Anticholinergics

Abstract

Provided are compounds of formula (I), pharmaceutical compositions, and methods of use relating to muscarinic acetylcholine receptors. The compounds herein are typically muscarinic acetylcholine receptor antagonists, such as M3 antagonists, that can be used to treat a variety of disorders, conditions, or diseases, such as hyperhidrosis. JPEG2023550798000065.jpg47170

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates generally to novel compounds, pharmaceutical compositions, methods for their preparation and use, such as to provide anticholinergic effects, in various embodiments. [Background technology]

[0002] Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form a G protein-coupled receptor complex in the cell membrane. Five subtypes of muscarinic receptors have been identified, designated M1-M5. M1, M3, and M5 receptors are G q M2 and M4 receptors bind to G i / o mAChRs are widely expressed in different tissues and cells and regulate many important functions in the central and peripheral nervous systems. In the bladder, M2 and M3 receptors are predominantly expressed in the detrusor muscle of various species. Both M1 and M3 receptors are expressed in salivary, sweat, apocrine, sublingual, and lacrimal glands, whereas M3 receptors are predominantly expressed in the parotid gland. In the gastrointestinal tract, both M2 and M3 receptors are expressed in smooth muscle, and M3 receptors are thought to play an important role in cholinergic stimulation of gastrointestinal motility. In the brain, M3 receptors are low in abundance, whereas M1, M2, M4, and M5 receptors are abundantly expressed in different regions. M1 and M4 receptors are expressed in the human eye. M2 and M3 receptors are expressed in the human heart and regulate heart rate and function. Muscarinic anticholinergics are used to treat a variety of diseases or disorders, including diarrhea, allergies, asthma, atrial fibrillation with bradycardia, motion sickness, anxiety, hyperhidrosis, slow heart rate, overactive bladder, respiratory diseases such as asthma and COPD, and neurological diseases such as Parkinson's disease and Alzheimer's disease.

[0003] A variety of muscarinic acetylcholine receptor antagonists have been reported, including the naturally occurring atropine and scopolamine, and various synthetic agents such as homatropine and eucatropine. However, there remains a need for new muscarinic antagonists for various indications. Summary of the Invention

[0004] The present disclosure is based in various embodiments on novel compounds / salts that can provide anticholinergic activity, more specifically, activity as muscarinic acetylcholine receptor antagonists.

[0005] Some embodiments of the present disclosure are directed to salts of formula I: JPEG0007755874000001.jpg63170In the formula, variable R 1 , R 2 , R 3 , R 4 , L 1 , X - , and j are defined herein. In some embodiments, the present disclosure provides salts of subformulas of formula I, such as formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6, as described herein. Salts of formula I herein are typically muscarinic receptor antagonists. Salts of formula I can typically be prepared from the corresponding compound of formula II, JPEG0007755874000002.jpg38170In the formula, variable R 1 , R 2 , R 3 , L 1 and j is defined herein. In some embodiments, the present disclosure also provides a pharmaceutically acceptable salt of a compound of Formula II (e.g., Formula II-1 or II-2).

[0006] Certain embodiments of the present disclosure are directed to pharmaceutical compositions comprising one or more compounds / salts of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts set forth in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein can be formulated for different routes of administration, such as oral administration, parenteral administration, topical administration, inhalation, eye drops, etc. For example, in some embodiments, the pharmaceutical composition can be formulated for topical administration, such as in the form of a topical solution, cream, ointment, mousse, gel, lotion, or powder.

[0007] Some embodiments of the present disclosure are directed to methods of treating or preventing a disorder, condition, or disease that may respond to antagonism of mAChRs, such as M3 receptors, in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts set forth in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0008] Some embodiments of the present disclosure are directed to methods of inhibiting the activity of mAChRs, such as M3 receptors, in a subject or biological sample. In some embodiments, the methods include contacting mAChRs, such as M3 receptors, with an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0009] In some specific embodiments, the present disclosure provides a method of treating hyperhidrosis in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Typically, administration is via a topical route. In some embodiments, one or more compounds / salts of the present disclosure can be administered as the sole active ingredient. In some embodiments, one or more compounds of the present disclosure can be used in combination with an additional therapy, for example, an additional therapy effective in treating hyperhidrosis.

[0010] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure generally relates to compounds useful as muscarinic anticholinergic agents. The compounds herein can be typically used to treat or prevent a variety of diseases or disorders mediated by such muscarinic cholinergic receptors as described herein, such as those mediated by the M3 receptor.

[0012] compound Formula I In some embodiments, the present disclosure provides a salt of Formula I: JPEG0007755874000003.jpg48170In formula, X - is the counterion, R 1 is hydrogen or an optionally substituted C 3-8 is carbocyclyl, L 1 is empty (null), C 1-4 Alkylene, or C 1-4 is heteroalkylene, R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 carbocyclyl, 4- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted; R 3 and R 4 are each independently hydrogen or C 1-6 is alkyl, j is 0, 1 or 2.

[0013] In some embodiments, salts of Formula I (including any of the applicable subformulas described herein) can contain one or more asymmetric centers and / or axial chirality and, therefore, can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. In some embodiments, salts of Formula I, where applicable, can exist in the form of individual enantiomers and / or diastereomers, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, where applicable, salts of Formula I (including any of the applicable subformulas described herein) can exist as isolated individual enantiomers substantially free of the other enantiomer (e.g., in amounts less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight, by HPLC area, or both). In some embodiments, where applicable, salts of Formula I (including any applicable sub-formulas described herein) can exist as isolated individual diastereomers substantially free of other diastereomers (e.g., less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight, by HPLC area, or both). In some embodiments, where applicable, salts of Formula I (including any applicable sub-formulas described herein) can also exist as a mixture of stereoisomers in any ratio, such as a racemic mixture.

[0014] In some embodiments, the salt of Formula I can have Formula I-1: JPEG0007755874000004.jpg47170, where the variables include any of those described herein in any combination.

[0015] In some embodiments, the salt of Formula I-1 can have Formula I-1-E1 or Formula I-1-E2. JPEG0007755874000005.jpg46170

[0016] In some embodiments, the salt of Formula I-1 can have Formula I-1-E3 or Formula I-1-E4. JPEG0007755874000006.jpg46170

[0017] In some embodiments, the salt of Formula I-1 may be a substantially pure stereoisomer having Formula I-1-E1, and may be substantially free of any of the corresponding isomeric forms I-1-E2, I-1-E3, and I-1-E4. For example, in some embodiments, the total amount of Formula I-1-E2, I-1-E3, and I-1-E4 of the four possible stereoisomers that may be present is less than 20%, less than 10%, less than 5%, or less than 1% by weight, HPLC area, or both, or none of Formula I-1-E2, I-1-E3, or I-1-E4 is detectable. In some embodiments, the salt of Formula I-1 may be a substantially pure stereoisomer having Formula I-1-E2, and may be substantially free of any of the corresponding isomeric forms I-1-E1, I-1-E3, and I-1-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-1-E1, Formula I-1-E3, and Formula I-1-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-1-E1, Formula I-1-E3, or Formula I-1-E4 is detectable. In some embodiments, the salt of Formula I-1 may be a substantially pure stereoisomer having Formula I-1-E3, and may be substantially free of any of the corresponding isomeric forms of Formula I-1-E1, Formula I-1-E2, and Formula I-1-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-1-E1, Formula I-1-E2, and Formula I-1-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-1-E1, Formula I-1-E2, or Formula I-1-E4 is detectable. In some embodiments, the salt of Formula I-1 may be a substantially pure stereoisomer having Formula I-1-E4, and may be substantially free of any of the corresponding isomeric forms of Formula I-1-E1, Formula I-1-E2, and Formula I-1-E3.For example, in some embodiments, the total amount of the four possible stereoisomers I-1-E1, I-1-E2, and I-1-E3 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of I-1-E1, I-1-E2, and I-1-E3 is detectable. In some embodiments, a given salt of Formula I-1 can exist in the form of a mixture of any two or more of the four possible stereoisomers I-1-E1, I-1-E2, I-1-E3, and I-1-E4 in any ratio.

[0018] In some embodiments, the salt of Formula I can have Formula I-2: JPEG0007755874000007.jpg56170, where the variables include any of those described herein in any combination.

[0019] In some embodiments, the salt of formula I-2 can have formula I-2-E1 or I-2-E2. JPEG0007755874000008.jpg50170

[0020] In some embodiments, the salt of formula I-2 can have formula I-2-E3 or I-2-E4. JPEG0007755874000009.jpg49170

[0021] In some embodiments, the salt of Formula I-2 may be a substantially pure stereoisomer having Formula I-2-E1, and may be substantially free of any of the corresponding isomeric forms I-2-E2, I-2-E3, and I-2-E4. For example, in some embodiments, the total amount of Formula I-2-E2, I-2-E3, and I-2-E4 of the four possible stereoisomers that may be present is less than 20%, less than 10%, less than 5%, or less than 1% by weight, HPLC area, or both, or none of Formula I-2-E2, I-2-E3, or I-2-E4 is detectable. In some embodiments, the salt of Formula I-2 may be a substantially pure stereoisomer having Formula I-2-E2, and may be substantially free of any of the corresponding isomeric forms I-2-E1, I-2-E3, and I-2-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-2-E1, Formula I-2-E3, and Formula I-2-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-2-E1, Formula I-2-E3, or Formula I-2-E4 is detectable. In some embodiments, the salt of Formula I-2 may be a substantially pure stereoisomer having Formula I-2-E3, and may be substantially free of any of the corresponding isomeric forms of Formula I-2-E1, Formula I-2-E2, and Formula I-2-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-2-E1, Formula I-2-E2, and Formula I-2-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-2-E1, Formula I-2-E2, or Formula I-2-E4 is detectable. In some embodiments, the salt of Formula I-2 may be a substantially pure stereoisomer having Formula I-2-E4, and may be substantially free of any of the corresponding isomeric forms of Formula I-2-E1, Formula I-2-E2, and Formula I-2-E3.For example, in some embodiments, the total amount of the four possible stereoisomers I-2-E1, I-2-E2, and I-2-E3 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of I-2-E1, I-2-E2, and I-2-E3 is detectable. In some embodiments, the salt of Formula I-2 can exist in the form of a mixture of any two or more of the four possible stereoisomers I-2-E1, I-2-E2, I-2-E3, and I-2-E4 in any ratio.

