Compounds, compositions and pharmaceutical compositions for treating myopia

Abstract

Provided herein are 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmetanil ester and amide compounds and compositions. Also provided herein are methods for preventing or delaying the onset of myopia in a subject in need thereof, comprising administering to the subject a compound or composition provided herein. Also provided herein are methods for delaying or preventing the progression of myopia in a subject in need thereof, comprising administering to the subject a compound or composition provided herein.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 800,312, filed February 1, 2019, U.S. Provisional Patent Application No. 62 / 801,515, filed February 5, 2019, and U.S. Provisional Patent Application No. 62 / 819,236, filed March 15, 2019, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) Provided herein are 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-yl metanil ester and amide compounds and compositions. Also provided herein are methods of preventing or slowing the onset of myopia in a subject in need thereof, comprising administering to the subject a compound or composition provided herein. Also provided herein are methods of slowing or preventing the progression of myopia in a subject in need thereof, comprising administering to the subject a compound or composition provided herein. [Background technology]

[0003] Myopia, otherwise known as nearsightedness or near-sightedness, is a type of refractive error of the eye that is typically characterized by distant objects appearing blurred because visual images are focused in front of the retina. Myopia is particularly prevalent in Asians, with reported prevalence rates of 70-90% in Asian countries. Myopia can be corrected with prescription lenses (e.g., spectacles or contact lenses) or refractive surgery (e.g., LASIK or phakic intraocular lens implantation). In addition, patients with high myopia are at increased risk of developing vision-threatening disorders such as retinal degeneration, tears and detachments, myopic choroidal neovascularization, myopic macular schisis and holes, posterior staphyloma, myopic macular degeneration, early-onset cataracts (in the 30s and 40s), open-angle glaucoma, and peripapillary atrophy, optic disc tilt, and pits. If left untreated, these disorders can lead to vision loss later in life. Also, children who develop myopia early are more likely to eventually develop high myopia. A recent Singapore-based paper pooling data from adult studies in Singapore, China, India and Malaysia showed that the pathological symptoms of myopia, especially staphyloma and chorioretinal atrophy, worsen with age, myopic refraction and axial length progression (Non-Patent Document 1). Therefore, the application of compounds or compositions that can delay the onset and / or progression of myopia in patients at an early age will have a significant beneficial impact on their lives, so that even if myopia progresses, it will result in a lower outcome than would have been the case if they had not been applied (e.g., -5.00D instead of -10.00D). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Chang et al. (2013) Summary of the Invention [Problem to be solved by the invention]

[0005] This application relates to compounds and compositions thereof for preventing or delaying the onset of myopia when administered before myopia occurs, or for preventing or reducing the progression of myopia when myopia is present. Without wishing to be bound by theory, it is believed that these compounds act by antagonizing one or more of the family of muscarinic receptors. Although much research has been done in the field of muscarinic receptors, there are common side effects such as blurred vision and a lack of truly selective antagonists. [Means for solving the problem]

[0006] In one aspect, the present disclosure provides a compound of formula I: [ka] or a polymorph, zwitterion, solvate, or pharma- ceutically acceptable salt thereof, wherein R and R' are independently H or lower alkyl, and A and B are independently CH, NR 1 or O, R 1 is H or lower alkyl, and X is hydrogen, hydroxyl, halogen, C1-C4 alkyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl. The attachment of the heteroatom to the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl system can be either endo or exo, but if the configuration is endo, then R and R' cannot both be hydrogen and A cannot be oxygen at the same time.

[0007] In another aspect, the present disclosure provides a compound of formula II [ka] or a polymorph, zwitterion, solvate, or pharma- ceutically acceptable salt thereof, wherein R and R' are independently H or lower alkyl, and A and B are independently CH2, CF3, CF2H, NR 1 or O, R 1 is H or lower alkyl, and X and Y are hydrogen, hydroxyl, halogen, C1-C4 alkyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl.

[0008] In another aspect, the present disclosure provides a compound of formula III [ka] or a polymorph, zwitterion, solvate, or pharma- ceutically acceptable salt thereof, wherein R and R' are independently H or lower alkyl, and A and B are independently CH, NR 1 or O, R 1 is H or lower alkyl, and X is hydrogen, hydroxyl, halogen, C1-C4 alkyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl. The attachment of the heteroatom to the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl system can be either endo or exo.

[0009] In another aspect, the present disclosure provides a compound of formula IV [ka] or a polymorph, zwitterion, solvate, or pharma- ceutically acceptable salt thereof, wherein R and R' are independently H or lower alkyl, and A and B are independently CH2, CF3, CF2H, NR 1 or O, R1 is H or lower alkyl, and X and Y are hydrogen, hydroxyl, halogen, C1-C4 alkyl, amino, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl.

[0010] In yet another aspect, the present disclosure provides a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IV), benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester, [ka] , the (3R,2'R)-enantiomer of EA-3167, [ka] where X is Cl, Br or I; [ka] where X is Cl, Br or I; [ka] or a polymorph, zwitterion, solvate, pharma- ceutically acceptable salt, or combination thereof, and a pharma- ceutically acceptable vehicle.

[0011] In another embodiment, the compound of formula (I), the compound of formula (II), the compound of formula (III), the compound of formula (IV), benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester, [ka] , the (3R,2'R)-enantiomer of EA-3167, [ka] where X is Cl, Br or I; [ka] where X is Cl, Br or I; [ka] or a polymorph, zwitterion, solvate, pharma- ceutically acceptable salt, or combination thereof, and a non-aqueous solvent. Suitable compounds can also be found in the publication Archiv der Pharmazie (Weinheim, Germany) Volume 306 Issue 12 Pages 943-7 1973, which is incorporated herein by reference. In addition, several natural products have been found to have the required structure, one example being Dokladi na Bulgarskata Akademiya naukite Volume57 Issue 5 Pages 41-44, 2004, although all natural products encompassed by formulas III and IV are specifically contemplated.

[0012] In yet another aspect, the disclosure provides a method for preventing or delaying the onset of myopia, comprising administering to a subject a composition comprising less than 0.1% of a compound of formula III or formula IV intraocularly. In some embodiments, the compound is present in the form of a pharma- ceutically acceptable salt. In some embodiments, the composition comprises about 0.01% of a compound of formula III or formula IV. In some embodiments, the composition comprises about 1.0%-0.0049% of a compound of formula III or formula IV. In some embodiments, the subject is a human between 4 and 21 years of age. In some embodiments, the subject is a human between 5 and 10 years of age. In some embodiments, the subject has pre-myopia. In some embodiments, the composition of a compound of formula III or formula IV is administered every other day, or at least once a day, or at least twice a day. In some embodiments, each administration is performed by instilling at least 1 drop, at least 2 drops, or at least 3 drops into each eye, each drop comprising about 20-100 microliters of the composition. In some embodiments, administration continues for at least 6 months, or at least 1 year, or at least 2 years, or at least 10 years or more. In some embodiments, the composition further comprises a non-aqueous formulation. In some embodiments, the composition further comprises a non-aqueous formulation comprising one or more partially fluorinated hydrocarbons (these are also known as semi-fluorinated alkanes, or SFAs). In some embodiments, the at least one pharma- ceutically acceptable additive is selected from the group consisting of benzalkonium chloride. In some embodiments, benzalkonium chloride is present in the composition at a concentration of about 0.01%. In some embodiments, no preservative additives are present in the composition. In some embodiments, the spherical equivalent (SE) of the eye is within the range of -1.00D to -0.49D prior to administration of the composition. In some embodiments, the SE is measured by an autorefractometer after administration of a controlled anesthesia. In some embodiments, the subject has no astigmatism, or has an astigmatism of 1.50D or less, measured by an autorefractometer without controlled anesthesia or without controlled anesthesia prior to administration of the composition.In some embodiments, the pupil of the eye has no dilation or has a dilation of 2 mm or less during administration of the composition, e.g., 1.9 mm or less, 1.8 mm or less, 1.7 mm or less, 1.5 mm or less, 1.49 mm or less. In some embodiments, the eye does not experience a clinically significant loss of accommodation or does not experience a loss of accommodation of 10 D or less, e.g., 9 D or less, 8.5 D or less, 8.8 D or less, or 8 D or less. In some embodiments, the eye does not experience a clinically significant loss of near vision due to loss of accommodation. In some embodiments, the onset of myopia is delayed by 6 months, 12 months, 18 months, 2 years, 3 years, 5 years, 6 years, 8 years, or more. In another aspect, the disclosure provides a method of reducing or preventing the progression of myopia, comprising administering intraocularly to a subject a composition of a compound of formula III or formula IV, the composition being administered no more than every other day, every third day, or every third day. In some embodiments, each administration is performed by instilling at least one drop, at least two drops, or at least three drops into the eye, each drop containing about 20-100 microliters of liquid. In some embodiments, the ocular SE is less than -1.50D prior to administration of the composition. In some embodiments, the ocular SE is within the range of -0.50D to -1.50D prior to administration of the composition. In some embodiments, the subject is between 4 and 21 years old. In some embodiments, the subject is between 5 and 9 years old. In some embodiments, the composition of the compound of formula III or formula IV is present in perfluorohexyl octane. In some embodiments, the composition of the compound of formula III or formula IV is present in perfluorohexyl octane comprises about 0.1% to 0.0049% compound of formula III or formula IV.

[0013] In some embodiments, the composition further comprises at least one pharma- ceutically acceptable excipient, hi some embodiments, the at least one pharma- ceutically acceptable excipient is selected from ethyl alcohol.

[0014] In some embodiments, the compositions of formula III and IV further comprise an additional therapeutic agent, or a polymorph, zwitterion, solvate, or pharma- ceutically acceptable salt of such additional therapeutic agent. In some embodiments, the compositions of formula III and IV further comprise at least one additional therapeutic agent that is a known muscarinic receptor antagonist. In some embodiments, the compositions of formula III and IV further comprise: [ka] , the (3R,2'R)-enantiomer of EA-3167, [ka] where X is Cl, Br, or I; [ka] where X is Cl, Br, or I; [ka] When used in combination with other drugs, the compound further comprises one or more additional actives which are known muscarinic receptor antagonists selected from the list below.

