HK1211031B - Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes - Google Patents

Description

Central corneal thickening reduction by use of hydrophilic ester prodrugs of beta-chlorocyclopentane

RELATED APPLICATIONS

The benefit of U.S. provisional patent application serial No. 61/693,437, filed on 8/27/2012, the disclosure of which is hereby incorporated by reference in its entirety.

Background

Glaucoma is one of the leading causes of blindness worldwide, with over 250 million people in the united states suffering from the disease and many millions at risk of developing glaucoma. As the population ages, the number of individuals suffering from glaucoma will continue to increase, as older people are disproportionately affected.

Based on its etiology, glaucoma can be classified into primary glaucoma and secondary glaucoma. Primary glaucoma, also known as congenital glaucoma, can occur in the absence of other ocular conditions and its underlying cause is unknown. However, it is known that the increased intraocular pressure (IOP) observed in primary glaucoma is due to obstruction of the aqueous humor that flows out of the eye. Secondary glaucoma results from another pre-existing ocular disease such as uveitis, intraocular tumors, enlarged cataracts, central retinal vein occlusion, ocular trauma, surgical procedures, and intraocular hemorrhage. In general, any disturbance to the flow of aqueous humor from the posterior chamber outward into the anterior chamber and then into schlemm's canal can lead to secondary glaucoma.

Current treatments for glaucoma aim to reduce pressure in the eye by reducing the amount of aqueous humor produced or alternatively by increasing fluid flow out of the eye using mechanical devices. Agents for topical administration for the treatment of glaucoma include miotics (e.g., miotics)Carpine、And) And epinephrine (e.g. adrenalineAnd) Which increases the outflow of fluid, β blockers (e.g.) Carbonic anhydrase inhibitors and α adrenergic agonists (e.g., as) Which reduces the amount of fluid; and prostaglandin analogs (e.g. prostaglandin) Which increases the outflow of fluid via the secondary drainage pathway.

Topical administration of ophthalmic compositions for the treatment of glaucoma requires that the drug penetrate through the cornea and into the anterior chamber containing aqueous humor, which is subsequently drained into the conventional outflow route. Intraocular pressure is reduced by drugs acting on schlemm's canal and the uveal-scleral route. Drug penetration across the cornea requires a balance of hydrophobic and hydrophilic characteristics. In order to diffuse into the cornea, the drug must be sufficiently soluble in the non-polar medium and it must be sufficiently soluble in the aqueous medium to diffuse out of the cornea into the aqueous humor.

Potentially useful drugs for the treatment of glaucoma may be delivered as prodrug esters. The use of prodrug esters that are enzymatically cleaved (e.g., in the cornea) to regenerate the active compound can enhance penetration of the drug into the anterior chamber via the cornea. However, many esters are too hydrophobic to diffuse out of the highly aqueous polar stroma (thickest layer) in the cornea and into the aqueous humor. Furthermore, such compounds are often insufficiently soluble to be formulated in aqueous solutions. There is a need in the art for ophthalmic compositions having the ability to penetrate through the cornea into the anterior chamber. At the same time, the composition needs to exhibit sufficient hydrophilic properties to be formulated in aqueous solution and soluble in the anterior chamber. Compositions and methods are provided herein that address these and other needs in the art.

Summary of The Invention

In one aspect, compounds having the formula:

or a pharmaceutically acceptable salt thereof. In the formula (I), R¹Is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. L is¹Is a bond, substituted or unsubstituted C₁-C₁₀Alkylene or substituted or unsubstituted 2-to 10-membered heteroalkylene. L is²Is a bond, substituted or unsubstituted C₁-C₁₀Alkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L is³Is a bond or substituted or unsubstituted C₁-C₁₀An alkylene group. R²Is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In another aspect, an ophthalmic pharmaceutical composition is provided comprising a compound provided herein and embodiments thereof, and a pharmaceutically acceptable carrier.

In another aspect, a method of treating an ophthalmic disorder in a human is provided. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound provided herein and embodiments thereof.

In another aspect, a method of reducing corneal thickening is provided. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound provided herein and embodiments thereof.

Detailed Description

I. Definition of

The abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to standard rules of valence known in the chemical arts.

When a substituent is represented by its conventional formula (written from left to right), it also includes the chemically identical substituent that would result from writing a structure from right to left, e.g., -CH₂O-is equivalent to-OCH₂-。

Unless otherwise specified, the term "alkyl" alone or as part of another substituent means a straight-chain (i.e., unbranched) or branched chain or combination thereof that may be fully saturated (referred to herein as "saturated alkyl"), mono-or polyunsaturated, and may include divalent and multivalent groups, having the specified number of carbon atoms (i.e., C)₁-C₁₀Meaning one to ten carbons). In some embodiments, all alkyl groups set forth as substituents for compounds provided herein are saturated alkyl groups. Examples of saturated hydrocarbon groups include, but are not limited to, the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl is alkyl having one or more double or triple bonds. An "alkoxy" group is an alkyl group attached to the rest of the molecule via an oxygen linker (-O-). An "alkylthio" group is an alkyl group attached to the rest of the molecule via a sulfur linker (-S-). "haloalkoxy" is alkoxy substituted with halogen. When halogen is fluorine, it is referred to herein as "fluoroalkoxy". The term "alkyl" includes saturated alkyls, alkenyls, and alkynyls. The saturated alkyl groups may have 1 to 10 or 1 to 6 carbon atoms. Unless otherwise specified, the term "alkenyl", alone or as part of another substituent, refers to a straight (i.e., unbranched) or branched hydrocarbon chain (e.g., two to ten or two to six carbon atoms) having one or more double bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), and the like. Unless otherwise statedIt is noted that the term "alkynyl", alone or as part of another substituent, refers to a straight (i.e., unbranched) or branched hydrocarbon chain (e.g., two to ten or two to six carbon atoms) having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-and 3-propynyl, 3-butynyl, and the like.

The terms "alkylene," "alkenylene," and "alkynylene," alone or as part of another substituent, refer to a divalent group derived from an alkyl, alkenyl, or alkynyl group, as exemplified by, but not limited to, the following: methylene, ethylene, -CH₂CH₂CH₂CH₂-vinylene and the like.

The term "amino" as used herein refers to-NH₂. The term "carboxy" as used herein refers to-COOH (including pharmaceutically acceptable salts thereof).

Unless otherwise specified, "heteroalkyl," alone or in combination with another term, refers to a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si or S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom O, N, P and S and Si can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH＝CH-O-CH₃、-Si(CH₃)₃、-CH₂-CH＝N-OCH₃、-CH＝CH-N(CH₃)-CH₃、-O-CH₃、-O-CH₂-CH₃and-CN. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃. Similarly, the term "heteroalkylene" alone or as anotherThe moiety of a substituent refers to a divalent group derived from a heteroalkyl group, as exemplified by, but not limited to: -CH₂-CH₂-S-CH₂-CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-. For heteroalkylene groups, heteroatoms can also occupy one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). As noted above, heteroalkyl groups as used herein include those groups attached to the rest of the molecule via a heteroatom.

Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl", alone or in combination with other terms, mean "alkyl" and "heteroalkyl" (e.g., having from 4 to 8 ring atoms) in non-aromatic cyclic form, respectively. In addition, for heterocycloalkyl, a heteroatom may occupy a position where the heterocycle is attached to the rest of the molecule. Heterocycloalkyl may include one or two members selected from N, O or S (O)_nWherein n' is an integer of 0 to 2, and the remaining ring atoms are carbon. A heterocycloalkyl or cycloalkyl ring is optionally fused to one or more aryl or heteroaryl rings as defined herein (e.g., where the aryl and heteroaryl rings are monocyclic). A heterocycloalkyl or cycloalkyl ring fused to a monocyclic aryl or heteroaryl ring may be referred to herein as a "bicyclic heterocycloalkyl" ring or a "bicyclic cycloalkyl" ring. In addition, one or two ring carbon atoms in the heterocycloalkyl ring may optionally be replaced by a-CO-group. More specifically, the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidino, 2-oxopiperidino, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, indolinyl, and the like. When the heterocycloalkyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. When a heterocycloalkyl group contains at least one nitrogen atom, it is also referred to herein as a heterocycloamino group and is a subset of heterocycloalkyl groups. When a heterocycloalkyl is a saturated ring and is not fused to an aryl or heteroaryl ring as described above, it may be referred to herein as a saturated monocyclic heterocycloalkyl. Cycloalkyl radicalsExamples of (b) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1, 2, 5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent refer to divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

Unless otherwise specified, the terms "halo" or "halogen," alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl as well as polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "is intended to include, but not be limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term "acyl" refers to-C (O) R, wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Unless otherwise indicated, the term "aryl" refers to an aromatic substituent which may be monocyclic or polycyclic (preferably 1 to 3 rings), which may be fused together (i.e., a fused ring aryl) or covalently attached. Fused ring aryl refers to multiple rings fused together, wherein at least one fused ring is an aryl ring (e.g., phenyl, 1-naphthyl, 2-naphthyl, or 4-biphenyl). The term "heteroaryl" refers to an aryl (or ring) containing one or more (e.g., 4) heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized, with the remaining ring atoms being carbon. Heteroaryl may be a monovalent monocyclic, bicyclic or tricyclic (e.g. monocyclic or bicyclic) aromatic group having 5 to 14 (e.g. 5 to 10) ring atoms, wherein one or more (e.g. one, two or three or four) ring atoms is a heteroatom selected from N, O or S. Examples include, but are not limited to, thienyl, isoindolyl, benzoxazolyl, pyridazinyl, triazolyl, tetrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, 2-benzimidazolyl, 5-indolyl, pyridazinyl, triazolyl, tetrazolyl, 1-pyrrolyl, 3-pyrrolyl, 5-oxazolyl, 4-isoxazolyl, 2-thiazolyl, 3-furyl, 2-thienyl, 3-thienyl, 2, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Thus, the term "heteroaryl" includes fused ring heteroaryl (i.e., multiple rings fused together wherein at least one fused ring is a heteroaromatic ring). A 5, 6-fused ring heteroaryl refers to two rings fused together, wherein one ring has a 5-membered ring and the other ring has a 6-membered ring, and wherein at least one ring is a heteroaryl ring. Likewise, a 6, 6-fused ring heteroaryl refers to two rings fused together, wherein one ring has a 6-membered and the other ring has a 6-membered, and wherein at least one ring is a heteroaryl ring. And 6, 5-fused ring heteroaryl refers to two rings fused together, wherein one ring has a 6-membered ring and the other ring has a 5-membered ring, and wherein at least one ring is a heteroaryl ring. The heteroaryl group may be attached to the rest of the molecule via a carbon or heteroatom. "arylene" and "heteroarylene," alone or as part of another substituent, refer to divalent radicals derived from aryl and heteroaryl, respectively.

The terms "arylalkyl" and "heteroarylalkyl" are intended to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced with, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like).

The term "oxo" as used herein refers to an oxygen double bonded to a carbon atom. The term "carbonyl" as used herein refers to the-c (o) -group.

SymbolThe point of attachment of the substituent is indicated as is conventional in the art.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocycloalkyl optionally substituted with alkyl" means that alkyl may, but need not, be present, and the description includes situations where heterocycloalkyl is substituted with alkyl as well as situations where heterocycloalkyl is not substituted with alkyl.

The term "alkylsulfonyl" as used herein refers to compounds having the formula-S (O)₂) -a moiety of R ', wherein R' is an alkyl group as defined above. R' can have the indicated number of carbons (e.g., "C₁-C₄Alkylsulfonyl ").

Unless otherwise specified, each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl," and "heteroaryl") is intended to include both substituted and unsubstituted forms of the indicated group.

Substituents for alkyl and heteroalkyl groups (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a plurality of groups selected from, but not limited to: -OR ', - (O), - (NR '), - (N-OR ', - (NR ' R ',), - (SR ',), - (si ' R ' R ', - (oc) (O) R ', - (c) (O) R ', - (CO) CO₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-N R″C(O)₂R′、-NR′-C(NR′R″R″′)＝NR″″、-NR-C(NR′R″)＝NR″″、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R″、-NRSO₂R', -CN andand-NO₂And numbers ranging from 0 to (2m '+ 1), where m' is the total number of carbon atoms in such group. R ', R ", R'" and R "" each independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. When a compound of the invention includes more than one R group, for example, each R group is independently selected as is each R ', R ", R'" and R "" group (when more than one of these groups is present). When R 'and R' are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 4, 5, 6 or 7 membered ring. For example, -NR' R "is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. As will be understood by those skilled in the art from the foregoing discussion of substituents, the term "alkyl" is intended to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF)₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃And the like).

Similar to the substituents described for alkyl, the substituents for aryl and heteroaryl are varied and may be selected from, for example: halogen, -OR ', -NR ' R ', -SR ', -halogen, -SiR ' R ' R ', -OC (O) R ', -C (O) R ', -CO₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR′R″、-NR″C(O)₂R′、-NR-C(NR′R″R″′)＝＝NR″″、-NR′-C(NR′R″)＝NR″′、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R″、-NR′SO₂R', -CN and-NO₂、-R′、-N₃、-CH(Ph)₂Fluorine (C)₁-C₄) Alkoxy and fluorine (C)₁-C₄) Alkyl groups ranging in number from 0 to the total number of open valences on the aromatic ring system; and wherein R ', R ' and R ' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitutedHeteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each R ', R ", R'" and R "" groups (when more than one of these groups is present).

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a compound of the formula-T-C (O) - (CRR')_q-U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer of 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a group of formula-A- (CH)₂)_rSubstitution of substituents of-B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S-, -S (O) -, -S (O)₂-、-S(O)₂NR' -or a single bond, and r is an integer of 1 to 4. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a group of formula- (CRR')_s-X′-(C″R″′)_d-wherein S and d are independently integers from 0 to 3, and X 'is-O-, -NR' -, -S (O)₂-or-S (O)₂NR' -. Substituents R, R ', R ", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

Unless otherwise indicated, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

As used herein, "substituent" refers to a group selected from the following moieties:

(A)-OH、-NH₂、-SH、-CN、-CF₃、-NO₂oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heteroaryl, substituted heteroarylSubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, substituted with at least one substituent selected from the group consisting of:

(i) oxo, -OH, -NH₂、-SH、-CN、-CF₃、-NO₂Halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, substituted with at least one substituent selected from the group consisting of:

(a) oxo, -OH, -NH₂、-SH、-CN、-CF₃、-NO₂Halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, substituted with at least one substituent selected from the group consisting of: oxo, -OH, -NH₂、-SH、-CN、-CF₃、-NO₂Halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

"size-limited substituent" or "size-limited substituent group" as used herein refers to a group selected from all substituents as described above for "substituent", wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C₁-C₂₀Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C₄-C₈Cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4-to 8-membered heterocycloalkyl.

"lower substituent" or "lower substituent group" as used herein refers to a group selected from all substituents as described above for "substituent", wherein each substituted or unsubstituted alkyl group is substituted or unsubstituted C₁-C₈Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C₅-C₇Cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-to 7-membered heterocycloalkyl.

Unless otherwise specified, the structures depicted herein are also intended to include all stereochemical forms of the structures; for example, the R and S configurations and the cis and trans configurations for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of the invention.

The compounds of the present invention may have asymmetric centers and/or geometric isomers. The compounds of the invention containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of the invention, unless the specific stereochemistry or isomeric form is specifically indicated. All possible tautomers and cis-trans isomers are within the scope of the invention as if individually and as mixtures thereof. In addition, the term alkyl as used herein includes all possible isomeric forms of alkyl, although only a few examples are listed. In addition, when a cyclic group such as aryl, heteroaryl, heterocycloalkyl is substituted, it includes all positional isomers, although only a few examples are listed. Furthermore, all polymorphs (including amorphous forms) and hydrates of the compounds disclosed herein are within the scope of the present invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention, as are enantiomers. The compounds of the present invention do not include those compounds known in the art to be too unstable to synthesize and/or isolate.

