Azabicyclo and diazepine derivatives for treating ocular diseases

Abstract

To provide compounds and compositions for use in methods of treating disorders relating to excessive growth of the eye.SOLUTION: The present invention provides azabicycio and diazepine derivatives useful as modulators of muscarinic receptors, represented by the formula (I) or (II) (where A is O or NR5, W is N or CH, X is -OH, -O-Y-Z or the like, R1 and R2 are each a C1-C20 alkyl group or the like, R3 and R4 are each H, a C1-C10 alkyl group or the like, Y is a bivalent group, which is a straight or branched C1-C20 alkyl, optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms and hydroxyls, and Z is H, -OH, an alkoxy group or the like).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to azabicyclo and diazepine derivatives useful as modulators of muscarinic receptors and methods of using same to treat disease. [Background technology]

[0002] Muscarinic receptors are targets of the excitatory neurotransmitter acetylcholine and are named based on the selective activation of the receptor by muscarinic acid. Muscarinic receptors are widely distributed throughout human tissues and are further classified into subtypes M1 to M5. Modulation of muscarinic receptors has been proposed as a therapeutic target for diseases ranging from overactive bladder to cognitive impairment (Abrams et al., Br. J Pharmacol 2006 July;148(5):565-578).

[0003] Myopia is a refractive error of the eye caused by excessive longitudinal growth of the eye. This elongation causes visual images to focus in front of the retina, typically resulting in blurred images of distant objects. Atropine, a nonselective muscarinic antagonist, has been reported to be effective as a topical 1% eye drop in the treatment of myopia (Chua et al., Ophthalmology 2006 Dec;113(12):2285-91). However, numerous side effects have been reported, including blurred near vision due to mydriasis (dilation of the pupil) and cycloplegia (inability to accommodate). Currently, corrective lenses are the primary means of correcting ocular length disorders such as myopia. However, while lenses optically correct refractive errors, they do not treat the underlying cause, which is excessive ocular growth. Therefore, there remains a need for methods to treat disorders associated with excessive ocular growth. Summary of the Invention [Means for solving the problem]

[0004] There remains a need for new treatments and therapies for excessive eye growth. The present invention provides compounds that are muscarinic modulators, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The present invention further provides methods for treating, preventing, or ameliorating disorders associated with excessive eye growth, comprising administering to a subject in need thereof an effective amount of a muscarinic modulator. Various embodiments of the present invention are described below.

[0005] Within certain aspects, provided herein are compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof: [ka] (In the ceremony Me=CH3; A=O or NR5; W=N or CH; X = -OH, -OYZ, -SYZ, or -NR5-YZ; R1 and R2 are H, D, hydroxyl, alkoxy, nitrile, halogen atoms, C1-C optionally substituted with halogen atoms. 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl are independently substituted as groups; or R1 and R2 are C1 to C 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl or independently substituted as a phenyl or benzyl group optionally substituted with one or more substituents selected from a group, a haloalkyl group, a hydroxyl, an alkoxy, a nitrile, a nitro, an amino, an amide, an ester, a sulfone, a sulfoxide, a sulfonamide, and a halogen atom; R1 and R2 contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and are C1-C 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl, a heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered ring optionally substituted with one or more substituents selected from haloalkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, or halogen atoms; R3 and R4 are hydrogen, C1 to C 10 Linear or branched chain, or Cyclic alkyl or independently substituted by haloalkyl groups; R3 and R4 can combine to form a 3- to 6-membered ring; R5 = H or C1 to C 20 , preferably C1 to C 10 , linear or branched alkyl group, C1-C 10 straight-chain or branched-chain haloalkyl groups; Y is a divalent radical having the following meaning: a) a linear or branched C1-C optionally substituted with one or more substituents selected from the group consisting of halogen atoms and hydroxyl 20 (Preferably C1 to C 10 ) alkyl; b) -C(O)(C1-C 10 alkyl)- or -C(O)(CH2) n C(O)O-(C1~C 10 alkyl)- or -(C1-C 10 alkyl)-; c) [ka] ; d) [ka] ; e) [ka] or f) [ka] In the formula, n is an integer from 0 to 20; R 6 and R 7 are independently H or C1 to C 10 Straight or branched chain alkyl group, C1-C 10 a straight or branched chain haloalkyl group; or R 6 and R 7 can combine to form a 3- to 6-membered ring; and Z is H, -OH, C 1~6 Alkoxy, -COOH, -NR 8 R 9 and; R 8 and R 9 teeth, Independently, C1-C optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms 20 , preferably C1 to C 10 Alkyl and or R 8 and R 9 can combine to form a 3- to 6-membered ring containing one or more heteroatoms selected from the group consisting of: [ka] ).

[0006] In another aspect, the present invention provides a pharmaceutical composition comprising (1) a therapeutically effective amount (preferably about 0.01 to about 10.0 weight percent, more preferably about 0.01 to about 5 weight / volume percent, or about 0.1 to 5.0 weight percent) of (a) a compound of the present invention and / or (b) a pharmaceutically acceptable salt thereof; and (2) one or more pharmaceutically acceptable carriers. In yet another aspect, the present invention provides a pharmaceutical composition comprising (1) a compound of the present invention and / or a pharmaceutically acceptable salt thereof; and (2) one or more pharmaceutically acceptable carriers.

[0007] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising: (1) a therapeutically effective amount (preferably about 0.01 to about 10.0 weight percent, more preferably about 0.01 to about 5 weight / volume percent, or about 0.1 to 5.0 weight percent) of (a) a compound of the present invention and / or (b) a pharmaceutically acceptable salt thereof; and (2) one or more therapeutically active agents. In yet another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising: (1) a compound of the present invention and / or a pharmaceutically acceptable salt thereof; and (2) one or more therapeutically active agents.

[0008] Specific preferred embodiments of the present invention will become apparent from the following more detailed description of certain preferred embodiments and from the claims. [Brief explanation of the drawings]

[0009] [Figure 1] 1H NMR spectrum of ethyl 2-fluoro-2-phenylacetate; [Figure 2] 1H NMR spectrum of 2-fluoro-2-phenylacetic acid; [Figure 3] 1H NMR spectrum of 2-fluoro-2-phenylacetyl chloride; [Figure 4] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-2-phenylacetate; [Figure 5] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-3-hydroxy-2-phenylpropanoate; [Figure 6] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-3-hydroxy-2-phenylpropanoate. [Figure 7]1H NMR spectrum of 2-methyl-2-phenylacetyl chloride; [Figure 8] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-2-phenylacetate; [Figure 9] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-3-hydroxy-2-phenylpropanoate; [Figure 10] 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-3-hydroxy-2-phenylpropanoate; [Figure 11] 1H NMR spectrum of 2,3-diphenylpropanoyl chloride; [Figure 12] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-diphenylpropanoate; [Figure 13] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-benzyl-3-hydroxy-2-phenylpropanoate; and [Figure 14] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-benzyl-3-hydroxy-2-phenylpropanoate. [Figure 15A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate. [Figure 15B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate. [Figure 16A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate. [Figure 16B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate. [Figure 17A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(hydroxymethyl)-2-phenylbutanoate. [Figure 17B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(hydroxymethyl)-2-phenylbutanoate. [Figure 18A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate. [Figure 18B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate. [Figure 19A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-fluoro-2-methyl-2-phenylpropanoate. [Figure 19B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-fluoro-2-methyl-2-phenylpropanoate. [Figure 20A]1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate. [Figure 20B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate. [Figure 21A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydroxy-2-phenylpropanoate. [Figure 21B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydroxy-2-phenylpropanoate. [Figure 22A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate. [Figure 22B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate [Figure 23A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate. [Figure 23B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate. [Figure 24A]1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate. [Figure 24B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate. [Figure 25A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate. [Figure 25B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate. [Figure 26A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate formate. [Figure 26B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate formate. [Figure 27A] 1H NMR spectrum of 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide. [Figure 27B] 13C NMR spectrum of 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide. [Figure 28A]1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate. [Figure 28B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate. [Figure 29A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate. [Figure 29B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate. [Figure 30A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate. [Figure 30B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate. [Figure 31A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methylpropanoate. [Figure 31B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methylpropanoate. [Figure 32A]1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-chlorophenyl)-3-hydroxy-2-methylpropanoate. [Figure 32B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-chlorophenyl)-3-hydroxy-2-methylpropanoate. [Figure 33A] 1H NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropanoate. [Figure 33B] FIG. 13C NMR spectrum of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropanoate. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention relates to a class of compounds having an atropine or pirenzepine residue, respectively, and pharmaceutically acceptable salts thereof. In a preferred embodiment, the present invention provides compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof: [ka] (In the ceremony Me=CH3; A=O or NR5; W=N or CH; X = -OH, -OYZ, -SYZ, or -NR5-YZ; R1 and R2 are H, D, hydroxyl, alkoxy, nitrile, halogen atoms, C1-C optionally substituted with halogen atoms. 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl are independently substituted as groups; or R1 and R2 are C1 to C 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl or independently substituted as a phenyl or benzyl group optionally substituted with one or more substituents selected from a group, a haloalkyl group, a hydroxyl, an alkoxy, a nitrile, a nitro, an amino, an amide, an ester, a sulfone, a sulfoxide, a sulfonamide, and a halogen atom; R1 and R2 contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and are C1-C 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl , a heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered ring optionally substituted with one or more substituents selected from haloalkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, or halogen atoms; R3 and R4 are hydrogen, C1 to C 10 Linear or branched chain, or Cyclic alkyl or independently substituted by haloalkyl groups; R3 and R4 can combine to form a 3- to 6-membered ring; R5 = H or C1 to C 20 , preferably C1 to C 10 , linear or branched alkyl group, C1-C 10 straight-chain or branched-chain haloalkyl groups; Y is a divalent radical having the following meaning: g) linear or branched C1-C optionally substituted with one or more substituents selected from the group consisting of halogen atoms and hydroxyl 20 (Preferably C1 to C 10 ) alkyl; h)-C(O)(C1-C 10 alkyl)- or -C(O)(CH2) n C(O)O-(C1~C 10 alkyl)- or -(C1-C 10 alkyl)-; i) [ka] ; j) [ka] ; k) [ka] or l) [ka] In the formula, n is an integer from 0 to 20; R 6 and R 7 are independently H or C1 to C 10 Straight or branched chain alkyl group, C1-C 10 a straight or branched chain haloalkyl group; or R 6 and R 7 can combine to form a 3- to 6-membered ring; and Z is H, -OH, C 1~6 Alkoxy, -COOH, -NR 8 R 9 and; R 8 and R 9 teeth, Independently, C1-C optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms 20 , preferably C1 to C 10 Alkyl and or R 8 and R 9 can combine to form a 3- to 6-membered ring containing one or more heteroatoms selected from the group consisting of: [ka] ).

[0011] In some embodiments, the compound of Formula (I) is atropine of Formula (IA): [ka] In the formula, Me, R1, and X are as defined above.