[0022] Typically, j in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4) is 0, 1, or 2. Preferably, j in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4) is 1. For example, in some embodiments, the salt of Formula I can be characterized as having Formula I-3 or I-4. JPEG0007755874000010.jpg49170

[0023] In some embodiments, the salt of formula I-3 can have formula I-3-E1 or I-13-E2. JPEG0007755874000011.jpg45170

[0024] In some embodiments, the salt of formula I-3 can have formula I-3-E3 or I-3-E4. JPEG0007755874000012.jpg45170

[0025] In some embodiments, the salt of Formula I-3 may be a substantially pure stereoisomer having Formula I-3-E1, and may be substantially free of the corresponding isomeric forms I-3-E2, I-3-E3, and I-3-E4. For example, in some embodiments, the total amount of Formula I-3-E2, I-3-E3, and I-3-E4 of the four possible stereoisomers that may be present is less than 20%, less than 10%, less than 5%, or less than 1% by weight, HPLC area, or both, or none of Formula I-3-E2, I-3-E3, or I-3-E4 is detectable. In some embodiments, the salt of Formula I-3 may be a substantially pure stereoisomer having Formula I-3-E2, and may be substantially free of the corresponding isomeric forms I-3-E1, I-3-E3, and I-3-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-3-E1, Formula I-3-E3, and Formula I-3-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-3-E1, Formula I-3-E3, or Formula I-3-E4 is detectable. In some embodiments, the salt of Formula I-3 may be a substantially pure stereoisomer having Formula I-3-E3, and may be substantially free of any of the corresponding isomeric forms of Formula I-3-E1, Formula I-3-E2, and Formula I-3-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-3-E1, Formula I-3-E2, and Formula I-3-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-3-E1, Formula I-3-E2, and Formula I-3-E4 are detectable. In some embodiments, the salt of Formula I-3 may be a substantially pure stereoisomer having Formula I-3-E4, and may be substantially free of any of the corresponding isomeric forms of Formula I-3-E1, Formula I-3-E2, and Formula I-3-E3.For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-3-E1, Formula I-3-E2, and Formula I-3-E3 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-3-E1, Formula I-3-E2, and Formula I-3-E3 is detectable. In some embodiments, the salt of Formula I-3 can exist in the form of a mixture of any two or more of the four possible stereoisomers of Formula I-3-E1, I-3-E2, I-3-E3, and I-3-E4 in any ratio.

[0026] In some embodiments, the salt of formula I-4 can have formula I-4-E1 or I-4-E2. JPEG0007755874000013.jpg54170

[0027] In some embodiments, the salt of formula I-4 can have formula I-4-E3 or I-4-E4. JPEG0007755874000014.jpg50170

[0028] In some embodiments, the salt of Formula I-4 may be a substantially pure stereoisomer having Formula I-4-E1, and may be substantially free of any of the corresponding isomeric forms I-4-E2, I-4-E3, and I-4-E4. For example, in some embodiments, the total amount of Formula I-4-E2, I-4-E3, and I-4-E4 of the four possible stereoisomers that may be present is less than 20%, less than 10%, less than 5%, or less than 1% by weight, HPLC area, or both, or none of Formula I-4-E2, I-4-E3, or I-4-E4 is detectable. In some embodiments, the salt of Formula I-4 may be a substantially pure stereoisomer having Formula I-4-E2, and may be substantially free of any of the corresponding isomeric forms I-4-E1, I-4-E3, and I-4-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-4-E1, Formula I-4-E3, and Formula I-4-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-4-E1, Formula I-4-E3, or Formula I-4-E4 is detectable. In some embodiments, the salt of Formula I-4 may be a substantially pure stereoisomer having Formula I-4-E3, and may be substantially free of any of the corresponding isomeric forms of Formula I-4-E1, Formula I-4-E2, and Formula I-4-E4. For example, in some embodiments, the total amount of the four possible stereoisomers of Formula I-4-E1, Formula I-4-E2, and Formula I-4-E4 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of Formula I-4-E1, Formula I-4-E2, and Formula I-4-E4 are detectable. In some embodiments, the salt of Formula I-4 may be a substantially pure stereoisomer having Formula I-4-E4, and may be substantially free of any of the corresponding isomeric forms of Formula I-4-E1, Formula I-4-E2, and Formula I-4-E3.For example, in some embodiments, the total amount of the four possible stereoisomers I-4-E1, I-4-E2, and I-4-E3 that may be present is less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or none of I-4-E1, I-4-E2, and I-4-E3 is detectable. In some embodiments, the salt of Formula I-4 can exist in the form of a mixture of any two or more of the four possible stereoisomers I-4-E1, I-4-E2, I-4-E3, and I-4-E4 in any ratio.

[0029] In some embodiments, L in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4) 1 may be empty, in which case the C(O)-O group in formula I is directly attached to the nitrogen-containing ring of formula I.

[0030] In some embodiments, L in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4) 1 is C such as CH2 1-4 It may also be alkylene.

[0031] In some preferred embodiments, L in formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-3, I-3-E1, I-3-E2, I-3-E3, or I-3-E4 1 is CH. For example, in some embodiments, a salt of formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-3, I-3-E1, I-3-E2, I-3-E3, or I-3-E4 can be characterized as having formula I-5. JPEG0007755874000015.jpg45170

[0032] In some preferred embodiments, L in formula I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-4, I-4-E1, I-4-E2, I-4-E3, or I-4-E4 1 is empty and R 1 is hydrogen. For example, in some embodiments, a salt of formula I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-4, I-4-E1, I-4-E2, I-4-E3, or I-4-E4 can be characterized as having formula I-6. JPEG0007755874000016.jpg45170

[0033] Typically, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5) 1 is hydrogen.

[0034] In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5) 1 also includes optionally substituted C groups such as cyclopentyl. 3-8 It may also be a carbocyclyl.

[0035] R in Formula I 2 A variety of groups are suitable as R in Formula I. 2is not hydrogen. However, in some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 R in Formula I may also be hydrogen. 2 is hydrogen, R 1 is typically not hydrogen.

[0036] In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 is an arbitrarily substituted C 1-6 For example, in some embodiments, R 2 is F, OH, R A , OR A C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from phenyl, 1-6 phenyl may be alkyl, where phenyl is substituted with halogen (e.g., F or Cl), OH, C 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 R at each occurrence is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkoxy. A are independently F, OH, and C 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkoxy 1-4 Alkyl or C3-6 In some embodiments, R 2 is C 3-6 Branched alkyl, e.g., isopropyl 3-6 It may also be alkyl.

[0037] In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 is an arbitrarily substituted C 3-8 It may also be a carbocyclyl.

[0038] In some preferred embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 is an optionally substituted C such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 For example, in some embodiments, R 2 is F, OH, R A , and OR A C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from 3-6 R in each occurrence may be cycloalkyl. A are independently F, OH, and C 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkoxy 1-4 Alkyl or C 3-6In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, more preferably cyclopentyl.

[0039] In some preferred embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 is, for example, an optionally substituted C 4-7 For example, in some embodiments, R 2 is F, OH, R A , and OR A C, which can be optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from 4-7 cycloalkenyl, where R A are independently F, OH, and C 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkoxy 1-4 Alkyl or C 3-6In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 may be cyclopentenyl; JPEG0007755874000017.jpg28170

[0040] In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 may be an optionally substituted phenyl. For example, in some embodiments, R 2 are F, Cl, OH, C 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) may be phenyl optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkoxy. 2 may be phenyl.

[0041] In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2 may be an optionally substituted 5- or 6-membered heteroaryl having 1 to 4 ring heteroatoms independently selected from N, O, and S, such as those described herein. In some embodiments, R in Formula I 2 may be an optionally substituted 5-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as oxazolyl, thiazolyl, etc. In some embodiments, the 5-membered heteroaryl is selected from F, Cl, OH, C 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) can be optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkoxy. 2 teeth, It may also be an oxazolyl such as JPEG0007755874000018.jpg17170.

[0042] In some embodiments, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 2may be an optionally substituted 6-membered heteroaryl having 1-2 ring heteroatoms independently selected from N, O, and S, such as, for example, pyridyl or pyrimidinyl, as disclosed herein. In some embodiments, the 6-membered heteroaryl is selected from F, Cl, OH, C, 1-4 Alkyl, Fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine-substituted C 1-4 It can be optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkoxy.

[0043] Typically, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 3 is C 1-6 It is alkyl, more preferably methyl.

[0044] Typically, R in Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) 4 is C 1-6 It is preferably alkyl, and more preferably methyl.

[0045] The anticholinergic activity of the salts of formula I is - Since the counterion X in formula I does not depend on the nature of -is not particularly limited. Typically, X in formula I (e.g., formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, I-6) - is a pharmaceutically acceptable counterion, e.g., a halide (e.g., F - , Cl - , Br - , or I - ). Other suitable counterions include those derived from a variety of inorganic or organic acids, such as sulfate, nitrate, phosphate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelic acid, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, and the like. In some embodiments, X - It is understood that X can also be derived from a polyvalent anion that counterbalances the cationic structure shown in Formula I so that the overall charge on X is minus one.

[0046] In some embodiments, the present disclosure also provides a salt selected from those shown in Table 1 below: JPEG0007755874000019.jpg109170X - is a pharmaceutically acceptable counterion.

[0047] In some embodiments, the present disclosure also provides a salt selected from those shown in Table 2 below: JPEG0007755874000020.jpg182170X - is a pharmaceutically acceptable counterion.

[0048] In some embodiments, to the extent applicable, the genus of compounds described herein also excludes any compounds or salts that were specifically known prior to the present disclosure. In some embodiments, to the extent applicable, any sub-genus of a species of compound or salt prior to the present disclosure that is entirely within the genus of compounds described herein can also be excluded from the genus herein. For example, to the extent applicable, glycopyrrolate or a precursor thereof is excluded from the genus of compounds / salts described herein in connection with Formula I or II.

[0049] Formula II Salts of formula I herein are typically prepared by reacting the corresponding amine having formula II with R 4 -Lg 1 R 4 It can be obtained by reacting with a group donor: JPEG0007755874000021.jpg37170Lg 1 is a leaving group such as a halide (e.g., I), Variable L 1 , R 1 , R 2 , R 3 , R 4 and j may have any of the respective definitions described herein in connection with formula I (including subformulas thereof), in any combination.

[0050] In some embodiments, the present disclosure also provides a compound of formula II, or a salt thereof: JPEG0007755874000022.jpg40170In formula, R 1 is hydrogen or optionally substituted C 3-8 is carbocyclyl, L 1 is, sky, C 1-4 Alkylene, or C 1-4 is heteroalkylene, R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8carbocyclyl, 4- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted; R 3 is hydrogen or C 1-6 is alkyl, j is 0, 1 or 2.

