8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate ester

Abstract

In one general aspect, the disclosure provides fatty acid esters of atropine, or pharma- ceutically acceptable salts thereof. Pharmaceutical compositions comprising these esters are also provided. In one example, the composition comprises a semi-fluorinated alkane vehicle, such as perfluorohexyl octane (F6H8). Methods of using fatty acid esters of atropine include areas of medicine where atropine is known to be useful. In one example, the disclosure provides methods of using the compounds as cycloplegics and / or mydriatics. TIFF2025503039000071.tif141158

Description

[Technical field]

[0001] Priority claim This application claims priority to U.S. Provisional Patent Application No. 63 / 301,657, filed January 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to esters, particularly fatty acid esters, of 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate (e.g., atropine), methods for their preparation, pharmaceutical compositions containing them, and their use as medicaments for treating and preventing diseases involving muscarinic acetylcholine receptors. [Background technology]

[0003] background Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form a G protein-coupled receptor complex in the cell membrane of certain neurons, such as ganglia. There are five subtypes of muscarinic acetylcholine receptors, named M1 through M5. M1, M3, and M5 receptors are G q M2 and M4 receptors are G-coupled proteins. i / oIt couples with proteins. M1 receptors are typically involved in excitatory postsynaptic potentials, secretion from the salivary glands and stomach, higher cognitive processes such as learning and spatial memory, and analgesia. M2 receptors are typically involved in slowing heart rate, reducing the force of atrial contraction, reducing the conduction velocity of the atrioventricular node, and homotropic inhibition. M3 receptors are typically involved in smooth muscle contraction, bronchoconstriction and pulmonary secretion, increasing intracellular calcium in the vascular endothelium, endocrine and exocrine gland hypersecretion (e.g., salivary glands and stomach), gastrointestinal hypermotility, ocular accommodation (miosis when M3 is stimulated, or pupillary dilation when M3 is inhibited), pupillary sphincter function, cerebral vasodilation, systemic vasodilation (depending on the location of M3), and induction of vomiting. M4 receptors are typically involved in movement (e.g., receptor activation causes decreased movement). M5 receptors are involved in many CNS functions. For example, atropine is a competitive antagonist of muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5 and can therefore regulate any of the aforementioned physiological processes. Summary of the Invention

[0004] overview The present disclosure is based, at least in part, on the recognition that fatty acid esters, including unsaturated fatty acid esters, of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate (also known as atropine) are useful as prodrugs. Hydrolytic and / or enzymatic cleavage of the ester functionality releases the parent compound (e.g., atropine), which acts as a competitive antagonist of muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5. Moreover, and importantly herein, fatty acid (e.g., saturated or unsaturated) ester prodrugs of the parent compound (e.g., atropine) exhibit superior solubility to atropine in fluorinated solvents, such as the semifluorinated alkane solvent F6H8 (perfluorohexyl octane). F6H8 is a pharma- ceutically acceptable amphiphilic liquid having two mutually immiscible moieties (hydrocarbon segment RH and perfluorinated segment RF) covalently bonded thereto. Thus, these fluorinated solvents are advantageously useful as liquid vehicles for delivering ester prodrugs of atropine to patients in need thereof. In one aspect, it has been surprisingly found that fatty acid esters of atropine (e.g., unsaturated and / or saturated fatty acid esters) are about 10 times, about 100 times, or about 1,000 times more soluble in semifluorinated alkane solvents such as F6H8 than atropine. In one example, it has been surprisingly found that saturated fatty acid esters of atropine are about 10 times, about 100 times, or about 1,000 times more soluble in semifluorinated alkane solvents such as F6H8 than atropine. In another example, it has been surprisingly found that fatty acid esters of atropine are about 10 times, about 100 times, about 1,000 times, or about 10,000 times more soluble in semifluorinated alkane solvents, such as F6H8, compared to atropine.

[0005] In one general aspect, the disclosure provides a compound of formula (I): TIFF2025503039000002.tif40128, or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2, n, and R 3 is as described herein.

[0006] In another general aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0007] In some embodiments, the pharma- ceutically acceptable carrier comprises a semi-fluorinated alkane. In some embodiments, the semi-fluorinated alkane is selected from perfluorohexyl octane (F6H8), perfluorohexyl hexane (F6H6), perfluorobutyl butane (F4H4), and perfluorohexyl ethane (F6H2). In some embodiments, the pharmaceutical composition is an ophthalmic composition. Suitable examples of ophthalmic compositions include eye drops that comprise an emulsion, suspension, or solution of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0008] In another general aspect, the disclosure provides a method of treating or preventing a disease or condition in which a muscarinic acetylcholine receptor is involved, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0009] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same is used to induce cycloplegic refraction in the eye of a subject, induce pupil dilation in the eye of a subject, treat amblyopia or strabismus in children, reduce symptoms of floaters, treat or prevent painful ciliary spasms, or treat progression of myopia in a pediatric subject.

[0010] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same is used to treat or prevent cardiac conditions such as slow heart rate (bradycardia), to reduce salivary secretion and bronchial secretion (e.g., before surgery), or to treat or prevent hyperhidrosis or intoxication. In these embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the same is administered to a subject by oral, intramuscular, intravenous, subcutaneous, intraosseous, or intratracheal routes, or by inhalation.

[0011] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs.Methods and materials are described herein for use in this application; other suitable methods and materials known in the art can also be used.Materials, methods, and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety.In case of conflict, the present specification, including definitions, will control.

[0012] Other features and advantages of the present application will become apparent from the following detailed description and figures, and from the claims. [Brief description of the drawings]

[0013] [Figure 1] 1 is a line plot showing pupil diameter change in rabbits following ophthalmic administration of vehicle, atropine oleate, atropine linoleate, and atropine sulfate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description In some embodiments, the present disclosure provides fatty acid ester prodrugs of tropane alkaloids, such as atropine, among others. Without being bound by any theory or speculation, it is believed and understood that administration of the ester to a patient and subsequent hydrolytic and / or enzymatic cleavage releases the parent alkaloid from its prodrug form and acts as a competitive antagonist of muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5. Thus, the compounds of the present disclosure are useful for treating or preventing diseases, disorders and conditions involving acetylcholine receptors.

[0015] In some embodiments, the compounds of the present disclosure are useful in treating uveitis and / or inducing cycloplegic refraction and / or mydriasis (pupil dilation) in the patient's eye. When used as a cycloplegic agent, the compounds of the present disclosure temporarily paralyze the ciliary muscle of the eye and simultaneously paralyze the accommodation reflex. This is useful, for example, during ophthalmic examinations, for example in young children, to obtain accurate refraction and true refractive error of the eye. The compounds may be useful in treating amblyopia or strabismus in children. The compounds are useful for reducing the symptoms of floaters. The compounds can also relieve painful ciliary muscle spasms in the eye. When used as a mydriatic agent for dilating the pupil, the compounds allow for examination of the retina and other deep structures of the eye. As mydriatic agents, the compounds are also useful for preventing the progression of myopia in children. When used to treat or prevent an ocular condition in a patient, the compounds may be administered and / or applied as any one of the topical / ophthalmic compositions as described herein (e.g., as eye drops of an emulsion, suspension, or solution).