[0012] definition Unless otherwise specified, the term "compounds of the present invention" or "compound of the present invention" refers to compounds of formula (I), its subformulas, and exemplified compounds, and salts thereof, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), and inherently formed moieties.

[0013] The term "effective amount" of a compound of the present invention described below refers to the amount of therapeutic compound necessary or sufficient to perform its intended function in a mammal, for example, to treat a muscarinic receptor-related disease or condition in the animal. The effective amount of a therapeutic compound may vary depending on factors such as the amount of causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compound of the present invention to affect a muscarinic receptor-related disease in the mammal. One of ordinary skill in the art would be able to consider the above factors and make a determination regarding the effective amount of the therapeutic compound without undue experimentation. In vitro or in vivo assays can also be used to determine the "effective amount" of the therapeutic compound described below. One of ordinary skill in the art would select an appropriate amount of the therapeutic compound for use in the above assays or as a therapeutic treatment.

[0014] The phrase "ophthalmically compatible" is art-recognized and refers to formulations, polymers, and other materials, and / or dosage forms that are suitable for use in contact with the ocular tissues of humans and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio as determined by one of skill in the art.

[0015] As used herein, a pharmaceutical composition is a composition suitable for pharmaceutical use. A composition suitable for pharmaceutical use may be sterile, homogeneous, and / or isotonic. In certain embodiments, the pharmaceutical composition may be prepared in the form of an aqueous solution, for example, in a pre-filled syringe or other single- or multi-dose container. In certain embodiments, the pharmaceutical composition of the present invention is ophthalmologically compatible and suitable for ocular administration to human subjects, for example, by topical application or other known delivery methods. In another embodiment, the pharmaceutical composition of the present invention is suitable for intravitreal administration. In yet another embodiment, the pharmaceutical composition of the present invention is suitable for administration by intravitreal injection. In yet another embodiment, the pharmaceutical composition is administered orally.

[0016] As used herein, the term "alkyl" is intended to include branched, straight-chain, and cyclic, substituted or unsubstituted saturated aliphatic hydrocarbon groups. An alkyl group is an alkyl group having from about 1 to about 24 carbon atoms ("C1-C 24 "), about 7 to about 24 carbon atoms ("C7 to C 24 "), about 8 to about 24 carbon atoms ("C8 to C 24 "), or from about 9 to about 24 carbon atoms ("C9 to C 24 "). An alkyl group can also contain from about 1 to about 8 carbon atoms ("C1-C8"), from about 1 to about 6 carbon atoms ("C1-C6"), or from about 1 to about 3 carbon atoms ("C1-C3"). Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl groups.

[0017] As used herein, the term "C2~6 "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 6 carbon atoms and attached to the rest of the molecule by a single bond. 20 Alkenyl" and "C2-C 10 "Alkenyl" shall be construed accordingly. 2~6 Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-4-enyl, and penta-1,4-dienyl.

[0018] As used herein, the term "C 2~6 "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from 2 to 6 carbon atoms and attached to the rest of the molecule by a single bond. 2~4 "Alkynyl" shall be construed accordingly. 2~6 Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and penta-1,4-diynyl.

[0019] As used herein, the term "C 1~6 "Alkoxy" is R a is the general definition of C 1~6 an alkyl group of the formula -OR a C 1~6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

[0020] "Halogen" refers to bromo, chloro, fluoro, or iodo.

[0021] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable 5- or 6-membered non-aromatic monocyclic ring group containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocyclyl group can be attached by either a carbon atom or a heteroatom. Examples of heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl.

[0022] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroaryl group can be attached by either a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl.

[0023] The present invention provides, in certain embodiments, novel pharmaceutical formulations, particularly novel pharmaceutical formulations in which the active ingredient comprises a muscarinic modulator of general formula (I) or (II) and / or a pharmaceutically acceptable salt thereof: [ka] (In the ceremony Me=CH3; A=O or NR5; W=N or CH; X = -OH, -OYZ, -SYZ, or -NR5-YZ; R1 and R2 are H, D, hydroxyl, alkoxy, nitrile, halogen atoms, C1-C optionally substituted with halogen atoms. 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl are independently substituted as groups; or R1 and R2 are C1 to C 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl or independently substituted as a phenyl or benzyl group optionally substituted with one or more substituents selected from a group, a haloalkyl group, a hydroxyl, an alkoxy, a nitrile, a nitro, an amino, an amide, an ester, a sulfone, a sulfoxide, a sulfonamide, and a halogen atom; R1 and R2 contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and are C1-C 20 (Preferably C1 to C 10 ) straight chain, branched chain, or Cyclic alkyl , a heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered ring optionally substituted with one or more substituents selected from haloalkyl groups, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, or halogen atoms; R3 and R4 are hydrogen, C1 to C 10 Linear or branched chain, or Cyclic alkyl or independently substituted by haloalkyl groups; R3 and R4 can combine to form a 3- to 6-membered ring; R5 = H or C1 to C 20 , preferably C1 to C 10 , linear or branched alkyl group, C1-C 10 straight-chain or branched-chain haloalkyl groups; Y is a divalent radical having the following meaning: a) a linear or branched C1-C optionally substituted with one or more substituents selected from the group consisting of halogen atoms and hydroxyl 20 (Preferably C1 to C 10 ) alkyl; b) -C(O)(C1-C 10 alkyl)- or -C(O)(CH2) n C(O)O-(C1~C 10 alkyl)- or -(C1-C 10 alkyl)-; c) [ka] ; d) [ka] ; e) [ka] or f) [ka] In the formula, n is an integer from 0 to 20; R 6 and R 7 are independently H or C1 to C 10 Straight or branched chain alkyl group, C1-C 10 a straight or branched chain haloalkyl group; or R 6 and R 7 can combine to form a 3- to 6-membered ring; and Z is H, -OH, C 1~6 Alkoxy, -COOH, -NR 8 R 9 and; R 8 and R 9 teeth, Independently, C1-C optionally substituted with one or more substituents selected from hydroxyl, amino, ester, carboxylic acid, and halogen atoms 20 , preferably C1 to C 10 Alkyl and or R 8 and R 9 can combine to form a 3- to 6-membered ring containing one or more heteroatoms selected from the group consisting of: [ka] ).

[0024] In some embodiments, the compound of Formula (I) is atropine of Formula (IA): [ka] In the formula, Me, R1, and X are as defined above.

[0025] In some embodiments, the compounds of Formula (I) and Formula (II) are selected from the group consisting of: (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-3-hydroxy-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-3-hydroxy-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-benzyl-3-hydroxy-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(hydroxymethyl)-2-phenylbutanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-fluoro-2-methyl-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydroxy-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate formate, 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate, (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(benzyloxy)phenyl)propanoate, and 6-((11-(2-(4-methylpiperazin-1-yl)acetyl)-11H-benzo[e]pyrido[3,2-b][1,4]diazepin-6-yl)oxy)hexyl nitrate.

[0026] Additional compounds of the invention include: [ka] [ka] [ka] .

[0027] The following paragraphs provide examples of compounds according to the invention: [Example]

[0028] Examples 1 to 3 [ka] NMR spectra were measured on a Bruker 400 MHz spectrometer or a Bruker 300 MHz spectrometer.

[0029] LCMS methods are detailed below (unless otherwise stated):

[0030] [Table 1]

[0031] [Table 2]

[0032] Abbreviation: DAST Diethylaminosulfur trifluoride DCM dichloromethane DMF Dimethylformamide RT room temperature

[0033] Example 1: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-3-hydroxy-2-phenylpropanoate [ka] Ethyl 2-fluoro-2-phenylacetate To a solution of ethyl mandelate (93 g, 0.52 mol) in DCM (1.5 L) at −78° C. was added DAST (81.8 mL, 0.62 mol) at a rate such that the T was below −60° C. The reaction mixture was stirred while allowing to warm to 0° C. After 1 h, the reaction was slowly basified with 1 N NaOH to a pH of approximately 7. The mixture was extracted with DCM. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a pale yellow oil (62.4 g, 66%). The material was used without purification. 1 H NMR(400MHz,CDCl3)δ 7.54-7.36(5H,m),5.77(1H,d,J=47.3Hz),4.32-4.16(2H,m),1.26(3H,t,J=7.2Hz). 1 The 1 H NMR spectrum is shown in Figure 1. [ka]

[0034] 2-Fluoro-2-phenylacetic acid To a solution of ethyl 2-fluoro-2-phenylacetate (32.4 g, 0.18 mol) in MeOH (100 mL) was added LiOH.HO (11.2 g, 0.27 mol) in water (15 mL), and the reaction was stirred at room temperature for 1 hour (a slight exotherm was observed). The reaction mixture was diluted with ethyl acetate and acidified to approximately pH 3 with 1N HCl. The product was extracted with ethyl acetate, and the combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the title compound as a white solid (27.4 g, 100%). The material was used without purification. 1 H NMR(400MHz,d6-DMSO)δ 13.47(1H,br s),7.48-7.37(5H,m),5.95(1H,d,J=47.6Hz). 1 The 1 H NMR spectrum is shown in Figure 2. [ka]

[0035] 2-Fluoro-2-phenylacetyl chloride To a solution of 2-fluoro-2-phenylacetic acid (27.4 g, 0.18 mol) in DCM (250 mL) at room temperature was added one drop of DMF. Oxalyl chloride (23.3 mL, 0.27 mol) was added, resulting in effervescence. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound as a pale yellow oil (30.1 g, 100%). The material was used without purification. 1 H NMR(400MHz,CDCl3)δ 7.54-7.43(5H,m),5.90(1H,d,47.6Hz). 1 The 1 H NMR spectrum is shown in Figure 3. [ka]

[0036] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-2-phenylacetate To a solution of tropine (27.1 g, 0.19 mol) in toluene (450 mL) was added 2-fluoro-2-phenylacetyl chloride (30.1 g, 0.17 mol), causing the formation of a precipitate. The reaction mixture was stirred at reflux for 1.5 hours. The reaction mixture was diluted with ethyl acetate and extracted with 1N HCl. The combined aqueous fractions were basified to approximately pH 13 with 1N NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a pale yellow oil that solidified on standing (33.5 g, 69%). 1 H NMR(400MHz,CDCl3)δ 7.51-7.37(5H,m),5.73(1H,d,J=47.9Hz),5.08(1H,t,J=5.3Hz),3.07-2.93(2H,m),2.22(3H,s) ,2.16-2.01(2H,m),1.97-1.85(1H,m),1.84-1.64(3H,m),1.56-1.48(1H,m),1.37-1.29(1H,m). 1 The 1 H NMR spectrum is shown in Figure 4. LCMS(ESI)[M+H] + 278,R t =0.70min. [ka]

[0037] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-3-hydroxy-2-phenylpropanoate To a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-fluoro-2-phenylacetate (33.5 g, 0.12 mol) in DMF (120 mL) was added paraformaldehyde (5.45 g, 0.18 mol). Freshly prepared sodium ethoxide (140 mg sodium in 3.6 mL ethanol) was added to this suspension to dissolve the solid. The reaction mixture was stirred at 40 °C for 5 minutes. The reaction mixture was diluted with ethyl acetate and extracted with 1N HCl. The combined aqueous fractions were basified to approximately pH 13 with 1N NaOH and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO ), and concentrated in vacuo to approximately 1 / 5 of their volume, at which point the product crystallized. The solid was collected by filtration and dried in vacuo to give the title compound as a white solid (25.0 g, 67%). The mother liquor was concentrated in vacuo and triturated with ethyl acetate to give a second crop of similar purity to the first. 1 H NMR(400MHz,CDCl3)δ 7.54-7.48(2H,m),7.45-7.35(3H,m),5.09(1H,t,J=5.2Hz),4.36(1H,dd,J= 29.2,13.2Hz),4.04(1H,dd,J=15.3,12.9Hz),3.10-2.99(2H,m),2.46(1H,br s),2.24(3H,s),2.18-2.06(2H,m),2.01-1.58(6H,m). 1 The 1 H NMR spectrum is shown in Figure 5. 13 C NMR(400MHz,CDCl3)δ 168.4,134.8,129.0,128.7,124.7,97.5(d,J=189Hz),69.8,67.1,59.6,40.4,36.3,25.3. 13 The C NMR spectrum is shown in Figure 6. LCMS(ESI)[M+H] + 308,R t =0.66min. QCLCMS(ESI)[M+H] + 308.2, R t=2.28 min. (94.2%), purity >99% by NMR.

