺ = 1055.9.

Chemical substance synthesis example 9:
Step 1: Ethyl N-acetyl-L-cysteinate

N-acetyl L-cysteine (470 mg, 2.88 mmol) was dissolved in ethanol (15 mL) and the reaction mixture was degassed with N ₂ and then cooled to 0°C. Thionyl chloride (210 μL, 2.88 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 4 hours. The solvent was evaporated under vacuum and the mixture was diluted with water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organics were dried (MgSO ₄ ), filtered and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (Biotage Isolera Four, 100 g KPSil column) to release ethyl N-acetyl-L-cysteinate by eluting with 75:25 isohexane-EtOAc→15:85 isohexane-EtOAc. Obtained as a pale yellow oil, which was crystallized after prolonged drying (vacuum oven) to give the title compound as a white solid (180 mg, 33%). ¹ H-NMR (400 MHz, CHCl ₃ ) δ6.47 (d, J = 5.7 Hz, 1H), 4.79-4.85 (m, 1H), 4.16-4.28 (m, 2H) , 2.78-3.22 (m, 2H), 2.03 (s, 3H), 1.17-1.36 (m, 4H).

Step 2: Ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate

2,2'-dipyridyl disulfide (1.98 g, 4.90 mmol) and ethyl (2R)-2-acetamido-3-sulfanyl-propanoate (0.195 g, 1.02 mmol) in a 1:1 mixture of water-MeOH (6.8 mL). The solution was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum and the crude product was purified by reverse phase preparative HPLC. Fractions containing the product were concentrated under reduced pressure to yield ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate (135 mg, 43%) as a colorless oil. LCMS (Method A): Rt = 1.96 min; [M+H] ⁺ =301.1.

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-ylS- (((R)-2-acetamido-3-ethoxy-3-oxopropyl)thio)-N-acetyl-L-cysteinate

To a solution of ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate (15.0 mg, 0.050 mmol) in chloroform (2.0 mL) were added TEA (10 μL, 0.060 mmol) and (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-ylacetyl-L-cysteinate (15.0 mg , 0.0168 mmol) was added. The mixture was stirred at room temperature for 28 hours. Evaporation of the solvent under vacuum gave the crude product as a yellow oil, which was purified by reverse phase preparative HPLC. DCM (10 mL) and potassium acetate (0.50 g) were added to each fraction containing the desired product. (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-ylS-(((R)-2-acetamido-3-ethoxy-3-oxopropyl)thio)-N- Acetyl-L-cysteinate (3.5 mg, 19%) was obtained as a white solid. LCMS (Method A): Rt. =1.57 minutes; [M+H] ⁺ =1083.9.

Chemical substance synthesis example 10:
(2R,2'R)-3,3'-(((R)-8-((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)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-acetamidopropanoic acid)

(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 5-((3R )-2-oxide-1,2-dithiolan-3-yl)pentanoate and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0600 mmol) was dissolved in THF. (15 mL). N-acetyl-L-cysteine (41.1 mg, 0.250 mmol) was added and the mixture was stirred at room temperature under N ₂ for 48 h. The solvent was evaporated under vacuum and the crude product was purified by reverse phase preparative HPLC. Fractions containing the desired product were combined and the solution was passed through a catch release cartridge (Biotage Isolute® NH2, 1 g) and washed with MeCN (2 CV). The wash was passed through a second catch release cartridge (Biotage Isolute® NH2, 1 g) and washed with MeCN (2 CV). Both cartridges were then eluted with 95:5 MeCN-AcOH (2CV), the solutions combined, frozen (-78°C), and the solvent evaporated under vacuum (lyophilization) to yield (2'S). -((2R,2'R)-3,3'-(((R)-8-((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)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-acetamidopropanoic acid) (14 mg, 15%) was obtained as a white solid. LCMS (Method A): Rt = 1.66 min; [M+H] ⁺ = 1262.2.