[0051] In some embodiments, the compound of formula II can have a formula according to formula II-1. JPEG0007755874000023.jpg47170

[0052] In some embodiments, the compound of formula II can have a formula according to formula II-2. JPEG0007755874000024.jpg41170

[0053] L in Formula II (e.g., Formula II-1 or II-2) 1 , R 1 , R 2 , R 3 The definitions of j include any of the respective definitions described herein in connection with Formula I (including subformulas thereof). For example, in some embodiments, L in Formula II 1 In some embodiments, L in Formula II may be empty. 1 is C such as CH2 1-4 In some embodiments, R in Formula II may be alkylene. 1 In some embodiments, R in Formula II may be hydrogen. 1 In some embodiments, R in Formula II can be cyclopentyl. 2 In some embodiments, R in Formula II may be hydrogen. 2 is, for example, a C such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which may be optionally substituted as described herein. 3-6 In some embodiments, R in Formula II may be cycloalkyl. 2is, for example, a C such as cyclopentenyl, which may be optionally substituted as described herein. 4-7 In some embodiments, j in Formula II is 1. In some embodiments, R in Formula II is cycloalkenyl. 3 is methyl. 1 , R 1 , R 2 , R 3 and other suitable groups or definitions of j include any combination of those discussed herein in connection with Formula I (including subformulas thereof).

[0054] In some embodiments, compounds of formula II-2 can also be used to prepare pharmaceutically acceptable salts, such as acid addition salts or quaternary salts, such as those having formula I.

[0055] Compounds of Formula II can be readily prepared by one of skill in the art in light of the present disclosure and can in turn be used to prepare the salts of Formula I discussed herein. Exemplary procedures are also provided in the Examples section.

[0056] For example, compounds of formula II can be prepared according to Scheme A shown below. Thus, compound A can be coupled with compound B under ester-forming conditions to give compound C, which can then be deprotected and optionally G can be converted to R 2 As will be appreciated by those skilled in the art, R 2 The group can also be introduced earlier in the synthesis. Thus, in some embodiments, R 2 may be the same as the G group. 2 In embodiments where R is not the same as R, it is typically obtained by reacting R under palladium-catalyzed cross-coupling conditions, etc. 2 The leaving group is a halide or sulfonate containing a leaving group capable of reacting with a donor (e.g., O-Ts, O-Ms, O-Tf). 1 is typically an oxygen protecting group, for example, as described herein. 1There is no particular limitation on the protecting groups suitable for L in the compound shown in Scheme A. 1 , R 1 , R 2 , R 3 The definitions of j include any of the respective definitions described herein in connection with Formula II (including subformulas thereof), in any combination. JPEG0007755874000025.jpg98170

[0057] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis", 4 th ed. P.G.M.Wuts; T.W. Greene, John Wiley, 2007, and the references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others are described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7 thThey can be prepared either by procedures described in standard reference texts such as "The Organic Synthesis of Benzyl Alcohols" (Wiley-VCH, 1999), "The Organic Synthesis of Benzyl Alcohols," and "Larock's Comprehensive Organic Transformations" (Wiley-VCH, 1999), or obvious modifications thereof, and updates available at the time of this filing.

[0058] Pharmaceutical Composition Certain embodiments are directed to pharmaceutical compositions comprising one or more compounds / salts of the present disclosure.

[0059] The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound / salt of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are well known in the art. Non-limiting examples of suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, wetting agents, lubricants, fragrances, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0060] Pharmaceutical compositions can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition includes a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, for example, to treat hyperhidrosis. In any of the embodiments described herein, the pharmaceutical composition can include a compound / salt selected from any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof.

[0061] The pharmaceutical compositions herein can be formulated for delivery via any known delivery route, including, but not limited to, oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration. For example, in some embodiments, the pharmaceutical compositions herein can be formulated for topical delivery. In some embodiments, the pharmaceutical compositions herein can be formulated for oral administration. In some embodiments, the pharmaceutical compositions herein can be formulated for parenteral administration. In some embodiments, the pharmaceutical compositions herein can be formulated for inhalation, such as an aerosol spray, dry powder, or the like. In some embodiments, the pharmaceutical compositions herein can be formulated as eye drops.

[0062] In some embodiments, pharmaceutical compositions can be formulated for oral administration. Oral formulations can be presented as discrete units, such as capsules, pills, wafers, or troches, each containing a predetermined amount of active compound; as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, cornstarch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerin, peanut oil, and the like. Contains raw oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0063] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous injection or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral formulations are known in the art. Non-limiting examples of suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic saline, water, and mixtures thereof.

[0064] In some embodiments, pharmaceutical compositions can be formulated for topical administration. Topical formulations containing one or more salts of the present disclosure can be prepared by mixing one or more salts with various carrier materials or pharmaceutically acceptable excipients. Suitable excipients for preparing topical formulations are known in the art. Some examples of suitable excipients include alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, PPG2, myristyl lactose propionate, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Topical formulations may further optionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propylhydroxybenzoate; sweetening agents; coloring agents; flavoring agents; and flavoring agents. When the excipient functions as a diluent, it may be a solid, semisolid, or liquid that functions as a vehicle, carrier, or medium for the salt. In some embodiments, the topical formulations herein may be in the form of a powder, suspension, emulsion, solution, syrup, alcoholic solution, ointment, topical cleanser, cleansing cream, skin gel, skin lotion, mousse, roll-on, aerosol, or non-aerosol spray of cream or gel formulation, and soft gelatin capsule. In some embodiments, the pharmaceutical composition may be formulated in the form of a topical solution, cream, ointment, mousse, gel, lotion, or powder. In some embodiments, the pharmaceutical composition can include excipients such as water, propylene glycol, citric acid, sodium citrate, tromethamine, alcohol (eg, ethanol), preservatives, and the like.For example, exemplary topical formulations comprising one or more salts of the present disclosure may be in the form of a topical solution, such as those having an aqueous vehicle, an alcoholic vehicle, an aqueous-alcoholic vehicle, etc., such as those comprising one or more of water, propylene glycol, citric acid, sodium citrate, tromethamine, alcohol (e.g., ethanol), preservatives, polymers, and other excipients. In some embodiments, the topical solution can be formulated as a wipe that can be stored in a leak-resistant pouch, for example, with a linear low-density polyethylene (LLDPE) liner. Exemplary topical formulations containing one or more salts of the present disclosure can be prepared similarly to the methods described in U.S. Patent Nos. 6,433,003, 8,618,160, 9,744,105, 10,052,267, 8,859,610, 9,259,414, 10,004,717, 10,543,192, and 10,548,875.

[0065] The compounds / salts of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents. When used in combination with one or more additional therapeutic agents, the compounds of the present disclosure or the pharmaceutical compositions herein can be administered to a subject simultaneously with such additional therapeutic agents or sequentially in any order. In some embodiments, a pharmaceutical composition can contain one or more compounds of the present disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition containing one or more compounds of the present disclosure can be included in a kit that also contains a separate pharmaceutical composition containing one or more additional therapeutic agents.

[0066] Pharmaceutical compositions can contain varying amounts of the compounds of the present disclosure, depending on various factors, such as the intended use and efficacy and selectivity of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound / salt of the present disclosure for treating hyperhidrosis. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound / salt of the present disclosure (e.g., for hyperhidrosis) and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound / salt of the present disclosure is an amount effective to treat a disorder, condition, or disease described herein, such as hyperhidrosis, and may depend on the person receiving treatment, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the efficacy of the compound, its clearance rate, and whether another drug is being administered concomitantly.

[0067] Method of Treatment / Use The compounds / salts of the present disclosure have various utilities.For example, the compounds of the present disclosure can be used as therapeutically active substances for the treatment and / or prevention of disorders, conditions or diseases associated with mAChR receptors, such as M3 receptors.Accordingly, some embodiments of the present disclosure also relate to a method of using one or more compounds of the present disclosure or pharmaceutical compositions herein to treat or prevent disorders, conditions or diseases that may respond to antagonism of mAChRs, such as M3 receptors, in a subject in need thereof, for example, to treat hyperhidrosis in a subject in need thereof.

[0068] In some embodiments, the present disclosure provides a method for treating or preventing a disorder, condition, or disease responsive to antagonism of M3 in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts set forth in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Disorders, conditions, or diseases that may respond to antagonism of M3 can include any of those described herein and known in the art, such as hyperhidrosis, chronic obstructive pulmonary disease (COPD), pupil dilation, abdominal pain, etc.

[0069] In some embodiments, the present disclosure provides a method for inhibiting the activity of mAChRs, such as M3 receptors, in a subject or biological sample. In some embodiments, the method includes contacting mAChRs, such as M3 receptors, with an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0070] Hyperhidrosis, a disorder characterized by excessive sweating—that is, sweating in excess of that required for body temperature regulation—occurs in up to 1% of the population, with women being the predominant group affected by this condition. The excessive sweating associated with hyperhidrosis can occur on the hands (palmar hyperhidrosis), armpits (axillary hyperhidrosis), or feet (plantar hyperhidrosis). Hyperhidrosis affects an estimated 8.8 million people in the United States alone, of whom 50.8% have axillary hyperhidrosis and 25–34% have palmar or plantar hyperhidrosis. The underlying causes of primary hyperhidrosis, or idiopathic hyperhidrosis, are not fully understood, but excessive activity of the sympathetic nervous system is widely believed to play a role, as sweating is generally known to be under the control of the sympathetic nervous system. Secondary hyperhidrosis can be distinguished from primary hyperhidrosis by being due to thyroid or pituitary disorders, diabetes mellitus, tumors, gout, menopause, or certain medications.

[0071] Various anticholinergic agents, such as eucatropine derivatives, oxybutynin, propantheline, benztropine, and various glycopyrrolate preparations, have been described as useful for treating hyperhidrosis. See, for example, US Patent Nos. 4,720,494, 6,433,003, 8,618,160, 9,744,105, 10,052,267, 8,859,610, 9,259,414, 10,004,717, 10,543,192, and 10,548,875, as well as the prescribing information for Qbrexza, updated in June 2018. For example, see the Examples section, where compounds or salts of the present disclosure can have similar or better anticholinergic effects than these agents and are also useful for treating hyperhidrosis.