[0038] Example 2: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-3-hydroxy-2-phenylpropanoate [ka] 2-Methyl-2-phenylacetyl chloride To a solution of 2-methyl-2-phenylacetic acid (7.65 g, 50.94 mmol) in DCM (60 mL) at room temperature was added one drop of DMF. Oxalyl chloride (8.9 mL, 0.102 mol) was added, resulting in effervescence. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to give the title compound as a pale yellow oil (8.6 g, 100%). The material was used without purification. 1 H NMR(300MHz,CDCl3)δ 7.43-7.26(5H,m),4.12(1H, quartet, J=7.1Hz),1.60(3H,d,J=7.1Hz). 1 The 1 H NMR spectrum is shown in Figure 7. [ka]

[0039] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-2-phenylacetate To a solution of tropine (6.5 g, 45.9 mmol) in toluene (40 mL) was added 2-methyl-2-phenylacetyl chloride (8.6 g, 51.0 mmol), resulting in the formation of a precipitate. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated in vacuo, the residue was triturated with diethyl ether, and the solid was then filtered off to give a white solid. This solid was partitioned between HO and DCM, then basified to a pH greater than 10 using 1N NaOH, and the product was extracted into DCM. The combined DCM extracts were washed with HO and brine, then passed through a phase separation cartridge and concentrated in vacuo to give the title compound as a pale yellow oil (11.43 g, 81%). 1 H NMR(300MHz,CDCl3)δ 7.36-7.21(5H,m),4.96(1H,t,J=5.4Hz),3.67(1H,quartet,J=7.2Hz),3.06-2.90(2H,m),2.21(3H,s), 2.13-1.96(2H,m),1.95-1.57(4H,m),1.54-1.44(1H,m),1.51(3H,d,J=7.2Hz),1.40-1.28(1H,m). 1 The 1 H NMR spectrum is shown in Figure 8. LCMS(ESI)[M+H] + 274, R t =0.79 min. [ka]

[0040] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-3-hydroxy-2-phenylpropanoate To a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methyl-2-phenylacetate (12.4 g, 45.36 mmol) in DMF (15 mL) was added paraformaldehyde (2.04 g, 68.04 mmol). Freshly prepared sodium ethoxide (52 mg sodium in 1.0 mL ethanol) was added to this suspension, causing dissolution of the solid. The reaction mixture was stirred at room temperature for 4 hours and then partitioned between HO and DCM. The combined DCM extracts were washed with HO and brine, passed through a phase separation cartridge, and concentrated in vacuo. The resulting oil was triturated with diethyl ether, at which point the product crystallized. The solid was collected by filtration and dried in vacuo to give the title compound as a white solid (10.5 g, 76%). 1 H NMR(400MHz,CDCl3)δ 7.38-7.25(5H,m),5.06(1H,t,J=4.1Hz),4.12(1H,dd,J=8.5,4.2Hz),3.62(1H,dd,J=8.7,6.0Hz),3.04-2.89(2H,m),2.55( 1H,t,J=5.2Hz),2.19(3H,s),2.15-2.00(2H,m),1.90-1.78(1H,m),1.74-1.57(6H,m),1.50-1.43(1H,m),1.23-1.11(1H,m). 1 The 1 H NMR spectrum is shown in Figure 9. 13 C NMR (400 MHz, CDCl3) δ 175.2, 140.2, 128.6, 127.3, 126.2, 69.7, 68.0, 59.6, 59.5, 52.2, 40.4, 36.6, 36.3, 25.4, 24.9, 19.5 (the chiral center results in non-equivalence of the tropane ring carbon atoms, so 16 signals are observed instead of 13). 13 The C NMR spectrum is shown in Figure 10. LCMS(ESI)[M+H] + 304,R t =0.69min. QC LCMS (ESI [M+H] + 304.2,R t=2.38min.(98.9%)

[0041] Example 3: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-benzyl-3-hydroxy-2-phenylpropanoate [ka] 2,3-Diphenylpropanoyl chloride To a solution of 2,3-diphenylpropanoic acid (16.0 g, 70.71 mmol) in DCM (80 mL) at room temperature, DMF (0.10 mL) was added and the mixture was cooled in an ice-water bath. Oxalyl chloride (12.3 mL, 141.42 mmol) was added, causing effervescence, and the cooling bath was removed. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to give the title compound as a pale yellow oil (17.3 g, 100%). The material was used without purification. 1 H NMR(300MHz,CDCl3)δ 7.33-7.07(10H,m),3.86(1H,dd,J=7.0,8.4Hz),3.41(1H,dd,J=13.8,8.4Hz),3.03(1H,dd,J=13.8,7.0Hz). 1 The 1 H NMR spectrum is shown in Figure 11. [ka]

[0042] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-diphenylpropanoate To a solution of tropine (9.49 g, 70.71 mmol) in toluene (70 mL) was added 2,3-diphenylpropanoyl chloride (17.30 g, 70.71 mmol), causing the formation of a precipitate. The reaction mixture was stirred at reflux for 2 hours and then concentrated in vacuo. The residue was triturated with diethyl ether, and the solid was filtered off to give a white solid. This solid was partitioned between HO and DCM, basified to a pH greater than 10 using 1N NaOH solution, and the product was extracted into DCM. The DCM extract was washed with HO and brine, then passed through a phase separation cartridge and concentrated in vacuo to give the title compound as a pale yellow oil (22.4 g, 90%). 1 H NMR(300MHz,CDCl3)δ 7.35-7.11(10H,m),4.90(1H,t,J=5.4Hz),3.79(1H,dd,J=6.5,9.0Hz),3.43(1H,dd,J=13.5,9.0Hz),3.03(1H ,dd,J=13.5,6.5Hz),2.97-2.87(2H,m),2.18(3H,s),2.05-1.92(2H,m),1.85-1.65(2H,m),1.56-1.30(4H,m). 1 The 1 H NMR spectrum is shown in Figure 12. LCMS(ESI)[M+H] + 350,R t =0.98min. [ka]

[0043] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-benzyl-3-hydroxy-2-phenylpropanoate To a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-diphenylpropanoate (22.40 g, 64.10 mmol) in DMF (30 mL) was added paraformaldehyde (3.27 g, 108.96 mmol). Freshly prepared sodium ethoxide (74 mg sodium in 1.3 mL ethanol) was added to this suspension, causing dissolution of the solid. The reaction mixture was stirred at room temperature for 3 h, and then HO was added. The precipitate was filtered off, washed with HO, and dried in vacuo to remove most of the HO. The resulting "wet" solid was partitioned between MeOH and DCM, and the phases were separated. The DCM extract was dried (MgSO), filtered, and concentrated in vacuo to cause crystallization of the product. The precipitate was filtered off and dried in vacuo to give the title compound as a white solid (18.18 g, 75%). 1 H NMR(400MHz,CDCl3)δ 7.39-7.16(8H,m),7.05-6.97(2H,m),5.09(1H,t,J=5.3Hz),4.12-3.95(2H,m),3.54-3.42(2H,m),3.02 -2.90(2H,m),2.19(3H,s),2.15-2.00(2H,m),1.84-1.58(4H,m),1.54-1.41(2H,m),1.28-1.19(1H,m). 1 The 1 H NMR spectrum is shown in Figure 13. 13 C NMR (400 MHz, CDCl3) δ 173.3, 139.9, 136.7, 130.5, 128.7, 128.1, 127.4, 126.8, 126.7, 68.1, 63.9, 59.5 (x2 signals), 56.5, 40.4, 38.9, 36.5, 36.4, 25.2, 25.0 (the chiral center results in non-equivalence of the tropane ring carbon atoms, so 20 signals are observed instead of 17). 13 The C NMR spectrum is shown in Figure 14. LCMS(ESI)[M+H] + 380,R t =0.90min. QC LCMS(ESI)[M+H] + 380.3,R t=3.19 min. (99.2%)

[0044] Example 4: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate [ka] Ethyl 2-(thiophen-2-yl)propanoate To a solution of diisopropylamine (4.5 mL, 32.3 mmol) in THF (100 mL) at −40° C., n-BuLi (12.9 mL, 2.5 M, 32.3 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 20 minutes and then cooled to −78° C. Ethyl 2-(thiophen-2-yl)acetate (5 g, 29.4 mmol) was added dropwise at such a rate that the T was less than −60° C. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to 0° C. Methyl iodide (2.2 mL, 35.3 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified on silica (80 g, 0-50% ethyl acetate in cyclohexane) to afford the title compound as a pale brown oil (3.3 g, 62%). 1 H NMR(400MHz,CDCl3)δ 7.20(1H,t,J=3.4Hz),6.95(2H,d,J=3.4Hz),4.22-4.12(2H,m),3.99(1H,q,J=7.2Hz),1.58(3H,d,J=7.1Hz),1.30-1.19(3H,m). [ka]

[0045] 2-(Thiophen-2-yl)propanoic acid To a solution of ethyl 2-(thiophen-2-yl)propanoate (5.9 g, 32.39 mmol) in methanol (40 mL) and water (15 mL) was added lithium hydroxide monohydrate (2.0 g, 48.4 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to approximately one-quarter volume, and the residue was extracted with EtOAc. The organic fraction was discarded, and the aqueous layer was acidified to approximately pH 3 with 1 N HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to yield the title compound as a yellow oil (5.0 g, 100%). 1 H NMR(400MHz,d6-DMSO)δ 7.26(1H,dd,J=5.2,1.6Hz),6.89(1H,dd,J=5.1,3.5Hz),6.87-6.80(1H,m),3.74(1H,q,J=7.0Hz),1.35(3H,d,J=7.0Hz). [ka]