Chemical substance synthesis example 11:
(2'S)-((2R,2'R)-3,3'-(((R)-8-(((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)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis( 2-methylpropanoyl)) di-L-proline

(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 5-((3R )-2-oxide-1,2-dithiolan-3-yl)pentanoate and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol) was dissolved in anhydrous THF (15 mL). Captopril (82 mg, 0.378 mmol) was added and the mixture was stirred at room temperature for 2 weeks. The solvent was evaporated under vacuum and the crude product was purified by reverse phase preparative HPLC. Fractions containing the desired product were combined, the solution was passed through a catch-release cartridge (Biotage Isolute NH2, 1 g), washed with MeCN (2 CV), and the product was eluted with 95:5 MeCN-AcOH (2 CV). did. The eluate was frozen (-78°C) and the solvent was evaporated (lyophilized) under vacuum to produce (2'S)-((2R,2'R)-3,3'-(((R) -8-(((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)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-methylpropanoyl))di-L-proline (15.0 mg, 17%) as a white solid. Obtained. LCMS (Method A): Rt = 1.93 min; [M+H] ⁺ = 1369.8.

Chemical substance synthesis example 12:
(2R,2'R)-3,3'-(((R)-8-((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)-8-oxooctane-1,3-diyl)bis(disulfanediyl))bis(2-(2-mercapto-2 - methylpropanamide) propanoic acid)

(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 5-((3R )-2-oxide-1,2-dithiolan-3-yl)pentanoate and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol) was dissolved in anhydrous THF (15 mL). Bucillamine (70.3 mg, 0.315 mmol) was added and the mixture was stirred at room temperature for 1 week. The solvent was evaporated under vacuum and the crude product was purified by reverse phase preparative HPLC. Fractions containing the desired product were combined, the solution was passed through a catch release cartridge (Biotage Isolute NH2, 1 g), washed with MeCN (2 CV), and the product was eluted with 95:5 MeCN-AcOH (2 CV). did. By freezing the solution (-78°C) and evaporating the solvent under vacuum (lyophilization), the (2R,2'R)-3,3'-(((R)-8-((2S,3R) ,4S,6R)-4-(dimethylamino)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-tri Hydroxy-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)-8-oxooctane- 1,3-diyl)bis(disulfanediyl))bis(2-(2-mercapto-2-methylpropanamido)propanoic acid) (5.0 mg, 17%) was obtained as a white solid. LCMS (Method F): Rt = 5.02 min; [(M+H)/2] ⁺ =690.7. LCMS (Method A): Rt = 2.00 min; [M+H] ⁺ = 1379.8.

Chemical substance synthesis example 13:
(4S,10R)-10-(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)oxy)-5-oxopentyl)-7,7-dimethyl-6-oxo-1,2,8,9-tetrathia-5-azacyclododecane-4-carboxylic acid and ( 4S,12S)-12-(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)oxy)-5-oxopentyl)-7,7-dimethyl-6-oxo-1,2,8,9-tetrathia-5-azacyclododecane-4-carboxylic acid

(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 5-((3R )-2-oxide-1,2-dithiolan-3-yl)pentanoate and (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 5-((3R)-1-oxide-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol) was dissolved in anhydrous THF (15 mL). Bucillamine (70.3 mg, 0.315 mmol) was added and the mixture was stirred at room temperature for 1 week. The solvent was evaporated under vacuum and the crude product was purified by reverse phase preparative HPLC. Fractions containing the desired product were passed through a catch release cartridge (Biotage Isolute NH2, 1 g) and washed with MeCN (2 CV) and the product was eluted with 95:5 MeCN-AcOH (2 CV). The solution was frozen (-78° C.) and the solvent was evaporated under vacuum (lyophilization) to give the title compound (7.0 mg, 1.5%) as a white solid. LCMS (Method E): Rt = 4.81 min. [(M+H)/2] ⁺ =580.1. LCMS (Method A) Rt = 1.90 min, [M+H] ⁺ = 1158.7.

The compounds provided herein (e.g., Table 1) may be those provided in any of the Chemical Synthesis Examples above, e.g. starting from azithromycin dihydrate, Chemical Synthesis Example 1 above. Prepared following a similar procedure.

II. Biological Evaluation Example 1: Rabbit Corneal Homogenate Stability Assay Determination of rabbit corneal homogenate stability of test compounds is performed using HPLC-MS. The assay was performed with two concentrations of rabbit corneal homogenate (0.15 mg/mL and 0.45 mg/mL total protein) so that the observed hydrolysis could be assigned to be esterase-dependent or not. do.