Unless otherwise indicated, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen removal by replacement with deuterium or tritium or carbon enrichment¹³C or¹⁴Compounds having the structure of the present invention in addition to carbon substitution of C are within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be used with radioactive isotopes, such as for example tritium (A), (B), (C), (³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) For radiolabelling. All isotopic variations of the compounds of the present invention, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present invention.

The terms "a" and "an" when used with reference to a group of substituents herein mean at least one. For example, when a compound is substituted with "one" alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.

Unless otherwise indicated, the term "derivative" in the context of the compounds disclosed herein refers to a compound obtained by chemical modification, e.g. by bonding of one or more substituents as described herein.

When a moiety is substituted with an R substituent, the group may be referred to as "R substituted. When a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. For example, when a moiety herein is R^1ASubstituted or notWhen substituted alkyl, plural R^1ASubstituents may be attached to each R^1AThe substituents are optionally on different alkyl moieties. When the R-substituted moiety is substituted with multiple R substituents, each R substituent may be distinguished herein using a prime (') symbol, such as R ', R ', etc. For example, when the moiety is R^1ASubstituted or unsubstituted alkyl and the moiety is substituted with multiple R^1AWhen substituted by a substituent, the plurality of R^1ASubstituents can be distinguished as R^1A′、R^1A″、R^1A"', and the like. In some embodiments, the plurality of R substituents is 3. In some embodiments, the plurality of R substituents is 2.

The description of the compounds of the present invention is limited by the chemical bonding principles known to those skilled in the art. Thus, when a group can be substituted with one or more of a number of substituents, such substitutions are selected so as to follow the principles of chemical bonding and result in a compound that is inherently stable and/or will be known to those skilled in the art to be potentially unstable under environmental conditions such as aqueous, neutral, and several known physiological conditions. For example, heterocycloalkyl or heteroaryl groups are attached to the rest of the molecule via a ring heteroatom according to chemical bonding principles known to those skilled in the art, thereby avoiding inherently unstable compounds.

The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, neat (neat) or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functionalities, acid addition salts may be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids, and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginine salts and analogs thereof, and salts of organic acids such as glucuronic or galacturonic acids and analogs thereof. See, e.g., Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Additional information on suitable pharmaceutically acceptable salts can be found in REMINGTON' S PHARMACEUTICAL compositions SCIENCES, 17 th edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference. Certain specific compounds of the invention contain both basic and acidic functionalities, which allow the compounds to be converted into base or acid addition salts.

Thus, the compounds disclosed herein may exist as salts. Examples of such salts include hydrochloride, hydrobromide, sulphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g. (+) -tartrate, (-) -tartrate or mixtures thereof including racemic mixtures), succinate, benzoate and salts formed with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

The term "prodrug" is used according to its plain ordinary meaning and is intended to refer to a compound that requires chemical or enzymatic conversion in order to release the active parent drug in vivo before the pharmacological effect is produced.

"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to a carrier or excipient useful in the preparation of pharmaceutical compositions, which are generally safe, non-toxic and biologically or otherwise desirable, and include carriers or excipients acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, a "pharmaceutically acceptable carrier/excipient" includes one and more than one such excipient.

The term "treatment" or "treatment" refers to any indicia of successful treatment or amelioration of an injury, pathological phenomenon, or condition, including any objective or subjective parameter, such as alleviation of symptoms; moderating; (iii) mitigation; or to make the injury, pathological phenomenon or condition more tolerable to the patient; a slower rate of deterioration or debilitation; the degradation endpoint is less debilitating; improving the physical or mental health of the patient. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including results of physical examination, neuropsychiatric testing, and/or psychiatric evaluation. For example, certain methods provided herein successfully treat cancer by reducing the incidence of cancer, inhibiting its growth, and or causing remission of cancer.

An "effective amount" of a compound is an amount sufficient to promote the treatment, prevention, or alleviation of one or more symptoms of a disease. An "effective amount" may also be considered a "therapeutically effective amount" when recited with reference to disease treatment. "alleviating" one or more symptoms (and grammatical equivalents of this phrase) refers to reducing the severity or frequency of symptoms, or eliminating symptoms. A "prophylactically effective amount" of a drug is an amount of the drug that will have a predetermined prophylactic effect when administered to a subject, for example, to prevent or delay the onset (or recurrence) of a disease, disorder, or condition, or to reduce the likelihood of the onset (or recurrence) of a disease, disorder, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of one dose, and may only occur after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations.

The term "topical" in the context of the methods described herein conventionally refers to administration of a compound or pharmaceutical composition that is incorporated into a suitable pharmaceutical carrier and administered at the site of topical treatment of a subject. Thus, the term "topical pharmaceutical composition" includes those pharmaceutical forms in which the compound is administered externally by direct contact with a topical treatment site (e.g., the eye or skin). The term "topical ocular pharmaceutical composition" refers to a pharmaceutical composition suitable for direct application to the eye. The term "topical epidermal pharmaceutical composition" refers to a pharmaceutical composition suitable for application to the epidermal layer of the skin, such as the eyelid, eyebrow, scalp, or body. The term "topical administration" refers to external administration by direct contact with a local treatment site. The term "topical epidermal administration" refers to administration externally by direct contact with the epidermis. The term "topical ocular administration" refers to external administration by direct contact with the eye.

Composition II

In one aspect, compounds having the formula:

or a pharmaceutically acceptable salt thereof, wherein, in formula (I), R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. L1 is a bond, substituted or unsubstituted C1-C10 alkylene, or substituted or unsubstituted 2-to 10-membered heteroalkylene. L2 is a bond, substituted or unsubstituted C1-C10 alkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L3 is a bond or a substituted or unsubstituted C1-C10 alkylene. R2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

L¹C which may be a bond, substituted or unsubstituted₁-C₁₀(e.g. C)₂-C₆) Alkylene, or substituted or unsubstituted 2-to 10-membered (e.g., 2-to 6-membered) heteroalkylene. In one embodiment, L¹Is substituted or unsubstituted C₁-C₁₀An alkylene group. In one embodiment, L¹Is substituted or unsubstituted C₂-C₆An alkylene group. In one embodiment, L¹Is unsubstituted C₂-C₆An alkylene group. In one embodiment, L¹Is unsubstituted propylene. In one embodiment, L¹Is a bond.

L¹C which may be linear or branched substituted or unsubstituted₁-C₆An alkylene group. In one embodiment, L¹Is straight-chain substituted or unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkylene group. In one embodiment, L¹Is branched substituted or unsubstituted C₁-C₆An alkylene group. In one embodiment, L¹Is unsubstituted C₁-C₆An alkylene group. In one embodiment, L¹Is unsubstituted C₂-C₆An alkylene group. In one embodiment, L¹Is a substituted or unsubstituted propylene group. In one embodiment, L¹Is unsubstituted propylene. L is¹C which may be saturated substituted or unsubstituted₁-C₁₀(e.g. C)₂-C₆) An alkylene group. As used herein, "saturated alkylene" refers to an alkylene consisting only of hydrogen and carbon atoms bonded exclusively by single bonds. Thus, in one embodiment, L¹Is unsubstituted saturated C₂-C₆An alkylene group. In one embodiment, L¹Is a substituted or unsubstituted 2-to 6-membered heteroalkylene. L is¹May be a linear or branched substituted or unsubstituted 2-to 6-membered heteroalkylene. In one embodiment, L¹Is a linear substituted or unsubstituted 2-to 6-membered heteroalkylene. In one embodiment, L¹Is a branched substituted or unsubstituted 2-to 6-membered heteroalkylene. L is¹May be a saturated substituted or unsubstituted 2-to 10-membered (e.g., 2-to 6-membered) heteroalkylene. As used herein, "saturated heteroalkylene" refers to heteroalkylene groups composed of hydrogen atoms, carbon atoms, and heteroatoms (e.g., S, N, O) bonded exclusively by single bonds. Thus, in one embodiment, L¹Is unsubstituted saturated 2-to 6-membered heteroalkylene.