[0046] 2-(Thiophen-2-yl)propanoyl chloride 2-(Thiophen-2-yl)propanoic acid (2.0 g, 12.8 mmol) was dissolved in thionyl chloride (10.0 mL, 137.1 mmol), and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a brown oil (2.24 g, 100%). 1 H NMR(400MHz,CDCl3)δ 7.30(1H,dd,J=5.1,1.2Hz),7.06-6.99(2H,m),4.39(1H,q,J=7.1Hz),1.70(3H,d,J=7.1Hz). [ka]

[0047] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(thiophen-2-yl)propanoate To a solution of 2-(thiophen-2-yl)propanoyl chloride (2.2 g, 12.6 mmol) in toluene (20 mL) was added tropine (1.62 g, 11.5 mmol) and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was diluted with EtOAc and extracted with 1N HCl, and the organic fraction was discarded. The aqueous phase was basified to approximately pH 12 with 6N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a brown oil, which was used crude in the next reaction (2.29 g, 71%). LCMS (ESI) [M+H] + 280 R t =0.72 min. [ka]

[0048] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-methyl-2-(thiophen-2-yl)propanoate To a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(thiophen-2-yl)propanoate (1.3 g, 4.7 mmol) and paraformaldehyde (0.21 g, 6.9 mmol) in DMF (10 mL) was added a solution of sodium ethoxide in ethanol (0.11 mL, 21%, 0.2 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with EtOAc and extracted with 1N HCl. The organic fraction was discarded. The aqueous fraction was basified to approximately pH 12 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the title compound as an off-white solid (760 mg, 52%). 1H NMR(400MHz,CDCl3)δ 7.24(1H,dd,J=4.6,1.4Hz),7.02-6.98(2H,m),5.03(1H,t,J=5.54Hz),4.1 3(1H,d,J=11.3Hz),3.74(1H,d,J=11.3Hz),3.08-2.94(2H,m),2.58(1H,br of the title compound. 1 H NMR and 13 The C NMR spectra are shown in Figures 15A and 15B, respectively. LCMS(ESI)[M+H] + 310R t =2.40min.

[0049] Example 5: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(hydroxymethyl)-2-phenylpropanoate [ka] To a solution of atropine (3.1 g, 10.8 mmol) and paraformaldehyde (1.6 g, 54.1 mmol) in DMF (5 mL) at 0 °C was added sodium ethoxide in ethanol (0.08 mL, 21%, 0.22 mmol), and the reaction was stirred at 0 °C for 5 min and then at room temperature for 1 h. The reaction mixture was filtered through Celite, and the filtrate was purified on silica (24 g, 0-40% (2 N NH in MeOH) in DCM). Half of the resulting material was repurified on C18 silica (50 g, 0-50% 0.02 M NH in MeCN) to give the title compound as an off-white solid (1.19 g, 67%). 1H NMR(400MHz,d6-DMSO)δ 7.35-7.27(2H,m),7.26-7.14(3H,m),4.88(1H,t,J=5.1Hz),4.74(1H,t,J=4.62Hz),4.06(2H,dd,J=10.2,4.9Hz),3.97(2H,dd,J=10.2,4 .7Hz),3.35(1H,s),2.92-2.83(2H,m),2.07(3H,s),1.92(2H,dt,J=14.4,4.1Hz),1.75-1.60(2H,m),1.50-1.36(4H,m).LCMS(ESI)[M+H] + 320R t =1.96 min. of the title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 16A and 16B, respectively.

[0050] Example 6: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(hydroxymethyl)-2-phenylbutanoate [ka] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-phenylbutanoate To a solution of 2-phenylbutyric acid (2.0 g, 12.2 mmol) in DCM (20 mL) at 0 °C, oxalyl chloride (2.1 mL, 24.4 mmol) and DMF (0.06 mL, 0.7 mmol) were added. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in toluene (10 mL). This solution was added to a solution of tropine (1.7 g, 12.18 mmol) in toluene (20 mL), and the reaction mixture was stirred at room temperature for 10 minutes and then at reflux for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was collected by filtration and washed with diethyl ether. The solid was dissolved in 1 N NaOH and extracted with DCM. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the title compound as a colorless oil (1.76 g, 50%).1 H NMR(400MHz,CDCl3)δ 7.35-7.21(5H,m),4.96(1H,t,J=5.1Hz),3.41,(1H,t,J=7.8Hz),3.06-2.91(2H,m),2.21(3H,s),2.18-1. 97(3H,m),1.94-1.70(4H,m),1.67-1.59(1H,m),1.52-1.36(2H,m),0.91(3H,t,J=7.4Hz).LCMS(ESI)[M+H] + 288 R t =0.84min. [ka]

[0051] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(hydroxymethyl)-2-phenylbutanoate To a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-phenylbutanoate (1.8 g, 6.1 mmol) and paraformaldehyde (0.28 g, 9.2 mmol) in DMF (6 mL) was added a solution of sodium ethoxide in ethanol (0.11 mL, 21%, 0.2 mmol), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and extracted with 1N HCl, and the organic fraction was discarded. The aqueous fraction was basified to approximately pH 12 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo. The residue was purified on silica (50 g, 0–18% (2N NH in MeOH in DCM) to give the title compound as an off-white solid (1.56 g, 80%). 1H NMR(400MHz,CDCl3)δ 7.38-7.21(5H,m),5.07(1H,t,J=5.32Hz),4.12(1H,d,J=11.1Hz),3.99(1H,d,J=11.1Hz),3.02-2.88(2H,m),2.57(1H,br s),2.28-1.99(7H,m),1.86-1.64(2H,m),1.61-1.43(3H,m),1.29-1.20(1H,m),0.94(3H,t,J=7.6Hz).LCMS(ESI)[M+H] + 318 R t =2.71 min. of the title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 17A and 17B, respectively.

[0052] Example 7: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate [ka] Methyl 3-cyclopropyl-2-phenylpropanoate To a solution of methyl 2-phenylacetate (2 g, 13.3 mmol) in THF (50 mL) at −78°C, LDA (7.3 mL, 2 M, 14.6 mmol) was added at a rate such that the T was less than −60°C. The reaction mixture was stirred at −78°C for 1 h. (Iodomethyl)cyclopropane (5 g, 27.5 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at −78°C for 30 min, then warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified on silica (40 g, 0–100% DCM in cyclohexane) to give the title compound as a yellow oil (2.6 g, 95%). 1H NMR(400MHz,CDCl3)δ 7.35-7.20(5H,m),3.71-3.64(4H,m),1.94-1.84(1H,m),1.78-1.69(1H,m),0.67-0.56(1H,m),0.46-0.34(2H,m),0.13-0.00(2H,m). [ka]

[0053] 3-Cyclopropyl-2-phenylpropanoic acid To a solution of methyl 3-cyclopropyl-2-phenylpropanoate (2.59 g, 12.7 mmol) in methanol (100 mL) and water (15 mL) was added lithium hydroxide monohydrate (1.33 g, 31.7 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to approximately one-quarter volume, diluted with 1 N HCl to approximately pH 1, and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the title compound as a yellow oil (2.44 g, 100%). 1 H NMR(400MHz,CDCl3)δ 7.37-7.21(5H,m),3.67(1H,t,J=8.0Hz),1.97-1.87(1H,m),1.79-1.69(1H,m),0.69-0.58(1H,m),0.47-0.38(2H,m),0.15-0.00(2H,m). [ka]

[0054] 3-Cyclopropyl-2-phenylpropanoyl chloride To a solution of 3-cyclopropyl-2-phenylpropanoic acid (2.44 g, 12.8 mmol) in DCM (100 mL) was added DMF (0.01 mL) and oxalyl chloride (1.7 mL, 19.2 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound as a pale yellow oil (2.68 g, 100%), which was used without purification. 1H NMR(400MHz,CDCl3)δ 7.41-7.27(5H,m),4.10(1H,t,J=7.3Hz),2.06-1.95(1H,m),1.86-1.77(1H,m),0.70-0.58(1H,m),0.52-0.38(2H,m),0.18-0.02(2H,m). [ka]

[0055] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-phenylpropanoate To a solution of tropine (2.68 g, 18.9 mmol) in toluene (20 mL) was added 3-cyclopropyl-2-phenylpropanoyl chloride (4.36 g, 20.8 mmol), and the reaction mixture was heated to reflux for 1.5 hours. The reaction mixture was extracted with 1 N HCl, and the organic fraction was discarded. The aqueous fraction was basified to approximately pH 12 with 6 N NaOH and extracted with ethyl acatatate. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (1.76 g, 50%). 1 H NMR(400MHz,CDCl3)δ 7.35-7.20(5H,m),4.96(1H,t,J=5.2Hz),3.63(1H,t,J=7.4Hz),3.06-2.91(2H,m),2.22(3H,s),2.14-1.83(4H,m) ,1.82-1.70(3H,m),1.68-1.60(1H,m),1.52-1.38(2H,m),0.68-0.58(1H,m),0.47-0.35(2H,m),0.14-0.01(2H,m). [ka]

[0056] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-(hydroxymethyl)-2-phenylpropanoate To a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-cyclopropyl-2-phenylpropanoate (1.76 g, 5.62 mmol) and paraformaldehyde (0.25 g, 8.42 mmol) in DMF, sodium ethoxide in ethanol (0.07 mL, 4 M, 1.12 mmol) was added, and the reaction mixture was stirred at 40 °C for 3 hours. An additional portion of sodium ethoxide (0.07 mL, 4 M, 1.12 mmol) was added, and the reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was diluted with EtOAc and extracted with 1 N HCl. The organic fraction was discarded, and the aqueous fraction was basified to approximately pH 12 with 6 N NaOH. The mixture was extracted with EtOAc, and the combined organic fractions were washed with brine, dried (MgSO ), and concentrated in vacuo. The resulting residue was purified on silica (40 g, 0-10% (7N NH3 in MeOH) in DCM) to afford the title compound as an off-white solid (0.23 g, 12%). 1 H NMR(400MHz,CDCl3)δ 7.39-7.22(5H,m),5.08(1H,t,J=5.48Hz),4.31-4.19(2H,m),3.04-2.92(2H,m),2.20(3H,s),2.15-2.03(3H,m),1.87-1. 65(3H,m),1.64-1.47(4H,m),1.31-1.20(1H,m),0.69-0.57(1H,m),0.52-0.39(2H,m),0.21-0.07(2H,m).LCMS(ESI)[M+H] + 344 R t =2.82 min. of the title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 18A and 18B, respectively.