[0015] In some embodiments, the average change in SE over two years after the start of administration of the composition is reduced by at least 20% compared to the control. In some embodiments, treating a patient, such as a patient with pre-myopia, reduces the change in refraction by at least 10%, at least 20%, at least 30%, or at least 40%, or at least 50%. In some embodiments, treating a patient with pre-myopia with a composition comprising a compound of formula III or formula IV reduces the further increase in axial length by at least 10%, at least 15%, at least 20%, or at least 30% over a period of 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, 2 years, or longer from the start of treatment. In some embodiments, treating a patient with pre-myopia with a composition comprising a compound of formula III or formula IV disclosed herein can reduce the change in refraction by at least 10%, at least 20%, at least 30%, or at least 40%.

[0016] In some embodiments, administration of a composition comprising a compound of Formula III or Formula IV disclosed herein reduces the change in refraction (i.e., the shift in myopic refractive error) by at least 10%, e.g., at least 20%, at least 30%, or at least 40%, at least 50%, compared to a control. In some embodiments, during treatment, the pupil of the patient's eye exhibits no dilation or a dilation of 1.9 mm or less, 1.8 mm or less, 1.7 mm or less, 1.5 mm or less, 1.49 mm or less during administration of a composition comprising a compound of Formula III or Formula IV. In some embodiments, the eye has no loss of accommodation or a loss of accommodation of 10 D or less, e.g., 9 D or less, 8.5 D or less, 8.8 D or less, or 8 D or less.

[0017] The present disclosure also provides the use of a compound of formula III or formula IV in the preparation of a composition for preventing or delaying the onset of myopia progression, the composition comprising a partially fluorinated hydrocarbon as a carrier.The compound of formula III can also be used to treat a number of other eye diseases, such as uveitis and early amblyopia. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 illustrates the superior stability of the SFA formulations of Table 8 compared to water-based formulations of other compounds provided herein. [Diagram 2] FIG. 2 illustrates the superior stability of the SFA formulations in Table 8 compared to water-based formulations of other compounds provided herein. [Diagram 3] FIG. 3 illustrates the superior stability of the SFA formulations in Table 8 compared to water-based formulations of other compounds provided herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] This disclosure refers to publications and patents. Any U.S. patents or U.S. patent application publications referenced herein are hereby incorporated by reference. All percentages, ratios, and proportions used herein are by weight unless otherwise specified.

[0020] Esters and amides of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanil are provided.Compositions and methods for treating myopia are provided.

[0021] "Alkyl" refers to a saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups (e.g., C1-C 20 Alkyl, C1-C 10 "Alkyl" refers to an alkyl group (C1-C4 alkyl, or C1-C4 alkyl). Examples of "alkyl" include groups such as methyl, ethyl, n-propyl, isopropyl, and n-butyl. Alkyl groups may be substituted or unsubstituted. Substituents may themselves be substituted. When substituted, the substituents are preferably, but not limited to, C1-C4 alkyl, aryl, amino, cyano, hydrogen, alkoxy, or hydroxyl. "C1-C4" alkyl refers to an alkyl group containing from 1 to 4 carbon atoms.

[0022] "Alkenyl" refers to unsaturated aliphatic hydrocarbon moieties, including straight-chain and branched-chain groups. The alkenyl moiety must contain at least one alkene. "Alkenyl" can be exemplified by groups such as ethenyl, n-propenyl, isopropenyl, n-butenyl, and the like. The alkenyl group may be substituted or unsubstituted. The substituents may themselves be substituted. If substituted, the substituents are preferably alkyl, halogen, or alkoxy. The substituents may themselves be substituted. The substituents may be placed on the alkene itself, on adjacent member atoms, or on the alkynyl moiety. "C2-C4 alkenyl" refers to an alkenyl group containing 2 to 4 carbon atoms.

[0023] "Alkynyl" refers to an unsaturated aliphatic hydrocarbon moiety, including straight and branched chains. The alkynyl moiety must contain at least one alkyne. "Alkynyl" can be exemplified by groups such as ethynyl, propynyl, n-butynyl, and the like. The alkynyl group may be substituted or unsubstituted. If substituted, the substituent is preferably alkyl, amino, cyano, halogen, alkoxyl, or hydroxyl. The substituent may itself be substituted. The substituent is not on the alkyne itself, but on adjacent member atoms of the alkynyl moiety. "C2-C4 alkynyl" refers to an alkynyl group containing 2 to 4 carbon atoms.

[0024] "Acyl" or "carbonyl" refers to the group -C(O)R where R is alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclic, heterocarbocyclic, alkylaryl, or alkylheteroaryl. Alkylcarbonyl refers to a group having an alkyl chain of 1 to 4 carbon atoms preceding the carbonyl moiety.

[0025] "Alkoxy" refers to the group -OR, where R is acyl, alkylalkenyl, alkylalkynyl, aryl, carbocyclic, heterocarbocyclic, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0026] "Amino" refers to the group -NR'R', where each R' is independently hydrogen, amino, hydroxyl, alkoxyl, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl. Two R' groups may themselves be linked to form a ring. The R' group may itself be further substituted, in which case the group also known as guanidyl is specifically contemplated under the term "amino".

[0027] "Aryl" refers to an aromatic carbocyclic group. An example of an "aryl" is phenyl. An aryl group may be substituted or unsubstituted. A substituent may itself be substituted. If substituted, the substituent is preferably, but not limited to, heteroaryl, acyl, carboxyl, carbonylamino, nitro, amino, cyano, halogen, or hydroxyl.

[0028] "8-Methyl-8-azabicyclo[3.2.1]octan-3-yl" is a bicyclic heteroaliphatic ring structure having the system number shown in the figure. [ka] A bicyclic ring is one that is attached to the rest of the molecule through carbon 3 in either an endo, exo, or a mixture of the two.

[0029] "Pyridin-4-ylmethanyl" refers to a heteroaromatic ring structure having the system number shown. [ka] where the ring system is attached to the rest of the molecule via a bond to a methyl which is itself attached to the ring at the 4-position.

[0030] "Carboxyl" refers to a -C(=O)O-C1-C4 alkyl group.

[0031] "Carbonyl" refers to the group -C(O)R, where each R is independently hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0032] "Carbonylamino" refers to -C(O)NR'R', where each R' is independently hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl. Two R' groups may themselves be joined to form a ring.

[0033] "Alkylaryl" refers to an alkyl group having an aryl substituent, such that the aryl group is attached via the alkyl group. "Alkylaryl" can be exemplified by benzyl.

[0034] "Alkylheteroaryl" refers to an alkyl group having a heteroaryl group such that the heteroaryl group is attached via the alkyl group.

[0035] "Carbocyclic group" or "cycloalkyl" means a monovalent saturated or unsaturated hydrocarbon ring. A carbocyclic group is monocyclic or a fused, spiro, or bridged bicyclic ring system. A monocyclic carbocyclic group contains 3 to 10 carbon atoms in the ring, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms. A bicyclic carbocyclic group contains 8 to 12 carbon atoms in the ring, preferably 9 to 10 carbon atoms. A carbocyclic group may be substituted or unsubstituted. The substituents may themselves be substituted. Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl. More preferred carbocyclic groups include cyclopropyl and cyclobutyl. The most preferred carbocyclic group is cyclopropyl. A carbocyclic group is not aromatic.

[0036] "Halogen" refers to a fluoro, chloro, bromo or iodo moiety. Preferably, the halogen is fluoro, chloro or bromo.

[0037] "Heteroaryl" or "heteroaromatic" refers to a monocyclic or bicyclic aromatic carbocyclic radical having one or more heteroatoms in the carbocyclic ring. Heteroaryl may be substituted or unsubstituted. If substituted, the substituent may itself be substituted. Preferred, but non-limiting, substituents are aryl, C1-C4 alkylaryl, amino, halogen, hydroxy, cyano, nitro, carboxyl, carbonylamino, or C1-C4 alkyl. Preferred heteroaromatic groups include isoquinolinyl, benzoisothiazolyl, benzoisothiadiazolyl, benzothiofuranyl, thienyl, furanyl, tetrazoyl, triazolyl, and pyridyl.

[0038] "Heteroatom" means an atom other than carbon contained in a ring of a heterocyclic or heteroaromatic group, or in the chain of a heterogroup. Preferably, the heteroatom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0039] "Heterocarbocyclic group" or "heterocycloalkyl" or "heterocyclic" means a monovalent saturated or unsaturated hydrocarbon ring containing at least one heteroatom. Heterocarbocyclic groups are monocyclic or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocarbocyclic groups contain 3 to 10 carbon atoms in the ring, preferably 4 to 7 carbon atoms, more preferably 5 to 6 carbon atoms. Bicyclic heterocarbocyclic groups contain 8 to 12 carbon atoms in the ring, preferably 9 to 10 carbon atoms. Heterocarbocyclic groups may be substituted or unsubstituted. The substituents may themselves be substituted. Preferred heterocarbocyclic groups include epoxy, tetrahydrofuranyl, azacidopentyl, azacyclohexyl, piperidyl, and homopiperidyl. More preferred heterocarbocyclic groups include piperidyl and homopiperidyl. The most preferred heterocarbocyclic group is piperidyl. A heterocarbocyclic group is not aromatic.

[0040] "Hydroxy" or "hydroxyl" refers to a chemical moiety consisting of -OH. An alcohol contains a hydroxy group. The hydroxy group can be free or protected. Another name for hydroxyl is hydroxyl.

[0041] "Linker" means a linear chain of n member atoms, where n is an integer from 1 to 4.

[0042] "Member atom" means a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom. A member atom may be substituted to its normal valence. If no substitution is specified, the substituent required for the valence is hydrogen.