[0016] In some embodiments, the compounds of the present disclosure are useful in any field of medicine where atropine, scopolamine, or hyoscyamine are advantageously used to treat or prevent a condition. In some embodiments, the compounds are useful for treating or preventing various cardiac diseases. For example, the compounds can treat or prevent symptoms of low heart rate (bradycardia). In some embodiments, the compounds are useful for treating bradycardia when the patient's heart rate is less than about 60 beats per minute. In this application, the compounds can be administered by IV injection. For symptomatic bradycardia, the usual dosage of atropine is about 0.5 mg to about 1 mg IV push, which can be repeated every 3 to 5 minutes up to a total dose of about 3 mg (maximum dose of about 0.04 mg / kg). The dosage of the compounds of the present disclosure can be adjusted accordingly based on the difference in molecular weight of atropine and the ester compounds of the present disclosure. The compounds of the present disclosure are also useful for treating second degree heart block Mobitz type 1, and third degree heart block with high Purkinje or AV nodal escape rhythm. In some embodiments, the compounds may be used to prevent low heart rates during intubation of children.

[0017] In some embodiments, the compounds of the present disclosure are useful for reducing salivation and bronchial secretions (e.g., before surgery). The action of atropine on the parasympathetic nervous system inhibits salivary and mucous glands. Thus, the compounds of formula (I) can inhibit sweating via the sympathetic nervous system. This is useful for treating hyperhidrosis and can also prevent death rattle in terminally ill patients.

[0018] In some embodiments, the compounds of the present disclosure are useful as antidotes for poisoning. For example, atropine serves as a treatment for poisoning by organophosphorus insecticides and nerve agents such as tabun, sarin, soman, and VX. In cases of nerve gas poisoning, maximum atropine administration is desirable. The compounds of formula (I) can be used in combination with the oxime pralidoxime chloride, or any other anti-poisoning dot provided herein. For systemic indications, the compounds can be administered by any of the routes described herein, for example, by oral, intramuscular, intravenous, subcutaneous, intraosseous, or intratracheal routes, or by inhalation.

[0019] therapeutic compounds In one general aspect, the disclosure provides a compound of formula (I): TIFF2025503039000003.tif40128, or a pharma- ceutically acceptable salt thereof, wherein: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C7-34 Alkenyl, and C 7-34 Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino.

[0020] In some embodiments, the compound of formula (I) is not atropine oleate or hyoscyamine oleate. In some embodiments, the compound of formula (I) is not atropine oleate. In some embodiments, the compound of formula (I) is not hyoscyamine oleate.

[0021] In some embodiments, R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 In some embodiments, R is selected from alkynyl. 1 is C 7-21 Alkyl, C 7-21 Alkenyl, and C 7-21 In some embodiments, R is selected from alkynyl. 1 is C 7-21 Alkyl, C 2-21 alkenyl (e.g., containing only one double bond), and C 2-21 alkynyl.

[0022] In some embodiments, R 1 is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, each of which is selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 In some embodiments, R is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino. 1 is C 3-10 In some embodiments, R 1 is 4-10 membered heterocycloalkyl. In some embodiments, R 1 is 5-14 membered heteroaryl. In some embodiments, R 1 is C 6-10 It is aryl.

[0023] In some embodiments, R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 alkynyl, each of which is selected from C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Optionally substituted with 1 or 2 substituents independently selected from aryl (and each of these cyclic groups may be substituted as described above).

[0024] In some embodiments, R 1 is C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, or C 6-10 Aryl (each of which is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; 1-6 In some embodiments, R 1 is C 3-10 Optionally substituted with cycloalkyl 1-6 In some embodiments, R 1 is optionally substituted with 4- to 10-membered heterocycloalkyl; 1-6 In some embodiments, R 1 is C optionally substituted with 5- to 14-membered heteroaryl; 1-6 In some embodiments, R 1 is C 6-10 C optionally substituted with aryl 1-6 It is an alkyl.

[0025] In some embodiments, R 1 is C 1-34 In some embodiments, R 1 is C 7-34 In some embodiments, R 1 is C 7-21 It is an alkyl.

[0026] In some embodiments, R 1 is C 1-6 For example, R 1 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, iso-butyl, n-pentyl, neo-pentyl, or n-hexyl. 1 C 1-6 A compound of formula (I) which is alkyl is administered to a patient to treat or prevent an ocular disease and / or in a pharmaceutical formulation which includes a semifluorinated alkane liquid vehicle as described herein.

[0027] In some embodiments, R 1 is C 7-11 For example, R 1 is a residue of a saturated medium-chain fatty acid, such as caproic acid (hexanoic acid), caprylic acid (octanoic acid), pelargonic acid (nonanoic acid), capric acid (decanoic acid), or undelyc acid (undecanoic acid).

[0028] In some embodiments, R 1 is C 12-21 For example, R 1 are residues of saturated long-chain fatty acids, such as lauric acid (dodecanoic acid), tridecylic acid (tridecanoic acid), myristic acid (tetradecanoic acid), pentadecylic acid (pentadecanoic acid), palmitic acid (hexadecanoic acid), margaric acid (heptadecanoic acid), stearic acid (octadecanoic acid), nonadecylic acid (nonadecanoic acid), arachidic acid (eicosanoic acid), or heneicosanoic acid (heneicosanoic acid).

[0029] In some embodiments, R 1 is C 22-34 For example, R 1 is a residue of a saturated very long chain fatty acid, such as lignoceric acid (tetracosanoic acid), cerotic acid (hexacosanoic acid), montanic acid (octacosanoic acid), lacceroic acid (dotriacontanoic acid), or gedaic acid (tetratriacontanoic acid).

[0030] In some embodiments, R 1 is C 2-34 In some embodiments, R is alkenyl. 1 is C 7-34 In some embodiments, R is alkenyl. 1 is C 7-21 In some embodiments, R is alkenyl. 1 Any of the alkenyl chains may contain 1, 2, 3, 4, 5, or 6 double bonds.

[0031] In some embodiments, R 1 is C 2-6 In some embodiments, R is alkenyl. 1 C containing one double bond 2-6 In some embodiments, R is alkenyl. 1 C contains two double bonds 4-6 For example, R 1 is selected from vinyl, propenyl, butenyl, or hexadienyl.

[0032] In some embodiments, R 1 is C 7-11 In some embodiments, R is alkenyl. 1 C containing one double bond 7-11 In some embodiments, R is alkenyl. 1 C contains two double bonds 7-11 For example, R 1 is a residue of an unsaturated medium-chain fatty acid, such as 5-caproic acid (dec-5-enoic acid), 4-caproic acid (dec-4-enoic acid), or 9-caproic acid (dec-9-enoic acid).

[0033] In some embodiments, R 1 is C 12-21 In some embodiments, R is alkenyl. 1 C containing one double bond 12-21 In some embodiments, R is alkenyl. 1 C contains two double bonds 12-21 For example, R 1are lauroleic acid (9-dodecenoic acid), sapienic acid (hexadec-6-enoic acid), palmitoleic acid (hexadec-9-enoic acid), myristoleic acid (tetradec-9-enoic acid), oleic acid (Z-octadec-9-enoic acid), and linoleic acid (octadeca-9,12-dienoic acid), palmitoleic acid (hexadec-9-enoic acid), elaidic acid (E-octadec-9,12-dienoic acid). In some embodiments, R is a residue of an unsaturated long chain fatty acid, such as octadec-9-enoic acid, vaccenic acid (octadec-11-enoic acid), linoelaidic acid, linolenic acid (octadeca-9,12-dienoic acid), vaccenic acid (octadec-11-enoic acid), petroselinic acid (octadec-6-enoic acid), oct-3-enoic acid, or arachidonic acid (icosa-5,8,11,14-tetraenoic acid). 1 Any double bonds within the alkenyl or alkynyl may be in the E or Z configuration.

[0034] In some embodiments, R 1 is C 22-34 For example, R 1 is the residue of an unsaturated very long chain fatty acid, such as nervonic acid (Z-tetracos-15-enoic acid), ximenic acid (Z-17-hexacosenoic acid), or lumequeic acid (Z-21-triacontenoic acid).