Homogenization of Rabbit Corneas Five rabbit corneas (eg New Zealand Whites) of approximately 50 mg each are cut into pieces and scraped with a scalpel and forceps until reduced to small (1-3 mm) thin pieces. Transfer these to tared vials, weigh accurately, and then dilute with 10 volumes of PBS aqueous solution pH 7.4.

The samples are cooled intermittently on ice, homogenized by shear for 3 minutes, and then centrifuged at 3000 rpm for 3 minutes. Pipette off the supernatant and transfer to a vial and determine the total protein concentration at 280 nm. Samples were stored at -78°C.

Preparation of rabbit corneal esterase assay stock solution:
Dilute 10 mM compound stocks to 100 μM in a 96 deep well plate. Add 10 μl of 10 mM compound stock to 990 μL of 50 mM HEPES, pH 7.5 buffer. Compounds are further diluted to 10 μM. Add 100 μL of 100 μM compound to 900 μL of 50 mM HEPES, pH 7.5 buffer. Dilute the esterase homogenate to 300ng/μL and 900ng/μL.

Assay conditions:
Set the heater shaker to 37°C. Pipette 75 μL of 300 or 900 ng/μL esterase homogenate into each of the required wells (2 minutes, 5 minutes, 10 minutes, 20 minutes, and 45 minutes) in a suitable 96-well plate (Run Plate). Seal the plate and then warm to 37°C for 5 minutes.

Place another 96-well PCR plate on ice (Kill Plate). To this, 100 μL of MeCN is added to each well and labeled at 0 min, 2 min, 5 min, 10 min, 20 min, and 45 min. Cover the plate to minimize evaporation.

For T=0 samples only, add 50 μL of 300 or 900 ng/μl esterase homogenate to 100 μL of cold MeCN stop solution followed by 50 μL of 10 μM compound solution. At the remaining time points, add 75 μL of 10 μM compound solution to the Run Plate starting with the T=45 min row and ending with the T=2 min row. At appropriate time points, add 100 μL of assay mixture to the wells of a matching kill plate containing 100 μL of cold MeCN. Samples are analyzed as soon as practicable by LCMS (Waters Xevo TQ-S or Micromass Ultima).

The parent conjugate and parent concentration were determined against the appropriate standard response curve, and the peak area of the parent conjugate in the linear region of the log-linear plot at each time point was used to calculate the half-life (T1/2) of the parent conjugate. Calculate.

Example 2: Aqueous Hydrolyzate Stability Assay Aqueous stability in test compounds was determined using HPLC-MS. A 10 mM stock solution of test compound is prepared in DMSO. Make a 100 μM solution by dissolving 10 μL of DMSO stock solution in 990 μL of 50 mM HEPES, pH 7.5 buffer, or 1:1 (v/v) acetonitrile:water. Final DMSO concentration is 1%. The solution was kept at room temperature and injected into the LCMS (Waters Xevo TQ-S or Micromass Ultima) without any delay. Perform additional injections at appropriate times.

The peak area of the parent conjugate in the linear region of the log-linear plot at each time point is used to calculate the half-life (T _1/2 ) of the parent conjugate.

Example 3: Aqueous Hydrolyzate Stability Assay Compounds with Slow Hydrolysis Rates Aqueous stability in test compounds was determined using ∪PLC-MS. Stock solutions of test compounds 10mM were prepared in dry DMSO or DMF. Make a 100 μM solution by dissolving 10 μL of DMSO or DMF stock solution in 990 μL of DPBS pH 7.4 buffer. This solution was used "as is" or immediately further diluted to 25 μM in DPBS. Final DMSO concentration was less than 1%. The solution was quickly loaded into an autosampler maintained at 37°C and injected into a UPLCMS (Waters Xevo TQ-S or G2-XS) without delay. Additional injections were made at appropriate times. The half-life of the parent compound was determined from the MS reaction.