[0043] "Ring" means a collection of member atoms in a ring. The ring may be carbocyclic, aromatic, or heterocyclic or heteroaromatic, and may be substituted or unsubstituted, saturated or unsaturated. The junction of the ring with the backbone may be a fused or spiro ring. The ring may be monocyclic or bicyclic. The ring contains at least three member atoms and up to ten member atoms. A monocyclic ring contains 3-7 member atoms and a bicyclic ring may contain 8-12 member atoms. The bicyclic ring may itself be a fused or spiro ring.

[0044] "Thioalkyl" refers to the group --S-alkyl.

[0045] "Sulfonyl" refers to the group -S(O)2R', where R' is alkoxy, alkyl, aryl, carbocyclic, heterocarbocyclic, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0046] "Sulfonylamino" refers to the group -S(O)2NR'R', where each R' is independently alkyl, aryl, heteroaryl, C1-C4 alkylaryl, or C1-C4 alkylheteroaryl.

[0047] "Pharmaceutically acceptable carrier" means a carrier useful for the preparation of a pharmaceutical composition that is generally compatible with the other components of the composition, is not deleterious to the recipient, and is not biologically or otherwise undesirable, as follows: "Pharmaceutically acceptable carrier" includes both one carrier and more than one carrier. Embodiments include carriers for topical, ocular, parenteral, intravenous, intraperitoneal intramuscular, sublingual, intranasal, and oral administration. "Pharmaceutically acceptable carrier" also includes preparations of aqueous dispersions, sterile powders for injection or dispersion.

[0048] As used herein, "additives" includes physiologically compatible additives useful in the preparation of pharmaceutical compositions. Examples of pharma-ceutically acceptable carriers and additives can be found, for example, in Remington Pharmaceutical Science, 18ih Ed.

[0049] As used herein, "pharmaceutical acceptable salt" refers to an ionizable therapeutic agent combined with a counterion to form a neutral complex. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0050] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0051] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.

[0052] "About" and "approximately" are interchangeable and mean plus or minus a percentage (e.g., ±5%) of the number, parameter, or characteristic so modified, as would be understood by one of ordinary skill in the art as appropriate for the scientific context in which the term is used. Furthermore, all numbers, values, and expressions indicating quantities used herein are subject to various uncertainties of measurement encountered in the art and therefore, unless otherwise indicated, all indicated values ​​can be understood to be modified by the term "about."

[0053] When a range of values ​​is disclosed herein, such range is continuous and includes both the minimum and maximum values ​​of the range, as well as all values ​​between such minimum and maximum values. Furthermore, when a range refers to an integer, all integers between the minimum and maximum values ​​of such range are included. In addition, when multiple ranges are provided to describe a feature or characteristic, such ranges can be combined. That is, unless otherwise indicated, all ranges disclosed herein should be understood to include any and all subranges contained therein. For example, a range of "1 to 10" should be interpreted as including any and all subranges between the minimum value of "1" and the maximum value of "10".

[0054] As used herein, "therapeutic agent" refers to a compound or substance in a pharmaceutical composition that is biologically active and provides the effect of the pharmaceutical composition.

[0055] As used herein, the term "pharmaceutical composition" means a composition that includes a therapeutic agent (i.e., a compound provided herein), excipients, carriers, etc. Generally, a pharmaceutical composition is administered to a patient rather than a therapeutic agent alone.

[0056] The term "treatment" refers to the application of one or more specific procedures used to improve a disease. In certain embodiments, the specific procedure is the administration of one or more pharmaceutical agents. "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention used in an attempt to change the natural course of the individual or cell. Treatment includes, but is not limited to, the administration of a therapeutic agent or pharmaceutical composition, and can be performed prophylactically or after contact with an agent that initiates or causes a pathological event. Treatment includes a desired effect on the symptoms or pathology of a disease or condition, including, for example, a minimal change or improvement in one or more measurable markers of the disease or condition being treated. Also included is "prophylactic" treatment, which can reduce the rate of progression of the disease or condition being treated, delay the onset of the disease or condition, or reduce the severity of the onset.

[0057] The term "zwitterion," as used herein, refers to a molecule or ion that has separate positively and negatively charged groups.

[0058] The term "solvate," as used herein, refers to a complex of a solute molecule with at least one solvent molecule.

[0059] The term "polymorph" or "polymorphism" as used herein refers to the ability of a solid material to exist in one or more forms or crystals. A crystalline form may be referred to herein as being characterized by graphical data. Such data include, for example, powder X-ray diffraction and solid-state NMR spectra. As is well known in the art, graphical data potentially provides additional technical information to further define each solid form (a so-called "fingerprint") that cannot necessarily be explained by numerical values ​​or peak positions alone.

[0060] The term "effective amount" or "therapeutically effective amount" refers to the amount of a therapeutic agent administered to a subject (e.g., a mammalian subject, i.e., a human subject), either in a single dose or as part of a series of doses, effective to produce the desired therapeutic effect (e.g., effective to affect, reduce, inhibit, or prevent the activation of a kinase, or effective to affect, reduce, inhibit, or prevent the activation of a kinase, or effective to produce a desired in vivo effect in an animal, preferably a human, such as a reduction in intraocular pressure).

[0061] As used herein, "administering" refers to administering a compound as needed to achieve a desired effect.

[0062] "Ocular disease" as used herein includes, but is not limited to, glaucoma, allergies, eye cancer, ocular neurodegenerative diseases such as DME and AMD, and dry eye.

[0063] The term "disease or condition associated with kinase activity" is used to mean a disease or condition that is treatable, in whole or in part, by the inhibition of one or more kinases.

[0064] The term "controlling a disease or condition" is used to mean altering the activity of one or more kinases in order to affect the disease or condition.

[0065] The term "contacting a cell" is used to mean contacting a cell in vitro or in vivo (ie, within a subject such as a mammal, including humans, cats and dogs).

[0066] The term "non-aqueous solvent" is used to mean a solvent or mixture of solvents containing less than 5% water by weight. Non-aqueous solvents include mixtures in which the primary solvent is a partially fluorinated hydrocarbon. Non-aqueous solvents may or may not have a preservative.

[0067] The term "partially fluorinated hydrocarbon" refers to a hydrocarbon in which some, but not all, of the hydrocarbon's hydrogen atoms have been replaced with fluorine atoms. Non-limiting examples include perfluorohexyloctane and perfluoropentylnonane. These are also known in the art as semifluorinated alkanes or SFAs.

[0068] The term "myopia" refers to a condition in a patient having at least one eye with an SE value greater than -0.5D, e.g., -1.0D, -2.0D. Depending on the context, "myopia" can also refer to an eye condition with an SE value greater than -0.5D.

[0069] The term "pre-myopia" refers to a condition in a patient having at least one eye with an SE value in the range of -0.49 D to 1.00 D. Depending on the context, myopia can also refer to an eye condition with an SE value in the range of -0.49 D to 1.00 D.

[0070] The term "low myopia" refers to a condition in a patient having at least one eye with an SE value in the range of -0.501 to -1.501. Depending on the context, "low 7 myopia" can also refer to an eye condition with an SE value in the range of -0.50D to -1.50D.

[0071] The term "high myopia" refers to a person having at least one eye with an SE value greater than -5.0 D. Depending on the context, "high myopia" can also refer to an eye condition with an SE value greater than -5.0 D.

[0072] The term "drop" refers to a tire a unit of measurement of volume equivalent to the amount dispensed into the eye as one drop from an eye dropper or eye dropper chamber. A drop, which is usually aqueous-based, contains 20 to 100 microliters of liquid. In some cases, a drop contains 30 microliters to 70 microliters, e.g., about 50 microliters of liquid. Some drops, particularly partially fluorinated hydrocarbon drops, may be smaller than 30 microliters.

[0073] (compound) In another aspect, the present disclosure provides a compound having formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X 1 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 2 is H or lower alkyl; X3 is H or lower alkyl; J 1 -CH2-, -N(R 1 )- or -O-, where R 1 is H or lower alkyl; Z 1 -CH2-, -N(R 2 )- or -O-, where R 2 is H or lower alkyl; When the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, J 1 is -O- and X 2 is lower alkyl, or X 3 is lower alkyl.

[0074] In some embodiments, the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation.

[0075] In some embodiments, the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the exo conformation.

[0076] In some embodiments, J 1 Ga-CH 2 - or -N(R 1 )-.

[0077] In some embodiments, J 1 If is -O-, then X 2 is lower alkyl, or X 3 is lower alkyl.

[0078] In some embodiments, Z 1 is CH2 or N(R 2 ).

[0079] In some embodiments, X 2 is lower alkyl, or X 3 is lower alkyl.

[0080] In some embodiments, X 1 But hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 It is carboxyl.

[0081] In some embodiments, X 1 But hydroxyl, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 It is carboxyl.

[0082] In some embodiments, X 1 But hydroxyl, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 It is carboxyl.

[0083] In some embodiments, Z 1 is -CH2- or -N(R 2 )- and X 1 But hydrogen, hydroxyl, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C1-4 Thioalkyl, or C 1-4 It is carboxyl.

[0084] In some embodiments, the compound is [ka] [ka] [ka] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof.

[0085] In another embodiment, the compound has formula (II) [ka] or a pharma- ceutically acceptable salt thereof; X 4 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 5 is H or lower alkyl; X 6 is H or lower alkyl; X 7 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 8 is phenyl, pyridinyl, pyrimidinyl or thienopyridinyl, X 9 is phenyl, pyridinyl, pyrimidinyl, furanyl or thiophenyl; X 10 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; X 11 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; Or X 10 and X 11 C along with the atoms to which they are attached 3-7 Cycloalkyl or C 3-7 Cycloalkyl-(X 12 ) p Forming X 12 are each independently hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or phenyl, and p is 0, 1, 2, or 3; J 2 -CH2-, -N(R 3 )- or -O-, where R 3 is H or lower alkyl; Z 2 -CH2-, -N(R 4 )- or -O-, where R 4is H or lower alkyl; n is 0 or 1.