[0035] In some embodiments, R 1 is C 2-34 In some embodiments, R is alkynyl. 1 is C 7-34 In some embodiments, R is alkynyl. 1 is C 7-21 In some embodiments, R is alkynyl. 1 Any of the alkynyl chains may contain one, two, or three triple bonds. In one example, the alkynyl chain contains one triple bond and one double bond. In another example, the alkynyl chain contains one triple bond and two double bonds.

[0036] In some embodiments, n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 1, 2, and 3. In some embodiments, n is 0.

[0037] In some embodiments, R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, and di(C 1-3 alkyl)amino.

[0038] In some embodiments, R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 It is selected from haloalkoxy, OH, NO2, CN, halo, and amino.

[0039] In some embodiments, R 3 is H.

[0040] In some embodiments, R 3 is C 1-6 Alkyl (eg, methyl, ethyl, propyl, or isopropyl).

[0041] In some embodiments, R 3 is C 1-6 and haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluorethyl, or 2-fluoroethyl).

[0042] In some embodiments, n is 0 and R 3 is C 1-3 It is an alkyl.

[0043] In some embodiments, the compound of formula (I) has the formula: TIFF2025503039000004.tif43128, or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the compound of formula (I) has the formula: TIFF2025503039000005.tif42128, or a pharma- ceutically acceptable salt thereof.

[0045] In some embodiments, the compound of formula (I) has the formula: TIFF2025503039000006.tif42128, or a pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, the compound of formula (I) has the formula: TIFF2025503039000007.tif42128, or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the compound of formula (I) is selected from atropine 5-caproate, atropine 4-caproate, atropine 5-lauroate, atropine sapienate, atropine palmitoleate, atropine myristoleate, atropine oleate, atropine vaccenate, atropine petroselinate, atropine 3-octenoate, atropine linoleate, atropine caprate, atropine caprylate, atropine laurate, atropine myristate, and atropine palmitate, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt thereof: TIFF2025503039000008.tif43128TIFF2025503039000009.tif191138TIFF2025503039000010.tif22394TIFF2025503039000011.tif206126.

[0049] In some embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt thereof: TIFF2025503039000012.tif176134TIFF2025503039000013.tif86128.

[0050] In some embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt thereof: TIFF2025503039000014.tif215134.

[0051] Pharmaceutically acceptable salts In some embodiments, the salts of the compounds of formula (I) are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compounds are pharma-ceutically acceptable acid addition salts. The salts retain the desired biological activity of the compounds identified above and exhibit minimal or no undesired toxicological effects.

[0052] The acid addition salt forms of the compounds of formula (I) can be obtained by treating the free base with a suitable acid, such as inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; or organic acids, for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic acid, and the like (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zurich, 2002, 329-345).

[0053] The compounds of formula (I) and their salts can be in the form of solvates, which are included in the scope of the present invention.Such solvates include, for example, hydrates, alcoholates (e.g., ethanol solvates), etc.The compounds according to the present invention can exist in different polymorphic forms.Although not explicitly shown in the above formula, such forms are intended to be included in the scope of the present disclosure.

[0054] Manufacturing method Compounds of formula (I), including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes. For example, the compounds described herein can be prepared using methods and procedures similar to those of Examples 1-2 herein. Those skilled in the art will know how to select and implement appropriate synthetic protocols and will recognize that the processes described are not the exclusive means by which the compounds provided herein may be synthesized, and that a wide repertoire of synthetic organic reactions is available for potential adoption in the synthesis of the compounds provided herein.

[0055] Suitable methods for the synthesis of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2 nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0056] The synthetic schemes set forth below illustrate how compounds according to the invention may be prepared, where R 1 is R as described herein for compounds of formula (I). 1 (referring to any of the groups). TIFF2025503039000015.tif42128

[0057] Those skilled in the art will be able to routinely modify and / or adapt the following schemes to synthesize any compound of the invention covered by formula I. The reactions for preparing the compounds provided herein can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of multiple solvents. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0058] Preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. Protective group chemistry is described, for example, in PGM Wuts and TW Greene, Protective Groups in Organic Synthesis, 4 th Ed., Wiley & Sons, Inc., New York (2006).

[0059] Pharmaceutical Compositions and Formulations The present disclosure provides a pharmaceutical composition comprising an effective amount of the compound of the present disclosure or its pharma- ceutically acceptable salt; and a pharma- ceutically acceptable carrier.The carrier is "acceptable" in the sense that it is compatible with the other components of the formulation, and, in the case of a pharma- ceutical acceptable carrier, is not harmful to its recipient in the amount used in medicine.The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein.

[0060] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0061] In some embodiments, the pharma- ceutically acceptable carrier is a semi-fluorinated alkane fluid. In one example, the semi-fluorinated alkane compound useful in the formulations of the present disclosure has the formula CF3(CF2): m (CH2) nIn some embodiments, m is an integer between 1 and 10, and n is an integer between 1 and 10. For example, m can be 1, 2, 3, 4, 5, or 6. In another example, n can be 1, 2, 3, 4, 5, or 6. Suitable examples of partially fluorinated alkane compounds include perfluorohexyl octane (F6H8), perfluorohexyl hexane (F6H6), perfluorobutyl butane (F4H4), and perfluorohexyl ethane (F6H2). In some embodiments, the concentration of the compound within the scope of the present claims in a pharmaceutical formulation containing a partially fluorinated alkane vehicle liquid is about 1 mg / mL to about 10 mg / mL. For example, the concentration is about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, or about 7 mg / mL. In one example, the formulation comprising a semifluorinated alkane fluid as a pharma- ceutically acceptable carrier can be any one of the ophthalmic formulations described herein, hi another example, the formulation comprising a semifluorinated alkane fluid as a pharma- ceutically acceptable carrier is an injectable composition suitable for intramuscular, intravenous, or subcutaneous administration.

[0062] The composition or dosage form may contain any one of the compounds and therapeutic agents described herein in the range of 0.005%-100%, with the remainder consisting of suitable pharma- ceutically acceptable excipients. Contemplated compositions may contain any one of the compounds and therapeutic agents provided herein in the range of 0.001%-100%, in one embodiment 0.1-95%, in another embodiment 75-85%, and in a further embodiment 20-80%, with the remainder consisting of any pharma- ceutically acceptable excipients described herein, or any combination of these excipients.

[0063] Route of administration and dosage form Pharmaceutical compositions of the present application include those suitable for any acceptable route of administration, including buccal, dermal, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, and intrapulmonary. These include intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumor, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0064] The compositions and preparations described herein can be conveniently presented in unit dosage form, for example, in the form of tablets, sustained release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy.See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparation methods include the step of combining the molecule to be administered with ingredients such as carriers, which constitute one or more accessory ingredients.In general, the compositions are prepared by uniformly and intimately combining active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0065] In some embodiments, any one of the compounds and therapeutic agents disclosed herein is administered orally.The compositions of the present application suitable for oral administration can be presented as separate units such as capsules, sachets, granules or tablets, each containing a predetermined amount (e.g., an effective amount) of active ingredient; as powders or granules; as a solution or suspension in aqueous or non-aqueous liquid; as an oil-in-water liquid emulsion; as a water-in-oil liquid emulsion; encapsulated in liposomes; or as a bolus, etc.Soft gelatin capsules can be useful for containing such suspensions, which can advantageously increase the compound absorption rate.For tablets for oral use, commonly used carriers include lactose, sucrose, glucose, mannitol, silicic acid and starch. Other acceptable excipients may include: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.Compositions suitable for oral administration include lozenges comprising the ingredient in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia.