Compounds with fast (less than 5 minutes) hydrolysis rates Aqueous stability in test compounds was determined using ∪PLC-MS. Stock solutions of test compounds 10mM were prepared in dry DMSO or DMF. The 50 μL DMSO or DMF stock solution was further diluted to 2.5 mM with 150 μL dry DMSO or DMF (as required). Make a 25 μM solution by dissolving 10 μL of 2.5 mM DMSO or DMF stock solution in 990 μL of DPBS pH 7.4 buffer. Final DMSO concentration was 1%. The solution was quickly loaded into an autosampler maintained at 37°C and injected into a UPLCMS (Waters Xevo TQ-S or G2-XS) without delay. Additional injections were made at appropriate times. The half-life of the parent compound was determined from the MS reaction.

Example 4: Mouse model of experimental dry eye disease Female C57BL/6 mice (6-8 weeks old) or female HEL BCR Tg mice (6-8 weeks old) were obtained commercially. Experimental dry eye is induced as described in Niederkorn et al. (J. Immunol. 2006, 176:3950-3957) and Dursun et al. (Invest. Ophthalmol. Vis. Sci. 2002, 43:632-638). Briefly, mice are exposed to desiccation stress in a perforated cage by providing constant airflow from fans positioned on both sides to maintain room humidity between 30% and 35%. Scopolamine hydrobromide (0.5 mg/0.2 mL, Sigma-Aldrich, St. Louis, MO) three times a day (8:00 a.m., 12:00 noon, 5:00 p.m.) on the left and right posterior sides. Inject subcutaneously into alternating hind-flanks to increase disease. Mice are exposed to desiccation stress for 3 weeks. Untreated control mice are maintained in a non-stressed environment at 50% to 75% relative humidity without exposure to pumped air. A test animal is exposed to a test compound, followed by obtaining tear fluid samples to determine the stability of the test compound and obtaining tissue samples to determine the presence of pro-inflammatory biomarkers.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Solutions for Topical Ophthalmic Use The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt thereof, as a solution at a concentration of 0.1-1.5% w/v. Formulated.

Claims (77)