[0086] In some embodiments, formula (II) is Formula (IIa) [ka] Formula (IIb) [ka] Formula (IIc) [ka] Formula (IId) [ka] Formula (IIe) [ka] Formula (IIf) [ka] Or, formula (IIg) [ka] It is.

[0087] In some embodiments, formula (II) is represented by formula (IIb-1): [ka] It is.

[0088] In some embodiments, X8 is phenyl or pyridinyl and X9 is phenyl, pyridinyl, furanyl or thiophenyl.

[0089] In some embodiments, X 4 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 It is an alkoxy.

[0090] In some embodiments, X 7 is hydrogen, halogen, or C 1-4 It is an alkyl.

[0091] In some embodiments, -Z 2 -X 6 is -OH or -NH2.

[0092] In some embodiments, X 10 is hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, or C 1-4 alkyl-phenyl, X 11 is hydrogen, or C 1-4 Alkyl or X 10 and X 11 C along with the atoms to which they are attached 3-7 Cycloalkyl or C 3-7 Forms cycloalkyl-phenyl.

[0093] In some embodiments, the compound is [ka] [ka] [ka] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof.

[0094] (composition) In another aspect, the present disclosure provides compositions comprising the compounds provided herein.

[0095] In some embodiments, the composition comprises a semi-fluorinated alkane.

[0096] In some embodiments, the present disclosure provides a composition comprising: A semifluorinated alkane; Formula (I) [ka] wherein X 1 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 2 is H or lower alkyl; X 3 is H or lower alkyl; J 1 -CH2-, -N(R 1 )- or -O-, where R 1 is H or lower alkyl; Z 1 -CH2-, -N(R 2 )- or -O-, where R 2 is H or lower alkyl; When the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, J 1 is -O- and X 2 is lower alkyl, or X 3is lower alkyl, or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof; or [ka] wherein X 4 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 5 is H or lower alkyl; X 6 is H or lower alkyl; X 7 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 8 is phenyl, pyridinyl, pyrimidinyl or thienopyridinyl, X 9 is phenyl, pyridinyl, pyrimidinyl, furanyl or thiophenyl; X 10 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; X11 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; Or X 10 and X 11 C along with the atoms to which they are attached 3-7 Cycloalkyl or C 3-7 Cycloalkyl-(X 12 ) p Forming X 12 are each independently hydrogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or phenyl, and p is 0, 1, 2, or 3; J 2 -CH2-, -N(R 3 )- or -O-, where R 3 is H or lower alkyl; Z 2 -CH2-, -N(R 4 )- or -O-, where R 4 is H or lower alkyl and n is 0 or 1, or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof.

[0097] In some embodiments, the present disclosure provides a composition, the composition comprising a semifluorinated alkane and a compound, the compound comprising: [ka] [ka] [ka] [ka] Benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester, [ka] , the (3R,2'R)-enantiomer of EA-3167, [ka] where X is Cl, Br or I; [ka] where X is Cl, Br or I; [ka] [ka] [ka] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof.

[0098] In some embodiments, the semifluorinated alkane is perfluorohexyloctane or perfluorohexylnonane.

[0099] In some embodiments, the composition is a non-aqueous composition.

[0100] In some embodiments, the compositions provided herein are pharmaceutical compositions comprising a compound provided herein or a composition provided herein and a pharma- ceutically acceptable excipient.

[0101] (Kits and manufactured products) The present specification also provides a kit comprising a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein, and instructions for use thereof.

[0102] The present disclosure also provides an article of manufacture comprising a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0103] (method) The compounds and compositions provided herein are useful for treating ocular diseases or conditions. Thus, in one aspect, the present disclosure provides a method for treating myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0104] The present specification also provides a method of slowing the progression of myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0105] The present specification also provides a method of delaying the onset of myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0106] The present specification also provides a method of treating a vision-threatening disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, a composition provided herein, or a pharmaceutical composition provided herein.

[0107] In some embodiments, the vision-threatening disease or disorder comprises peripheral lattice degeneration, fissures, detachments, myopic choroidal neovascularization, myopic macular schisis, myopic macular hole, posterior staphyloma, myopic macular degeneration, early-onset cataract, open-angle glaucoma, peripapillary atrophy, optic disc tilt, optic disc pits, or combinations thereof.

[0108] (General synthesis scheme) The 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanil ester and amide compounds provided herein are synthesized according to the general schemes set forth below. [ka]

[0109] According to Scheme 1, the selected ester (S1) is reacted with an esterase enzyme, such as pig liver esterase, to form the desired intermediate (S2). The alcohol (S2) is extracted and purified if necessary, and then proceeded to Scheme 2. [ka]

[0110] According to Scheme 2, the selected acid (S4) is activated with a suitable reagent such as EDC and coupled with 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanyl alcohols (S5) or amines (S8) using standard coupling techniques to form the desired intermediates (S6, S9, S12 and S15). The protected amines of (S6) or the protected alcohols of (S8, S10, S12 and S15) are reacted with HCl in methylene chloride to directly generate the amides (S11). [ka]

[0111] In some embodiments, administration of an additional therapeutic agent along with a compound provided herein allows for the other therapeutic agent to be administered at a lower dose for a longer period of time.

[0112] The compositions containing the alkyl, ester and amide derivatives of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanyl of formula I, II or III can be obtained in the form of various salts or solvates. As the salts, physiologically acceptable salts or salts available as raw materials are used.

[0113] The composition may contain one or more isoforms of formula I or II or III or IV, if present. If racemates exist, each enantiomer or diastereomer may be used separately or in any ratio. If tautomers exist, all possible tautomers are specifically contemplated.

[0114] Pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers or additives. Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for administration, for example, by solid administration, eye drops, in oily topical formulations, by injection, inhalation (either through the mouth or nose), by implants, including bioerodible implants placed either before or after the eye, or by oral, buccal, parenteral or rectal administration. Techniques and formulations are generally described in "Reminington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions should usually be sterile and stable under the conditions of manufacture and storage.

[0115] The compositions provided herein may comprise a safe and effective amount of the subject compound and a pharma- ceutically acceptable carrier. As used herein, a "safe and effective amount" refers to an amount of the compound that is sufficient to induce a significant positive change in the condition to be treated, within the scope of sound medical judgment, but low enough to avoid serious side effects (reasonable benefit / risk ratio). The amount of the safe and effective compound will vary according to the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of the concomitant therapy, the particular pharma- ceutically acceptable carrier used, and similar factors, within the knowledge and expertise of the attending physician.

[0116] The route by which the compound provided herein (Component A) is administered and the form of the composition will determine the type of carrier (Component B) used. The composition may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral) or local administration (e.g., topical application to the skin, eye, liposome delivery system, or iontophoresis).

[0117] Carriers for systemic administration typically include at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavorings, g) sweeteners, h) antioxidants, j) preservatives, k) lubricants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, q) biodegradable polymers, r) plasticizers, combinations thereof, etc. All carriers are optional in systemic compositions.

[0118] Component a) is a diluent. Suitable diluents for solid dosage forms include sugars such as glucose, lactose, dextrose and sucrose, diols such as propylene glycol, calcium carbonate, sodium carbonate, sugar alcohols such as glycerin, mannitol and sorbitol. The amount of component a) in a systemic or topical composition is usually about 50% to about 90%.

[0119] Component b) is a lubricant. Examples of lubricants suitable for solid dosage forms include solid lubricants including silica, talc, stearic acid and its magnesium and calcium salts, and calcium sulfate, and liquid lubricants such as polyethylene glycol, peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, theobroma oil, and other vegetable oils. The amount of component b) in the systemic or topical composition is usually about 5% to about 10%.

[0120] Component c) is a binder. Suitable binders for solid dosage forms include polyvinylpyrrolidone, aluminum magnesium silicate, starches such as corn starch and potato starch, gelatin, tragacanth, and celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, methovir cellulose, microcrystalline cellulose, sodium carboxymethylcellulose. The amount of component c) in systemic compositions is usually about 5 to about 50%, and for ocular solid dosage forms it can be up to 99%.

[0121] Component d) is a disintegrant. Disintegrants suitable for solid dosage forms include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of component d) in a systemic or topical composition is usually about 0.1 to about 10%.

[0122] Ingredient e) for solid dosage forms is a colorant, such as an FD&C dye. If used, the amount of ingredient e) in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0123] Ingredient f) for solid dosage forms is a flavoring such as menthol, peppermint, fruit flavors, etc. If used, the amount of ingredient f) in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0124] In the case of solid dosage forms, component g) is a sweetener such as aspartame, saccharin, etc. The amount of component g) in a systemic or topical composition is typically from about 0.001% to about 1%.

[0125] Ingredient h) are antioxidants such as butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of ingredient h) in a systemic or topical composition is typically from about 0.1 to about 5%.

[0126] Ingredient i) is a preservative such as benzalkonium chloride, methylparaben, sodium benzoate, etc. The amount of ingredient i) in a systemic or topical composition is typically about 0.01 to about 5%.

[0127] Ingredient k) for solid dosage forms is a lubricant such as silicon dioxide. The amount of ingredient k) in a systemic or topical composition is typically about 1 to about 5%.

[0128] Ingredient m) is a solvent such as partially fluorinated hydrocarbons, water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, phosphate buffer, etc. The amount of ingredient m) in the systemic or topical composition is typically about 0 to about 100%.

[0129] Ingredient n) is a suspending agent. Suitable suspending agents include AVICEL® RC-591 (FMC Corporation, Philadelphia, PA) and sodium alginate. The amount of ingredient n) in a systemic or topical composition is typically about 1 to about 8%.

[0130] Ingredient o) is a surfactant such as lecithin, polysorbate 80, sodium lauryl sulfate, and TWEENS® from Atlas Powder Company, Wilmington, Del. Suitable surfactants include those disclosed in CTFA Cosmetic ingredient Handbook, 1992, pp. 587-592, Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337, and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 238-239. The amount of ingredient o) in a systemic or topical composition is typically about 0.1 to about 5%.

[0131] Component p) is a surfactant.