[0072] In some embodiments, the present disclosure provides a method of treating hyperhidrosis in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein. For the treatment of hyperhidrosis, administration is typically by topical route. In some embodiments, the hyperhidrosis is primary hyperhidrosis. In some embodiments, the hyperhidrosis is secondary hyperhidrosis. In some embodiments, the hyperhidrosis is primary axillary hyperhidrosis. In some embodiments, the hyperhidrosis is primary palmar hyperhidrosis. In some embodiments, the hyperhidrosis is primary plantar hyperhidrosis. Typically, the subject is an adult subject or a pediatric patient aged 9 years or older.

[0073] The treatment method herein is not limited to hyperhidrosis. For example, in some embodiments, the present disclosure also provides a method for treating peptic ulcers associated with excessive gastric acid production in a subject in need thereof. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1 to 12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0074] In some embodiments, the present disclosure also provides a method for reducing drooling in a subject in need thereof, e.g., a child between the ages of 3 and 16. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts set forth in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0075] In some embodiments, the present disclosure also provides a method of reducing gastric or respiratory tract secretions in a subject in need thereof. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0076] In some embodiments, the present disclosure also provides a method of protecting the heart and nervous system in a subject in need thereof, e.g., a patient under general anesthesia. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein.

[0077] In some embodiments, the present disclosure also provides a method of treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. In some embodiments, the methods of treating COPD herein can include administering to a subject one or more additional therapeutic agents effective in the treatment of COPD, including those known in the art, such as bronchodilators, beta-adrenergic receptor agonists, and anti-inflammatory agents, including, but not limited to, inhaled steroids, oral steroids, phosphodiesterase-4 inhibitors, JAK inhibitors, TYK2 inhibitors, NLRP3 inhibitors, PI3K inhibitors, SYK inhibitors, BTK inhibitors, IRAK1 and / or IRAK4 inhibitors, theophylline, antibiotics, etc.

[0078] In some embodiments, the present disclosure also provides a method of inducing pupil dilation in a subject in need thereof. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formulas I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Typically, the method of inducing pupil dilation involves administering a compound of the present disclosure formulated as eye drops.

[0079] In some embodiments, the present disclosure also provides a method of treating abdominal pain in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound / salt of Formula I (e.g., Formula I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Typically, the method of treating abdominal pain comprises orally administering a compound of the present disclosure.

[0080] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, administration can be orally, nasally, topically, transdermally, pulmonary, by inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In some embodiments, administration is topical. In some embodiments, administration is oral. In some embodiments, administration is parenterally.

[0081] As discussed herein, the compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments of the methods described herein, the compounds of the present disclosure can be administered as the only active ingredient. In some embodiments, one or more compounds of the present disclosure can be used in combination with an additional therapy, for example, an additional therapy effective in treating hyperhidrosis. In some embodiments of the methods described herein, one or more compounds of the present disclosure can also be co-administered to a subject in need thereof with an additional therapeutic agent, for example, an agent effective in treating hyperhidrosis, simultaneously or sequentially in any order.

[0082] Dosage regimens, including doses, for the methods described herein can be varied and adjusted, and can depend on the person being treated, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the effectiveness of the compound, its clearance rate, and whether another drug is being co-administered.

[0083] definition It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

[0084] It is also meant to be understood that a particular embodiment of a variable moiety herein may be the same or different from another particular embodiment having the same identifier.

[0085] Suitable groups in the compounds of Formula I and II, or subformulas thereof, are independently selected, where applicable. The described embodiments of the present disclosure can be combined. Such combinations are contemplated and within the scope of the present disclosure. For example, R in Formula I 1 , R 2 , R 3 , R 4 , L 1 , X - , and the definition of any one or more of j, where applicable, 1 , R 2 , R 3 , R 4 , L 1 , X - and j may be combined with any one or more other definitions thereof, and compounds resulting from such combinations are intended to be within the scope of the present disclosure. Other combinations of variables in other formulas are understood to be similar.

[0086] JPEG0007755874000026.jpg7170 indicates the point at which the displayed moiety is attached to the remainder of the molecule. Note that JPEG0007755874000027.jpg6170.

[0087] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional groups and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0088] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers, including racemic mixtures. Where stereochemistry is specifically depicted, with respect to that particular chiral center or axial chirality, unless contradicted by context, the compound may exist predominantly as the stereoisomer as depicted, with less than 20%, less than 10%, less than 5%, less than 1%, etc., or undetectable amounts of other stereoisomers by weight, by HPLC area, or both. The presence and / or amount of stereoisomers can be determined by one of skill in the art in light of the present disclosure, including by use of chiral HPLC.

[0089] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C1-6 ” is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 is intended to include.

[0090] As used herein, the term "compound of the disclosure," or, where applicable, "salt of the disclosure," refers to a compound / salt described herein according to Formula I (e.g., I-1, I-1-E1, I-1-E2, I-1-E3, I-1-E4, I-2, I-2-E1, I-2-E2, I-2-E3, I-2-E4, I-3, I-3-E1, I-3-E2, I-3-E3, I-3-E4, I-4, I-4-E1, I-4-E2, I-4-E3, I-4-E4, I-5, or I-6), Formula II (e.g., Formula II-1 or II-2), or a salt / salt of the disclosure. " refers to any of the salts, any of Examples 1-12, or any of the salts shown in Tables 1 or 2 herein, its isotopically labeled compounds (such as deuterated analogs in which one or more hydrogen atoms are replaced with deuterium atoms at an abundance greater than their natural abundance), possible regioisomers, its possible stereoisomers (including diastereoisomers, enantiomers, and racemic mixtures), its tautomers, its conformers, and / or its possible pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound is combined with water or a solvent, respectively.

[0091] The compounds of the present disclosure may exist in isotopically labeled or isotopically enriched forms containing one or more atoms with atomic masses or mass numbers different from the atomic masses or mass numbers most abundant in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine are 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl, and 125 Compounds containing other isotopes of these and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0092] As used herein, the phrase "administration" of a compound or salt, "administering" a compound or salt or other variations means providing a compound or salt or a prodrug of a compound or salt to an individual in need of treatment.

[0093] As used herein, the term "alkyl," when used by itself or as part of another group, refers to a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, alkyl refers to an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 In one embodiment, the alkyl group can be a straight chain C 1-10 In another embodiment, the alkyl group is a branched C 3-10 In another embodiment, the alkyl group is a straight-chain C 1-6 In another embodiment, the alkyl group is a branched C 3-6 In another embodiment, the alkyl group is a straight-chain C 1-4 It is an alkyl group. For example, C 1-4Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene," when used by itself or as part of another group, refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH-CH-CHCH-, -CH-CH-CH-, -CH-CH-, and the like.

[0094] As used herein, the term "alkenyl," by itself or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, an alkenyl group is a C 2-6 In another embodiment, the alkenyl group is C 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0095] As used herein, the term "alkynyl," by itself or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one to three, carbon-carbon triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, an alkynyl group is C 2-6 In another embodiment, the alkynyl group is C 2-4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0096] As used herein, the term "alkoxy" when used by itself or as part of another group refers to a group of the formula OR a1 refers to the radical of R a1 is alkyl.

[0097] As used herein, the term "cycloalkoxy" when used by itself or as part of another group refers to a group of the formula OR a1 refers to the radical of R a1 is cycloalkyl.

[0098] As used herein, the term "haloalkyl," when used by itself or as part of another group, refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In preferred embodiments, a haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is selected from the group consisting of C 1-10 In one embodiment, the haloalkyl group is C 1-6 In one embodiment, the haloalkyl group is C 1-4 It is a haloalkyl group.

[0099] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight- or branched-chain alkyl group having 2 to 14 carbons, e.g., 2 to 10 carbons in the chain, in which one or more of the carbons are replaced with a heteroatom selected from S, O, P, and N; the nitrogen, phosphine, and sulfur atoms can be optionally oxidized; and the nitrogen heteroatom can be optionally quaternized. The heteroatoms S, O, P, and N can be placed at any position within the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When a heteroalkyl is referred to as substituted, substituents can replace one or more hydrogens attached to the heteroalkyl carbon atoms and / or heteroatoms. In some embodiments, heteroalkyl refers to a heteroalkyl as defined herein having 1 to 4 carbon atoms, C 1-4 Heteroalkyl. C 1-4Examples of heteroalkyl include, but are not limited to, C heteroalkyl such as -CH-CH-N(CH)-CH; C heteroalkyl such as -CH-CH-O-CH, CH-CH-NH-CH, -CH-S-CH-CH, -CH-CH-S(O)-CH, CH-CH-S(O)-CH; C heteroalkyl such as -CH-CH-OH, -CH-CH-NH, -CH-NH(CH), -O-CH-CH; and C heteroalkyl such as -CH-OH, -CH-NH, -O-CH. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-O-CHCH- and -O-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linker is implied by the direction in which the formula of the linker is written. When a "heteroalkyl" is recited followed by -NR'R ’’ When specific heteroalkyl groups such as -NR'R" are recited, it will be understood that the terms heteroalkyl and -NR'R" are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are recited for clarity. Thus, the term "heteroalkyl" refers to -NR'R". ’’ This should not be construed as excluding certain heteroalkyl groups such as or .

[0100] "Carbocyclyl" or "carbocyclic," when used by itself or as part of another group, refers to a ring system having at least three carbon atoms, e.g., 3 to 10 ring carbon atoms ("C 3-10"carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms, including cyclohexane, cyclohexane, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene," when used by itself or as part of another group, refers to a divalent radical derived from a carbocyclyl group, as defined herein.

[0101] In some embodiments, a "carbocyclyl" is fully saturated and is also referred to as a cycloalkyl. In some embodiments, a cycloalkyl can have from 3 to 10 ring carbon atoms ("C 3-10 In a preferred embodiment, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" when used by itself or as part of another group refers to a cycloalkylene group, such as It refers to a divalent radical derived from JPEG0007755874000028.jpg19170, etc.

[0102] "Heterocyclyl" or "heterocyclic," by itself or as part of another group, refers to a radical of a three or more membered ring, such as a 3- to 14-membered non-aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic ring systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings, and the point of attachment may be on either ring. As used herein, the term "heterocyclylene" by itself or as part of another group refers to a divalent radical derived from a heterocyclyl group, as defined herein. The heterocyclyl or heterosilylene can be optionally linked to the remainder of the molecule through a carbon or nitrogen atom.

[0103] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0104] "Aryl," by itself or as part of another group, refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 "aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl. As used herein, the term "arylene," when used by itself or as part of another group, refers to a divalent radical derived from an aryl group, as defined herein.