Formula (Ia):
or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R is substituted (e.g., straight or branched) alkyl, substituted (e.g., straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., further substituted with (e.g., oxo and/or thiol) (N-)substituted with alkyl), substituted alkyl is substituted with one or more (alkyl) substituents, and at least one (alkyl) substituent is independently -SH, substituted or Unsubstituted (e.g., unsaturated) cycloalkyl, and substituted heteroalkyl selected from the group consisting of dithiolanyl oxide, substituted with one or more (heteroalkyl) substituents, alkyl) substituents are independently selected from the group consisting of -SH, -COOH, and thioalkyl, wherein the substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl is further optionally substituted.
A compound, or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a bond. The compound according to claim 1, wherein L is -(C=O)(OCR ⁸ R ⁹ ) _z - or -(C=O)(OCR ⁸ R ⁹ ) _z O-, or a pharmaceutically acceptable compound thereof Possible salts or solvates. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein L is -(C=O)OCH(CH ₃ )- or -(C=O)OCH(CH ₃ )O- Solvate. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is absent. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. Claims 3 to 6, wherein L is -(C=O)OCH( _CH3 )- or -(C=O)OCH( _CH3 )O-, and X is absent or -O-. or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a bond and X is absent. R is a substituted (e.g. straight-chain or branched) alkyl, the (e.g. straight-chain or branched) alkyl is substituted with one or more (alkyl) substituents, each of the (alkyl) substituents Independently, thiol, amino, acetamido, substituted unsaturated cycloalkyl (e.g., substituted with one or more C ₁ -C ₄ alkyl), and substituted heterocycloalkyl (e.g., dithiolanyl oxide). ), or a pharmaceutically acceptable salt or solvate thereof. L is a bond; (alkyl) substituents are each independently thiol, amino, acetamido, substituted unsaturated cycloalkyl (e.g., substituted with one or more C ₁ -C ₄ alkyl), and a substituted heterocycloalkyl (e.g., dithiolanyl oxide), or a pharmaceutically acceptable salt or solvate thereof. R is
11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof. Substitutions in which R comprises (e.g., in the (e.g., linear or branched) heteroalkyl chain) one or more esters, one or more amides, and/or one or more disulfides (e.g., 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, which is straight-chain or branched-chain) heteroalkyl. 13. A compound according to claim 12, wherein R is a substituted (e.g., linear or branched) heteroalkyl comprising one ester (e.g., within the (e.g., linear or branched) heteroalkyl chain), or A pharmaceutically acceptable salt or solvate thereof. 12. R is a substituted or unsubstituted (e.g. straight or branched) heteroalkyl comprising one or two amides (e.g. in the (e.g. straight or branched) heteroalkyl chain) or a pharmaceutically acceptable salt or solvate thereof. 12. R is a substituted or unsubstituted (e.g. straight or branched) heteroalkyl (e.g. containing one or two disulfides in the (e.g. straight or branched) heteroalkyl chain) or a pharmaceutically acceptable salt or solvate thereof. From claim 12, wherein R is a substituted or unsubstituted (e.g. linear or branched) heteroalkyl containing one disulfide (e.g. in the (e.g. linear or branched) heteroalkyl chain) 16. A compound according to any one of Item 15, or a pharmaceutically acceptable salt or solvate thereof. Substituted or unsubstituted (e.g. linear or branched) R contains one or two disulfides and/or one amide (e.g. in the (e.g. linear or branched) heteroalkyl chain) 17. A compound according to any one of claims 12 to 16, or a pharmaceutically acceptable salt or solvate thereof, which is heteroalkyl. R is substituted (e.g., straight-chain or branched) heteroalkyl, the (e.g., straight-chain or branched) heteroalkyl is substituted with one or more (heteroalkyl) substituents, and (heteroalkyl)-substituted The groups are each independently thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, thiol, oxo, and optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., carboxylic acid). 18. A compound according to any one of claims 12 to 17, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of: L is a bond, X is absent, R is a substituted (e.g., straight or branched) heteroalkyl, and the (e.g., straight or branched) heteroalkyl is one or more (heteroalkyl) substituents are each independently substituted with thioalkyl, amino, carboxylic acid, C ₁ -C ₆ alkyl, acetamido, thiol, oxo, and optionally substituted (e.g., N 19. A compound according to any one of claims 12 to 18, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a bond) heterocycloalkyl (e.g. optionally substituted with a carboxylic acid). Or a solvate. R is
20. A compound according to any one of claims 12 to 19, or a pharmaceutically acceptable salt or solvate thereof. 21. A compound according to any one of claims 12 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R is substituted branched heteroalkyl. R-X-L is