L¹May be a substituted or unsubstituted alkylene group or a substituted or unsubstituted heteroalkylene group. In one embodiment, L¹Is R^L1-substituted or unsubstituted C₁-C₁₀(e.g. C)₂-C₆) Alkylene or R^L1-substituted or unsubstituted 2 to 10-membered (e.g. 2 to 6-membered) heteroalkylene, wherein R^L1Independently at each occurrence is hydroxy or halogen (e.g., chloro, fluoro). In another embodiment, R^L1Is a hydroxyl group. In yet another embodiment, R^L1Is fluorine.

In one embodiment, L¹Is R^L1-substituted or unsubstituted C₂-C₆An alkylene group. In another embodiment, R^L1Is a hydroxyl group. In yet another embodiment, R^L1Is fluorine. In another embodiment, R^L1Is chlorine. In one embodiment, L¹Is substituted or unsubstituted C₁-C₆Alkylene, in one embodiment, L¹Is unsubstituted C₁-C₆An alkylene group. In one embodiment, L¹Is unsubstituted C₁、C₂、C₃、C₄、C₅Or C₆An alkylene group. In one embodiment, L¹Is a substituted or unsubstituted propylene group.

In one embodiment, L¹Is R^L1-substituted or unsubstituted C₂-C₆Alkylene, wherein R^L1Is hydroxy or halogen. When L is¹Is R^L1-substituted alkylene or R^L1When it is a substituted heteroalkylene radical, L¹Can be at least oneR^L1-substituted by a substituent and each R^L1The substituents may be optionally different. For example, when L is¹In the context of formula (I) is R^L1When substituted or unsubstituted alkylene, a single R^L1The substituent may be linked to L¹Alkylene or multiple R^L1The substituent may be linked to L¹Alkylene and each R^L1The substituents may be optionally different (e.g., hydroxy or halogen).

For the compounds provided herein (including embodiments thereof), L²May be a substituted or unsubstituted arylene group, a substituted or unsubstituted heteroarylene group or a substituted or unsubstituted alkylene group. In one embodiment, L²Is substituted or unsubstituted C₅-C₁₀(e.g. C)₅) Arylene, substituted or unsubstituted 5-to 10-membered (e.g., 5-to 6-membered) heteroarylene, or substituted or unsubstituted C₁-C₁₀(e.g. C)₂-C₆) An alkylene group. L is²May be unsubstituted C₅-C₁₀(e.g. C)₅) Arylene, unsubstituted 5-to 10-membered (e.g. 5-to 6-membered) heteroarylene, or unsubstituted C₁-C₁₀(e.g. C)₂-C₆) An alkylene group. Thus, in one embodiment, L²Is unsubstituted arylene, unsubstituted heteroarylene or unsubstituted alkylene. In some other embodiments, L²Is unsubstituted heteroarylene. In some other embodiments, L²Is pyridylene, thienylene, pyridylene or furanylene. In yet other embodiments, L²Is thiophene-2, 5-diyl. In yet other embodiments, L²Is a propylene-1, 3-diyl group. The terms "pyridylene", "thienylene", "pyrrolylene" and "furanylene" refer to the divalent forms of pyridine, thiophene, pyrrole and furan, respectively, as is conventional in the art.

In one embodiment, L²Is R^L2-substituted or unsubstituted arylene, R^L2-substituted or unsubstituted heteroAryl or R^L2-substituted or unsubstituted C₁-C₁₀(e.g. C)₂-C₆) Alkylene, wherein R^L2Is hydroxy or halogen. In another embodiment, L²Is R^L2-substituted or unsubstituted heteroarylene. In one embodiment, L²Is R^L2Substituted arylenes (e.g. C)₅-C₁₀Arylene). In one embodiment, L²Is R^L2Substituted heteroarylenes (e.g. 5-to 6-membered heteroarylenes). In one embodiment, L²Is R^L2Substituted alkylene (e.g. C)₁-C₁₀Alkylene). When L is²Is R^L2-substituted arylene, R^L2-substituted heteroarylene or R^L2When it is a substituted alkylene group, L²Can be substituted by at least one R^L2-substituted by a substituent and each R^L2The substituents may be optionally different. For example, when L is²Is R^L2When substituted or unsubstituted alkylene, a single R^L2The substituent may be linked to L²Alkylene or multiple R^L2The substituent may be linked to L²Alkylene and each R^L2The substituents may be optionally different (e.g., hydroxy or halogen).

For the compounds provided herein (including embodiments thereof), R²May be a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. In one embodiment, R²Is substituted or unsubstituted C₁-C₁₀Alkyl or substituted or unsubstituted 2 to 10 membered heteroalkyl. In one embodiment, R²Is substituted or unsubstituted C₁-C₁₀An alkyl group. In one embodiment, R²Is a substituted or unsubstituted 2-to 10-membered heteroalkyl group, wherein R^2AIndependently at each occurrence is halogen, hydroxy, R^2B-substituted or unsubstituted alkyl, R^2B-substituted or unsubstituted heteroalkyl, R^2B-substituted or unsubstituted cycloalkyl, R^2B-substituted or unsubstituted heterocycloalkyl, R^2B-substituted or unsubstituted aryl or R^2B-substituted or unsubstituted heteroaryl; r^2BIndependently at each occurrence is halogen, hydroxy, R^2C-substituted or unsubstituted alkyl, R^2C-substituted or unsubstituted heteroalkyl, R^2C-substituted or unsubstituted cycloalkyl, R^2C-substituted or unsubstituted heterocycloalkyl, R^2C-substituted or unsubstituted aryl or R^2C-substituted or unsubstituted heteroaryl; r^2CIndependently at each occurrence is halogen, hydroxy, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In one embodiment, R²Is R^2A-substituted or unsubstituted C₁-C₁₀Alkyl or R^2A-substituted or unsubstituted 2 to 10 membered heteroalkyl. R^2AIndependently at each occurrence is halogen, hydroxy, R^2B-substituted or unsubstituted alkyl, R^2B-substituted or unsubstituted heteroalkyl, R^2B-substituted or unsubstituted cycloalkyl, R^2B-substituted or unsubstituted heterocycloalkyl, R^2B-substituted or unsubstituted aryl or R^2B-substituted or unsubstituted heteroaryl. R^2BIndependently at each occurrence is halogen, hydroxy, R^2C-substituted or unsubstituted alkyl, R^2C-substituted or unsubstituted heteroalkyl, R^2C-substituted or unsubstituted cycloalkyl, R^2C-substituted or unsubstituted heterocycloalkyl, R^2C-substituted or unsubstituted aryl or R^2C-substituted or unsubstituted heteroaryl. R^2CIndependently at each occurrence is halogen, hydroxy, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In one embodimentIn the scheme, R²Is R^2A-substituted or unsubstituted C₁-C_1oAn alkyl group. In one embodiment, R²Is R^2A-substituted or unsubstituted 2 to 10 membered heteroalkyl.

In one embodiment, R^2AIs R^2B-substituted or unsubstituted alkyl or R^2B-substituted or unsubstituted heteroalkyl. In one embodiment, R^2AIs R^2B-substituted or unsubstituted alkyl. In one embodiment, R^2AIs R^2B-substituted or unsubstituted heteroalkyl.

In one embodiment, R^2AIs halogen or hydroxy. In one embodiment, R^2AIs a halogen. In one embodiment, R^2AIs a hydroxyl group.

In one embodiment, R²By a single substituent R^2AOr a plurality of substituents R^2AIs substituted in which R^2AIs independently selected at each occurrence. In one embodiment, R^2AAt each occurrence is halogen. In one embodiment, R^2AAt each occurrence is a hydroxyl group.