[0105] "Aralkyl," when used by itself or as part of another group, refers to an alkyl substituted with one or more aryl groups, preferably one aryl group. Examples of aralkyls include benzyl, phenethyl, and the like. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

[0106] "Heteroaryl," by itself or as part of another group, refers to the radical of a 5- to 14-membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in the cyclic arrangement) having ring carbon atoms and at least one, preferably 1 to 4, ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, etc.), the point of attachment may be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene," when used by itself or as part of another group, refers to a divalent radical derived from a heteroaryl group, as defined herein.

[0107] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0108] "Heteroaralkyl," when used by itself or as part of another group, refers to an alkyl substituted with one or more heteroaryl groups, preferably one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0109] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the respective groups, whether unsubstituted or substituted. Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent whose substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by, for example, rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any structure is substituted, the substituents can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1 to 5 substituents. Substituents may be carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituents, where applicable. Any two of the substituents may be combined to form an optionally substituted ring structure, such as a carbocyclyl (e.g., cycloalkyl), heterosilyl, aryl, or heteroaryl ring. Substitution may occur at any available carbon, oxygen, or nitrogen atom, forming a spirocyclic ring. Typically, substitutions herein do not result in OO, ON, SS, SN (excluding SO-N bonds), heteroatom-halogen, or -C(O)-S bonds, or three or more consecutive heteroatoms, except for O-SO-O, O-SO-N, and N-SO-N. However, some such bonds or linkages may be tolerated in a stable aromatic system.

[0110] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfato, sulfonate, sulfamoyl, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl, each of which can be substituted where appropriate.

[0111] Exemplary substituents are alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -aryl-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halo, -NO, -CN, -SF, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)-alkyl, -S(O)-aryl, -S(O) -aryl, -S(O)-heteroaryl, -S(O)-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)-alkylene-aryl, -S(O)-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH, -C(=NH)-NH, -C(=NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y1)(Y2), -C(O)N(Y1)(Y2) and -S(O)N(Y1)(Y2). wherein Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0112] Some examples of suitable substituents are (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10) cycloalkyl groups, halogen (F, Cl, Br, or I), halogenated (C1-C8) alkyl groups (such as, but not limited to, -CF3), -O-(C1-C8) alkyl groups, -OH, -S-(C1-C8) alkyl groups, -SH, -NH(C1-C8) alkyl groups, -N((C1-C8) alkyl) groups, -NH2, -C(O)NH2, -C(O)NH(C1-C8) alkyl groups, -C(O)N((C1-C8) alkyl)2, -NHC(O)H, -NHC(O)(C1-C8) alkyl groups, -NHC(O)(C3-C8) cycloalkyl groups, -N((C 1-C8)alkyl)C(O)H, -N((C1-C8)alkyl)C(O)(C1-C8)alkyl group, -NHC(O)NH2, -NHC(O)NH(C1-C8)alkyl group, -N((C1-C8)alkyl)C(O)NH2 group, -NHC(O)N((C1-C8)alkyl)2 group, -N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 group, -N((C1-C8)alkyl)C(O)NH((C1-C8)alkyl), -C(O)H, -C(O)(C1-C8)alkyl group, -CN, -NO2, -S(O)(C1-C8)alkyl group, -S(O)2(C1-C8)alkyl group, -S(O)2N((C1-C8)alkyl)2 group, -S(O)2NH(C1-C8)alkyl group, -S(O)2NH(C3-C8)cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1-C8)alkyl group, -N((C1-C8)alkyl)S(O)2(C1-C8)alkyl group, -(C1-C8)alkyl-O-(C1-C8)alkyl group, -O-(C1-C8)alkyl-O-(C1-C8)alkyl group, -C(O)OH, -C(O)O(C1-C8)alkyl group, NHOH, NHO(C1 -C8) alkyl group, -O-halogenated (C1-C8) alkyl group (such as, but not limited to, -OCF3), -S(O)2-halogenated (C1-C8) alkyl group (such as, but not limited to, -S(O)2CF3), -S-halogenated (C1-C8) alkyl group (such as, but not limited to, -SCF3), -(C1-C6) heterocycle (such as, but not limited to, pyrrolidine, tetrahydrofuran, pyran, or morpholine), -(C1-C6) heteroaryl (such as, but not limited to, tetrazole, imidazole, furan, pyrazine, or pyrazole),-phenyl, -NHC(O)O-(C1-C6)alkyl group, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl group, -C(=NH)-(C1-C6)alkyl group, -C(=NOH)-(C1-C6)alkyl group, or -C(=NO-(C1-C6)alkyl)-(C1-C6)alkyl group.

[0113] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amido, sulfonamido, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3-10 Carbocyclyl, C 6-10 Examples of substituents include, but are not limited to, aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, etc. For example, exemplary carbon atom substituents are F, Cl, —CN, —SOH, —SOH, —OH, —OC 1-6 Alkyl, -NH2, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), -SH, -SC 1-6 Alkyl, -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 It can include aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl. Alternatively, two geminal substituents can be joined to form =O.

[0114] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14Examples of suitable nitrogen protecting groups include, but are not limited to, aryl and 5- to 14-membered heteroaryl. Alternatively, two substituents attached to the nitrogen atom may be joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring. Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be further substituted as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates such as a carbobenzyloxy (Cbz) group, a p-methoxybenzylcarbonyl (Moz or MeOZ) group, a tert-butyloxycarbonyl (BOC) group, a Troc group, and a 9-fluorenylmethyloxycarbonyl (Fmoc) group; those that form amides such as acetyl and benzoyl; those that form benzylamines such as benzyl, p-methoxybenzyl and 3,4-dimethoxybenzyl; those that form sulfonamides such as tosyl and nosyl; and others such as p-methoxyphenyl.

[0115] Exemplary oxygen atom substituents are acyl groups, esters, sulfonates, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyl (4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.), those that form silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), those that form acetals or ketals such as tetrahydropyranyl (THP), those that form esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, and those that form carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0116] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can remain essentially unchanged, for a period of time sufficient to use the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0117] In some embodiments, an "optionally substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocycle, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein is each independently unsubstituted or substituted with F, Cl, -OH, protected hydroxyl, oxo (where applicable), NH, protected amino, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 and cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from F, —OH, oxo (if applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and Fluoro Substituted C 1-4 In some embodiments, the "optionally substituted" aryl, arylene, heteroaryl, or heteroarylene groups herein are each independently unsubstituted or substituted with one, two, or three substituents selected from F, Cl, -OH, -CN, NH, protected amino, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4alkyl), -S(=O)(C 1-4 alkyl), -SO2(C 1-4 alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 and cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from F, —OH, oxo (if applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl, C 1-4 Alkoxy and Fluoro Substituted C 1-4 Optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0118] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0119] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformate.

[0120] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0121] The terms "tautomer" or "tautomeric" refer to two or more interconvertible compounds resulting from tautomerization. The exact ratio of tautomers will vary depending on several factors, such as temperature, solvent, and pH. Tautomerization is known to those skilled in the art. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0122] The term "subject" (also referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0123] As used herein, the terms "treat," "treating," "treatment," and the like refer to relieving, alleviating, or ameliorating a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or its associated symptoms. As used herein, the terms "treat," "treating," "treatment," and the like can include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or condition, or the likelihood of a previously controlled disease or condition recurring, in a subject who does not have, but is at risk of, or susceptible to, recurrence of the disease or condition or recurrence of the disease or condition. The term "treat" and cognate terms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0124] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein sufficient to achieve the intended use, including, but not limited to, the prevention or treatment of disease. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the manner of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells and / or tissues. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which the compound is delivered.

[0125] As used herein, the singular forms "a," "an," and "the" include plural references unless expressly stated or clearly clear from the context that this is not intended.

[0126] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B, A or B, A alone, and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0127] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and should not be referenced in connection with interpreting the description of the subject technology. Features described under one heading or one subheading of this disclosure may be combined with features described under other headings or subheadings in various embodiments. Furthermore, not all features under a single heading or a single subheading may be used together in an embodiment.

[0128] Example The various starting materials, intermediates, and compounds of the embodiments herein can be isolated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, as appropriate. Crystallization of these compounds can be performed using conventional methods, such as melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of steps for carrying out the synthesis of the products described herein are described in more detail below.

[0129] Example 1: Synthesis of (3R)-3-(2-hydroxy-2-(2-(oxazol-2-yl)phenyl)acetoxy)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate JPEG0007755874000029.jpg33170JPEG0007755874000030.jpg35170JPEG0007755874 000031.jpg37170JPEG0007755874000032.jpg37170JPEG0007755874000033.jpg37170

[0130] Step 1: To a solution of 2-(2-bromophenyl)acetic acid (S-1) (10 g, 0.047 mol) in MeOH (100 mL), concentrated H2SO4 (15.2 mL, 0.28 mol) was added dropwise. After the addition, the resulting mixture was heated to reflux for 16 h. The solvent was evaporated, and the residue was poured into ice water (100 mL). The mixture was extracted with EA (50 mL x 2), dried, and concentrated to give the crude product, methyl 2-(2-bromophenyl)acetate (S-2). MS (ESI) m / z 229.1.

[0131] Step 2: A mixture of methyl 2-(2-bromophenyl)acetate (S-2) (10 g, crude, 0.0467 mol), NBS (9 g, 0.051 mol), and AIBN (3.83 g, 0.023 mol) in CCl (100 mL) was heated at 80 °C under N for 16 h. The solvent was removed, and the residue was diluted with DCM (150 mL), washed with water and brine, dried over NaSO, and concentrated to give methyl 2-bromo-2-(2-bromophenyl)acetate (S-3).

[0132] Step 3: To a solution of 4-methoxyphenol (S-4) (4.45 g, 0.0359 mol) in dry THF (250 mL) at 0 °C, NaH (2.154 g, 0.054 mol) was added portionwise under N2. The resulting mixture was stirred at 0 °C for 30 min, followed by the addition of 2-bromo-2-(2-bromophenyl)methyl acetate (S-3) (15 g, crude product, 0.047 mol) and TBAI (776 mg, 0.007 mol). The resulting reaction mixture was stirred at room temperature for an additional 16 h. The reaction was quenched with aqueous NH4Cl (100 mL) at 0 °C and then extracted with EA (50 mL × 2). The combined organic phase was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=95:5 to 90:10) to give methyl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-5). 1 HNMR(400MHz,CDCl3):7.72-7.64(m,2H),7.43-7.38(m,1H),7.29-7.24(m,1H) ,6.98-6.94(m,2H),6.88-6.84(m,2H),6.10(s,1H),3.81(s,3H),3.79(s,3H).