22. A compound according to any one of claims 12 to 21, or a pharmaceutically acceptable salt or solvate thereof. 9. A compound according to any one of claims 1 to 8, wherein R is substituted heterocycloalkyl (e.g. N-substituted with alkyl (e.g. further substituted with oxo and/or thiol)), or A pharmaceutically acceptable salt or solvate thereof. R is
or a pharmaceutically acceptable salt or solvate thereof. R comprises one or more radicals of keratolytic groups (e.g., one or more radicals of keratolytic groups may each independently be a radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), Radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical, N-acetylcysteine (NAC) radical. 25. A radical selected from the group consisting of cysteine (Cys) radical, glutathione (GSH) radical, captopril (Cap) radical, and bucillamine (Buc) radical), according to any one of claims 1 to 24. A described compound, or a pharmaceutically acceptable salt or solvate thereof. R comprises one or more keratolytic (thiol) radicals, each of the one or more keratolytic (thiol) radicals independently being a (thiol) radical of thioglycolic acid (TGA). , (thiol) radical of thiolactic acid (TLac), (thiol) radical of dihydrolipoic acid (diHLip), (thiol) radical of N-acetylcysteine (NAC), (thiol) radical of cysteine (Cys), glutathione (GSH) 26. A compound according to any one of claims 1 to 25, selected from the group consisting of the (thiol) radical of , the (thiol) radical of captopril (Cap), and the (thiol) radical of bucillamine (Buc), or A pharmaceutically acceptable salt or solvate thereof. The radical is one or more of Lac-Lac, Cys-Cys, diHLip-NAC-NAC, diHLip-NAC, diHLip-Cap-Cap, diHLip-Cap, diHLip-Cys-Cys, diHLip-Cys, diHLip-Lipox. - Lipox, or diHLip-Lipox, or any combination thereof, according to any one of claims 25 to 26, or a pharmaceutically acceptable salt or solvate thereof. R is
28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof. The compound has the structure:
29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, provided that the compound is other than a compound having the following. Formula (Ib):
or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R ^x is
and
R ^1a and R ^1b are each independently -H or -SR ^1c ,
R ^1c is each independently substituted or unsubstituted (e.g., straight chain or branched) alkyl (e.g., each independently, carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted with one or more (alkyl) substituents selected from the group consisting of substituted heterocycloalkyl (e.g. N-linked pyrrolidinyl substituted with -COOH), or substituted or unsubstituted (e.g. straight or branched chain) heteroalkyl (e.g., _one or more ( _heteroalkyl ) is substituted with a substituent), and
R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f each independently represent H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or two of R ^2a and R ^2b , R ^2c and R ^2d , or R ^2e and R ^2f together with the atoms to which they are bonded are C ₃ - forming _C5 cycloalkyl,
m is an integer from 1 to 10,
n and o are each independently an integer from 0 to 3,
A compound, or a pharmaceutically acceptable salt or solvate thereof. Claim 30, wherein R ^2a , R ^2b , R ^2c , R ^2d , R ^2e , and R ^2f are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl. A described compound, or a pharmaceutically acceptable salt or solvate thereof. 32. The compound according to any one of claims 30 to 31, or a pharmaceutically acceptable salt or salt thereof, wherein ^R2a , ^R2b , ^R2c , ^R2d , ^R2e , and ^R2f are each H. Solvate. o is 0 and R ^x is
33. A compound according to any one of claims 30 to 32, or a pharmaceutically acceptable salt or solvate thereof. o is 0, n is 2, and R ^x is
34. A compound according to any one of claims 30 to 33, or a pharmaceutically acceptable salt or solvate thereof. 35. A compound according to any one of claims 30 to 34, or a pharmaceutically acceptable salt or solvate thereof, wherein m is an integer from 3 to 5. R ^x is
and
During the ceremony,
R ^1a and R ^1b are each independently -H or -SR ^1c ,
R ^1c is each independently a substituted or unsubstituted (e.g., straight or branched) alkyl (e.g., each independently a carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, optionally substituted substituted or unsubstituted (e.g. directly substituted with one or more (alkyl) substituents selected from the group consisting of (chain or branched) heteroalkyl (e.g., one or more (heteroalkyl) each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) substituted with a substituent),
36. A compound according to any one of claims 30 to 35, or a pharmaceutically acceptable salt or solvate thereof. Any of claims 30 to 36, wherein R ^1a is -H or -SR ^1c , R ^1b is -SR ^1c , or R ^1a is -SR ^1c and R ^1b is -H or -SR ^1c . A compound according to item 1, or a pharmaceutically acceptable salt or solvate thereof. 38. A compound according to any one of claims 30 to 37, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^1a and R ^1b are each -SR ^1c . R ^x is
and
During the ceremony,
R ^1c is each independently substituted or unsubstituted (e.g., straight chain or branched) alkyl (e.g., each independently, carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted with one or more (alkyl) substituents selected from the group consisting of substituted heterocycloalkyl (e.g. N-linked pyrrolidinyl substituted with -COOH), or substituted or unsubstituted (e.g. straight or branched chain) heteroalkyl (e.g., _one or more ( _heteroalkyl ) is substituted with a substituent),