[0057] Example 8: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-fluoro-2-methyl-2-phenylpropanoate [ka] To a solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-methyl-2-phenylpropanoate (392 mg, 1.29 mmol) in DCM at 0 °C, DAST (0.51 mL, 3.9 mmol) was added, and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with saturated aqueous Na2CO3 and extracted with DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified on silica (4 g, 0-12% (2N NH3 in MeOH) in DCM). The resulting residue was then purified by SFC (YMC Amylose-C, 15% MeOH + 0.1% Et2NH) to give the title compound as a pale yellow oil (26 mg, 6%). 1 H NMR(400MHz,CDCl3)δ 7.39-7.27(5H,m),5.06(1H,t,J=5.4Hz),4.97(1H,dd,J=47.0,8.7Hz),4.55(1H,dd,J=47.0,8.7Hz),3.05-2.94(2 H,m),2.21(3H,s),2.14-2.01(2H,m),1.91-1.73(2H,m),1.72(3H,d,J=2.1Hz),1.66-1.49(4H,m).LCMS(ESI)[M+H] + 306 R t =3.10 min. of the title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 19A and 19B, respectively.

[0058] Example 9: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate [ka] 4,4,4-trifluoro-2-phenylbutanoyl chloride To a solution of 4,4,4-trifluoro-2-phenylbutanoic acid (410 mg, 1.9 mmol) and DMF (0.1 mL) in DCM (25 mL) at 0° C., oxalyl chloride (0.33 mL, 3.8 mmol) was added and the reaction was stirred at 0° C. for 1 h and then at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give the product as a yellow oil (445 mg, 100%). 1 H NMR(400MHz,CDCl3)δ 7.47-7.36(3H,m),7.33-7.27(2H,m),4.29(1H,dd,J=10.2,7.3Hz),3.24-3.05(1H,m),2.65-2.46(1H,m). [ka]

[0059] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-phenylbutanoate To a solution of tropine (236 mg, 1.7 mmol) in toluene (7 mL), 4,4,4-trifluoro-2-phenylbutanoyl chloride (445 mg, 1.9 mmol) in toluene (3 mL) was added, and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was triturated with diethyl ether. The solid was dissolved in 1N NaOH and extracted with DCM. The combined organic fractions were washed with brine, dried (NaSO), and concentrated in vacuo to give the title compound as a yellow solid (390 mg, 61%). 1 H NMR(400MHz,CDCl3)δ 7.40-7.24(5H,m),4.97(1H,t,J=5.5Hz),3.83(1H,dd,J=8.7,5.4Hz),3.21-3.07(1H,m),3.07-3.02(1H,m),2.95-2.89(1H,m),2.57-2. 42(1H,m),2.21(3H,s),2.14-2.05(1H,m),2.05-1.85(2H,m),1.81-1.57(3H,m),1.46-1.39(1H,m),1.30-1.20(1H,m).LCMS(ESI)[M+H] + 342 Rt =0.88min. [ka]

[0060] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-(hydroxymethyl)-2-phenylbutanoate To a suspension of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 4,4,4-trifluoro-2-phenylbutanoate (390 mg, 1.1 mmol) and paraformaldehyde (51 mg, 1.7 mmol) in DMF (3 mL) was added sodium ethoxide in ethanol (0.3 mL, 0.2 M, 0.06 mmol), and the reaction was stirred at room temperature for 2 hours. Additional paraformaldehyde (40 mg, 1.3 mmol) and sodium ethoxide in ethanol (0.15 mL, 1.5 M, 0.2 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with DCM, and the combined organic fractions were washed with brine, dried (NaSO), and concentrated in vacuo. The resulting residue was purified on silica (12 g, 0-10% (2N NH3 in MeOH) in DCM) to give the title compound as a white solid (105 mg, 24%). 1 H NMR(400MHz,CDCl3)δ 7.44-7.23(5H,m),5.09(1H,t,J=5.4Hz),4.31(2H,br s),3.17-3.03(2H,m),3.02-2.93(2H,m),2.19(3H,s),2.12-2.03(2H,m), 1.88-1.69(3H,m),1.64-1.48(2H,m),1.42-1.23(2H,m).LCMS(ESI)[M+H] + 372 R t =2.95 min. 1 H NMR and 13 The C NMR spectra are shown in Figures 20A and 20B, respectively.

[0061] Example 10: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydroxy-2-phenylpropanoate [ka] A solution of AD-mix-α (1.3 g) in a mixture of water (5.0 mL) and tert-butanol (5 mL) was stirred at room temperature for 15 minutes to give a clear yellow solution, which was cooled to approximately 0 °C in an ice-water bath. A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-phenylacrylate (250 mg, 0.921 mmol) in tert-butanol (1.0 mL) was added, and the resulting solution was stirred at 0 °C for 3 hours and then allowed to warm to room temperature overnight. The reaction mixture was treated with excess NaSO and then partitioned between water and DCM. The aqueous layer was separated and further extracted with DCM, and the combined organic extracts were washed with brine, dried (NaSO), and concentrated in vacuo. The resulting residue was purified on silica (12 g, 0–10% in DCM (2N NH in MeOH)) to give enantiomerically enriched (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydroxy-2-phenylpropanoate as a gum (110 mg, 39%).

[0062] In another procedure, a solution of AD-mix-β (1.3 g) in a mixture of water (5.0 mL) and tert-butanol (5 mL) was stirred at room temperature for 15 minutes to give a clear yellow solution, which was cooled to approximately 0 °C in an ice-water bath. A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-phenylacrylate (250 mg, 0.921 mmol) in tert-butanol (1.0 mL) was added, and the resulting solution was stirred at 0 °C for 3 hours and then allowed to warm to room temperature overnight. The reaction mixture was treated with excess NaSO and partitioned between water and DCM. The aqueous layer was separated and further extracted with DCM, and the combined organic extracts were washed with brine, dried (NaSO), and concentrated in vacuo. The resulting residue was purified on silica (12 g, 0–10% in DCM (2N NH in MeOH)) to give the opposite enantiomerically enriched (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2,3-dihydroxy-2-phenylpropanoate as a gum (126 mg, 45%).

[0063] A portion of the AD-mix-α reaction product (95 mg, 0.311 mmol) was dissolved in acetonitrile (1 mL) to give a clear solution. Similarly, a portion of the AD-mix-β reaction product (95 mg, 0.311 mmol) was dissolved in acetonitrile (1 mL) to give a clear solution. The two solutions enriched with the opposite enantiomers were then combined, diluted with water (2 mL), and lyophilized to give the racemic title compound as a white solid (190 mg). 1 H NMR(400MHz,CDCl3)δ 7.60-7.53(2H,m),7.42-7.30(3H,m),5.06(1H,t,J=5.5Hz),4.32(1H,d,J=11.5Hz),4.16(1H,br s),3.82(1H,d,J=11.5Hz),3.13-3.03(2H,m),2.41(1H,br s),2.26(3H,s),2.20-2.07(2H,m),2.06-1.88(3H,m),1.84-1.76(1H,m),1.71-1.1.53(2H,m).LCMS(ESI)[M+H]+ 306.2 R t =1.97 min. of the title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 21A and 21B, respectively.

[0064] Example 11: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate [ka] tert-Butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate A stirred solution of nortropine (12.72 g, 100 mmol) in DCM (150 mL) was treated with triethylamine (27.9 mL, 20.24 g, 200 mmol) and cooled in ice. Solid di-tert-butyl dicarbonate (32.74 g, 150.0 mmol) was then added over 10 min, and the addition vessel was rinsed with DCM (50 mL). Vigorous gas evolution was observed, and the resulting mixture was stirred for 2 h while warming to room temperature, then for 16 h at room temperature. The resulting mixture was diluted with DCM (100 mL), washed with 10% citric acid (aqueous) solution, brine (50 mL), and the layers were separated. The combined organic fractions were dried (NaSO), filtered, and concentrated in vacuo to give a cream-colored solid. The solid residue was triturated with diethyl ether (30 mL) and sonicated to give a free-flowing solid that was collected by filtration, 19.67 g (86%). 1 H NMR(400MHz,CDCl3)δ 4.29-4.06(3H,m),2.26-1.87(6H,m),1.75-1.65(2H,m),1.55(1H,d,J=1.5Hz),1.45(9H,s).LCMS(ESI)[M+H] + Not observed, R t =1.21min. [ka]

[0065] tert-Butyl (1R,3r,5S)-3-((2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate A solution of 2-phenylpropionyl chloride (8.20 g, 48.63 mmol) in toluene (50 mL) was added to a stirred mixture of tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (10.05 g, 44.21 mmol) and triethylamine (12.3 mL, 8.95 g, 88.42 mmol) in toluene (50 mL). The resulting suspension was heated to reflux with vigorous stirring for 24 h to give the product as an off-white suspension. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL) and HO (100 mL). The aqueous layer was separated and further extracted with EtOAc (2 × 100 mL). The combined extracts were washed with 5% citric acid (aq) solution, saturated NaHCO3 (aq), and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (16.21 g, 102%). 1 H NMR(400MHz,CDCl3)δ 7.37-7.22(5H,m),5.06(1H,t,J=5Hz),4.24-3.90(2H,m),3.68(1H,q,J=7Hz),2.23-1.90(2H,m),1.86 -1.57(5H,m),1.54-1.46(1H,m),1.52(3H,d,J=7Hz),1.43(9H,s),1.38-1.27(1H,m).LCMS(ESI)[M+H] + Not observed R t =1.98min. [ka]

[0066] tert-Butyl (1R,3r,5S)-3-((3-hydroxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate A stirred slurry of tert-butyl (1R,3r,5S)-3-((2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.19 g, 20.0 mmol) in DMF (15 mL) was treated with paraformaldehyde (0.90 g, 30 mmol), followed by 21% sodium ethoxide solution (0.37 mL, 1.00 mmol) and stirred at room temperature for 18 h. A second portion of 21% sodium ethoxide solution (0.37 mL, 1.00 mmol) was added and stirring continued for an additional 2 h. LCMS showed shifted peaks but no mass ions. The reaction mixture was diluted with DCM (200 mL) and washed with water and brine. The organic layer was separated, dried (NaSO), filtered, and concentrated in vacuo to give the crude product as a yellow oil. The residue was purified on silica (120 g, 0-50% EtOAc in cyclohexane) to give the title compound as a white solid, (5.29 g, 68%). 1 H NMR(400MHz,CDCl3)δ 7.39-7.24(5H,m),5.16(1H,t,J=5Hz),4.14(1H,dd,J=6,11Hz),4.19-3.89(2H,m),3.62(1H,dd,J=8,11Hz),2.43(1H,dd,J=6,8 Hz),2.29-1.91(2H,m),1.84-1.70(1H,m),1.70(3H,s),1.70-1.46(4H,m),1.43(9H,s),1.25-1.08(1H,m).LCMS(ESI)[M+H-Boc] + 290,R t =1.60min. [ka]