[0133] Step 4: To a solution of methyl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-5) (1.0 g, 3.13 mmol) in MeOH (10 mL), THF (10 mL), and water (10 mL), LiOH (160 mg, 3.8 mmol) was added, and the resulting reaction mixture was stirred at 40 °C for 16 h. MeOH and THF were removed in vacuo, and the residue was diluted with HCl (1 N, 20 mL). It was extracted with EA (30 mL × 3), dried, and concentrated to give 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetic acid (S-6).

[0134] Step 5: To a solution of 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetic acid (S-6) (2.0 g, 5.931 mmol) in dry DCM (20 mL) was added (COCl) (0.75 mL, 8.897 mmol) and DMF (1 drop) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated in vacuo to give 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetyl chloride (S-7) (2.1 g, crude product). The crude product was used in the next step without further purification.

[0135] Step 6: To a solution of 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetyl chloride (S-7) (2.1 g, 5.91 mmol) in dry DCM (20 mL) was added (R)-1-methylpyrrolidin-3-ol (S-8) (717 mg, 7.09 mmol) and TEA (1.8 g, 17.73 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified by silica gel column chromatography eluting with MeOH:DCM (0-5%) to give (R)-1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-9). MS (ESI) m / z 422.1 [M+H] + .

[0136] Step 7: A mixture of (R)-1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-9) (509 mg, 1.2 mmol), 2-(tributylstannyl)oxazole (S-10) (862 mg, 2.4 mmol), and Pd(PPh3)4 (277 mg, 0.24 mmol) in dioxane (15 mL) was stirred at 100 °C under N2 for 16 h. The solvent was removed, and the residue was purified by prep-TLC (DCM / MeOH = 10:1) to give (R)-1-methylpyrrolidin-3-yl 2-(4-methoxyphenoxy)-2-(2-(oxazol-2-yl)phenyl)acetate (S-11). MS (ESI) m / z 409.4 [M+H] + .

[0137] Step 8: To a solution of (R)-1-methylpyrrolidin-3-yl 2-(4-methoxyphenoxy)-2-(2-(oxazol-2-yl)phenyl)acetate (S-11) (80 mg, 0.2 mmol) in MeCN (15 mL) and water (15 mL) was added cerium ammonium nitrate (CAN) (550 mg, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 20 h. The solvent was removed in vacuo, and the residue was diluted with HO and extracted with EA (15 mL x 3). The combined organic phases were dried and concentrated. The residue was purified by prep-HPLC to give (R)-1-methylpyrrolidin-3-yl 2-hydroxy-2-(2-(oxazol-2-yl)phenyl)acetate (S-12).

[0138] Step 9: To a solution of (R)-1-methylpyrrolidin-3-yl 2-hydroxy-2-(2-(oxazol-2-yl)phenyl)acetate (S-12) (9 mg, 0.03 mmol) in 2-butanone (3 mL) was added CHI (43 mg, 0.3 mol). The reaction mixture was loaded into a sealed tube and heated at 75 °C overnight. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to give (3R)-3-(2-hydroxy-2-(2-(oxazol-2-yl)phenyl)acetoxy)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate (Example 1). 1 H NMR (400MHz,D2O):7.94-7.90(m,2H),7.57-7.51(m,2H),7.42-7.36(m,1H),7.29-7.214( m,1H),6.01-5.95(m,1H),5.42(br,1H),3.76-3.33(m,3H),3.05(s,3H),2.77-2.69(m 3H),2.66-2.51(m,2H),2.17-2.08(m,1H),1.89-1.79(m,1H).MS(ESI)m / z 317.1[M+H] + .

[0139] Examples 2 and 3: Synthesis of (3R)-3-(2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetoxy)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate JPEG0007755874000034.jpg35170JPEG0007755874000035.jpg36170JPEG0007755874 000036.jpg37170JPEG0007755874000037.jpg34170JPEG0007755874000038.jpg31170

[0140] Step 1: To a solution of 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetyl chloride (S-7) (2.1 g, 5.91 mmol) in dry DCM (20 mL) was added (R)-1-methylpyrrolidin-3-ol (S-8) (717 mg, 7.09 mmol) and TEA (1.8 g, 17.73 mmol) in an ice bath. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with MeOH:DCM (0-5%) to give (R)-1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-13). MS(ESI)m / z 422.1[M+H] + .

[0141] Step 2: To a solution of (R)-1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-13) (1.57 g, 3.74 mmol) in CHCN / HO (30 mL / 6 mL) was added CAN (6.14 g, 11.206 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The organic layer was washed with HCl (0.5 M, 20 mL x 2). The aqueous layer was basified with aqueous NaCO to pH = 9. The mixture was extracted with EA (30 mL x 3). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated to give (R)-1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-hydroxyacetate (S-14) (600 mg, crude product), which was used directly in the next step without further purification. MS (ESI) m / z 316.0 [M+H] + .

[0142] Step 3: (R)-1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-hydroxyacetate (S-14) (480 mg, 1.529 mmol), cyclopent-1-en-1-ylboronic acid (S-15) (257 mg, 2.293 mmol), KPO in 1,4-dioxane (15 mL) 4( A mixture of Pd(dppf)Cl (972 mg, 4.587 mmol) and Pd(dppf)Cl (112 mg, 0.153 mmol) was heated at 110 °C for 16 h under a nitrogen atmosphere. The mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with MeOH:DCM (0-10%) to give a diastereomeric mixture of (R)-1-methylpyrrolidin-3-yl 2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetate. This was further separated into a fast-eluting isomer S-16a and a slow-eluting isomer S-16b on a Daicel column IH eluting with Hex-EtOH (9:1).

[0143] Step 4: To a solution of S-16a (70.0 mg, 0.233 mmol) in 2-butanone (3 mL) was added CHI (3 drops). The mixture was stirred at 75 °C for 4 hours. The mixture was concentrated and purified by prep-HPLC to give (R)-3-(-2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetoxy)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate (Example 2). 1 H NMR(400MHz,D2O):δ=7.47-7.39(m,4H),5.89(t,J=2.0Hz,1H),5.71(s,1H),5.57(t,J=6Hz,1H),3.89-3.77(m,2H),3.61-3.48(m MS (ESI)m / z 316.2[M+H] + .

[0144] Example 3 was prepared from S-16b in the same manner as Example 2. 1 H NMR(400MHz,D2O):δ=7.46-7.37(m,4H),5.89(t,J=2.0Hz,1H),5.72 (s,1H),5.61(br,1H),3.82-3.78(dd,1H),3.71-3.57(m,2H),3.53(d,1H),3.16(s,3H),2.81-2.75(m ,1H),2.76(s,3H),2.73-2.68(m,2H),2.59-2.55(m,2H),2.42-2.34(m,1H),2.05(quint,2H).MS(ESI) m / z 316.2[M+H] + .

[0145] Examples 4 and 5: Synthesis of (3S)-3-(2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetoxy)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate JPEG0007755874000039.jpg31170

[0146] Examples 4 and 5 were synthesized starting from (S)-1-methylpyrrolidin-3-ol in the same manner as described for Examples 2 and 3, where Example 4 was derived from the fast-eluting isomer of (S)-1-methylpyrrolidin-3-yl 2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetate, and Example 5 was derived from the corresponding slow-eluting isomer. 1 The H NMR looked the same as in Example 3 and 1 1 H NMR looks the same as in Example 2.

[0147] Examples 6 and 7: Synthesis of (R)-2-((2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetoxy)methyl)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate JPEG0007755874000040.jpg32170JPEG0007755874000041.jpg31170JPEG0007755874 000042.jpg32170JPEG0007755874000043.jpg33170JPEG0007755874000044.jpg37170

[0148] Step 1: To a solution of (R)-(1-methylpyrrolidin-2-yl)methanol (0.68 g, 5.9 mmol) and TEA (1.19 g, 11.8 mmol) in DCM (20 mL) was added 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetyl chloride (S-7) (2.1 g, 5.9 mmol) in DCM (10 mL) at 0 °C over 20 min. The resulting reaction mixture was stirred at 45 °C for 2 h. The mixture was quenched with HO and extracted with DCM. The combined organic phase was dried over NaSO and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to give ((R)-1-methylpyrrolidin-2-yl)methyl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-17). MS (ESI) m / z 433.9 [M+H] + .

[0149] Step 2: To a solution of ((R)-1-methylpyrrolidin-2-yl)methyl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-17) (2.1 g, 4.9 mmol) in CHCN / HO (10 mL / 10 mL) was added CAN (8.0 g, 14.6 mmol). The resulting reaction mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was diluted with water (50 mL) and extracted with EA (50 mL). The aqueous solution was adjusted to pH = 9 using NaCO solution. The resulting mixture was extracted with EA (100 mL x 2). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated to give the crude product ((R)-1-methylpyrrolidin-2-yl)methyl 2-(2-bromophenyl)-2-hydroxyacetate (S-18) (0.9 g, yield: 56.6%), which was used directly in the next step without further purification. MS (ESI) m / z 327.9 [M+H] + .

[0150] Step 3: A mixture of ((R)-1-methylpyrrolidin-2-yl)methyl 2-(2-bromophenyl)-2-hydroxyacetate (S-18) (0.8 g, 2.4 mmol), cyclopent-1-en-1-ylboronic acid (S-15) (0.4 g, 3.6 mmol), KPO (1.01 g, 4.8 mmol), and Pd(dppf)Cl (0.18 g, 0.24 mmol) in dioxane / HO (10 mL / 1 mL) was stirred at 100 °C under N overnight. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL). The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by prep-HPLC to give a diastereomeric mixture of ((R)-1-methylpyrrolidin-2-yl)methyl 2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetate (S-19) (0.25 g, 32.5% yield) as a brown oil. Further separation on a Daicel chiral column IH eluted with hexane:EtOH (9:1, containing 0.3% DEA) gave S-19a as the fast-eluting isomer and S-19b as the slow-eluting isomer.

[0151] Step 4: To a solution of S-19a (30 mg, 0.095 mmol) in 2-butanone (1 mL) was added CHCl (1 mL). The resulting reaction mixture was loaded into a sealed tube and stirred at 65° C. for 2 hours. The mixture was concentrated and purified by prep-HPLC (0.1% TFA as an additive) to give one enantiomer of (R)-2-((2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetoxy)methyl)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate (Example 6). 1 H NMR(400MHz,D2O):7.36-7.26(m,4H) 5.79-5.78(t,J=2.2Hz,1H),5.63(s,1H),4.68-4.64(m,1H),4.28-4.22(m,1H),3.74-3.67(m,1H),3.36-3.28(m,2H),2.7 0(s,3H),2.67(s,3H),2.64-2.58(m,2H),2.51-2.44(m,2H),2.26-2.20(m,1H),2.07-1.82(m,5H).MS(ESI)m / z330.2[M+H] + .