39. A compound according to any one of claims 30 to 38, or a pharmaceutically acceptable salt or solvate thereof. R ^1a and R ^1b are each independently a radical of one or more keratolytic groups (e.g., the radical of one or more keratolytic groups is each independently a radical of glycolic acid (GA) Radical, thioglycolic acid (TGA) radical, lactic acid (Lac) radical, thiolactic acid (TLac) radical, lipoic acid (Lip) radical, lipoic acid sulfoxide (Lipox) radical, dihydrolipoic acid (diHLip) radical , a radical of N-acetylcysteine (NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)), Claims A compound according to any one of 30 to 39, or a pharmaceutically acceptable salt or solvate thereof. R ^1a and R ^1b are each independently a (thiol) radical of one or more keratolytic groups, and the (thiol) radical of one or more keratolytic groups is each independently a thioglycol (thiol) radical of acid (TGA), (thiol) radical of thiolactic acid (TLac), (thiol) radical of dihydrolipoic acid (diHLip), (thiol) radical of N-acetylcysteine (NAC), (thiol) radical of cysteine (Cys) (thiol) radical, (thiol) radical of glutathione (GSH), (thiol) radical of captopril (Cap), and (thiol) radical of bucillamine (Buc). A compound according to item 1, or a pharmaceutically acceptable salt or solvate thereof. The radical is [Lac-Lac]・, [Lac-NAC]・, [Cys-Cys]・, [diHLip-NAC-NAC]・, [diHLip-NAC]・, [diHLip-Cap-Cap]・, Claims comprising [diHLip-Cap]·, [diHLip-Cys-Cys]·, [diHLip-Cys]·, [diHLip-Lipox-Lipox]·, or [diHLip-Lipox]·, or any combination thereof 42. A compound according to any one of 40 to 41, or a pharmaceutically acceptable salt or solvate thereof. R ^1a and R ^1b are each independently -H, or
43. A compound according to any one of claims 30 to 42, or a pharmaceutically acceptable salt or solvate thereof. R ^x is
44. A compound according to any one of claims 30 to 43, or a pharmaceutically acceptable salt or solvate thereof. Formula (Ic):
or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R ^y is
and
R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl,
p is an integer from 1 to 10,
q is an integer from 1 to 3;
A compound, or a pharmaceutically acceptable salt or solvate thereof. 46. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. 47. A compound according to any one of claims 45 to 46, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1 and p is an integer from 3 to 5. 48. A compound according to any one of claims 45 to 47, wherein R ^4a and R ^4b are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl, or Pharmaceutically acceptable salts or solvates. 49. A compound according to any one of claims 45 to 48, or a pharmaceutically acceptable salt or solvate thereof, wherein ^R4a and ^R4b are each H. R ^y is
50. A compound according to any one of claims 45 to 49, or a pharmaceutically acceptable salt or solvate thereof. Formula (Id):
or a pharmaceutically acceptable salt or solvate (e.g., or stereoisomer) thereof, having the structure:
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
^Rz is
and
R ⁵ is -SR ^1c ,
R ^1c is substituted or unsubstituted (e.g., straight chain or branched) alkyl (e.g., each independently carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted heterocyclo alkyl (e.g. N-linked pyrrolidinyl substituted with -COOH), or substituted or unsubstituted (e.g. linear or branched); ) of heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituents each independently selected from the group consisting of carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl) ) and
R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,
R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ¹⁰ and R ¹¹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl,
s is an integer from 1 to 10,
A compound, or a pharmaceutically acceptable salt or solvate thereof. 52. The compound of claim 51, wherein R ⁶ and R ⁷ are each independently H, or substituted or unsubstituted alkyl (e.g., C ₁ -C ₃ alkyl optionally substituted with oxo). or a pharmaceutically acceptable salt or solvate thereof. 53. A compound according to any one of claims 51 to 52, or a pharmaceutically acceptable salt or solvate thereof, wherein ^R6 and ^R7 are each H. 54. A compound according to any one of claims 51 to 53, wherein R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl, or Pharmaceutically acceptable salts or solvates. 55. A compound according to any one of claims 51 to 54, or a pharmaceutically acceptable salt or solvate thereof, wherein ^R10 and ^R11 are each independently H. 56. A compound according to any one of claims 51 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1 to 3. R ⁵ is
57. A compound according to any one of claims 51 to 56, or a pharmaceutically acceptable salt or solvate thereof. Formula (Ia'):
A compound represented by the structure, or a pharmaceutically acceptable salt or solvate thereof,
During the ceremony,
L is a bond, -(C=O)(OCR ⁸ R ⁹ ) _z -, or -(C=O)(OCR ⁸ R ⁹ ) _z O-,
R ⁸ and R ⁹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ⁸ and R ⁹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl;
z is 1 to 6,
X is absent or -O-;