[0132] Component q) is a biodegradable polymer. PLA or PLA polymers are specifically contemplated, as well as PEA polymers.

[0133] Component r) is a plasticizer. It lowers the TM of the polymer, allowing it to be processed at lower temperatures or other conditions, making it easier to manufacture. Non-limiting examples.

[0134] The amounts of components A and B in a systemic composition will vary depending on the type of systemic composition prepared and the particular derivative selected for component A and the material for component B, but generally, the systemic composition will contain 0.01%-50% component A and 50-99.99% component B.

[0135] Compositions for parenteral administration generally comprise A) 0.1-10% of a compound provided herein, and B) 90-99.9% of a carrier comprising a) a diluent and m) a solvent, in one embodiment, a) comprises propylene glycol and m) comprises ethanol or ethyl oleate.

[0136] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of component A), usually at least about 5%, more particularly about 25% to about 50%. Orally administered compositions further contain about 50% to about 95% of component B), more particularly about 50% to about 75% of component B).

[0137] The tablet can be a compressed tablet, a powder tablet, an enteric coated tablet, a sugar coated tablet, a film coated tablet, or a multiple compressed tablet. Tablets are usually composed of component A and component B, which is a carrier containing a component selected from the group consisting of a) a diluent, b) a lubricant, c) a binder, d) a disintegrant, e) a colorant, f) a flavorant, g) a sweetener, k) a lubricant, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid, croscarmellose, and the like. Lubricants include magnesium stearate, stearic acid, and talc. Colorants include FD&C dyes and can be added for appearance. Chewable tablets preferably contain g) a sweetener such as aspartame or saccharin, f) a flavoring such as menthol, peppermint, or fruit flavors, or a combination thereof.

[0138] Capsules (including implants, sustained release formulations, and sustained release formulations) typically contain component A and a carrier comprising one or more of the above-mentioned a) diluents in a capsule made of gelatin. Granules typically contain component A, preferably further comprising k) a lubricant, such as silicon dioxide, to improve flow properties, and implants can be biodegradable or non-biodegradable. Implants can be prepared using known biocompatible formulations.

[0139] The choice of material in the carrier for an oral composition depends on secondary considerations including, but not limited to, taste, cost, and storage stability.

[0140] The solid compositions may also be coated in a conventional manner, typically with a pH-dependent or time-dependent coating, to allow component A to be released in the gastrointestinal tract in the vicinity of the desired application or at various locations and places to extend the desired action. The coating typically comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Rohm & Haas GMBH, Darmstadt, Germany), waxes and shellac.

[0141] Compositions for oral administration can also be in the form of liquids. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. Oral liquid compositions generally contain a carrier comprising components A and B, i.e., components selected from the group consisting of a) diluents, e) colorants, f) flavorants, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants. Oral liquid compositions preferably contain one or more components selected from the group consisting of e) colorants, f) flavorants, and g) sweeteners.

[0142] Other compositions useful for achieving systemic delivery of the subject compounds include implants, sublingual, buccal, and nasal dosage forms. Such compositions usually include one or more soluble or biodegradable filler substances, such as a) diluents (including sucrose, sorbitol, and mannitol), and c) binders (e.g., acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose). Such compositions may further include b) lubricants, e) colorants, f) flavorings, g) sweeteners, h) antioxidants, and k) glidants. Implant formulations include q) biodegradable polymers, and optionally r) plasticizers.

[0143] In one embodiment, the compounds provided herein are administered topically. Topical compositions that can be applied topically to the eye can be in any form known in the art, non-limiting examples of which include solids, gellable drops, sprays, ointments, or sustained or non-sustained release units placed in the conjunctival fornix, intraocular cavity, aqueous humor, vitreous humor, or another suitable location of the eye.

[0144] Topical compositions that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. The topical composition comprises component A, which is the compound described above, and component B, which is a carrier. The carrier of the topical composition preferably aids in the penetration of the compound into the eye. Component B may further comprise one or more optional ingredients.

[0145] The dosage range of the compound for systemic administration is about 0.0001 to about 1000 μg / kg of body weight per day, preferably about 0.1 to about 100 pg / kg of body weight, and most preferably about 1 to about 50 pg / kg of body weight per day. These dosages are based on the daily dosage, although the cumulative weekly or monthly dosages can also be used to calculate clinical needs.

[0146] The dosage may vary depending on the patient being treated, the condition being treated, the severity of the condition being treated, the route of administration, etc., in order to obtain the desired effect.

[0147] The compounds provided herein are useful in reducing intraocular pressure. Thus, these compounds are useful in treating glaucoma. The preferred route of administration for treating glaucoma is topical.

[0148] The exact amount of each component in a topical composition depends on a variety of factors. The amount of component A added to a topical composition is determined by the IC 50 For example, the IC of a drug 50 When the IC of the drug is 1 nM, the amount of component A is about 0.0001 to about 0.3%. 50 When the IC of the drug is 10 nM, the amount of component A) is about 0.001 to about 1%. 50 When the IC of the drug is 100 nM, the amount of component A is about 0.01 to about 10%. 50 is 1000 nM, the amount of component A is 1-100%, preferably 5%-50%. If the amount of component A is outside the range specified above (i.e., if it is low), the efficacy of the treatment may decrease. The remainder of the composition up to 100% is component B.

[0149] The amount of carrier employed in combination with component A is sufficient to provide a practical amount of the composition for administration per unit dose of pharmaceutical. Techniques and compositions for making dosage forms useful in the methods provided herein are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2001, eds. (1982); nd Ed., (1976).

[0150] Component B may comprise a single component or a combination of two or more components, and in topical compositions, component B comprises a topical carrier. Suitable topical carriers include one or more components selected from the group consisting of partially fluorinated hydrocarbons, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetric alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More specifically, carriers for skin application include partially fluorinated hydrocarbons, propylene glycol, dimethyl isosorbide, and water, and even more specifically, partially fluorinated hydrocarbons, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetric alcohols.

[0151] The topical composition carrier may further comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.

[0152] Component q) is an emollient. The amount of component q) in a skin-based topical composition is usually about 5 to about 95%. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl sulfurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohol, and the like. Specific emollients for use on the skin include petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for use on the skin include stearyl alcohol and polydimethylsiloxane.

[0153] Component r) is a propellant. The amount of component r) in the topical composition is usually about 0 to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.

[0154] Ingredient s) is a solvent. The amount of ingredient s) in the topical composition is usually about 0 to about 95%. Suitable solvents include partially fluorinated hydrocarbons, water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols.

[0155] Component t) is a humectant. The amount of component t) in the topical composition is usually 0-95%. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A specific humectant includes glycerin.

[0156] Component u) is a thickening agent. The amount of component u) in a topical composition is typically about 0 to 95%.

[0157] Ingredient v) is a powder. The amount of ingredient v) in the topical composition is usually 0-95%. Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified aluminum magnesium silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. Specific powders for ophthalmic application include beta-cyclodextrin, hydroxypropyl cyclodextrin, and sodium polyacrylate. For gel-administered ophthalmic formulations, sodium polyacrylate may be used.

[0158] Component w) is a fragrance. The amount of component x) in the topical composition is generally about 0 to about 0.5%, particularly about 0.001 to about 0.1%. For ophthalmic use, fragrances are generally not used.

[0159] Component x) is a pigment. Pigments suitable for skin applications include inorganic pigments, organic lake pigments, pearlescent pigments and mixtures thereof. Useful inorganic pigments provided herein include those selected from the group consisting of rutile or anatase titanium dioxide, which is coded in the color index with reference number CI 77,891, black, yellow, red and brown iron oxides, which are coded with reference numbers CI 77,499, 77,492 and 77,491, manganese violet (CI 77,742), ultramarine blue (CI 77,007), chromium oxide (CI 77,288), chromium hydrate (CI 77,289) and ferric blue (CI 77,510).

[0160] Useful organic pigments and lakes provided herein include D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI 15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&C Orange No. 10 ...13 (CI 15,630), D&C Red No. 13 (CI 15,630 D&C Yellow No. 6 (CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), dyes or lakes based on Cochineal Carmine (CI 75,570), or mixtures thereof.

[0161] Useful pearlescent pigments provided herein include those selected from the group consisting of white pearlescent pigments such as titanium oxide, mica coated with bismuth oxychloride, colored pearlescent pigments such as titanium mica doped with iron oxide, ferric blue, titanium mica doped with chromium oxide, titanium mica doped with organic pigments of the types mentioned above, as well as those based on bismuth oxychloride, and mixtures thereof. The amount of pigment in the topical composition is generally about 0 to about 10%. For ophthalmic applications, pigments are generally not used.

[0162] In another embodiment, a topical pharmaceutical composition for ocular administration is prepared, generally comprising component A and component B (a carrier), e.g., purified water and one or more components selected from the group consisting of y) sugars or sugar alcohols such as dextran, particularly mannitol and dextran 70, z) cellulose or derivatives thereof, aa) salts, bb) sodium EDTA (disodium edetate), and cc) a pH adjusting agent.

[0163] Examples of z) cellulose derivatives suitable for use in topical pharmaceutical compositions for ocular administration include sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, in particular hydroxypropyl-methylcellulose.

[0164] Examples of aa) salts suitable for use in topical pharmaceutical compositions for ocular administration include mono-, di-, and tri-sodium phosphate, sodium chloride, potassium chloride, and combinations thereof.

[0165] cc) Examples of pH adjusting agents include HCl or NaHO in an amount sufficient to adjust the pH of a topical pharmaceutical composition for ocular administration to between 4.5 and 7.5.

[0166] Component A may be included in a kit that includes component A, a systemic or topical composition as described above, or both, and information, instructions, or both that the kit can be used to treat cosmetic and medical conditions in a mammal, particularly a human. The information and instructions can be in the form of words, pictures, or both, etc. Additionally or alternatively, the kit may include the drug, composition, or both, and preferably information, instructions, or both, regarding how to apply the drug or composition to have the benefit of treating or preventing cosmetic and medical conditions in a mammal, such as a human.