[0066] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection or infusion solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The preparations may be provided in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition that requires only the addition of a sterile liquid carrier, for example, water for injection, saline (for example, 0.9% saline) or 5% dextrose solution, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injection solutions may be, for example, in the form of a sterile injectable aqueous or oleaginous suspension. The suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0067] The pharmaceutical composition of the present application may be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present application with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum and releases active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

[0068] The pharmaceutical compositions of the present application can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to the techniques well known in the art of pharmaceutical formulations, and can be prepared as a solution in saline with benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. For example, see U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration can be found in Ilium, L., J Pharm Pharmacol, 56, 3-17, 2004 and Ilium, L., Eur J Pharm Sci, 11, 1-18, 2000.

[0069] The topical composition of the present disclosure can be prepared and used in the form of aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, or soap.In some aspects, the composition is in any form commonly used in the technical field of cosmetics and skin care formulations.The topical composition can be in emulsion form.Topical administration of the pharmaceutical composition of the present application is particularly useful when the desired treatment concerns areas or organs that are easily accessible by topical application. In some embodiments, the topical composition comprises any one of the compounds and therapeutic agents disclosed herein in combination with one or more additional ingredients, carriers, excipients, or diluents, including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (moisturizers), emulsifiers, film forming / retentive agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrubbing agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / cleansing agents, penetration enhancers, and thickeners.

[0070] In some embodiments, the topical composition is an ophthalmic formulation, for example for intraocular administration. Suitable examples of ophthalmic formulations include eye drops, saline drops, suspensions, ointments, emulsions, nanoemulsions, oils, gels, hydrogels, and solutions. Any one of these ophthalmic formulations can be administered directly to the cornea, pupil, retina, choroid, sclera, and / or iris of the eye, for example, using a plastic or latex applicator (e.g., a disposable applicator), an eye dropper, a glass pipette, or a rubber bulb. These formulations may contain a partially fluorinated alkane liquid vehicle, for example, as described above. In addition, the ophthalmic formulation may contain water, saline, dextrose solution, cellulose or its derivatives (e.g., hydroxypropylmethylcellulose), a surfactant such as polysorbate 20, a chelating agent, or a cyclodextrin.

[0071] Dosage and Regimen In the pharmaceutical compositions of the present application, the compounds of the present disclosure (e.g., compounds of formula (I)) are present in an effective amount (e.g., a therapeutically effective amount). The effective dose may vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, the use of excipients, the possibility of co-administration with other therapeutic treatments such as the use of other drugs, and the judgment of the treating physician.

[0072] In some embodiments, the effective amount of a compound (e.g., Formula (I) or a pharma- ceutically acceptable salt thereof) in an ophthalmic formulation can range, for example, from about 0.0001% to about 10% (e.g., from about 0.0001% to about 1%; from about 0.001% to about 1%; from about 0.01% to about 1%; from about 0.1% to about 1%). In some embodiments, the effective amount of a compound of Formula (I) is about 0.001%, about 0.01%, about 0.1%, or about 0.1%, or about 1%.

[0073] In some embodiments, an effective amount (e.g., in a systemic formulation) of a compound (e.g., of Formula (I) or a pharma- ceutically acceptable salt thereof) can be, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 50 mg / kg; about 0.1 mg / kg to about 10 mg / kg; about 0.1 mg / kg to about 5 mg / kg; about 0.1 mg / kg to about 2 mg / kg; about 0.1 mg / kg to about 1 mg / kg; or about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, the effective amount of the compound of formula (I) is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0074] The aforementioned dosages can be administered daily (e.g., as a single dose or as two or more divided doses, e.g., once a day, twice a day, three times a day, or four times a day) or non-daily (e.g., every other day, every second day, every third day, weekly, twice a week, biweekly, monthly).

[0075] kit The present invention also includes pharmaceutical kits, which are useful in the treatment of disorders, diseases and conditions, for example, as mentioned herein, and include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present disclosure.Such kits can further include one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharma-ceutically acceptable carriers, additional containers, etc.Instructions, either as inserts or labels, indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing components, can also be included in the kit.The kit can optionally include additional therapeutic agents, as described herein.

[0076] Use in combination The compound of the present disclosure can be used in combination with at least one drug or therapy that is useful in treating or preventing diseases involving muscarinic acetylcholine receptor.Suitable examples of such drugs include muscarinic acetylcholine receptor agonists and / or antagonists, or their pharmaceutically acceptable salts.

[0077] Suitable examples of muscarinic receptor agonists include acetylcholine, arecoline, oxotremorine, muscarine, carbachol, nebracetam, bethanechol, pilocarpine, and desmethylclozapine, or its pharmaceutically acceptable salt.Suitable examples of muscarinic receptor antagonists include atropine, hyoscyamine, scopolamine, diphenhydramine, dimenhydrinate, dicycloverine, tolterodine, oxybutynin, ipratropium, pirenzepine, telenzepine, tripitramine, gallamine, methoctramine, darifenacin, tiotropium, chlorpromazine, and haloperidol, or its pharmaceutically acceptable salt.

[0078] In some embodiments, the compound of formula (I) can be administered in combination with a cycloplegic agent, such as atropine, cyclopentolate, homatropine, scopolamine, or tropicamide, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of formula (I) can be administered in combination with a mydriatic agent, such as tropicamide, phenylephrine, cyclopentolate, atropine, scopolamine, or homatropine, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compounds of formula (I) may be administered in combination with an agent for treating bradycardia, such as atropine or another anticholinergic, an inotropic agent (dopamine, dobutaime, dopexamine, adrenaline, isoproterenol, noradrenaline, or a pharma- ceutically acceptable salt thereof).

[0080] In some embodiments, the compounds of formula (I) may be administered in combination with hyperhidrosis medications such as formaldehyde, aluminum chlorohydrate, or anticholinergics (propantheline, glycopyrronium bromide or glycopyrrolate, oxybutynin, methantheline, or benzatropine).

[0081] In some embodiments, the compounds of formula (I) can be administered in combination with an antidote to poisoning, such as atropine, benztropine, botulinum antitoxin, cysteine, bicarbonate, glucagon, or pyridoxine, or a pharma- ceutically acceptable salt thereof.

[0082] The compounds of the present disclosure may be administered to a patient simultaneously with the additional therapeutic agent (in the same pharmaceutical composition or dosage form or in different compositions or dosage forms) or sequentially (the additional therapeutic agent may be administered in a separate pharmaceutical composition or dosage form before or after administration of the compound of the present disclosure).

[0083] definition As used herein, the term "about" means approximately (eg, plus or minus approximately 10% of the indicated value).

[0084] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0085] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places in this specification.Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as allowed by valence.For example, the term "pyridine ring" or "pyridinyl" can refer to pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0086] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substitution can occur at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by the valence of the atom.

[0087] Throughout the definition, "C n-m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 etc.

[0088] The term "alkyl," as used herein, refers to a saturated monovalent hydrocarbon moiety having linear or branched moieties or combinations thereof and containing the specified number (e.g., 2 to 22) of carbon atoms. One methylene (-CH2-) group of an alkyl can be replaced by an oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or a divalent C 3-8 The alkyl groups can be independently substituted with halogen atoms, hydroxyl groups, cycloalkyl groups, amine groups, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulfonic acid groups, phosphoric acid groups, nitro groups, amide groups, and sulfonamide groups.