R is substituted alkyl, substituted heteroalkyl, or substituted heterocycloalkyl, where substituted alkyl is substituted with one or more alkyl substituents, and at least one alkyl substituent is independently substituted or unsubstituted. cycloalkyl and substituted heterocycloalkyl, the substituted heteroalkyl is substituted with one or more heteroalkyl substituents, and at least one heteroalkyl substituent is independently -COOH, substituted selected from the group consisting of heterocycloalkyl, and thioalkyl, wherein the substituted alkyl or substituted heteroalkyl is further optionally substituted;
A compound, or a pharmaceutically acceptable salt or solvate thereof. 59. A compound according to any one of claims 1 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R is substituted alkyl, and alkyl is substituted with substituted heterocycloalkyl. 60. A compound according to any one of claims 1 to 59, or a pharmaceutically acceptable compound thereof, wherein R is a substituted heteroalkyl containing one or more ester, amide, or disulfide bonds within the heteroalkyl chain. salt or solvate. R is substituted heteroalkyl, heteroalkyl is substituted with -COOH, _-CH SH, and/or optionally substituted N-linked heterocycloalkyl, and substituted with one or more other substituents 61. A compound according to any one of claims 1 to 60, wherein each substituent is independently selected from the group consisting of acetamido, amino, _C1 - _C6 alkyl, thiol, and oxo, or Pharmaceutically acceptable salts or solvates. R is a substituted heteroalkyl containing two disulfide bonds in the heteroalkyl chain, the heteroalkyl is substituted with -COOH or a substituted N-linked heterocycloalkyl, and with one or more other substituents 62. A compound according to any one of claims 1 to 61, or a pharmaceutically acceptable compound thereof, further substituted, wherein each substituent is independently selected from the group consisting of acetamide and C ₁ -C ₆ alkyl. Possible salts or solvates. 63. According to any one of claims 1 to 62, R is a substituted heteroalkyl containing one disulfide bond in the heteroalkyl chain, and the heteroalkyl is substituted with acetamido, -COOH, and -SH. A compound, or a pharmaceutically acceptable salt or solvate thereof. 64. A compound according to any one of claims 1 to 63, or a pharmaceutically acceptable compound thereof, wherein R is heterocycloalkyl N-substituted with alkyl, said alkyl being further substituted with oxo and/or thiol. Acceptable salts or solvates. R is
and
During the ceremony,
R ^4a and R ^4b are each independently H, halogen, or substituted or unsubstituted alkyl,
p is an integer from 1 to 10,
q is an integer from 1 to 3;
65. A compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt or solvate thereof. 66. A compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1 and p is an integer from 3 to 5. 67. A compound according to any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein ^R4a and ^R4b are each H. R is
68. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt or solvate thereof. R is
and
During the ceremony,
R ⁵ is -SR ^1c ,
R ^1c is substituted alkyl or substituted heteroalkyl,
Alkyl is substituted with one or more alkyl substituents, each independently from carboxylic acid, -SH, thioalkyl, acetamido, amino, oxo, and optionally substituted heterocycloalkyl. the heteroalkyl is substituted with one or more heteroalkyl substituents, each heteroalkyl substituent being independently selected from the group consisting of oxo, carboxylic acid, amino, thioalkyl, thiol, acetamido, and C ₁ -C ₃ alkyl;
R ⁶ and R ⁷ are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl,
R ¹⁰ and R ¹¹ are each independently H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, or R ¹⁰ and R ¹¹ together with the atoms to which they are bonded form a C ₃ -C ₅ cycloalkyl,
s is an integer from 1 to 10,
69. A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt or solvate thereof. A compound according to any one of claims 1 to 69, or a pharmaceutically acceptable compound thereof, wherein R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are each H and s is 1-3. salt or solvate. 71. A compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^{1c is} heteroalkyl substituted with a carboxylic acid. 72. Any of claims 1-71, wherein R ^1c is alkyl substituted with one or more alkyl substituents, each alkyl substituent being independently selected from the group consisting of carboxylic acid and acetamide. A compound according to item 1, or a pharmaceutically acceptable salt or solvate thereof. R ⁵ is
73. A compound according to any one of claims 1 to 72, or a pharmaceutically acceptable salt or solvate thereof. 74. A pharmaceutical composition comprising a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 75. A pharmaceutical composition according to any one of claims 1 to 74, suitable for topical ocular administration. 76. A method of treating a skin or eye disease or disorder in an individual, the method comprising administering to said individual a compound according to any one of claims 1 to 75. 77. The method of any one of claims 1-76, wherein the skin or eye disease or disorder is associated with keratosis, microbial infiltration, microbial infection, inflammation, or any combination thereof.