R²Is R^2A-substituted or unsubstituted C₁-C₁₀(e.g. C)₂-C₈) Alkyl and R^2AIs a hydroxyl group. Thus, in one embodiment, R²Is R^2A-substituted or unsubstituted C₁-C₁₀Alkyl and R^2AIs a hydroxyl group. In one embodiment, R²Is R^2A-substituted or unsubstituted C₃-C₆Alkyl and R^2AIs a hydroxyl group. When R is²Is R^2A-substituted C₁-C₁₀(e.g. C)₂-C₈) Alkyl and R^2AWhen it is hydroxy, R²By at least one (e.g. one, two, three, four, five or six) R^2A-substituent substitution. For example, R²May be R^2A-substituted C₃Alkyl radical, wherein R^2AIs a first hydroxyl group and a second hydroxyl group, wherein the first hydroxyl group is bonded to C₃C of alkyl₂(the number of carbons is 2) and a second hydroxy is attached to C₃C of alkyl₃(the carbon number is 3). In one embodiment, R²Is R^2A-substituted C₄Alkyl radical, R^2AIs a first hydroxyl group, a second hydroxyl group and a third hydroxyl group, wherein the first hydroxyl group is connected to C₄C of alkyl₂The second hydroxyl is connected to C₄C of alkyl₃And the third hydroxyl is connected to C₄C of alkyl₄. In one embodiment, R²Is R^2A-substituted C₅Alkyl radical, R^2AIs a first hydroxyl group, a second hydroxyl group, a third hydroxyl group and a fourth hydroxyl group, wherein the first hydroxyl group is connected to C₅C of alkyl₂The second hydroxyl is connected to C₅C of alkyl₃The second hydroxyl is connected to C₅C of alkyl₄And the fourth hydroxyl group is bonded to C₅C of alkyl₅. In one embodiment, R²Is R^2A-substituted C₆Alkyl radical, R^2AIs a first hydroxyl group, a second hydroxyl group, a third hydroxyl group, a fourth hydroxyl group and a fifth hydroxyl group, wherein the first hydroxyl group is connected to C₆C of alkyl₂The second hydroxyl is connected to C₆C of alkyl₃The second hydroxyl is connected to C₆C of alkyl₄The fourth hydroxyl group being bonded to C₆C of alkyl₅And a fifth hydroxyl group is bonded to C₆C of alkyl₆. Is referred to herein as being linked to R^2ASubstituted (e.g. C)₅) C of alkyl₃The hydroxy group of (A) is at R^2A-a hydroxyl group bonded to carbon at position 3 of the substituted alkyl group. In the context of the compounds of formula (I), R^2ACarbon 3 of the substituted alkyl group is a carbon separated by three bonds from the oxygen forming one bond with the carbonyl group of the compound. In the context of formula (I), the oxygen bonded to the carbonyl group is indicated by an asterisk in the structure:

for the compounds provided herein (including embodiments thereof), L³C which may be substituted or unsubstituted₁-C₆(e.g. C)₂-C₅) An alkylene group. In one embodiment, L³Is unsubstituted C₁、C₂、C₃、C₄、C₅Or C₆An alkylene group. In one embodiment, L³Is unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkylene group. In one embodiment, L³Is unsubstituted C₂-C₅(e.g. C)₃-C₅) An alkylene group. In one embodiment, L³Is an unsubstituted ethylene group.

For the compounds provided herein (including embodiments thereof), R¹May be R^1A-substituted or unsubstituted aryl or R^1A-substituted or unsubstituted heteroaryl and R^1AIs halogen, unsubstituted C₁-C₆Alkyl, -CF₃、-OCF₃OR-OR^1BAnd R is^1BIs unsubstituted C₁-C₆An alkyl group. In one embodiment, R¹Is R^1ASubstituted or unsubstituted aryl (e.g. C)₅-C₁₀Aryl) or R^1A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl), wherein R^1AIs halogen (e.g. fluorine or chlorine), unsubstituted C₁-C₆(e.g. C)₂-C₅) Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkyl group. In one embodiment, R¹Is R^1ASubstituted (e.g. C)₅-C₁₀) Aryl or R^1ASubstituted (e.g. 5 to 10 membered) heteroaryl, wherein R^1AIs halogen, unsubstituted C₁-C₆(e.g. C)₂-C₅) Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkyl group. When R is¹Is R^1ASubstituted aryl radicals (e.g. C)₅-C₁₀Aryl) or R^1AWhen substituted (e.g. 5-to 10-membered heteroaryl), R¹Can be substituted by at least one R^1A-substituted by a substituent and each R^1AThe substituents may optionally be different (e.g. halogen, unsubstituted C₁-C₆Alkyl, CF₃、-OCF₃OR-OR^1B). For example, when R is¹Is R^1AWhen substituted aryl, a single R^1ASubstituents may be attached to R¹Aryl or multiple R^1ASubstituents may be attached to R¹Aryl and each R^1AThe substituents may be optionally different (e.g., halogen, unsubstituted C₁-C₆Alkyl, CF₃、-OCF₃OR-OR^1B). In one embodiment, R¹Is R^1A-substituted 5 to 10 membered heteroaryl, wherein R^1AIs halogen, unsubstituted C₂-C₅Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkyl group. In one embodiment, R¹Is R^1A-substituted C₅-C_1oAryl, wherein R^1AIs halogen, unsubstituted C₂-C₅Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkyl group. In one embodiment, R¹Is R^1A-substituted phenyl, wherein R^1AIs halogen, unsubstituted C₂-C₅Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆(e.g. C)₂-C₅) An alkyl group. In one embodiment, R¹Is R^1A-substituted phenyl, wherein R^1AIs a halogen. In one embodiment, R¹Is R^1A-substitutionIn which R is^1AIs chlorine. In one embodiment, R¹Having the formula:wherein R is^1A' and R^1A"independently is halogen, unsubstituted C₁-C₆Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆An alkyl group.

In one embodiment, the compound has the structure of the formula:

when the compound has the structure of formula (III), n is 1 to 10, and R^2DIndependently at each occurrence is hydrogen or hydroxy. In formula (III), n may be 1, 2, 3,4, 5, 6, 7, 8, 9 or 10. In one embodiment, 1, 2, 3,4, 5 or 6R^2DThe substituent is not hydrogen. In one embodiment, 2R^2DThe substituent is not hydrogen. In one embodiment, 3R^2DThe substituent is not hydrogen. In one embodiment, 4R^2DThe substituent is not hydrogen. In one embodiment, 5R^2DThe substituent is not hydrogen. In one embodiment, 6R^2DThe substituent is not hydrogen. In one embodiment, 1R^2DThe substituent is a hydroxyl group. In one embodiment, 2R^2DThe substituent is a hydroxyl group. In one embodiment, 3R^2DThe substituent is a hydroxyl group. In one embodiment, 4R^2DThe substituent is a hydroxyl group. In one embodiment, n is greater than 1, for example 2, 3,4, 5, 6, 7, 8, 9 or 10. In one embodiment, n is 3 and 2R^2DThe substituent is a hydroxyl group. In one embodiment, n is 4 and 3R^2DThe substituent is a hydroxyl group. In one embodiment, n is 5 and 4R^2DThe substituent is a hydroxyl group. In one embodiment, R²Is not hydroxyethyl.

In one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

in one embodiment, the compound has the structure of the formula:

the compounds described herein (including embodiments thereof), e.g. compounds having the structure of any one of formulae (I), (III), (IV), (V), (VI), (VII), or derivatives, isomers or enantiomers thereof, may be provided, where appropriate, as pharmaceutically acceptable salts as defined herein, wherein the compounds allow the formation of pharmaceutically acceptable salts. In one embodiment, provided herein is a compound having the structure of any one of formulas (I), (III), (IV), (V), (VI), (VII), or a pharmaceutically acceptable salt of an isomer or enantiomer thereof, wherein the compound allows for the formation of a pharmaceutically acceptable salt.