[0167] The following illustrative examples should be construed as non-limiting.

[0168] Specific procedures for the preparation of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-yl metanil esters and amides are set forth in the Examples below.

[0169] All temperatures are degrees Celsius. Reagents and starting materials were either purchased commercially or prepared according to published literature procedures.

[0170] Unless otherwise indicated, purification by HPLC was performed by redissolving the compound in a small volume of DSMO, where appropriate, and filtering through a 0.45 micron (nylon disk) syringe filter. The solution was then purified using, for example, a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column, with a typical initial elution mixture of 40-80% MeOH:H2O selected as appropriate for the target compound. This initial gradient was maintained for 0.5 min, then increased to 100% MeOH:0% H2O over 5 min. 100% MeOH was maintained for an additional 2 min, before re-equilibrating back to the initial gradient. Typical total run time was 8 min. The resulting fractions were analyzed, combined if necessary, and evaporated to yield the purified product.

[0171] Proton magnetic resonance ( 1H NMR spectra were obtained using a Varian INOVA 800 MHz ( 1 H) NMR spectrometer, Varian INOVA 500 MHz ( 1 H) NMR spectrometer, Varian Mercury 300 MHz ( 1 H) NMR spectrometer, or Varian Mercury 200 MHz ( 1 H NMR spectrometer. All spectra were measured in the solvent indicated. Chemical shifts are reported in ppm downfield of tetramethylsilane. 1 H NMR is based on the residual proton peaks of each solvent peak. Interproton coupling constants are reported in Hertz (Hz).

[0172] Analytical LCMS spectra were obtained using a Waters ZQ MS ESI instrument equipped with an Alliance 2695 HPLC and a 2487 dual wavelength UV detector. Spectra were analyzed at 254 nm and 230 nm. Samples were run on a Waters Symmetry C18 4.6x75mm 3.5pm column with or without a guard column (3.9x20mm 5pm). Gradients were run with mobile phase A: 0.1% formic acid in H2O, mobile phase B: ACN at a flow rate of 0.8mL / min. The two gradients are shown in Table 1. [Table 1]

[0173] MS probe settings were: cone voltage 38 mV, desolvation temperature 250° C. Variations on these methods are described below.

[0174] The following preparations show procedures for the preparation of intermediates and methods for the preparation of alkyl, ester and amide derivatives of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-ylmethanil.

[0175] (Example) Example 1: Preparation of (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoate [ka] To 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoic acid in CHCl was added EDC, DMAP and 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoic acid and the solution was stirred overnight. The mixture was poured into NaHCO(sat), extracted with CHCl, dried (NaSO), filtered and evaporated to give crude 2. Column chromatography EtOAc-Hexane gave pure (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoate.

[0176] Example 2: Preparation of (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate dihydrochloride [ka] To (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoate in CHCl was added 4N HCl-dioxane and the solution was stirred overnight. The solvent was evaporated and dried to give (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate dihydrochloride (E3).

[0177] By following the procedures described above and substituting the appropriate starting materials, certain compounds provided herein, including those in Table 2, can be prepared. Table 2 [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0178] Using techniques known in the art, the following compounds were synthesized: [ka] [ka] and [ka] can be manufactured.

[0179] Example 3: Induction of form deprivation myopia in mice Mice are a good preclinical model to evaluate pharmacological treatments for myopia because the mouse eye has a structure and biochemistry very similar to the human eye, and previous studies have confirmed the usefulness of myopia models in mice. The mouse eye also has similar pharmacological targets as the human eye. Results show that 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analogs can be administered topically before the eye experiences a myopia-inducing treatment, avoiding some or all of the myopic changes. The association of all muscarinic receptor types present in fibroblasts in the sclera, the tough outer connective tissue that covers the eyeball, has been shown to be similar in mouse and human eyes.

[0180] In general, form deprivation myopia ("FDNT") in mice can be reliably produced by placing -IOD lenses on the mouse eyes for six weeks. This results in an increase in axial length and refractive error in the mouse eye. In this procedure, the eye is administered an 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analog once daily for 1-14 days prior to placing the -IOD lens on the eye. Initial experimental groups (n=8 / group) were: a) no lens placed, and treatment with an 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analog started on day 21 and continued for four weeks; b) on day 35 after two weeks of treatment with an 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analog, the -IOD lens was placed and lens treatment continued for four weeks; c) 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analog was placed on the eye for four weeks after placing the -IOD lens on the eye for four weeks; ]octan-3-yl analog after one week of treatment, with -IOD lenses fitted on day 35 and continued lens treatment for four weeks; d) no prior treatment with an 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analog, with lenses fitted on day 35 and continued for four weeks; and e) a control group without lenses or an 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analog.

[0181] After initiating experimental treatment, mice are monitored weekly for changes in axial length and refractive error using previously published procedures. Refractive index and biometry are performed weekly. Axial length is measured using an in vivo low-coherence optical interferometer (OLCTAcMaster). Refraction is measured with an automated decentering photorefractor. Details of the methods have been described previously (Barathi VA & Beuerman RW, 2011; Barathi et al 2013).

[0182] Example 4: Effect of eye drops of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analogues prior to induction of form deprivation myopia in a mouse model (method) Animals: Pair-fed B6J (Mus musculus) mice were obtained from Jackson Lab and progeny were used. Unmedicated control animals were housed in groups of six, and experimental animals were housed individually in standard mouse cages at postnatal day 21, housed on a 12:12-h light-dark schedule at 25°C, and provided with mouse pellets and water ad libitum.

[0183] Mouse myopia model:- An IOD contact lens (light grey PMMA contact lens, diameter 8.5 mm, base curve 8 mm, refractive index 1.43 (axial), thickness 0.5 mm) was placed on the right eye on day 21 by gluing it onto an annular section of Velcro, followed by attaching it to a matching section of Velcro that had been previously sutured to the skin around the eye. The spectacle lens was washed daily in dim light, and the left eye was left uncovered to serve as a control. All optical devices were removed on day 63 of life.

[0184] (Treatment Protocol) Delayed FDM was induced in four groups of mice (groups 1–4): group 1 (n=6, 3 batches) was treated with 1% topical 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analogue at day 35, 10 μL daily for 4 weeks; group 2 (n=6, 3 batches) was treated with 1% topical 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analogue at day 21, 10 μL daily for 2 weeks, followed by -IOD lens wear for 4 weeks to induce myopia (pATG+LIM); group 3 (n=6, 3 batches) was treated with -IOD lens alone to induce myopia (lens wear at day 21, continued for 6 weeks); and group 4 (n=3 [both eyes untreated control], 3 batches) served as untreated control. In all groups, the right eye was used for the experiments and the left eye served as the contralateral control, and experimentally induced myopia in mice, whether induced or pharmacologically mediated, was consistently found to affect the contralateral side.

[0185] Ocular biometric assessment: Refractive and biometric measurements were recorded weekly until the end of the study. Axial length was measured by in vivo low-coherence optical interferometry (OLCI-AcMaster). Refraction was measured with an automated decentering photorefractor. Details of the methods have been described previously (Barathi VA et al, 2013; Barathi VA & Beuerman RW, 2011).

[0186] Statistical analysis: Statistical analysis was performed using SPSS software (Version 11.0, Chicago, 145 USA). All results were expressed as mean ± standard error of the mean (SEM). All values ​​of the lens-induced eyes were statistically compared with those of the fellow eyes within the same group using paired-samples t-tests. Between the experimental and normal groups, an independent-samples t-test was performed using the mean interocular differences. Statistical analysis between groups was performed by one-way analysis of variance (ANOVA), with p<0.05 considered statistically significant.

[0187] (result) Treatment with 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analogs delayed the induction of myopia. Treatment is effective in reducing the effects on axial length and refraction that would otherwise be expected. Eyes that received 8-methyl-8-azabicyclo[3.2.1]octan-3-yl analogs before inducing myopia (-10D lenses for 4 weeks) maintained hyperopia.

[0188] Topical pharmaceutical compositions for the treatment of myopia are prepared by conventional methods and formulated as shown in Table 3. [Table 3]

[0189] The compounds provided herein are used as derivatives of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-yl metanyl esters. When the compounds are administered topically to the eye once a day, the compositions reduce the rate of progression of myopia.

[0190] Example 5 [ka] Repeat Example 1 using 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanamide methanesulfonate (E23) provided herein. When administered as one drop twice daily, the composition substantially reduces the rate of progression of myopia in 6 year old human subjects.

[0191] Example 6 Example 1 is repeated using 8-methyl-8-azabicyclo[3.2.1]octan-3-yl and pyridin-4-yl methanilamides provided herein. When administered as a drop twice daily, the composition prevents the onset of myopia in pre-myopic patients.

[0192] Example 7 Repeat Example 1 using 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorophenyl)-3-hydroxypropanoate toluenesulfonate as provided herein. When administered as a single drop three times a day, the composition substantially reduces allergy symptoms and relieves dry eye syndrome.

[0193] Example 8 [ka] Example 1 is repeated substantially using the R isomer (E22R) of 8-methyl-8-azabicyclo[3.2.1]octan-3yl 3-hydroxy-2-methyl-2-phenylpropanoate hydrochloride provided herein. When administered as a drop as needed, the composition substantially reduces redness, congestion and eye irritation.

[0194] Example 9 Example 1 is repeated substantially using 8-methyl-8-azabicyclo[3.2.1]octan-3yl 3-hydroxypropanoate hydrochloride (E44S) as provided herein. When administered as a single drop four times daily, the composition substantially slows the rate of progression of myopia.

[0195] Example 10 [ka] Example 1 is repeated using the S-isomer (E21) of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methyl-2-phenylpropanoate hydrochloride provided herein. When administered as a single drop twice daily, the composition substantially reduces intraocular pressure.

[0196] Example 11 [ka] Example 1 is repeated substantially using (S)-3-amino-2-(4-(hydroxymethyl)phenyl)-N-((1R,3-endo,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)propanamide ditosylate (E20S) as provided herein. When administered as a single drop twice daily, the composition substantially reduces intraocular pressure, allergic symptoms, and relieves dry eye syndrome.