[0067] tert-Butyl (1R,3r,5S)-3-((3-methoxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate A stirred suspension of sodium hydride (0.24 g, 60%, 6.01 mmol) in dry THF (10 mL) was cooled to 0 °C, and a solution of tert-butyl (1R,3r,5S)-3-((3-hydroxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.95 g, 5.01 mmol) in dry THF (10 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h, then the reaction mixture was cooled to -6 °C, and methyl iodide (0.34 mL, 5.5 mmol) was added. The mixture was allowed to warm slowly to room temperature over 3 h. The reaction mixture was quenched by the addition of aqueous NH4Cl (20 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified on silica (80 g, 0-25% EtOAc in cyclohexane) to give the title compound as a colorless syrup (1.54 g, 76%). 1 H NMR(400MHz,CDCl3)δ 7.37-7.21(5H,m),5.12(1H,t,J=5.3Hz),4.19-3.94(2H,m),3.99(1H,d,J=8.7Hz),3.62(1H,d,J=8.7Hz),3.387 (3H,s),2.23-1.93(2H,m),1.80-1.66(2H,m),1.65(3H,s),1.62-1.45(4H,m),1.43(9H,s).LCMS(ESI)[M+H-Boc] + 304,R t =1.81min. [ka]

[0068] (1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate hydrochloride To a stirred solution of tert-butyl (1R,3r,5S)-3-((3-methoxy-2-methyl-2-phenylpropanoyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.10 g, 2.73 mmol) in dioxane (2.0 mL) was added 4N HCl in dioxane (2.0 mL), and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to give the crude product as a colorless syrup (1.18 g, 100%), which was used without purification. 1 H NMR(400MHz,CDCl3)δ 9.47(2H,br s), 7.38-7.21(5H,m),5.10(1H,t,J=4.5Hz),3.99(1H,d,J=8.7Hz),3.93-3.83(2H,m),3.60(1H, d,J=8.7Hz),3.37(3H,s),2.59-2.45(2H,m),2.04-1.54(6H,m),1.64(3H,s).LCMS(ESI)[M+H] + 304,R t =1.52 min. [ka]

[0069] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate Crude (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-methoxy-2-methyl-2-phenylpropanoate hydrochloride (1.18 g, 2.73 mmol) was dissolved in formic acid (4.0 mL) and treated with 37% formaldehyde solution (0.81 mL, 10.9 mmol), and the reaction mixture was heated at reflux for 17 hours. The reaction mixture was cooled to room temperature and loaded onto an SCX-2 cartridge (50 g) pre-wetted with DCM. The cartridge was washed with DCM (400 mL), MeOH (200 mL), and the product was eluted with 2M NH3 in MeOH (200 mL). The basic eluent was concentrated in vacuo, and the residue was purified by HPLC on a Kinetix Axia C18 RP column (long) using 5-50% CH3CN in HO (0.1% HCOOH) at 18 mL / min over a 10 min ramp with UV at 194 nm. Relevant fractions were combined and lyophilized to give the product as a colorless syrup (415 mg, 48%) containing 0.75 equivalents of formate and 0.25 equivalents of DCM. 1 H NMR(400MHz,CDCl3)δ 7.37-7.24(5H,m),5.09(1H,t,J=5.1Hz),3.99(1H,d,J=8.7Hz),3.62(1H,d,J=8.7Hz),3.49-3.42(2H,m),3.3 8(3H,s),2.65-2.50(2H,m),2.50(3H,s),1.933-1.84(2H,m),1.74-1.60(4H,m),1.64(3H,s).LCMS(ESI)[M+H] + 318.3,R t =3.05 min. 1 H NMR and 13 The C NMR spectra are shown in Figures 22A and 22B, respectively.

[0070] Example 12: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate [ka] Methyl 3-(4-methoxyphenyl)-2-phenylpropanoate Potassium tert-butoxide (2.15 g, 19.16 mmol) was added to a stirred solution of methyl phenyl acetate (2.00 g, 13.32 mmol) in dry THF (20 mL) at 0 °C. After stirring for 15 min, a solution of 4-methoxybenzyl bromide in dry THF (10 mL) was added dropwise, keeping the temperature below 5 °C. The resulting mixture was stirred for 10 min and then allowed to warm to room temperature overnight. The resulting mixture was diluted with EtOAc (150 mL), washed with HO (50 mL), then brine (50 mL), and the layers were separated. The organic layer was dried (NaSO) and concentrated in vacuo. The residue was purified on silica (25 g) with 0–50% EtOAc in cyclohexane to give the title compound as a pale yellow oil (1.0 g, 27%), which was used impure without further purification. 1 H NMR(400MHz,CDCl3)δ7.30(4H,d,J=4.2Hz),7.26(1H,m),7.03(2H,m),6.77(2H,m),4.06(1H,m),3.76(6H,s),3.34(1H,m),2.96(1H,m). [ka]

[0071] 3-(4-Methoxyphenyl)-2-phenylpropanoic acid Methyl 3-(4-methoxyphenyl)-2-phenylpropanoate (1.1 g, 4.07 mmol) in THF (20 mL) and MeOH (5 mL) at room temperature was treated with 2N NaOH (aq) (4 mL, 8.0 mmol) and stirred for 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with HO (60 mL) and washed with EtOAc. The aqueous fraction was acidified to pH 1.0 with 1N HCl and extracted with EtOAc. The combined organic fractions were dried (MgSO) and concentrated in vacuo to give the crude product as a colorless oil that crystallized on standing (881 mg 84%). LCMS R t =1.28 min,255.1(MH)- Used without purification. 1 H NMR(400MHz,CDCl3)δ 7.32-7.26(5H,d,m),7.03(2H,m),6.77(2H,m),3.82(1H,dd,J=6.9,8.5Hz),3.76(3H,s),3.35(1H,dd,J=6.96,14.7Hz). [ka]

[0072] 3-(4-Methoxyphenyl)-2-phenylpropanoyl chloride A stirred solution of 3-(4-methoxyphenyl)-2-phenylpropanoic acid (450 mg, 1.76 mmol) in DCM (5.0 mL) containing DMF (10 μL) was treated dropwise with oxalyl chloride (200 μL, 2.29 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes and then allowed to warm to room temperature and stir for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was azeotroped with toluene (2×10 mL) to give the crude title compound (483 mg, 100%). It was used immediately without purification. [ka]

[0073] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-methoxyphenyl)-2-phenylpropanoate Crude 3-(4-methoxyphenyl)-2-phenylpropanoyl chloride (483 mg, 1.76 mmol) was stirred with tropine (248 mg, 1.76 mmol) in dry toluene (5 mL) at 100 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was treated with DCM (30 mL) and HO (20 mL) and basified to pH 10 with 1 N NaOH (aq). The organic layer was separated, washed with brine, dried (MgSO), and concentrated in vacuo. The resulting residue was purified on silica (12 g 0-10% MeOH in DCM) to give the title compound as a light brown oil (277 mg, 41%). 1 H NMR(400MHz,CDCl3)d 7.31-7.26(m,5H),7.07-7.04(m,2H),6.80-6.75(m,2H),4.91(dd,J=5.2,5.2Hz,1H),3.77-3.76(m,3H),3.37(dd,J=9.0,13 .8Hz,1H),3.06-2.94(m,3H),2.25(s,3H),2.16-2.10(m,2H),1.84-1.72(m,2H),1.60-1.48(m,4H),1.42-1.35(m,1H).LCMS 0.99min,380.1(M+H) + . [ka]

[0074] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate 1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-methoxyphenyl)-2-phenylpropanoate (200 mg, 0.53 mmol) in DMF (3 mL) was treated with paraformaldehyde (160 mg, 5.33 mmol), followed by 21% sodium ethoxide solution (4 μL, 0.05 mmol), and the reaction mixture was stirred at 50 °C for 24 h. The reaction mixture was diluted with DCM (15 mL) and filtered through Celite. The filtrate was concentrated to a low volume in vacuo and purified on silica (12 g, 0-10% MeOH in DCM) to give the title compound as a white solid (187 mg, 86%). 1 H NMR(400MHz,CDCl3)7.37-7.33(2H,m),7.26(3H,s),6.96-6.90(2H,m),6.76-6.71(2H,m),5.09(1H,dd,J=5.3,5.3Hz),4.08-3.96(2H, LCMS 3.30min,410.0(M+H) + .The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 23A and 23B, respectively.

[0075] Example 13: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate [ka] 3-(4-chlorophenyl)-2-phenylpropanoic acid n-Butyllithium (2.5 M in hexane, 15.3 mL, 38.3 mmol) was added dropwise to a cooled solution of N,N-diisopropylamine (5.6 mL, 40.0 mmol) in dry THF (20 mL) under a nitrogen atmosphere, maintaining the temperature below 0°C. The resulting LDA solution was stirred for 20 minutes and then cooled to −78°C in a dry ice / acetone bath. A solution of methyl phenyl acetate (5.0 g, 33.3 mmol) in dry THF (20 mL) was added dropwise via syringe, maintaining the temperature below −55°C. After stirring for 2 hours, a solution of 4-chlorobenzyl chloride (4.8 mL, 36.6 mmol) in dry THF (10 mL) was added, and the resulting mixture was stirred overnight while warming to room temperature. The mixture was diluted with EtOAc (100 mL) and water (50 mL), and the aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo, and the residue was dissolved in a mixture of methanol (20 mL) and THF (100 mL), and aqueous sodium hydroxide (2 M, 35 mL, 70 mmol) was added. The resulting cloudy solution was stirred for 22 h and then concentrated in vacuo. The residue was partitioned between hydrochloric acid (1 N, 50 mL) and EtOAc (100 mL). The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to give the title compound as an off-white solid (8.62 g, 99%). 1 H NMR(400MHz,CDCl3):δ 7.35-7.24(5H,m),7.21-7.15(2H,m),7.04-6.98(2H,m),3.80(1H,dd,J=7.5,8Hz),3.36(1H,dd,J=8,13.9Hz),3.0(1H,dd,J=7,13.9Hz). [ka]

[0076] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-chlorophenyl)-2-phenylpropanoate A stirred solution of 3-(4-chlorophenyl)-2-phenylpropanoic acid (3.30 g, 12.7 mmol) in DCM (30 mL) containing DMF (45 μL) was treated dropwise with oxalyl chloride (2.2 mL, 25.3 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes, then allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was azeotroped with toluene (20 mL) to give crude 3-(4-chlorophenyl)-2-phenylpropanoyl chloride, which was dissolved in dry toluene (50 mL). Tropine (1.62 g, 11.51 mmol) and triethylamine (4.8 mL, 34.52 mmol) were added, and the mixture was stirred at 100 °C for 4 hours, cooled to room temperature, and stirred overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO 3 , water, brine, dried (Na 2 SO 4 ), and concentrated in vacuo. The residue was purified by chromatography on silica (80 g, 0-10% (2M NH in MeOH) gradient in DCM) to give the pure title compound as a viscous orange oil (2.24 g, 50%). A second crop of impure title compound (0.54 g, 12%) was also isolated as a brown oil. 1 H NMR (400 MHz, CDCl): δ 7.35-7.23(5H,m),7.22-7.16(2H,m),7.09-7.02(2H,m),4.90(1H,t,J=5.4Hz ),3.73(1H,dd,J=6.9,8.7Hz),3.39(1H,dd,J=8.7,13.8Hz),3.00(1H,dd,J=6. 9,13.8Hz),2.99-2.94(1H,m),2.96-2.88(1H,m),2.18(3H,s),2.07-1.94(2H ,m),1.86-1.64(2H,m),1.56-1.41(3H,m),1.34-1.25(1H,m);LCMS(ESI)[M+H] + 384.1. [ka]