[0152] Example 7 was prepared from S-19b. 1 H NMR(400MHz,D2O):7.38-7.31(m,4H)5.80-5.79(t,J=2.0Hz,1H),5.65(s,1H),4.50-4.38(m,2H),3.85-3.81(m,1H),3.41-3.37(m,2H) ),2.69(s,3H),2.63-2.58(m,5H),2.51-2.46(m,2H),2.24-2.22(m,1H),2.04-1.83(m,4H),1.71-1.66(m,1H).MS(ESI)m / z330.2[M+H] + .

[0153] Examples 8 and 9: Synthesis of (S)-2-((2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetoxy)methyl)-1,1-dimethylpyrrolidin-1-ium trifluoroacetate JPEG0007755874000045.jpg21170

[0154] Examples 8 and 9 were synthesized starting from (S)-(1-methylpyrrolidin-2-yl)methanol in the same manner as described for Examples 6 and 7, where Example 8 was derived from the fast-eluting isomer of ((S)-1-methylpyrrolidin-2-yl)methyl 2-(2-(cyclopent-1-en-1-yl)phenyl)-2-hydroxyacetate, and Example 9 was derived from the corresponding slow-eluting isomer. 1 The H NMR looked the same as in Example 6 and the same as in Example 9. 1 1 H NMR looks the same as Example 7.

[0155] Example 10: Synthesis of 3-[2-(2-cyclopentyl-phenyl)-2-hydroxy-acetoxy]-1,1-dimethyl-pyrrolidinium chloride JPEG0007755874000046.jpg36170JPEG0007755874000047.jpg32170JPEG0007755874000048.jpg33170

[0156] Step 1: To a solution of 1-methylpyrrolidin-3-ol (300 mg, 2.97 mmol) and TEA (400 mg, 3.95 mmol) in DCM (15 mL), 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetyl chloride (S-7) (710 mg, 1.98 mmol) was added over 10 min at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with HO and extracted with DCM. The combined organic phases were dried over NaSO and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to give 1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-20). MS (ESI) m / z 422.1 [M+H] + .

[0157] Step 2: To a mixture of 1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-20) (710 mg, 1.69 mmol) in dioxane / HO (25 mL / 5 mL) was added cyclopent-1-en-1-ylboronic acid (S-5) (491 mg, 2.53 mmol), KCO (699 mg, 5.07 mmol), and Pd(dppf)Cl (123 mg, 0.169 mmol). The resulting mixture was degassed and filled with N. The reaction mixture was then stirred at 110 °C overnight. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL). The organic phase was washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give 1-methylpyrrolidin-3-yl(2-cyclopent-1-enylphenyl)-(4-methoxyphenoxy)acetate (S-21). MS (ESI) m / z 408.2 [M+H] + .

[0158] Step 3: To a solution of 1-methylpyrrolidin-3-yl(2-cyclopent-1-enylphenyl)-(4-methoxyphenoxy)acetate (S-21) (330 mg, 0.81 mmol) in 2-butanone (5 mL) was added KCO (20 mg, 0.081 mmol) and CHI (571 mg, 4.05 mmol). The resulting reaction mixture was loaded into a sealed tube and stirred at 75 °C overnight. The mixture was concentrated and purified by prep-HPLC to give 3-[2-(2-cyclopent-1-enylphenyl)-2-(4-methoxyphenoxy)acetoxy]-1,1-dimethyl-pyrrolidinium trifluoroacetate (S-22). MS (ESI) m / z 422.3 [M] + .

[0159] Step 4: A mixture of 3-[2-(2-cyclopent-1-enyl-phenyl)-2-(4-methoxy-phenoxy)-acetoxy]-1,1-dimethyl-pyrrolidinium trifluoroacetate (S-22) (81 mg, 0.189 mmol) and Pd / C (∼20 mg, 20 wt%) in MeOH (10 mL) was degassed and charged with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 16 h. The reaction mixture was filtered through Celite and concentrated to give the crude product, 3-[2-(2-cyclopentyl-phenyl)-2-(4-methoxy-phenoxy)-acetoxy]-1,1-dimethyl-pyrrolidinium trifluoroacetate (S-23), which was used directly in the next step. MS (ESI) m / z 424.3 [M] + .

[0160] Step 5: To a mixture of the crude product 3-[2-(2-cyclopentyl-phenyl)-2-(4-methoxy-phenoxy)-acetoxy]-1,1-dimethyl-pyrrolidinium trifluoroacetate (S-23) (80 mg, 0.189 mmol) in CH3CN / HO (5 mL / 5 mL), CAN (625 mg, 1.14 mmol) was added in two portions at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was diluted with water (10 mL) and extracted with EA (10 mL x 2). The aqueous solution was adjusted to pH = 9 using Na2CO3 solution and extracted again with EA (10 mL x 2). The combined organic phase was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (0.1% TFA as additive), and the product was treated with a few drops of HCl and lyophilized to give 3-[2-(2-cyclopentyl-phenyl)-2-hydroxy-acetoxy]-1,1-dimethyl-pyrrolidinium chloride (Example 10). 1H NMR (400 MHz, DO, mixture of two diastereomers): 7.44-7.42 (m, 2H, both diastereomers), 7.36-7.33 (m, 2H, both diastereomers), 7.27-7.20 (m, 2H, both diastereomers), 5.72 (s, 1H, diastereomer 1), 5.70 (s, 1H, diastereomer 2), 5.54 (br, 2H, both diastereomers), 3.81-3.68 (m, 3H, both diastereomers). mer), 3.63-3.41 (m, 5H, both diastereomers), 3.12 (s, 3H, diastereomer 1), 3.08 (3, 3H, diastereomer 2), 2.86 (s, 3H, diastereomer 1), 2.73-2.64 (m, 5H, both diastereomers), 2.32-2.29 (m, 1H, diastereomer 1), 2.08-1.92 (m, 5H, both diastereomers), 1.77-1.51 (m, 12H, both diastereomers). MS(ESI) m / z 318.2 [M] + .

[0161] Example 11: Synthesis of 3-(2-([1,1'-biphenyl]-2-yl)-2-hydroxyacetoxy)-1,1-dimethylpyrrolidin-1-ium chloride JPEG0007755874000049.jpg39170JPEG0007755874000050.jpg35170JPEG0007755874000051.jpg37170

[0162] Step 1: A mixture of methyl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-5) (1.06 g, 3.02 mmol), phenylboronic acid (553 mg, 4.53 mmol), KOAc (444 mg, 4.53 mmol), and Pd(PPh) (175 mg, 0.15 mmol) in CHCN / HO (75 mL / 16 mL) was degassed and filled with N. The resulting mixture was then heated at 80 °C overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give methyl 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetate (S-24). MS (ESI) m / z 366.2 [M+18] + .

[0163] Step 2: To a solution of methyl 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetate (S-24) (908 mg, 2.6 mmol) in MeOH / THF / HO (10 mL / 10 mL / 10 mL) was added LiOH.HO (131 mg, 3.12 mmol). The resulting mixture was stirred at 40 °C overnight. The reaction mixture was concentrated. The residue was diluted with water (10 mL), acidified with dilute HCl to pH 2, and extracted with EA (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over NaSO, and concentrated to give 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetic acid. MS (ESI) m / z 333.2 [M−H] - .

[0164] Step 3: To a mixture of 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetic acid (890 mg, 2.6 mmol) in DCM (15 mL) was added dropwise DMF (1 drop) and oxalyl dichloride (500 mg, 3.9 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was then concentrated to give biphenyl-2-yl-(4-methoxy-phenoxy)-acetyl chloride (S-25), which was used directly in the next step.

[0165] Step 4: To a mixture of 1-methylpyrrolidin-3-ol (240 mg, 2.36 mmol) and TEA (290 mg, 2.83 mmol) in DCM (20 mL) at 0 °C, a mixture of 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetyl chloride (S-25) (900 mg, 2.60 mmol) in DCM (10 mL) was added dropwise over 20 min. After the addition, the mixture was stirred for an additional 2 h, and the temperature was allowed to slowly warm to room temperature. LCMS showed the reaction was complete. The mixture was quenched with water and extracted with DCM (30 mL x 3). The combined organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give 1-methylpyrrolidin-3-yl 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetate (S-26). MS (ESI) m / z 418.2 [M+H] + .

[0166] Step 5: A pressure tube charged with 1-methylpyrrolidin-3-yl 2-([1,1'-biphenyl]-2-yl)-2-(4-methoxyphenoxy)acetate (S-26) (840 mg, 1.85 mmol) and MeI (1.15 mL, 18.5 mmol) in 2-butanone (10 mL) was sealed and heated at 75 °C for 16 h. The cooled reaction mixture was concentrated, and the residue was purified by prep-HPLC (0.1% TFA as additive), and the product fraction was treated with HCl and lyophilized to give 3-(2-([1,1'-biphenyl]-2-yl)-2-hydroxyacetoxy)-1,1-dimethylpyrrolidin-1-ium chloride (S-27) as a yellow oil. MS (ESI) m / z 432.2 [M] + .

[0167] Step 6: To a mixture of 3-[2-biphenyl-2-yl-2-(4-methoxy-phenoxy)-acetoxy]-1,1-dimethyl-pyrrolidinium trifluoroacetate (S-27) (314 mg, 0.73 mmol) in CHCN / HO (10 mL / 10 mL), CAN (800 mg, 1.46 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by prep-HPLC (0.1% TFA as an additive) to give 3-(2-biphenyl-2-yl-2-hydroxy-acetoxy)-1,1-dimethyl-pyrrolidinium trifluoroacetate (Example 11). 1 H NMR(400MHz,D2O):7.50-7.39(m,6H),7.38-7.35(m,3H),5.41(s,1H),5.36(br,1H),3.73-3.66(m,1H),3.60-3.41(m,3H),3.23-3.12 (m,3H),2.83-2.72(m,3H),2.64-2.56(m,1H),2.20-1.98(m,1H). MS (ESI) m / z 326.2 [M] + .