Pharmaceutical composition

In another aspect, an ophthalmic pharmaceutical composition is provided that includes a compound provided herein and embodiments thereof (e.g., a compound of formula (I), (III), (IV), (V), (VI), (VII), or a derivative, isomer, or enantiomer thereof). In one embodiment, the compound has the structure of formula (I). In one embodiment, the compound has the structure of formula (III). In one embodiment, the compound has the structure of formula (IV). In one embodiment, the compound has the structure of one of formulas (IVa) - (IVb). In one embodiment, the compound has the structure of formula (V). In one embodiment, the compound has the structure of one of formulas (Va) - (Vd). In one embodiment, the compound has the structure of formula (VI). In one embodiment, the compound has the structure of one of formulas (VIa) - (VIh). In one embodiment, the compound has the structure of formula (VII). In one embodiment, the compound has a structure of one of formulas (VIIa) - (VIIp).

In one embodiment, the pharmaceutical composition is a solution, emulsion, gel or foam. In one embodiment, the pharmaceutical composition is a solution. In one embodiment, the pharmaceutical composition is an emulsion. In one embodiment, the pharmaceutical composition is a gel. In one embodiment, the pharmaceutical composition is a foam.

A. Preparation

The compounds and pharmaceutical compositions disclosed herein can be prepared and administered in a variety of forms including solutions, emulsions, gels, or foams. Accordingly, pharmaceutical compositions contemplated herein comprise a pharmaceutically acceptable carrier or excipient and one or more compounds described herein. By "solution" is conventionally meant a liquid pharmaceutical composition in which a compound (e.g., a compound described herein) is at least partially dissolved, preferably completely dissolved, and which may be administered in liquid form. An "emulsion" conventionally refers to a mixture of two or more immiscible liquids, one compound (e.g., a compound described herein or a solution thereof) dispersed in another compound (e.g., a carrier as described herein). "gel" conventionally refers to a highly viscous solution, emulsion, or colloidal suspension of a compound in a continuous fluid phase, resulting in a viscous semi-rigid fluid. "colloid" conventionally refers to a composition comprising a continuous medium having distributed throughout it small particles that do not settle under the influence of gravity. "foam" conventionally refers to compositions that include a continuous medium (i.e., solutions, emulsions, gels, and the like) having a gas (e.g., air) dispersed therein.

Pharmaceutical compositions contemplated herein may be prepared by combining a therapeutically effective amount of at least one compound as described herein as the active ingredient with one or more conventional pharmaceutically acceptable excipients and by preparing a unit dosage form suitable for topical use. Therapeutically effective amounts are generally between about 0.0001 and about 5% (w/v), preferably between about 0.001 to about 1.0% (w/v) in liquid formulations including solutions, emulsions, gels and foams. PHARMACEUTICAL mixtures suitable for use in the present invention include those described in, for example, PHARMACEUTICAL SCIENCES (17 th edition, Mack pub. co., Easton, PA) and WO 96/05309, the teachings of both of which are incorporated herein by reference.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself or it may be the appropriate number of any of these in packaged form.

Some compounds may have limited solubility in water and therefore may require surfactants or other suitable co-solvents in the composition. Such co-solvents include: polysorbates 20, 60, and 80; pluronic (Pluronic) F-68, F-84 and P-103; a cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically used at levels between about 0.01% and about 2% by weight.

A viscosity greater than that of a simple aqueous solution may be desirable to reduce variability in dispensing the formulation, reduce physical separation of components of a suspension or emulsion of the formulation, and/or otherwise improve the formulation. Such viscosity generating agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically used at levels between about 0.01% and about 2% by weight.

The compositions of the present invention may additionally include components that provide sustained release and/or comfort. Such components include high molecular weight anionic mucomimetic polymers, gel-forming polysaccharides, and finely divided pharmaceutical carrier substrates. These components are discussed in more detail in U.S. patent nos. 4,911,920; 5,403,841, respectively; 5,212,162, respectively; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. U.S. patent application publication No. US2011-0124736a1 (also equivalent to U.S. patent application serial No. 12/940,711) is hereby incorporated by reference in its entirety.

For ophthalmic applications, solutions are preferably prepared using physiological saline solution as the primary vehicle. The pH of the ophthalmic solution should preferably be maintained between 4.5 and 8.0 with a suitable buffer system, neutral pH being preferred but not essential. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

Various buffers and means for adjusting the pH may be used as long as the resulting formulation is ophthalmically acceptable. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as desired.

Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic formulations of the present invention. Such vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin, and purified water.

Tonicity agents may be added as needed or appropriate. Including but not limited to salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmically acceptable tonicity adjusting agent.

Ophthalmically acceptable antioxidants for use in the present invention include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene.

Other excipient components that may be included in the ophthalmic formulation are chelating agents. The preferred chelating agent is edetate disodium, although other chelating agents may be used instead of or in combination therewith.

Ophthalmic formulations of the present invention are suitably packaged in a form suitable for metered use, such as in containers equipped with an orifice, to facilitate application to the eye. Vials suitable for unit dose administration are typically made of a suitable inert, non-toxic plastic material and typically contain between about 0.5 and about 15ml of a solution, emulsion, gel or foam. A package may contain one or more unit doses.

Preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five unit doses, with typical unit doses being 1 to about 8, preferably 1 to about 3, drops.

Typically, the compound is repeatedly administered topically to the body part to be treated (e.g., the eye) for a period of time. Preferred dosing regimens will generally include periodic administration for a treatment period of at least one month, more preferably at least three months, and most preferably at least six months. Regular administration may be 1, 2, 3,4 or even more times per day.

Methods of treatment

In another aspect, a method of treating an ophthalmic disorder in a human is provided. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound provided herein and embodiments thereof (e.g., a compound of formula (I), (III), (IV), (V), (VI), (VII), or a derivative, isomer, or enantiomer thereof). In one embodiment, the administration is topical administration. In one embodiment, the disease is macular degeneration. In one embodiment, the disease is caused by intraocular pressure. In one embodiment, the disease is glaucoma.

In one embodiment, a combination therapy is provided with a-blocker (or-adrenergic antagonist) including carteolol, levobunolol, metiprolol, timolol hemihydrate, timolol maleate, a 1-selective antagonist such as betaxolol and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, a combination therapy is provided with adrenergic agonists, including non-selective adrenergic agonists such as epinephrine, epinephrine hydrochloride, and dipivefrin and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof, and 2-selective adrenergic agonists such as apraclonidine, brimonidine and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, a combination therapy with carbonic anhydrase inhibitors (including acetazolamide, dichloramide, methazolamide, brinzolamide, dorzolamide and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof) is provided.

In one embodiment, a combination therapy is provided with a cholinergic agonist, including direct-acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, a combination therapy is provided with a cholinesterase inhibitor such as dimethomorph bromide, diethoxyphosphathiocholine, physostigmine and its analogs, or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, a method is provided for using glutamate antagonists or other neuroprotective agents such as Ca²⁺Channel blockers such as memantine, amantadine, rimantadine, nitroglycerin, dextrorphan, methamphetamine, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepineCombination therapy of bepridil, diphenylbutylpiperidine, diphenylpiperazine, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101, 606, tibalosin, 2309BT and 840S, flufenitrozine, nicardipine, nifedipine, nimodipine, barnidipine, verapamil, lidofloxacin, clonidine, amiloride and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, a combination therapy with a prostamide, such as bimatoprost, or a pharmaceutically acceptable salt or prodrug thereof is provided.

In one embodiment, a combination therapy with prostaglandins (including travoprost, UF0-21, treprostinil, fluprostenol, 13, 14-dihydro-treprostinil, isopropyl unoprostone, latanoprost, and analogs thereof) is provided.

In one embodiment, a combination therapy with cannabinoids, including CB1 agonists such as WIN-55212-2 and CP-55940 and analogs thereof, or pharmaceutically acceptable salts or prodrugs thereof, is provided.

In another aspect, a method of reducing corneal thickening is provided. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a compound provided herein and embodiments thereof (e.g., a compound of formula (I), (III), (IV), (V), (VI), (VII), or a derivative, isomer, or enantiomer thereof). In one embodiment, the subject has glaucoma. In one embodiment, the subject has ocular hypertension.