[0077] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-chlorobenzyl)-2-phenylpropanoate A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-chlorophenyl)-2-phenylpropanoate (2.22 g, 5.78 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.26 g, 8.7 mmol). A 21% solution of sodium ethoxide in ethanol (0.29 mL, 0.6 mmol) was added, and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water (50 mL) and EtOAc (100 mL), and the aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with 5% w / w aqueous lithium chloride solution (2 × 25 mL), brine, dried (NaSO), and filtered through a plug of Celite. The solution was concentrated in vacuo and the residue was purified on silica (40 g, 0.5-10% (2M NH3 in MeOH) in DCM) to give the title compound as a white solid (0.86 g, 36%). 1 H NMR(400MHz,d6-DMSO):δ 7.35-7.27(2H,m),7.27-7.21(1H,m),7.20-7.14(2H,m),7.09-7.01(2H,m),6.88-6.79(2H,m),5.14(1H,broad t,J=4Hz),4.90(1H,t,J=4.8Hz),3.98(1H,dd,J=4.2,10Hz),3.74(1H,dd,J=3.8,10Hz),3.36(1H,d,J=13Hz),3.23(1H,d,J=13H z),2.90-2.84(1H,m),3.84-2.78(1H,m),2.06(3H,s),1.99-1.87(2H,m),1.72-1.27(5H,m),1.13-1.03(1H,m);LCMS(ESI)[M+H] + 414.2. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 24A and 24B, respectively.

[0078] Example 14: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate [ka] 3-(2-chlorophenyl)-2-phenylpropanoic acid n-Butyllithium (2.5 M in hexane, 15.3 mL, 38.3 mmol) was added dropwise to a cooled solution of N,N-diisopropylamine (5.6 mL, 39.95 mmol) in dry THF (20 mL) under a nitrogen atmosphere, maintaining the temperature below 0°C. The resulting LDA solution was stirred for 20 minutes and then cooled to −74°C in a dry ice / acetone bath. A solution of methyl phenyl acetate (5.0 g, 33.3 mmol) in dry THF (20 mL) was added dropwise via syringe, maintaining the temperature below −55°C. After stirring for 1 hour, a solution of 2-chlorobenzyl chloride (4.8 mL, 36.6 mmol) in dry THF (10 mL) was added, and the resulting mixture was stirred overnight while warming to room temperature. The mixture was diluted with EtOAc (50 mL) and saturated aqueous ammonium chloride (10 mL). The organic layer was separated, washed with brine, dried (NaSO), and concentrated in vacuo to give crude methyl 3-(2-chlorophenyl)-2-phenylpropanoate as an orange syrup. This was dissolved in a mixture of methanol (60 mL) and water (20 mL), and lithium hydroxide (0.80 g, 33.29 mmol) was added. The resulting cloudy solution was stirred for 40 hours and then concentrated in vacuo to give an orange aqueous solution, which was diluted with hydrochloric acid (1 M, 20 mL), water (30 mL), and EtOAc (100 mL). The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (NaSO), and concentrated in vacuo to give the title compound as a mixture with unreacted methyl 3-(2-chlorophenyl)-2-phenylpropanoate. The mixture was redissolved in THF (50 mL), methanol (10 mL), and aqueous sodium hydroxide (2 M, 17 mL, 34 mmol), and the resulting cloudy solution was stirred at room temperature overnight. The solvent was concentrated in vacuo, and the residue was partitioned between water (50 mL), hydrochloric acid (1 M, 50 mL), and EtOAc (100 mL). The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to give the title compound as an off-white solid (4.10 g, 94%). 1H NMR(400MHz,CDCl3):δ 7.35-7.24(6H,m),7.16-7.08(1H,m),7.07-7.03(2H,m),4.00(1H,dd,J=6.7,8.5Hz),3.49(1H,dd,J=8.5,13.8Hz),3.15(1H,dd,J=6.7,13.8Hz). [ka]

[0079] 1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(2-chlorophenyl)-2-phenylpropanoate A stirred solution of 3-(2-chlorophenyl)-2-phenylpropanoic acid (3.30 g, 12.7 mmol) in DCM (30 mL) containing DMF (45 μL) was treated with oxalyl chloride (2.2 mL, 25.3 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the crude product was azeotroped with toluene (20 mL). The residue was dissolved in dry toluene (50 mL), tropine (1.62 g, 11.5 mmol) and triethylamine (4.8 mL, 34.5 mmol) were added, and the mixture was stirred at 110° C. for 4 hours, cooled to room temperature, and stirred overnight. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated NaHCO, water, brine, dried (NaSO), and concentrated in vacuo. The residue was purified on silica (120 g, 0-10% (2M NH3 in MeOH) in DCM) to give the pure title compound as a viscous orange oil (3.26 g, 73%). 1 H NMR(400MHz,CDCl3)δ 7.37-7.22(6H,m),7.16-7.04(3H,m),4.91(1H,t,J=5.4Hz),3.95(1H,dd,J=6.5,9Hz),3.51(1H,dd,J=9,13.5Hz),3.16(1H,dd,J=6.5, 13.5Hz),2.97-2.88(2H,m),2.18(3H,s),2.05-1.94(2H,m),1.86-1.63(2H,m),1.55-1.40(3H,m),1.35-1.26(1H,m);LCMS(ESI)[M+H]+ 384.1. [ka]

[0080] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(2-chlorobenzyl)-2-phenylpropanoate A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(2-chlorophenyl)-2-phenylpropanoate (1.92 g, 5.0 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.23 g, 7.5 mmol). A 21% solution of sodium ethoxide in ethanol (0.25 mL, 0.5 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours and then heated to 45°C overnight. A second portion of paraformaldehyde (0.23 g, 7.5 mmol) and a 21% solution of sodium ethoxide in ethanol (0.25 mL, 0.5 mmol) were added, and the mixture was stirred at 45°C for 4.5 hours and then at 80°C for 1.5 hours. Heating was stopped, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and EtOAc (100 mL), and the aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with 5% w / w aqueous lithium chloride solution (2 × 25 mL), brine, dried (NaSO), filtered through Celite, and concentrated in vacuo. The residue was purified on silica [40 g, 0.5-10% (2M NH in MeOH)] in DCM to give the title compound as a white solid (1.0 g, 48%). 1H NMR(400MHz,d6-DMSO):δ 7.26-7.18(4H,m),7.17-7.10(3H,m),6.99-6.91(2H,m),5.21(1H,broad t,J=4Hz),4.99(1H,t,J=5.2Hz),4.06-3.94(2H,m),3.51(1H,d,J=14Hz),3.46(1H,d,J=14Hz),2.93-2.87(1H,m),2.86-2.79(1H ,m),2.07(3H,s),2.03-1.89(2H,m),1.76-1.62(1H,m),1.62-1.49(3H,m),1.42-1.33(1H,m),1.22-1.10(1H,m);LCMS(ESI)[M+H] + 414.2. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 25A and 25B, respectively.

[0081] Example 15: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate formate [ka] 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoic acid tert-Butyldimethylchlorosilane (3.16 g, 21.0 mmol) was added to a stirred solution of 3-(4-hydroxyphenyl)-2-phenylpropanoic acid (2.42 g, 10.0 mmol) and imidazole (2.04 g, 29.97 mmol) in dry DMF (40 mL), and the resulting mixture was stirred at room temperature overnight. An additional portion of tert-butyldimethylchlorosilane (0.75 g, 5.0 mmol) was added, and stirring was continued for 2 h. The reaction mixture was diluted with EtOAc, washed with water, saturated aqueous lithium chloride solution, and brine, dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil. The oil was dissolved in methanol (40 mL), potassium carbonate (1.52 g, 11.0 mmol) was added, and the resulting suspension was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and DCM. The aqueous phase was acidified to pH 3 by careful addition of 1 M hydrochloric acid. The aqueous layer was separated and further extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to give the crude title compound as a pale yellow oil. This was purified by silica chromatography (80 g, 0-20% EtOAc gradient in DCM) to give the title compound as a pale yellow oil (1.58 g, 44%). 1 H NMR(400MHz,CDCl3):δ 7.32-7.22(5H,m),6.95-6.89(2H,m),6.71-6.64(2H,m),3.79(1H,apparent t,J=8Hz),3 .32(1H,dd,J=8.2,13.9Hz),2.95(1H,dd,J=7.2,13.9Hz),0.95(9H,s),0.15(6H,s). [ka]

[0082] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoate A stirred solution of 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoic acid (1.30 g, 3.65 mmol) in DCM (20 mL) containing 1 drop of DMF (45 μL) was treated dropwise with oxalyl chloride (0.64 mL, 7.3 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 10 min, then the cooling bath was removed and the reaction mixture was stirred overnight while warming to room temperature. The mixture was concentrated in vacuo, and the crude acid chloride intermediate was azeotroped with toluene (20 mL) to give 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-phenylpropanoyl chloride as a pale yellow oil. This was dissolved in dry toluene (20 mL) and tropine (0.51 g, 3.7 mmol) and triethylamine (1.5 mL, 11.0 mmol) were added. The resulting mixture was stirred at 110° C. for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with water, saturated NaHCO, brine, dried (NaSO), and concentrated in vacuo. The product was purified on silica (25 g, 0-10% (2M NH in MeOH) in DCM) to give the pure title compound as a colorless syrup (0.778 g, 44%). 1 H NMR(400MHz,CDCl3):δ 7.34-7.21(5H,m),7.02-6.94(2H,m),6.73-6.66(2H,m),4.90(1H,t,J=5. 3Hz),3.73(1H,dd,J=6.6,9Hz),3.35(1H,dd,J=9,13.8Hz),2.95(1H,dd,J= 6.6,13.8Hz),2.98-2.89(2H,m),2.19(3H,s),2.05-1.94(2H,m),1.87-1. 68(2H,m),1.60-1.51(2H,m),1.50-1.35(3H,m),0.96(9H,s),0.16(6H,s). [ka]

[0083] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxybenzyl)-2-phenylpropanoate formate A solution of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-((tert-butyldimethylsilyl)oxy)-phenyl)-2-phenylpropanoate (0.77 g, 1.61 mmol) in DMF (10 mL) was treated with paraformaldehyde (0.072 g, 2.4 mmol), and 21% sodium ethoxide in ethanol (0.06 mL, 0.16 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 6.5 hours, and a second portion of paraformaldehyde (0.072 g, 2.4 mmol) and 21% sodium ethoxide in ethanol (0.06 mL, 0.15 mmol) was added, and the mixture was stirred overnight. A third portion of paraformaldehyde (0.072 g, 2.4 mmol) and a 21% solution of sodium ethoxide in ethanol (0.06 mL, 0.15 mmol) were added, and stirring was continued at room temperature for 3 days. The reaction mixture was diluted with EtOAc (100 mL), washed with water, 5% aqueous lithium chloride, brine, dried (NaSO), and concentrated in vacuo. The product was partially purified on 15 μm silica (4 g, 0-20% (2 M NH in MeOH) in DCM) to give the impure title compound as a white solid, which was purified by reverse-phase preparative HPLC using a Kinetix Axia® C18 21.2 × 250 mm column, 18 mL / min, eluting with a gradient of 10-60% MeCN in water containing 0.1% HCOOH, with UV monochromatic detection at 220 nm, to give the title compound as a white solid (0.273 g, 38%). 1H NMR(400MHz,d6-DMSO):δ 8.31(1H,s),7.34-7.26(2H,m),7.26-7.19(1H,m),7.10-7.02(2H,m),6.63(2H,dm,J=8. 5Hz),6.49(2H,dm,J=8.5Hz),4.91(1H,t,J=4.9Hz),4.48-3.60(3H,bs),3.95(1H,d,J=10 Hz),3.77(1H,d,J=10Hz),3.26(1H,d,J=13.3Hz),3.25-3.16(2H,m),3.13(1H,d,J=13.3H z),2.28(3H,s),2.19-2.09(2H,m),1.80-1.41(5H,m),1.26-1.17(1H,m);LCMS(ESI)[MH] + 396.4. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 26A and 26B, respectively.