[0089] The term "alkenyl," as used herein, refers to a monovalent or divalent hydrocarbon radical having at least one double bond (e.g., 1, 2, 3, 4, 5, or 6 double bonds) and derived from a saturated alkyl, having the specified number of carbon atoms (e.g., 2 to 22). The alkenyl can be in the E or Z configuration (e.g., each of the double bonds in an alkenyl can independently be in the E or Z configuration). An alkenyl group is a C 1-8 It may be substituted by alkyl.

[0090] The term "alkynyl," as used herein, refers to a monovalent or divalent hydrocarbon radical having at least one triple bond (e.g., 1, 2, 3, 4, 5, or 6 triple bonds) and derived from a saturated alkyl, having the specified number of carbon atoms (e.g., 2-20). An alkynyl group is optionally selected from the group consisting of C 1-8 It may be substituted by alkyl.

[0091] The term "cycloalkyl" as used herein refers to a monovalent or divalent group derived from a saturated cyclic hydrocarbon, for example of 3 to 8 carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl is substituted with halogens, nitro groups, cyano groups, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -C 1-6 Alkyl group, -C 2-6 Alkenyl group, -C 2-6Alkynyl group, C 3-8 It can be independently substituted with a cycloalkyl group, a carboxylic acid group, an ester group, a ketone group, an aldehyde group, an amide group, an amine group, a sulfonamide group, or a hydroxyl group.

[0092] The term "cycloalkenyl" as used herein refers to a monovalent or divalent group of, for example, 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond and / or at least one triple bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted with halogen atoms, nitro groups, cyano groups, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -C 1-6 Alkyl group, -C 2-6 Alkenyl group, -C 2-6 Alkynyl group, carboxylic acid group, ester group, ketone group, aldehyde group, amide group, amine group, sulfonamide group, C 3-8 It can be independently substituted by a cycloalkyl group or a hydroxyl group.

[0093] The term "heterocycle" as used herein refers to a 3-10 membered ring, which may be aromatic or non-aromatic, saturated or unsaturated, monocyclic or polycyclic, containing at least one heteroatom selected from O or N or S or a combination of at least two thereof, interrupting a carbocyclic ring structure. The heterocycle may be interrupted by C=O; the S heteroatom may be oxidized. The heterocycle may be monocyclic or polycyclic. The heterocycle moiety may be selected from halogens, nitro groups, cyano groups, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -C 1-6 Alkyl group, -C 2-6 Alkenyl group, -C 2-6 Alkynyl group, carboxylic acid group, ester group, ketone group, aldehyde group, amide group, amine group, sulfonamide group, C 3-8 It can be substituted by a cycloalkyl group or a hydroxyl group.

[0094] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A 5-membered heteroaryl ring is a heteroaryl having a ring having 5 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl having a ring having six ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0095] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted by one or two independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group may be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0-3 double bonds. In some embodiments, the heterocycloalkyl group contains 0-2 double bonds. Also included within the definition of heterocycloalkyl are moieties in which one or more aromatic rings are fused (i.e., have a common bond) to a cycloalkyl ring, e.g., benzo or thienyl derivatives such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings may be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and having one or more oxidized ring members.In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0096] The term "aryl" as used herein refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removing one hydrogen. Aryl can be monocyclic or polycyclic. Aryl can be substituted with halogen atoms, nitro groups, cyano groups, -OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -C 1-6 Alkyl group, -C 2-6 Alkenyl group, -C 2-6 Alkynyl group, carboxylic acid group, ester group, ketone group, aldehyde group, amide group, amine group, sulfonamide group, C 3-8 It can be substituted by a cycloalkyl group or a hydroxyl group. Typically, the aryl is a phenyl. Preferred substitution sites on the aryl are the meta and para positions.

[0097] The term "cyano," as used herein, represents a group of the formula "-CN."

[0098] The term "nitro" as used herein represents a group of the formula "-NO2".

[0099] The term "amide" as used herein refers to a compound of the formula "-C(O)NR x R y " group, where R x and R y may be, identically or independently, H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above.

[0100] The term “amine” or “amino” as used herein refers to a group of the formula “—NR x R y " group, where Rx and R y may be, identically or independently, H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyl, as defined above.

[0101] As used herein, "C n-m The term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

[0102] As used herein, "di(C n-m The term "-N(alkyl)amino" refers to a group of formula -N(alkyl)2, where each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0103] The term "ketone" as used herein refers to an organic compound having a carbonyl group attached to a carbon atom, e.g., -(CO)R x where R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyl as defined above.

[0104] The term "aldehyde" as used herein represents a group of the formula "-C(O)H".

[0105] The term "ester" as used herein refers to an ester of the formula "-C(O)OR x " group, where R xcan be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyl as defined above.

[0106] The term "sulfonamide" as used herein refers to a compound of the formula "-S(O)NR x R y " group, R x and R y may be, identically or independently, H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyl, as defined above.

[0107] The term "sulfoxide" as used herein represents a group of the formula "-S=O".

[0108] As used herein, alone or in combination with other terms, "C n-m The term "haloalkyl" refers to an alkyl group having 1 to 2s+1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, where the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0109] As used herein, "C n-m "Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An example of a haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0110] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br.

[0111] As used herein, the term "carboxy" refers to the group -C(O)OH.

[0112] As used herein, the term "carbamyl" refers to a group of formula -C(O)NH2. As used herein, the term "aminosulfonyl" refers to a group of formula -S(O)2NH2. As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O)2NH2.

[0113] The formula "H", as used herein, represents a hydrogen atom.

[0114] The formula "O," as used herein, represents an oxygen atom.

[0115] The formula "N," as used herein, represents a nitrogen atom.

[0116] The formula "S", as used herein, represents a sulfur atom.

[0117] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure, including racemic mixtures. Compounds identified herein by name or structure as one particular tautomer are intended to include other tautomers unless otherwise indicated. Compound names were created using software such as Chem Bio Draw Ultra version 14.0, and the names were not further verified for accuracy.

[0118] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomers. In some embodiments, the compounds have the (R)-configuration. In some embodiments, the compounds have the (S)-configuration. Some compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. This stereocenter may be present in the R or S configuration, the R and S designations being used correspondingly to the rules set out in Pure Appli. Chem. (1976), 45, 11-13.

[0119] The present invention includes all pharma- ceutically acceptable isotopically enriched compounds. Any compound of the present invention may contain protium. 1 Deuterium instead of H (or H) 2 H (or D), or 12 Instead of C 13 The compounds may contain one or more isotope atoms that are enriched or different from the natural ratio, such as the use of C enriched materials. Similar substitutions can be used for N, O, and S. The use of isotopes can aid in the analytical and therapeutic aspects of the invention. For example, the use of deuterium can increase the in vivo half-life by changing the metabolism (rate) of the compounds of the invention. These compounds can be prepared according to the preparations described by using isotopically enriched reagents.

[0120] The compounds provided herein also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond, with the accompanying migration of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. For example, prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lacta-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers can be in equilibrium or sterically fixed in one form by appropriate substitution.

[0121] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some aspects, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some aspects, an in vitro cell may be a cell in cell culture. In some aspects, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0122] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" ocular tissue with a compound of the invention includes administering a compound of the invention to an individual or patient, such as a human, having ocular tissue in need of treatment, as well as introducing a compound of the invention into a sample, including, for example, cells or purified preparations containing ocular tissue.

[0123] As used herein, the terms "individual," "patient," or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human. In some embodiments, a human subject may be of any age, e.g., 0-100 years old. As used herein, "pediatric subject" and "child" are used interchangeably and refer to a subject 0-18 years old, e.g., 1, 2, 5, 10, 12, 14 years old.

[0124] As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is desired by a researcher, veterinarian, physician or other clinician.