[0197] The topical pharmaceutical composition for preventing and treating myopia is prepared by conventional methods and formulated as shown in Table 4. [Table 4]

[0198] The topical pharmaceutical composition for preventing and treating myopia is prepared by conventional methods and formulated as shown in Table 5. [Table 5]

[0199] The topical pharmaceutical composition for preventing and treating myopia is prepared by conventional methods and formulated as shown in Table 6. [Table 6]

[0200] The topical pharmaceutical composition for preventing and treating myopia is prepared by conventional methods and formulated as shown in Table 7. [Table 7]

[0201] A topical pharmaceutical composition for preventing and treating myopia may be prepared by conventional methods and formulated as shown in Table 8. [Table 8]

[0202] Figures 1, 2 and 3 show the superior stability of the above SFA formulations (Table 8) compared to water-based formulations for the compounds provided herein.

[0203] A topical ointment pharmaceutical composition for the prevention and treatment of myopia may be prepared by conventional methods and formulated as shown in Table 9. [Table 9]

[0204] Example 12: Preparation of Salt Forms Methanesulfonic acid (2.5 eq. or 1.2 eq.) is added dropwise to a stirred solution of a compound provided herein (5.0 g 1 eq.) in DCM (dichloromethane) (10 vol). The reaction mixture is stirred at room temperature for 4 hours and the reaction is complete by HPLC. Then, a stepwise solvent switch from dichloromethane to 2-BuOH is performed. The DCM solvent solution is removed by distillation under vacuum. Then, 2-BuOH is added twice to the residue, followed by vacuum distillation. 2-BuOH (10 vol) is added to the residue and the reaction mixture is stirred at room temperature for 15 hours.

[0205] The dimesylate or monomesylate salt is filtered under nitrogen and isolated as a solid. Wash with 2-BuOH (2×1 vol) and heptane (2×1 vol) and dry the solid in a vacuum oven at 50° C. for 15 hours. Various salt forms of the compounds provided herein can be prepared according to this procedure.

[0206] (Example 13) Synthesis of endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate dihydrochloride (3) [ka] To 3-((tert-butoxycarbonyl)amino)-2-phenylpropanoic acid in CHCl was added DCC, DMAP and Tropine and the solution was stirred at room temperature overnight. The mixture was then filtered, extracted with NaHCO(sat) and NaCl(sat), dried (NaSO), filtered and evaporated. Column chromatography 0-5% MeOH-CHCl afforded pure endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(tert-butoxycarbonyl)amino-2-phenylpropanoate (2).

[0207] To endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-amino-2-phenylpropanoate (2, 30%) in CHCl was added HCl (4N in dioxane) and the solution was stirred overnight. The solvent was evaporated to give endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(tert-butoxycarbonyl)amino-2-phenylpropanoate dihydrochloride (3, >90%).

[0208] Example 14 Synthesis of endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-phenylbutanoate (5) [ka] To 4,4,4-trifluoro-2-phenylbutanoic acid (4) in CHCl was added DCC, DMAP and tropine and the solution was stirred at room temperature overnight. The mixture was then filtered and extracted with NaHCO(sat) and NaCl(sat), dried (NaSO), filtered and evaporated. Column chromatography 0-10% MeOH-CHCl gave pure endo 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-phenylbutanoate (5,36%).

[0209] Example 15 Synthesis of exo-3-hydroxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide (7) [ka] To the tropic acid (6) in MeOH, exo-8-methyl-3-amino-azabicyclo[3.2.1]octane and DMTMM were added and the solution was stirred at room temperature overnight. The mixture was evaporated and taken up in EtOAC and NaHCO3 (sat.). The pH of the aqueous solution was adjusted to pH 10 with K2CO3 solution and further extracted with 2-methyl-THF. The solvent was dried (Na2SO4), filtered and evaporated. Column chromatography 0%-90% (EtOH / 2N NH3-MeOH (85 / 15)-CH2Cl2 gave pure exo-3-hydroxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide (7, 30%).

[0210] Example 16 Synthesis of 3-hydroxy-N-((6-methoxypyridin-3-yl)methyl)-2-phenylpropanamide (8) [ka] To the tropic acid in MeOH (6), (6-methoxypyridin-3-yl)methanamine and DMTMM were added and the solution was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organics were washed with NaCl (sat), dried (MgSO4), filtered and evaporated. Column chromatography 0-8% MeOH-CH2Cl2 gave 3-hydroxy-N-((6-methoxypyridin-3-yl)methyl)-2-phenylpropanamide (8, 51%).

[0211] Using most of the procedures set forth in Examples 13-16, substituting the appropriate starting materials, the compounds in Table 10 were prepared. [Table 10-1] [Table 10-2] [Table 10-3]

[0212] Example 17: Storage and stability of compounds and compositions The compounds provided herein are prepared and placed in a container for storage at ambient or elevated temperatures. When the compounds are stored in a polyolefin plastic container, discoloration of the compounds is reduced, whether dissolved or suspended in a liquid composition (e.g., aqueous or organic liquid solution) or as a solid, as compared to polyvinyl chloride plastic containers. Without being bound by theory, the container reduces exposure of the compounds to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV-B light) or about 320 nm-380 nm (UV-A light)). Some containers also include a second component with the ability or capacity to reduce exposure of the contents of the container to infrared radiation. Containers used include those made from polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly those made from polyethylene, polypropylene, or combinations thereof. The container can be further placed in a second container, for example, a paper, cardboard, or foil container, to further reduce exposure of the contents of the container to UV, visible light, or infrared radiation. Compounds and compositions that benefit from reduced discoloration, decomposition, or both during storage include eye drop solutions comprising the compounds or compositions provided herein. Eye drop solutions may require storage lasting up to three months or longer. The container described herein may be an eye drop container. The container can be in any form suitable for containing the contents, for example, a bag or a bottle.

[0213] Other suitable containers and packaging are described, for example, in International Publication Nos. WO 2018 / 159700, WO 2018 / 159701, and WO 2018 / 159702, and Japanese Patent No. 6236167, the contents of which are incorporated herein by reference.

[0214] The compositions placed in the described containers can include boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, ethylenediaminetetraacetic acid, or combinations thereof, as well as water or other suitable solvent vehicle.

[0215] [Note] [Appendix 1] The compound has the formula (I): [ka] or a pharma- ceutically acceptable salt thereof, X 1 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 2 is H or lower alkyl; X 3 is H or lower alkyl; J 1 -CH2-, -N(R 1 )- or -O-, where R 1 is H or lower alkyl; Z 1 -CH2-, -N(R 2 )- or -O-, where R 2 is H or lower alkyl; When the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, J 1 is -O- and X 2 is lower alkyl, or X3 is lower alkyl; A compound characterized by:

[0216] [Appendix 2] the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation; 2. The compound according to claim 1,

[0217] [Appendix 3] the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the exo conformation; 2. The compound according to claim 1,

[0218] [Appendix 4] J 1 Ga-CH 2 - or -N(R 1 )-is, 4. The compound according to claim 1, wherein

[0219] [Appendix 5] J 1 If is -O-, then X 2 is lower alkyl, or X 3 is lower alkyl; 5. The compound according to claim 1, wherein

[0220] [Appendix 6] Z 1 is CH2 or N(R 2 ), 6. The compound according to claim 1, wherein

[0221] [Appendix 7] X 2 is lower alkyl, or X 3 is lower alkyl; 7. The compound according to claim 1, wherein

[0222] [Appendix 8] X1 But hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, 8. The compound according to any one of claims 1 to 7,

[0223] [Appendix 9] X 1 But hydroxyl, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, 8. The compound according to any one of claims 1 to 7,

[0224] [Appendix 10] X 1 But hydroxyl, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, 8. The compound according to any one of claims 1 to 7,

[0225] [Appendix 11] Z 1 is -CH2- or -N(R 2 )-and X 1 But hydrogen, hydroxyl, C 1-4Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, 2. The compound according to claim 1,

[0226] [Appendix 12] The compound is [ka] [ka] [ka] [ka] or an analog, derivative, solvate, zwitterion, polymorph, or a pharma- ceutically acceptable salt thereof; A compound characterized by:

[0227] [Appendix 13] The compound is represented by formula (II) [ka] or a pharma- ceutically acceptable salt thereof; X 4 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 5 is H or lower alkyl; X 6 is H or lower alkyl; X 7 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 8 is phenyl, pyridinyl, pyrimidinyl or thienopyridinyl, X 9 is phenyl, pyridinyl, pyrimidinyl, furanyl or thiophenyl; X 10 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; X 11 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; Or X 10 and X 11 C along with the atoms to which they are attached 3-7 Cycloalkyl or C 3-7 Cycloalkyl-(X 12 ) p Forming X 12 are each independently a halogen, a hydroxyl, or a C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or phenyl, and p is 0, 1, 2, or 3; J 2 -CH2-, -N(R 3 )- or -O-, where R 3 is H or lower alkyl; Z 2 -CH2-, -N(R 4 )- or -O-, where R 4 is H or lower alkyl; n is 0 or 1; A compound characterized by:

[0228] [Appendix 14] Formula (II) is Formula (IIa) [ka] Formula (IIb) [ka] Formula (IIc) [ka] Formula (IId) [ka] Formula (IIe) [ka] Formula (IIf) [ka] Or, formula (IIg) [ka] That is, 14. The compound according to claim 13,

[0229] [Appendix 15] Formula (II) is represented by formula (IIb-1) [ka] That is, 14. The compound according to claim 13,

[0230] [Appendix 16] X 8 is phenyl or pyridinyl, X 9 is phenyl, pyridinyl, furanyl, or thiophenyl; 14. The compound according to claim 13,

[0231] [Appendix 17] X 4 are hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is an alkoxy; 17. The compound according to any one of claims 13 to 16,

[0232] [Appendix 18] X 7 is hydrogen, halogen, or C 1-4 is alkyl, 18. The compound according to any one of claims 13 to 17,

[0233] [Appendix 19] -Z 2 -X 6 is -OH or -NH2; 19. The compound according to any one of claims 13 to 18,

[0234] [Appendix 20] X 10 is hydrogen, C 1-4 Alkyl, C3-7 Cycloalkyl, or C 1-4 alkyl-phenyl, X 11 is hydrogen, or C 1-4 is alkyl, or X 10 and X 11 C along with the atoms to which they are attached 3-7 Cycloalkyl or C 3-7 forming a cycloalkyl-phenyl; 20. The compound according to any one of claims 13 to 19,

[0235] [Appendix 21] The compound is [ka] [ka] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof.