In one embodiment, a method of using a compound disclosed herein for the manufacture of a medicament for treating glaucoma or ocular hypertension is provided. In one embodiment, the compound has the structure of any one of formulas (I), (III), (IV), (V), (VI), or (VII). In one embodiment, the compound has the structure of formula (I). In one embodiment, the compound has the structure of formula (III). In one embodiment, the compound has the structure of formula (IV). In one embodiment, the compound has the structure of one of formulas (IVa) - (IVb). In one embodiment, the compound has the structure of formula (V). In one embodiment, the compound has the structure of one of formulas (Va) - (Vd). In one embodiment, the compound has the structure of formula (VI). In one embodiment, the compound has the structure of one of formulas (VIa) - (VIh). In one embodiment, the compound has the structure of formula (VII). In one embodiment, the compound has a structure of one of formulas (VIIa) - (VIIp).

V. examples

The abbreviations used herein have their usual meaning in the chemical arts. Specific abbreviations include the following: TBDMSO (tert-butyl dimethyl sulfoxide): (tert-butyldimethylsilyl) oxy; DMF: dimethylformamide; EDC: 1-ethyl-3- [ 3-dimethylaminopropyl radical]A carbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; THF: tetrahydrofuran; bu₄NF: tetrabutylammonium fluoride.

EXAMPLE 1 Synthesis of 2, 3-dihydroxypropyl (R) -5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylate (Compound 3).

An exemplary synthesis of compound 3 is provided in scheme 1 below.

5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylic acid ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl ester (Compound 2).

(R) - (-) -2, 2-dimethyl-1, 3-dioxolane-4-methanol (572.2mg, 4.33mmol) was added to a solution of compound 1 in formic acid (200mg, 0.433mmol), 4- (dimethylamino) pyridine (55.3mg, 0.453mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (91.3mg, 0.476mmol) in DMF (3.0mL) at 23 ℃. After stirring for 16 h, the reaction solution was diluted with EtOAc and diluted with 1N HCl, saturated NaHCO₃The aqueous solution was then washed with brine. The organic portion was dried (MgSO)₄) Filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 2: 1 hexanes/EtOAc) to afford 211.7mg (85%) of acetonide protected ester 2 as a clear viscous oil. Ester 2(249.0mg, 0.433mmol) was stirred in a mixture of 1N HCl: THF (1: 1, 3.0mL) at 23 deg.C for 24 h. The reaction mixture was then diluted with EtOAc and water, saturated NaHCO₃The aqueous solution was then washed with brine. The organic portion was dried (MgSO)₄) Filtered and concentrated in vacuo. By flash column chromatographyThe residue was purified (silica gel, 1: 1 hexanes/EtOAc followed by 100% EtOAc) to give 158.8mg (68%) of the bishydroxy ester compound 3 as a clear viscous oil.

Scheme 1:

EXAMPLE 2 Synthesis of ((S) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl 5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylate (Compound 4).

Using 100mg (0.216mmol) of compound 1 formic acid and 42.8mg (0.324mmol) of (S) - (+) -2, 2-dimethyl-1, 3-dioxolane-4-methanol according to the procedure described above for the preparation of compound 2, 72.3mg (58%) of acetonide protected ester compound 4 was obtained.

EXAMPLE 3 Synthesis of 2, 3-dihydroxypropyl (S) -5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylate (Compound 5).

Using 72.3mg (0.125mmol) of ester 4, 43.5mg (65%) of bishydroxy ester compound 5 was obtained as a clear viscous oil according to the procedure described above for the preparation of compound 3.

EXAMPLE 4 Synthesis of 5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylic acid ((4R, 5R) -5- (hydroxymethyl) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl ester (Compound 6).

Using 100mg (0.216mmol) of Compound 1 in formic acid and 52.5mg (0.324mmol) of (4R, 5R) -2, 2-dimethyl-1, 3-dioxolane-4, 5-dimethanol, 41.5mg (31%) of acetonide protected ester Compound 6 was obtained according to the procedure described above for the preparation of Compound 2.

EXAMPLE 5 Synthesis of (2R, 3R) -2, 3, 4-trihydroxybutyl 5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylate (Compound 7).

Using 41.5mg (0.069mmol) of ester 6, 27.6mg (71%) of trihydroxyester compound 7 was obtained as a clear viscous oil according to the procedure described above for the preparation of compound 3.

EXAMPLE 6 Synthesis of 5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylic acid ((4S, 5S) -5- (hydroxymethyl) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl ester (Compound 8).

Using 100mg (0.216mmol) of formic acid 1 and 52.5mg (0.324mmol) ((4S, 5S) -2, 2-dimethyl-1, 3-dioxolane-4, 5-dimethanol, according to the procedure described above for the preparation of compound 2, 71.9mg (55%) of acetonide protected ester compound 8 was obtained.

EXAMPLE 7 Synthesis of (2S, 3S) -5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylic acid 2, 3, 4-trihydroxybutyl ester (Compound 9).

Using 71.9mg (0.118mmol) of ester 8 gave 39.2mg (59%) of trihydroxyester compound 9 as a clear viscous oil according to the procedure described above for the preparation of compound 3.

EXAMPLE 8 Synthesis of 5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylic acid ((4R, 4 'S, 5R) -2, 2, 2', 2 '-tetramethyl- [4, 4' -bis (1, 3-dioxolane) ] -5-yl) methyl ester (Compound 10).

According to the procedure described above for the preparation of compound 2, using 100mg (0.216mmol) of formic acid 1 and 60.1mg (0.259mmol) of ((4S, 4 'S, 5R) -2, 2, 2', 2 '-tetramethyl- [4, 4' -bis (1, 3-dioxolane) ] -5-yl) methanol, 79.2mg (52%) of diacetone compound protected ester compound 10 was obtained.

EXAMPLE 9 Synthesis of (2R, 3R, 4S) -5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylic acid 2, 3,4, 5-tetrahydroxypentyl ester (11).

Using 79.2mg (0.117mmol) of ester 10 gave 11.8mg (17%) of ester compound 11 as a clear viscous oil according to the procedure described above for the preparation of compound 3.

EXAMPLE 10 Synthesis of 2-hydroxy-2- ((4R, 4 'R, 5R) -2, 2, 2', 2 '-tetramethyl- [4, 4' -bis (1, 3-dioxolane) ] -5-yl) ethyl (S) -5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylate (Compound 12).

According to the procedure described above for the preparation of compound 2, using 100mg (0.216mmol) of formic acid 1 and 67.9mg (0.259mmol) of (S) -1- ((4R, 4 'R, 5R) -2, 2, 2', 2 '-tetramethyl- [4, 4' -bis (1, 3-dioxolane) ] -5-yl) ethane-1, 2-diol, 90.1mg (59%) of diacetone compound protected ester compound 12 was obtained.

EXAMPLE 11 Synthesis of 2, 3,4, 5, 6-pentahydroxyhexyl 5- (3- ((1R, 2R, 3R, 5R) -5-chloro-2- (3, 5-dichlorophenethyl) -3-hydroxycyclopentyl) propyl) thiophene-2-carboxylate (Compound 13).

The use of 65.8mg (0.093mmol) of ester 12 according to the procedure described above for the preparation of compound 3 gave 43.5mg (75%) of ester 13 as a clear viscous oil.