[0168] Example 12: Synthesis of 3-(2-hydroxy-2-(2-isopropylphenyl)acetoxy)-1,1-dimethylpyrrolidin-1-ium chloride JPEG0007755874000052.jpg29170JPEG0007755874000053.jpg44170JPEG0007755874000054.jpg34170

[0169] Step 1: A mixture of 1-methylpyrrolidin-3-yl 2-(2-bromophenyl)-2-(4-methoxyphenoxy)acetate (S-20) (500 mg, 1.19 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (240 mg, 1.43 mmol), KCO (328 mg, 2.38 mmol), and Pd(PPh) (137 mg, 0.12 mmol) in dioxane / HO (10 mL / 1 mL) was stirred at 100 °C overnight under N. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL × 2). The combined organic phase was washed with brine, dried over NaSO, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with EA to give 1-methylpyrrolidin-3-yl 2-(4-methoxyphenoxy)-2-(2-(prop-1-en-2-yl)phenyl)acetate (S-28). MS (ESI) m / z 382.2 [M+H] + .

[0170] Step 2: To a solution of 1-methylpyrrolidin-3-yl 2-(4-methoxyphenoxy)-2-(2-(prop-1-en-2-yl)phenyl)acetate (S-28) (300 mg, 0.78 mmol) in MeOH (5 mL) was added Pd / C (80 mg). The mixture was stirred under H2 at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 1-methylpyrrolidin-3-yl 2-(2-isopropylphenyl)-2-(4-methoxyphenoxy)acetate (S-29). MS (ESI) m / z 384.2 [M+H] + .

[0171] Step 3: To a mixture of 1-methylpyrrolidin-3-yl 2-(2-isopropylphenyl)-2-(4-methoxyphenoxy)acetate (S-29) (270 mg, 0.71 mmol) in CHCN / HO (5 mL / 5 mL) was added CAN (1.16 g, 2.11 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was then diluted with water (10 mL) and extracted with EA (20 mL). The aqueous solution was adjusted to pH 9 using NaCO solution. The resulting mixture was extracted with EA (20 mL × 2). The combined organic phases were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated to give 1-methylpyrrolidin-3-yl 2-hydroxy-2-(2-isopropylphenyl)acetate (S-30) as a brown solid, which was used in the next step without further purification. MS (ESI) m / z 278.2[M+H] + .

[0172] Step 4: To a mixture of 1-methylpyrrolidin-3-yl 2-hydroxy-2-(2-isopropylphenyl)acetate (S-30) (100 mg, 0.29 mmol) in 2-butanone (2 mL) was added CHCl (1 mL). The mixture was stirred at 65° C. for 2 hours. The reaction mixture was concentrated to give the crude product. The crude product was purified by prep-HPLC (0.1% TFA as additive). The product was treated with HCl and lyophilized to give 3-(2-hydroxy-2-(2-isopropylphenyl)acetoxy)-1,1-dimethylpyrrolidin-1-ium chloride, Example 12. 1 H NMR(400MHz,D2O):7.44(d,J=8Hz,1H),7.40-7.35(m,1H),7.27-7.22(m,2H),5.71(d,J=9.2Hz,1H),5.54(br,1H),3.83-3.71(m, 2H),3.64-3.45(m,2H),3.31-3.21(m,1H),3.13,3.08(s,3H),2.90,2.73(s,3H),2.71-2.66(m,1H),2.34-2.30(m,1H),2.13-2.06 (m, 1H),1.24-1.13(m,6H).MS(ESI)m / z 292.2 [M] + .

[0173] Biological Example 1: In vitro assay for determining IC50 Compound efficacy was evaluated using the FLIPR assay. CHO-K1 cells stably expressing M3 receptors were cultured at 37°C in medium (90% Ham's F-12 nutrient mixture, Gibco; 10% fetal bovine serum, Biosera; 200 μg / mL hygromycin, and penicillin (100 U / mL) / streptomycin (100 μg / mL), Invitrogen) in a cell culture incubator (ThermoFisher, 5% CO2) until 100% confluency was reached. Cells were harvested using 0.25% trypsin / EDTA and spun down at 300 × g for 5 minutes. 5 × 10 cells were collected. 5Cells were resuspended in medium at a cell density of 10,000 cells / mL. 20 microliters of the cell suspension (10,000 cells / well) was transferred to a 384-well plate and cultured for 24 hours before assay. DMSO was used as a blank control, and scopolamine (MedChemExpress) was used as a positive antagonist control. Compounds were prepared in DMSO (stock concentration: 1 mM) and serially diluted 3x (10 concentrations) in a 384-LDV plate (Labcyte). 90 nL of serially diluted compound was transferred from the 384-LDV plate to a compound plate (PerkinElmer) using an Echo 550 (Labcyte), and 30 μL of assay buffer (1x HBSS with 20 mM HEPES, pH 7.4, Sigma) was added to each well. For FLIPR assays, the medium was removed, and 20 μL of 1× loading dye (assay buffer with 2 μM Fluo-8 AM, AAT Bioquest; 1 mM probenecid and 0.0025% Pluronic® F-127, Sigma) was added to each well. The plates were incubated at 37°C for 1 hour (avoiding exposure to light). For FLIPR assays, the excitation wavelength was set at 470 / 495 nm, and the emission wavelength was set at 515 / 575 nm (Molecular Devices). The assay was performed in both agonist and antagonist modes. For agonist mode, 10 μL of diluted compound was transferred to cell culture wells and incubated at room temperature for 10 minutes. For antagonist mode, 10 μL of compound diluted in 8 nM acetylcholine (EC80, MedChemExpress) was added to each well and incubated at room temperature for 10 minutes. The RFU value was calculated by subtracting the minimum value from the maximum value of the FLIPR signal. The inhibitory effect of a compound on acetylcholine-induced calcium flux was calculated as % effect = (RFU サンプル -RFU DMSO ) / (RFU スコポラミン -RFU DMSO ) × 100. Dose-response curve fitting and IC for each compound were performed using XLFit. 50 The values ​​were calculated. The IC50s are listed in the table below. * means IC50 > 1000 nM, ** means 10-100 nM, *** < 10 nM. JPEG0007755874000055.jpg76170

[0174] The Summary and Abstract sections may describe one or more example embodiments of the invention, but not all, as contemplated by the inventors, and are therefore not intended to limit the scope of the invention and the appended claims in any way.

[0175] The present invention has been described above with the help of functional building blocks that illustrate the implementation of certain functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of description. Alternate boundaries can be defined so long as the certain functions and relationships thereof are appropriately performed.

[0176] For aspects of the invention described as genus, all individual species are considered individually as separate aspects of the invention. When an aspect of the invention is described as "comprising" a feature, it is contemplated that the embodiment also "consists of" or "consists essentially of" that feature.

[0177] The foregoing description of specific embodiments sufficiently clarifies the general nature of the present invention so that others, by applying knowledge within the skill of the art, can readily modify and / or adapt such specific embodiments to various uses without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It should be understood that the phrases or terminology herein are intended to be descriptive rather than limiting, as the terms or phrases herein would be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0178] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0179] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0180] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If the meaning or definition of a term in this document conflicts with the meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

Claims

1. A salt having formula I, In the formula, X － is the counterion, R １ is hydrogen, L １ is a single bond, C １－４ Alkylene, or C １－４ is heteroalkylene, R ２ is C ３－８ carbocyclyl, 4- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted; R ３ and R ４ are each independently hydrogen or C １－６ is alkyl, A salt characterized in that j is 0, 1 or 2.

2. 2. The salt of claim 1, having a formula according to formula I-1 or I-2.

3. L １ is CH ２ 2. The salt of claim 1, wherein:

4. L １ is CH ２ 3. The salt according to claim 2, wherein

5. R ２ teeth, (i) F, OH, R Ａ , and OR Ａ C of cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with one or more substituents independently selected from ３－６ cycloalkyl, and R Ａ are independently F, OH, C １－４ Alkyl, fluorine-substituted C １－４ Alkyl, C １－４ Alkoxy and fluorine-substituted C １－４ C optionally substituted with one or more substituents independently selected from alkoxy １－４ Alkyl or C ３－６ C is cycloalkyl ３－６ cycloalkyl; (ii) F, OH, R Ａ , and OR Ａ C of cyclopentenyl optionally substituted with one or more substituents independently selected from ４－７ cycloalkenyl, and R Ａ are independently F, OH, C １－４ Alkyl, fluorine-substituted C １－４ Alkyl, C １－４ Alkoxy and fluorine-substituted C １－４ C optionally substituted with one or more substituents independently selected from alkoxy １－４ Alkyl or C ３－６ C is cycloalkyl ４－７ cycloalkenyl; (iii) F, Cl, OH, C １－４ Alkyl, fluorine-substituted C １－４ Alkyl, C １－４ Alkoxy and fluorine-substituted C １－４ phenyl optionally substituted with one or more substituents independently selected from alkoxy; (iv) oxazolyl, thiazolyl, and other 5-membered heteroaryls having 1 to 3 ring heteroatoms independently selected from N, O, and S, and including F, Cl, OH, C １－４ Alkyl, fluorine-substituted C １－４ Alkyl, C １－４ Alkoxy and fluorine-substituted C １－４ a 5-membered heteroaryl optionally substituted with one or more substituents independently selected from alkoxy; or (v) a 6-membered heteroaryl having 1 to 2 ring heteroatoms independently selected from N, O, and S, such as pyridyl or pyrimidinyl, and including F, Cl, OH, C １－４ Alkyl, fluorine-substituted C １－４ Alkyl, C １－４ Alkoxy and fluorine-substituted C １－４ The salt according to any one of claims 1 to 4, which is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from alkoxy.

6. R ３ The salt according to any one of claims 1 to 4, wherein is methyl.

7. R ４ The salt according to any one of claims 1 to 4, wherein is methyl.

8. The salt according to any one of claims 1 to 4, wherein j is 1.

9. X － The salt according to any one of claims 1 to 4, wherein is a pharmaceutically acceptable counterion.

10. A salt selected from those shown in Table 1 or 2, wherein X － is a pharmaceutically acceptable counterion. Table 1 Table 2

11. A pharmaceutical composition comprising the salt of any one of claims 1 to 4 and 10, and optionally a pharmaceutically acceptable carrier.

12. 1. A compound having formula II or a salt thereof: In the formula, R １ is hydrogen, L １ is a single bond, C １－４ Alkylene, or C １－４ is heteroalkylene, R ２ is C ３－８ carbocyclyl, 4- to 8-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted; R ３ is hydrogen or C １－６ is alkyl, A compound or a salt thereof, wherein j is 0, 1 or 2.

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