[0236] [Appendix 22] A composition comprising a compound according to any one of claims 1 to 21.

[0237] [Appendix 23] Semifluorinated alkanes, and Formula (I) [ka] wherein X 1 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C1-4 Carboxyl, X 2 is H or lower alkyl; X 3 is H or lower alkyl; J 1 -CH2-, -N(R 1 )- or -O-, where R 1 is H or lower alkyl; Z 1 -CH2-, -N(R 2 )- or -O-, where R 2 is H or lower alkyl; When the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the endo conformation, J 1 is -O- and X 2 is lower alkyl, or X 3 is lower alkyl; or a pharma- ceutically acceptable salt thereof, or Formula (II) [ka] wherein X 4 is hydrogen, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 5 is H or lower alkyl; X 6 is H or lower alkyl; X 7 is hydrogen, hydroxyl, halogen, C 1-4Alkyl, amino, nitro, cyano, C 1-4 Carbonyl, C 1-4 Carbonylamino, C 1-4 Alkoxy, C 1-4 Sulfonyl, C 1-4 Sulfonylamino, C 1-4 Thioalkyl, or C 1-4 Carboxyl, X 8 is phenyl, pyridinyl, pyrimidinyl or thienopyridinyl, X 9 is phenyl, pyridinyl, pyrimidinyl, furanyl or thiophenyl; X 10 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; X 11 are hydrogen, halogens, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Thioalkyl, or C 1-4 alkyl-phenyl; Or X 10 and X 11 C along with the atoms to which they are attached 3-7 Cycloalkyl or C 3-7 Cycloalkyl-(X 12 ) p Forming X 12 are each independently a halogen, a hydroxyl, or a C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, or phenyl, and p is 0, 1, 2, or 3; J 2 -CH2-, -N(R 3 )- or -O-, where R 3 is H or lower alkyl; Z 2 -CH2-, -N(R 4)- or -O-, where R 4 is H or lower alkyl; n is 0 or 1; or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof; Including, A composition comprising:

[0238] [Appendix 24] A semifluorinated alkane and a compound, The compound is [ka] [ka] [ka] [ka] Benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αR)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, (αS)-benzeneacetic acid, α-(hydroxymethyl)-(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, endo-benzeneacetic acid, α-(hydroxymethyl)-8-(methyl-d3)-8-azabicyclo[3.2.1]oct-3-yl ester, [ka] , the (3R,2'R)-enantiomer of EA-3167, [ka] where X is Cl, Br or I; [ka] where X is Cl, Br or I; [ka] [ka] [ka] or an analog, derivative, solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof; A composition comprising:

[0239] [Appendix 25] The semifluorinated alkane is perfluorohexyl octane or perfluorohexyl nonane; 25. The composition according to claim 23 or 24,

[0240] [Appendix 26] The composition is a non-aqueous composition. 26. The composition according to any one of claims 22 to 25.

[0241] [Appendix 27] A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a composition according to any one of claims 22 to 26, and a pharma- ceutically acceptable excipient.

[0242] [Appendix 28] A method for treating myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of appendices 1 to 21, a composition according to any one of appendices 22 to 26, or a pharmaceutical composition according to appendix 27.

[0243] [Appendix 29] A method of inhibiting the progression of myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of appendices 1 to 21, a composition according to any one of appendices 22 to 26, or a pharmaceutical composition according to appendix 27.

[0244] [Appendix 30] A method of delaying the onset of myopia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of appendices 1-21, a composition of any one of appendices 22-26, or a pharmaceutical composition of appendix 27.

[0245] [Appendix 31] A method of treating a vision-threatening disease or disorder in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of appendices 1 to 21, a composition according to any one of appendices 22 to 26, or a pharmaceutical composition according to appendix 27.

[0246] [Appendix 32] The vision-threatening disease or disorder comprises peripheral lattice degeneration, fissures, detachments, myopic choroidal neovascularization, myopic macular schisis, myopic macular hole, posterior staphyloma, myopic macular degeneration, early-onset cataract, open-angle glaucoma, peripapillary atrophy, optic disc tilt, optic disc pits, or a combination thereof; 32. The method of claim 31,

[0247] [Appendix 33] A kit comprising a compound according to any one of appendices 1 to 21, a composition according to any one of appendices 22 to 26, or a pharmaceutical composition according to appendices 27, together with instructions therefor.

[0248] [Appendix 34] 27. An article of manufacture comprising a compound according to any one of claims 1 to 21, a composition according to any one of claims 22 to 26, or a pharmaceutical composition according to claim 27.

Claims

1. The compound has the formula (I): 【Chemistry 1】 or a solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof; X １ Hydroxyl, halogen, C １－４ Alkyl, amino, nitro, cyano, -C(O)(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)(C 1-4 alkyl), C １－４ alkoxy, -S(O)2(C1-4 alkyl), -S(O)2N(C1-4 alkyl)(C1-4 alkyl), -S(C1-4 alkyl) or -C(=O)O(C1-4 alkyl); X ２ is H or C １－４ is alkyl, X ３ is H or C １－４ is alkyl, J １ Ga-CH ２ -, -N(R １ )- or -O-, where R １ is H or C １－４ is alkyl, Z １ Ga-CH ２ -, -N(R ２ )- or -O-, where R ２ is H or C １－４ is alkyl, the 8-methyl-8-azabicyclo[3.2.1]octan-3-yl moiety is in the exo conformation; A compound characterized by:

2. J １ Ga-CH ２ -, or -N(R １ ) - is The compound according to claim 1 .

3. J １ When is -O-, X ２ C １－４ is alkyl, or X ３ C １－４ is alkyl, 3. The compound according to claim 1 or 2.

4. Z １ CH ２ , or N(R ２ ) A compound according to any one of claims 1 to 3.

5. X ２ C １－４ is alkyl, or X ３ C １－４ is alkyl, A compound according to any one of claims 1 to 4.

6. X １ hydroxyl, C １－４ Alkyl, amino, nitro, cyano, -C(O)(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)(C 1-4 alkyl), C １－４ alkoxy, -S(O) 2 (C 1-4 alkyl), -S(O) 2 N(C 1-4 alkyl)(C 1-4 alkyl), -S(C 1-4 alkyl) or -C(=O)O(C 1-4 alkyl); A compound according to any one of claims 1 to 5.

7. X １ hydroxyl, C １－４ alkyl, amino, nitro, cyano, -C(O)(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)(C 1-4 alkyl), -S(O) 2 (C 1-4 alkyl), -S(O) 2 N(C 1-4 alkyl)(C 1-4 alkyl), -S(C 1-4 alkyl) or -C(=O)O(C 1-4 alkyl); A compound according to any one of claims 1 to 5.

8. Z １ Ga-CH ２ -or-N(R ２ ) - and X １ hydroxyl, C １－４ Alkyl, amino, nitro, cyano, -C(O)(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)(C 1-4 alkyl), C １－４ alkoxy, -S(O) 2 (C 1-4 alkyl), -S(O) 2 N(C 1-4 alkyl)(C 1-4 alkyl), -S(C 1-4 alkyl) or -C(=O)O(C 1-4 alkyl); The compound according to claim 1 .

9. The compound is 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 or a solvate, zwitterion, or polymorph thereof, or a pharma- ceutically acceptable salt thereof; A compound characterized by:

10. A composition comprising a compound according to any one of claims 1 to 9.

11. A method for producing a semifluorinated alkane comprising the steps of: A composition comprising:

12. The semifluorinated alkane is perfluorohexyl octane or perfluorohexyl nonane; The composition of claim 11.

13. The composition is a non-aqueous composition.

13. The composition according to any one of claims 10 to 12.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a composition according to any one of claims 10 to 13, and a pharma- ceutically acceptable excipient.

15. A pharmaceutical composition for treating myopia in a subject in need thereof, comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 13, or a pharmaceutical composition according to claim 14, wherein the compound, the composition or the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

16. A pharmaceutical composition for inhibiting the progression of myopia in a subject in need thereof, comprising a compound described in any one of claims 1 to 9, a composition described in any one of claims 10 to 13, or a pharmaceutical composition described in claim 14, wherein the compound, composition, or pharmaceutical composition is administered to the subject in a therapeutically effective amount.

17. A pharmaceutical composition for delaying the onset of myopia in a subject in need thereof, comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 13, or a pharmaceutical composition according to claim 14, wherein the compound, composition or pharmaceutical composition is administered to the subject in a therapeutically effective amount.

18. A pharmaceutical composition for treating a vision-threatening disease or disorder in a subject in need of such treatment, comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 13, or a pharmaceutical composition according to claim 14, wherein the compound, the composition, or the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

19. The vision-threatening disease or disorder comprises peripheral lattice degeneration, fissures, detachments, myopic choroidal neovascularization, myopic macular schisis, myopic macular hole, posterior staphyloma, myopic macular degeneration, early-onset cataract, open-angle glaucoma, peripapillary atrophy, optic disc tilt, optic disc pits, or a combination thereof; 19. The pharmaceutical composition of claim 18.

20. A kit comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 13, or a pharmaceutical composition according to claim 14, together with instructions therefor.

21. 15. An article of manufacture comprising a compound according to any one of claims 1 to 9, a composition according to any one of claims 10 to 13, or a pharmaceutical composition according to claim 14.

Images