VI. embodiment

Embodiment 1. a compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹Is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; l is¹Is a bond, substituted or unsubstituted C₁-C₁₀Alkylene or substituted or unsubstituted 2-to 10-membered heteroalkylene; l is²Is a bond, substituted or unsubstituted C₁-C_1oAn alkylene group, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group; l is³Is a bond or substituted or unsubstituted C₁-C_1oAn alkylene group; and R is²Is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 2. the compound of embodiment 1 wherein R²Is R^2A-substituted or unsubstituted C₁-C₁₀Alkyl or R^2A-substituted or unsubstituted 2 to 10 membered heteroalkyl, wherein R^2AIndependently at each occurrence is halogen, hydroxy, R^2B-substituted or unsubstituted alkyl, R^2B-substituted or unsubstituted heteroalkyl, R^2B-substituted or unsubstituted cycloalkyl, R^2B-substituted or unsubstituted heterocycloalkyl, R^2B-substituted or unsubstituted aryl or R^2B-substituted or unsubstituted heteroaryl; r^2BIndependently at each occurrence is halogen, hydroxy, R^2C-substituted or unsubstituted alkyl, R^2C-substituted or unsubstituted heteroalkyl, R^2C-substituted or unsubstituted cycloalkyl, R^2C-substituted or unsubstituted heterocycloalkyl, R^2C-substituted or unsubstituted aryl orR^2C-substituted or unsubstituted heteroaryl; r^2CIndependently at each occurrence is halogen, hydroxy, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

Embodiment 3. the compound of embodiment 2 wherein R²Is substituted or unsubstituted C₁-C₁₀An alkyl group.

Embodiment 4. the compound of any of embodiments 2 or 3 wherein R^2AIs R^2B-substituted or unsubstituted alkyl or R^2B-substituted or unsubstituted heteroalkyl.

Embodiment 5. the compound of any one of embodiments 2 to 4 wherein R^2AIs R^2B-substituted or unsubstituted alkyl.

Embodiment 6. the compound of any one of embodiments 2 to 5 wherein R^2AIs halogen or hydroxy.

Embodiment 7. the compound of embodiment 6 wherein R^2AIs a hydroxyl group.

Embodiment 8. the compound of any one of embodiments 1 to 7 wherein L¹Is substituted or unsubstituted C₁-C₆An alkylene group.

Embodiment 9 a compound of any one of embodiments 1 to 8 wherein L¹Is unsubstituted C₁-C₆An alkylene group.

Embodiment 10 a compound of any one of embodiments 1 to 8 wherein L¹Is a substituted or unsubstituted propylene group.

Embodiment 11A compound of embodiment 1 wherein L¹Is R^L1-substituted or unsubstituted C₁-C₁₀Alkylene or R^L1-substituted or unsubstituted 2 to 10 membered heteroalkylene, wherein R^L1Independently at each occurrence is halogen or hydroxy.

Embodiment 12. the compound of embodiment 11 wherein R^L1Is a hydroxyl group.

Embodiment 13. the compound of embodiment 11 wherein R^L1Is fluorine.

Embodiment 14. the compound of embodiment 11 wherein L¹Is R^L1-substituted or unsubstituted C₁-C₁₀An alkylene group.

Embodiment 15. the compound of embodiment 14 wherein R^L1Is a hydroxyl group.

Embodiment 16. the compound of embodiment 14 wherein R^L1Is fluorine.

Embodiment 17A compound of embodiment 11 wherein L¹Is R^L1-substituted or unsubstituted C₂-C₆An alkylene group.

Embodiment 18. the compound of embodiment 17 wherein R^L1Is a hydroxyl group.

Embodiment 19. the compound of embodiment 17 wherein R^L1Is fluorine.

Embodiment 20A compound of embodiment 11 wherein L¹Is unsubstituted C₂-C₆An alkylene group.

Embodiment 21. the compound of embodiment 11 wherein L¹Is unsubstituted propylene.

Embodiment 22 a compound of any one of embodiments 1 to 21 wherein L²Is a substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene or substituted or unsubstituted C₁-C₁₀An alkylene group.

Embodiment 23 a compound of any one of embodiments 1 to 21 wherein L²Is R^L2Substituted or unsubstituted arylene, R^L2-substituted or unsubstituted heteroarylene or R^L2-substituted or unsubstituted C₁-C₁₀Alkylene, wherein R^L2Is hydroxy or halogen.

Embodiment 24A compound of embodiment 1 wherein L²Is R^L2Substituted or unsubstituted heteroarylene.

Embodiment 25 embodiment 1 to24, wherein L²Is unsubstituted arylene, unsubstituted heteroarylene or unsubstituted alkylene.

Embodiment 26. the compound of embodiment 25 wherein L²Is unsubstituted heteroarylene.

Embodiment 27. the compound of embodiment 25 wherein L²Is unsubstituted pyridylene, unsubstituted thienylene, unsubstituted pyridylene or unsubstituted furanylene.

Embodiment 28. the compound of embodiment 25 wherein L²Is thiophene-2, 5-diyl.

Embodiment 29A compound of embodiment 25 wherein L²Is a propylene-1, 3-diyl group.

Embodiment 30 a compound of any one of embodiments 1 to 29 wherein R²Is R^2A-substituted or unsubstituted C₁-C₁₀Alkyl radical, wherein R^2AIs a hydroxyl group.

Embodiment 31. the compound of any one of embodiments 1 to 30, wherein R²Is R^2A-substituted C₃-C₅Alkyl radical, wherein R^2AIs a hydroxyl group.

Embodiment 32 a compound of any one of embodiments 1 to 31 wherein L³Is unsubstituted C₁-C₆An alkylene group.

Embodiment 33 a compound of any one of embodiments 1 to 32 wherein L³Is an unsubstituted ethylene group.

Embodiment 34 a compound of any one of embodiments 1 to 33 wherein R¹Is R^1A-substituted or unsubstituted aryl or R^1A-substituted or unsubstituted heteroaryl, wherein R^1AIs halogen, unsubstituted C₁-C₆Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆An alkyl group.

Embodiment 35. the compound of any one of embodiments 1 to 34, wherein R¹Is R^1A-substituted phenyl, wherein R^1AIs halogen, unsubstituted C₁-C₆Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆An alkyl group.

Embodiment 36. the compound of any one of embodiments 1 to 35,

wherein R is¹Having the formula:wherein R is^1A' and R^1A"independently is halogen, unsubstituted C₁-C₆Alkyl, -CF₃、-OCF₃OR-OR^1BWherein R is^1BIs unsubstituted C₁-C₆An alkyl group.

Embodiment 37. the compound of embodiment 1 having the formula:

wherein n is 1 to 10;

and is

R^2DIndependently at each occurrence is hydrogen or hydroxy.

Embodiment 38 an ophthalmic pharmaceutical composition comprising a compound of any one of embodiments 1 to 37 and a pharmaceutically acceptable carrier.

Embodiment 39 a method of treating an ophthalmic disease in a human comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 37.

Embodiment 40 the method of embodiment 39, wherein said administering is topical administration.

Embodiment 41 the method of embodiment 39, wherein said disease is glaucoma.

Embodiment 42 the method of embodiment 39, wherein said disease is macular degeneration.

Embodiment 43 the method of embodiment 39, wherein the disease is caused by intraocular pressure.

Embodiment 44. a method of reducing corneal thickening, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 37.

Embodiment 45 the method of embodiment 44, wherein the subject has glaucoma.

Embodiment 46 the method of embodiment 44, wherein said subject has ocular hypertension.

Claims (18)

1. A compound having the structure of formula:

wherein

n is 2, 3,4, 5, 6, 7, 8, 9 or 10;

R^2Dindependently at each occurrence is hydrogen or hydroxy; and is

2.3, 4, 5 or 6R^2DThe substituent is not hydrogen.

2. The compound of claim 1, having the formula:

3. the compound of claim 1, having the formula:

4. the compound of claim 1, having the formula:

5. the compound of claim 1, having the formula:

6. the compound of claim 1, having the formula:

7. the compound of claim 1, having the formula:

8. the compound of claim 1, having the formula:

9. the compound of claim 1, having the formula:

10. an ophthalmic pharmaceutical composition comprising a compound of any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. Use of a compound according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of an ophthalmic disorder in a human.

12. The use of claim 11, wherein the medicament is for topical administration.

13. The use of claim 11, wherein the disease is glaucoma.

14. The use of claim 11, wherein the disease is macular degeneration.

15. The use of claim 11, wherein the disease is caused by intraocular pressure.

16. Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for reducing corneal thickening in a subject.

17. The use of claim 16, wherein the subject has glaucoma.

18. The use of claim 16, wherein the subject has ocular hypertension.