[0125] As used herein, the term "treat" or "treatment" refers to 1) inhibiting the disease, e.g., inhibiting the disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder (i.e., arresting further progression of the symptoms and / or symptomology), or 2) ameliorating the disease, e.g., ameliorating the disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder (i.e., reversing the symptoms and / or symptomology).

[0126] As used herein, the term "preventing" or "prevention" of a disease, condition or disorder refers to reducing the risk of development of a disease, condition or disorder in a subject or group of subjects (e.g., a subject or population of subjects predisposed to or susceptible to a disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to reducing the likelihood of developing a disease, condition or disorder and / or symptoms associated therewith. In some embodiments, preventing a disease, condition or disorder refers to completely or nearly completely preventing the development of a disease, condition or disorder.

[0127] Numbered Aspects Compounds of formula (I), their pharma- ceutically acceptable salts, compositions containing same (including pharmaceutical compositions), and methods of their use may be described with reference to the following numbered embodiments.

[0128] Aspect 1 is a compound of formula (I): TIFF2025503039000016.tif40128 or a pharma- ceutically acceptable salt thereof, During the ceremony: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; With the proviso that the compound of formula (I) is not atropine oleate or hyoscyamine oleate, A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0129] Aspect 2 is a compound of the formula: TIFF2025503039000017.tif43128, or a pharma- ceutically acceptable salt thereof.

[0130] Aspect 3 is R 3 C 1-6 The compound according to embodiment 1 or 2, wherein R is alkyl.

[0131] Aspect 4 is a compound according to any one of aspects 1 to 3, wherein n is selected from 1, 2, and 3.

[0132] Aspect 5 is R 2 But, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 The compound according to embodiment 4, wherein the alkoxy group is selected from haloalkoxy, OH, NO2, CN, halo, and amino.

[0133] Aspect 6 is a compound according to any one of aspects 1 to 3, wherein n is 0.

[0134] Aspect 7 is directed to a compound of formula (I) having the formula: TIFF2025503039000018.tif42128, or a pharma- ceutically acceptable salt thereof.

[0135] Aspect 8 is directed to a compound of formula (I) having the formula: TIFF2025503039000019.tif42128, or a pharma- ceutically acceptable salt thereof.

[0136] Aspect 9 is directed to compounds of formula (I) having the formula: TIFF2025503039000020.tif42128, or a pharma- ceutically acceptable salt thereof.

[0137] Aspect 10 is a compound comprising R 1 But, C 7-21 Alkyl, C 7-21 Alkenyl, and C 7-21 alkynyl.

[0138] Aspect 11 is R 1 But, C 7-34 Alkenyl and C 7-34 alkynyl.

[0139] Aspect 12 is R 1 But, C 7-21 Alkenyl and C 7-21 alkynyl.

[0140] Aspect 13 is R 1 C 7-21 The compound according to embodiment 12, wherein said compound is alkenyl.

[0141] Aspect 14 is R 1 C containing one double bond 7-21The compound according to embodiment 13, wherein said compound is alkenyl.

[0142] Aspect 15 is R 1 C containing two double bonds 7-21 The compound according to embodiment 13, wherein said compound is alkenyl.

[0143] Aspect 16 is R 1 C containing one double bond 12-21 The compound according to embodiment 13, wherein said compound is alkenyl.

[0144] Aspect 17 is R 1 C containing two double bonds 12-21 The compound according to embodiment 13, wherein said compound is alkenyl.

[0145] Aspect 18 is R 1 C 7-21 13. The compound according to embodiment 12, wherein said compound is alkynyl.

[0146] Aspect 19 is R 1 C 7-21 The compound according to any one of aspects 1 to 9, wherein R is alkyl.

[0147] Aspect 20 relates to a compound selected from the group consisting of any one of the following compounds: TIFF2025503039000021.tif100138TIFF2025503039000022.tif206138TIFF2025503039000023.tif21393TIFF2025503039000024.tif86128, or a pharma- ceutically acceptable salt thereof.

[0148] Aspect 21 is any one of the following compounds: TIFF2025503039000025.tif87134TIFF2025503039000026.tif175128, or a pharma- ceutically acceptable salt thereof.

[0149] Aspect 22 is directed to a compound selected from the group consisting of any one of the following compounds: The compound according to embodiment 1, selected from TIFF2025503039000027.tif171137, or a pharma- ceutically acceptable salt thereof.

[0150] Aspect 23 is a pharmaceutical composition comprising a compound according to any one of aspects 1 to 22, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0151] Example 24 is the pharmaceutical composition of Example 23, wherein the pharma- ceutically acceptable carrier comprises a semifluorinated alkane.

[0152] Example 25 is a pharmaceutical composition according to Example 24, wherein the semifluorinated alkane is selected from perfluorohexyl octane (F6H8), perfluorohexyl hexane (F6H6), perfluorobutyl butane (F4H4), and perfluorohexyl ethane (F6H2).

[0153] Embodiment 26 is a method for treating or preventing a disease or condition involving a muscarinic acetylcholine receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 22, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of embodiments 23 to 25.

[0154] Example 27 is the method of Example 26, wherein a compound of any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof, is used to induce cycloplegic refraction in the eye of the subject.

[0155] Example 28 is the method of Example 26, wherein a compound of any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof, is used to induce mydriasis in an eye of a subject.

[0156] Example 29 is the method of example 26, wherein the disease or condition is painful ciliary muscle spasm in the eye.

[0157] Example 30 is the method of Example 26, wherein a compound of any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof, is used to reduce symptoms of floaters.

[0158] Example 31 is the method of Example 26, wherein a compound of any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof, is used as a patch therapy for a child with amblyopia or strabismus.

[0159] Example 32 is the method of example 26, wherein the disease or condition is progression of myopia.

[0160] Example 33 is the method according to any one of Examples 27 to 32, wherein the pharmaceutical composition according to any one of Examples 23 to 25 is an ophthalmic composition.

[0161] Example 34 is the method of Example 33, wherein the ophthalmic composition comprises eye drops comprising an emulsion, suspension, or solution of the compound of any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof.

[0162] Example 35 is the method of example 26, wherein the disease or condition is heart disease.

[0163] Example 36 is the method of example 35, wherein the cardiac condition is slow heart rate (bradycardia).

[0164] Example 37 is a method according to Example 26, wherein a compound according to any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof, is used to reduce salivary and bronchial secretions.

[0165] Example 38 is the method of example 26, wherein the disease or condition is hyperhidrosis.

[0166] Embodiment 39 is the method of embodiment 26, wherein the disease or condition is addiction.

[0167] Example 40 is a method according to any one of Examples 35 to 39, wherein a compound according to any one of Examples 1 to 22, or a pharma- ceutically acceptable salt thereof, is administered to a subject by oral, intramuscular, intravenous, subcutaneous, intraosseous, or intratracheal route, or by inhalation.

[0168]

[0023] Embodiment 41 is a method for reducing symptoms of floaters in a subject, for patch therapy for children with amblyopia or strabismus, or for treating or preventing a condition selected from painful ciliary muscle spasm and progression of myopia in an eye of a subject, comprising: The method comprises reacting a compound of formula (I): administering to an eye of a subject an ophthalmic composition comprising TIFF2025503039000028.tif40128 or a pharma- ceutical acceptable salt thereof; During the ceremony: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; This is the method.

[0169] Aspect 42 is directed to a compound of formula (I) having the formula: TIFF2025503039000029.tif42128, or a pharma- ceutically acceptable salt thereof.

[0170] Aspect 43 is R 1 But, C 1-34 Alkyl, C 2-34 Alkenyl, and C 2-34 43. The method of embodiment 42, wherein said alkyl group is selected from alkynyl.

[0171] Example 44 is the method of example 41, wherein the ophthalmic composition comprises a semifluorinated alkane.

[0172] Example 45 is the method of example 44, wherein the semifluorinated alkane is selected from perfluorohexyl octane (F6H8), perfluorohexyl hexane (F6H6), perfluorobutyl butane (F4H4), and perfluorohexyl ethane (F6H2).

[0173] Aspect 46 is directed to a compound of formula (I) comprising any one of the following compounds: TIFF2025503039000030.tif43128TIFF2025503039000031.tif191139TIFF2025503039000032.tif203136TIFF2025503039000033.tif212105TIFF2025503039000034.tif41128, or a pharma- ceutically acceptable salt thereof.

[0174] Aspect 47 is directed to a compound of formula (I) comprising any one of the following compounds: TIFF2025503039000035.tif132134TIFF2025503039000036.tif130128, or a pharma- ceutically acceptable salt thereof.

[0175] Aspect 48 is directed to a compound of formula (I) comprising any one of the following compounds: TIFF2025503039000037.tif43134TIFF2025503039000038.tif214119, or a pharma- ceutically acceptable salt thereof.

[0176] Aspect 49 is i) A compound of formula (I): TIFF2025503039000039.tif40128 or a pharma- ceutically acceptable salt thereof, During the ceremony: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO2, CN, halo, amino, C 1-3 Alkylamino, di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; a compound of formula (I), or a pharma- ceutically acceptable salt thereof; ii) a pharma- ceutically acceptable carrier comprising a semifluorinated alkane; A pharmaceutical composition comprising:

[0177] Embodiment 50 is the pharmaceutical composition of embodiment 49, wherein the semifluorinated alkane is selected from perfluorohexyl octane (F6H8), perfluorohexyl hexane (F6H6), perfluorobutyl butane (F4H4), and perfluorohexyl ethane (F6H2).

[0178] Aspect 51 is R 1 But, C 7-21 Alkyl, C 7-21 Alkenyl, and C 7-21 50. The pharmaceutical composition according to embodiment 49, wherein said aryl group is selected from alkynyl.

[0179] Aspect 52 is R 1 But, C 7-21 Alkenyl and C 7-21 50. The pharmaceutical composition according to embodiment 49, wherein said aryl group is selected from alkynyl.

[0180] Aspect 53 is directed to a compound of formula (I) comprising any one of the following compounds: 50. The pharmaceutical composition of embodiment 49, wherein the compound is selected from the group consisting of TIFF2025503039000040.tif191129TIFF2025503039000041.tif206139TIFF2025503039000042.tif21294TIFF2025503039000043.tif86128, or a pharma- ceutically acceptable salt thereof.

[0181] Aspect 54 is directed to a compound of formula (I) comprising any one of the following compounds: 50. The pharmaceutical composition of embodiment 49, wherein the compound is selected from TIFF2025503039000044.tif87134TIFF2025503039000045.tif175128 or a pharma- ceutically acceptable salt thereof.

[0182] Aspect 55 is directed to a compound of formula (I) comprising any one of the following compounds: 50. The pharmaceutical composition of embodiment 49, wherein the compound is selected from TIFF2025503039000046.tif173134TIFF2025503039000047.tif84128 or a pharma- ceutically acceptable salt thereof.

[0183] Embodiment 56 is a method for treating or preventing a disease or condition involving a muscarinic acetylcholine receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described in any one of embodiments 47 to 53.

[0184] Example 57 is the method of example 56, wherein the pharmaceutical composition is an ophthalmic composition. EXAMPLES

[0185] General method Generally, characterization of the compounds is performed using NMR spectra, recorded on 300 and / or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm relative to either internal TMS or solvent signals. All reagents, solvents, and catalysts for which synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, or MIC-scientific, Ltd; however, some known intermediates have been or can be prepared according to published procedures. Some compounds of the present disclosure can generally be prepared in one step from commercially available literature starting materials. Generally, compounds of this disclosure were purified by column chromatography (autocolumn) on a Teledyne-ISCO CombiFlash equipped with a silica column unless otherwise noted. The following abbreviations are used throughout the examples: TIFF2025503039000048.tif134128

[0186] Example 1 - Synthesis of 3-(((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-3-oxo-2-phenylpropyl (9Z)-octadec-9-enoate (atropine oleate) (compound 1) TIFF2025503039000049.tif41128

[0187] To a solution of (1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate (atropine) (500 mg, 1.29 mmol) in CHCl (10 mL) was added TEA (653 mg, 6.45mmol) and oleoyl chloride (519 mg, 1.29 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was concentrated in vacuo. The mixture was purified by silica gel column (CHCl: MeOH = 0-10:1) to give the title compound (120 mg, 28% yield) as a pale yellow oil. TIFF2025503039000050.tif45150

[0188] Example 2 - Synthesis of 3-(((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)-3-oxo-2-phenylpropyl (9Z,12Z)-octadeca-9,12-dienoic acid (atropine linoleate) (compound 2) TIFF2025503039000051.tif41128

[0189] To a solution of atropine (1 g, 0.0035 mol) in CHCl (10 mL) was added 4-DMAP (1.28 g, 0.0105 mol), EDCI (0.34 g, 0.0017 mol) and (9Z,12Z)-octadeca-9,12-dienoic acid (linoleic acid) (1.47 g, 0.0052 mol). The reaction mixture was stirred at 25° C. for 2 h. LCMS showed the reaction was successful. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (ACN / HO (0.1% FA)) to give the title compound (118 mg, 6% yield) as a yellow solid. Chromatography column: Xbridge-C18 150×19 mm, 5 μm. Mobile phase: ACN / H2O (0.1% FA), gradient: 30 / 70. TIFF2025503039000052.tif39149

[0190] Example 3 – Fatty acid esters of atropine The following compounds 3 (atropine caprate), 4 (atropine caprylate), 5 (atropine laurate), 6 (atropine myristate), 7 (atropine palmitate), 8 (atropine (Z)-dec-5-enoate), 9 (atropine octadec-11-enoate), 10 (atropine (Z)-octadec-6-enoate), 11 (atropine (E)-oct-3-enoate), 12 (atropine octadec-6-enoate), 13 (atropine dec-4-enoate), 14 (atropine dodec-5-enoate), 15 (atropine hexadec-6-enoate), 16 (atropine hexadec-9-enoate), and 17 (atropine tetradec-9-enoate) were prepared from atropine and the corresponding fatty acids according to the methods and procedures described in Examples 1 and 2.

[0191] TIFF2025503039000053.tif134128TIFF2025503039000054.tif23191TIFF2025503039000055.tif22191T IFF2025503039000056.tif147128TIFF2025503039000057.tif151128TIFF2025503039000058.tif232128

[0192] Example 4 – Dissolution of atropine prodrug in F6H8 The solubility of saturated and unsaturated fatty acid ester prodrugs of atropine (compounds 1-7 described in Examples 1-3) was tested in perfluorohexyloctane (F6H8).

[0193] HPLC sample preparation Approximately 5 mg of atropine prodrug compound was weighed into a 2 mL centrifuge tube, followed by the addition of 1 ml perfluorohexyl octane (F6H8). The mixture was ultrasoned for 3 minutes, then shaken for 10 minutes, which was repeated three times. The mixture was then allowed to stand for 30 minutes, at which point sample preparation was complete. 100 μL of the mixture was placed into another centrifuge tube, followed by the addition of 0.5 mL of acetonitrile. The resulting mixture was shaken for 3 minutes, then centrifuged for 3 minutes. The supernatant was collected, followed by the addition of 0.5 mL of acetonitrile to the centrifuge tube, shaken for 3 minutes, then centrifuged for 3 minutes. The above composition was centrifuged, and the supernatant was filtered through a 0.45 micron filter without further dilution. Each sample was prepared for HPLC analysis.

[0194] Analysis of HPLC samples Samples were analyzed using a Shim-pack GIST C18, 5 μm HPLC column (250 mm×4.6 mm ID, 5 μm) and gradient elution from 100% water to 0.05% trifluoroacetic acid in 100% acetonitrile over 25 min at a flow rate of 1.1 ml / min. Chromatograms were monitored by UV at 214 nm. Retention times of the tested compounds were recorded as follows:

[0195] TIFF2025503039000059.tif183128

[0196] Solubility test results The solubility of various atropine prodrugs, as well as cholesterol and cholesteryl stearate in F6H8 was determined by HPLC and the results are shown in the table below.

[0197] TIFF2025503039000060.tif64128

[0198] Consideration of the solubility differences between atropine, cholesterol, and their esters. The solubility of cholesterol in F6H8 was measured to be 79.65 μg / mL, and the solubility of cholesteryl stearate, a saturated fatty acid ester of cholesterol, in F6H8 was measured to be 26.23 μg / mL. Thus, both cholesterol and cholesteryl stearate were poorly soluble in F6H8, and stearate fatty acid esterification of cholesterol did not improve solubility in F6H8. On the other hand, the solubility of atropine in F6H8 was poor, measured to be 129 μg / mL, but saturated and unsaturated fatty acid esterification of atropine surprisingly showed a significant improvement in solubility in F6H8.

[0199] Example 5 – Formulation of Atropine Oleate in F6H8 The following formulations of atropine prodrugs were prepared in F6H8 matrix: 4 mg of atropine oleate (compound 1) was mixed with 1 mL of perfluorohexyl octane (F6H8) and stirred for 1 hour to homogenize, producing a 0.4% atropine oleate formulation. 0.5 mL of the 0.4% atropine oleate formulation was then added with 0.5 mL of perfluorohexyl octane (F6H8) and stirred for 1 hour to produce a 0.2% atropine oleate formulation. Additionally, 0.5 mL of the 0.2% atropine oleate formulation was added with 0.5 mL of perfluorohexyl octane (F6H8) and stirred for 1 hour to produce a 0.1% atropine oleate formulation. All three formulations of 0.4%, 0.2%, and 0.1% atropine oleate formulations were filtered through a 0.2 μm filter to produce the final formulations of 0.4%, 0.2%, and 0.1% atropine oleate.

[0200] Example 6 – Formulation of Atropine Linoleate in F6H8 The following formulation of atropine prodrug was prepared in F6H8 matrix: 4 mg of atropine linoleate (compound 2) was mixed with 1 mL of perfluorohexyl octane (F6H8) and homogenized by stirring for 1 hour to produce a 0.4% atropine linoleate formulation. The atropine linoleate formulation was filtered through a 0.2 μm filter to produce the final formulation of 0.4% atropine linoleate.

[0201] Example 7 – In vivo pharmacological studies in Dutch striped rabbits Three female Dutch Belted rabbits were randomly assigned by Provantis or Excel based on body weight to each group selected from vehicle, positive control of 0.01% atropine sulfate monohydrate in saline, 0.4% atropine oleate, and 0.4% atropine linoleate. Test compounds were administered to each animal by topical instillation of 40 μL of eye drop formulation once on day 1. Pupil size was measured in both eyes of all animals at baseline (30 min before dosing), 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after dosing. Pupil size was measured in both eyes of all animals on three non-consecutive days during acclimation before dosing began. The light intensity in the procedure room was set so that the animals' pupil size was approximately 6-7 mm. The light intensity in the procedure room for pupil size measurements should be maintained constant throughout the pupil size measurement procedures of the study. The change in pupil size from baseline was calculated separately for each eye of each individual animal for each post-dosing time point. The mean and standard error of the pupil size change from baseline were calculated for each group for each post-dosing time point, and the mean pupil change from baseline was plotted against the time point comparisons.

[0202] The experimental results are summarized in Figure 1. Pupil size was dilated by approximately 5% from baseline at 1 or 2 hours after administration for 0.01% atropine sulfate monohydrate as a positive control, but was barely changed from baseline for vehicle as a negative control. 0.4% atropine oleate in F6H8 formulation showed comparable pupil size dilation to 0.01% atropine sulfate monohydrate (positive control) and maintained pupil dilation throughout the measurement period. On the other hand, 0.4% atropine linoleate showed a greater than 10% change from baseline in pupil size diameter change and remained significantly dilated from baseline throughout the measurement period. Figure 1: Pupil size change from baseline in rabbits after single eye drop administration of test article formulation, positive control and negative control.

[0203] Other Aspects While the present application has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to be illustrative, and not limiting, of the scope of the present application, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. Compounds of formula (I): or a pharma- ceutically acceptable salt thereof, During the ceremony: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO 2 ,CN,Halo,Amino,C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO 2 ,CN,Halo,Amino,C 1-3 Alkylamino, di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; With the proviso that the compound of formula (I) is not atropine oleate or hyoscyamine oleate, A compound of formula (I), or a pharma- ceutically acceptable salt thereof.

2. The compound of formula (I) has the formula:

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

3. The compound is any one of the following compounds: or a pharma- ceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound of any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

5. 5. The pharmaceutical composition of claim 4, wherein the pharma- ceutically acceptable carrier comprises a semifluorinated alkane.

6. A method for treating or preventing a disease or condition involving a muscarinic acetylcholine receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 4 to 5.

7. 7. The method of claim 6, wherein the compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, is used to induce cycloplegic refraction in the eye of a subject, to induce mydriasis in the eye of a subject, to reduce symptoms of floaters, to be used as a patch therapy for children with amblyopia or strabismus, to reduce salivary secretions and bronchial secretions.

8. 7. The method of claim 6, wherein the disease or condition is painful ciliary muscle spasms in the eye, progression of myopia, heart disease, hyperhidrosis, or poisoning.

9. 1. A method for reducing symptoms of floaters in a subject, for patch therapy for children with amblyopia or strabismus, or for causing a condition selected from cycloplegic refraction and mydriasis in the eye of a subject, for treating or preventing a condition selected from painful ciliary spasm and progression of myopia in the eye, comprising: The method comprises reacting a compound of formula (I): or a pharma- ceutical acceptable salt thereof, During the ceremony: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO 2 ,CN,Halo,Amino,C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO 2 ,CN,Halo,Amino,C 1-3 Alkylamino, di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; method.

10. i) A compound of formula (I): or a pharma- ceutically acceptable salt thereof, During the ceremony: R 3 , H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO 2 ,CN,Halo,Amino,C 1-3 Alkylamino, di(C 1-3 alkyl)amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; n is selected from 0, 1, 2, 3, 4, and 5; and R 1 is C 7-34 Alkyl, C 7-34 Alkenyl, C 7-34 Alkynyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, wherein said C 7-34 Alkyl, C 7-34 Alkenyl, and C 7-34 Alkynyl is C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 aryl, and the C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-14 membered heteroaryl, and C 6-10 Each of the aryl groups is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH, NO 2 ,CN,Halo,Amino,C 1-3 Alkylamino, di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, amino, carbamyl, carboxy, aminosulfonyl, and aminosulfonylamino; a compound of formula (I), or a pharma- ceutically acceptable salt thereof; ii) a pharma- ceutically acceptable carrier comprising a semifluorinated alkane; 23. A pharmaceutical composition comprising:

11. A method for treating or preventing a disease or condition involving a muscarinic acetylcholine receptor, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 10.

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