[0084] Example 16: Synthesis scheme of 2-fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide [ka] 2-Fluoro-3-hydroxy-2-phenylpropanoic acid A stirred mixture of methyl 2-fluoro-2-phenylpropanoate (1.49 g, 7.62 mmol) and paraformaldehyde (0.55 g, 18.3 mmol) in DMF (5 mL) was treated with 21% sodium ethoxide in ethanol (0.43 mL, 1.14 mmol), and the resulting orange suspension was stirred at room temperature for 3.5 hours. The mixture was diluted with EtOAc, washed with hydrochloric acid, 5% aqueous lithium chloride, and brine, dried (NaSO), and concentrated in vacuo to give crude methyl 2-fluoro-3-hydroxy-2-phenylpropanoate as an orange oil (1.82 g). This was dissolved in a mixture of water (9 mL) and methanol (20 mL), followed by the addition of lithium hydroxide (0.44 g, 18.3 mmol), and the resulting mixture was stirred at room temperature for 4 hours. A solution of hydrogen chloride in 1,4-dioxane (4N, 5 mL, 20 mmol) was added and the mixture was concentrated in vacuo to give the crude title compound as a dark cream solid (2.21 g, quantitative). This material was used without purification. 1 H NMR(400MHz,d6-DMSO):δ 7.58-7.29(5H,m),4.11(1H,dd,J=12.3,30.7Hz),3.79(1H,dd,J=12.3,17.6Hz),3.10-3.09(2H+water,broad s). [ka]

[0085] 2-Fluoro-3-hydroxy-N-((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-phenylpropanamide HATU (3.77 g, 9.9 mmol) was added in three portions to a stirred, ice-cold solution of crude 2-fluoro-3-hydroxy-2-phenylpropanoic acid (2.21 g, 7.6 mmol), 8-methyl-8-azabicyclo[3.2.1]octan-3-amine (1.18 g, 8.4 mmol), and DIPEA (4.0 mL, 22.9 mmol) in DMF (20 mL). The resulting orange mixture was allowed to warm to room temperature and stirred for 40 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water and EtOAc. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with 5% aqueous lithium chloride solution, brine, dried (NaSO), and concentrated in vacuo to give an orange gum. The product was purified on silica (40 g, 15 μm pore size silica, 5-20% (2M NH 3 in MeOH) in DCM) to give the title compound as a pale yellow solid (0.631 g, 27%). 1 H NMR(400MHz,d6-DMSO):δ 7.84(1H,bs),7.63-7.47(2H,m),7.44-7.33(3H,m),5.45(1H,t,J=5.8Hz),4.12(1H,ddd,J=6.3,12 .3,33Hz),3.80-3.67(2H,m),3.61-3.47(2H,m),2.49(3H,bs),2.25-1.86(8H,m);LCMS(ESI)[M+H] + 307.2. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 37A and 37B, respectively.

[0086] Example 17: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate [ka] Methyl 3-(4-fluorophenyl)-2-phenylpropanoate 2 M lithium diisopropylamine (10 mL, 20 mmol) in THF / heptane / ethylbenzene was added to a stirred solution of methyl phenyl acetate (3.00 g, 20.0 mmol) in dry THF (40 mL) under argon at −30° C. After stirring for 15 min, the reaction mixture was allowed to warm to 0° C. and stirred for 30 min. The reaction mixture was cooled to −30° C., and a solution of 4-fluorobenzyl bromide (4.10 g, 21.7 mmol) in dry THF (10 mL) was added dropwise, maintaining the temperature below −25° C. The resulting mixture was stirred for 10 min and then allowed to warm to room temperature over 16 h. The solvent was removed in vacuo, and the residue was diluted with EtOAc, washed with water and brine, and the layers were separated. The organic fraction was dried (NaSO) and concentrated in vacuo. The residue was purified on silica (40 g, 0-10% MTBE in cyclohexane) to give the title compound as a pale yellow oil (1.51 g, 29%), which was impure but used without further purification. 1 H NMR(400MHz,CDCl3):δ 7.33-7.26(5H,m),7.08-7.03(2H,m),6.93-6.88(2H,m),3.81-3.77(1H,m),3.37(1H,dd,J=8.7,13.8Hz),2.99(1H,ddd,J=4.1,6.7,13.5Hz). [ka]

[0087] 3-(4-fluorophenyl)-2-phenylpropanoic acid Methyl 3-(4-fluorophenyl)-2-phenylpropanoate (1.51 g, 5.9 mmol) was stirred in THF (30 mL) and MeOH (3 mL) and treated with 2 M NaOH (aq) (12 mL, 24.0 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo, and the residue was diluted with HO and washed with EtOAc. The aqueous fraction was acidified to pH 1.0 with 1 M HCl and extracted with EtOAc. The combined organic extracts were dried (MgSO) and concentrated in vacuo to give the title compound as a light brown oil that crystallized on standing (1.13 g, 79%). The material was used without purification. 1 H NMR(400MHz,CDCl3):δ 7.34-7.27(5H,m),7.06(2H,ddd,J=3.1,5.3,11.8Hz),6.93-6.88(2H,m),3.81(1H,dd,J =7.1,8.4Hz),3.37(1H,dd,J=8.4,13.9Hz),3.01(1H,dd,J=7.1,13.9Hz);LCMS(ESI)[MH] - 243. [ka]

[0088] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-fluorophenyl)-2-phenylpropanoate A stirred solution of 3-(4-fluorophenyl)-2-phenylpropanoic acid (1.13 g, 4.6 mmol) in DCM (10 mL) containing DMF (200 μL) was treated dropwise with oxalyl chloride (573 μL, 6.6 mmol) under argon at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes and then allowed to warm to room temperature and stir for 18 hours. The solvent was removed in vacuo, and the residue was azeotroped with toluene (2×15 mL) to give the crude acid chloride, which was stirred with (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (790 mg, 5.6 mmol) in dry toluene (10 mL) at 100° C. under argon for 4 hours. The reaction mixture was concentrated in vacuo and the residue was treated with DCM (60 mL) and HO (40 mL) and basified with 1 M NaOH (aq) to pH 10. The organic fraction was separated, washed with brine, dried (MgSO) and concentrated in vacuo to give the crude product as a pale yellow oil (1.27 g), which was used crude without purification. 1 H NMR(400MHz,CDCl3):δ 7.26(4H,s),7.19-7.07(3H,m),6.94-6.89(2H,m),4.99-4.89(1H,m),3.73(1H,dd,J=6.8,8.8Hz),3.40(1H,dd,J=8.8,1 3.8Hz),3.03-2.88(3H,m),2.36-2.32(2H,m),2.25-2.20(3H,m),2.09-1.43(5H,m),1.36-1.25(1H,m);LCMS(ESI)[M+H] + 368.1. [ka]

[0089] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-fluorobenzyl)-3-hydroxy-2-phenylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(4-fluorophenyl)-2-phenylpropanoate (154 mg, 0.4 mmol) in DMF (3 mL) was treated with paraformaldehyde (160 mg, 5.3 mmol), followed by 21% sodium ethoxide solution (4 μL, 0.05 mmol) and stirred at 50 ± 5 °C for 24 h. The reaction mixture was cooled, diluted with DCM (15 mL), and filtered through Celite. The filtrate was concentrated to a low volume in vacuo and purified on silica (4 g, 0–10% 2M NH3 / MeOH in DCM) to give the title compound as a white solid (108 mg). This was further purified by HPLC, Kinetix Axia C18 RP column (long) using 10–60% CH3CN in HO [0.1% HCOOH] at 18 mL / min over a 10 min gradient (UV at 200 nm) to give the title compound as a white solid (64 mg, 38%). 1 H NMR(400MHz,CDCl3):δ 7.38-7.27(3H,m),7.16-7.12(2H,m),6.90-6.85(4H,m),5.15(1H,t,J=5.1Hz),4.12-4.08(1H,m),3.98(1H,d,J=10.6Hz,),3. 50-3.34(4H,m),2.61-2.53(3H,m),2.52(4H,s),1.91-1.80(2H,m),1.75(2H,d,J=16.4Hz),1.62-1.48(2H,m);LCMS(ESI)[M+H] + 398.3. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 28A and 28B, respectively.

[0090] Example 18: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate [ka] Methyl 2-phenyl-3-(p-tolyl)propanoate Potassium tert-butoxide (4.08 g, 22.1 mmol) was added to a stirred solution of methyl phenyl acetate (3.00 g, 20 mmol) in dry THF (30 mL) at 0 °C under argon. After stirring for 15 min, a solution of 4-methylbenzyl bromide in dry THF (10 mL) was added dropwise, maintaining the temperature below 5 °C. The resulting mixture was stirred for 10 min and then allowed to warm to room temperature over 16 h. The resulting mixture was diluted with EtOAc and washed with water and then brine. The organic fraction was dried (NaSO) and concentrated in vacuo to give the crude product as a yellow oil. This was purified on silica (40 g 0–25% EtOAc in cyclohexane) to give the title compound as a pale yellow oil (3.60 g 70%), which was used impure without further purification. [ka]

[0091] 2-phenyl-3-(p-tolyl)propanoic acid Methyl 2-phenyl-3-(p-tolyl)propanoate (3.60 g, 14.2 mmol) in THF (60 mL) and MeOH (6 mL) was treated with 2 M NaOH (aq) (20 mL, 40 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (100 mL) and washed with EtOAc. The aqueous fraction was acidified to pH 1.0 with 1 M HCl and extracted with EtOAc. The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound as a light brown oil that crystallized on standing (1.67 g, 49%). Used without purification. 1 H NMR(400MHz,CDCl3):δ 7.31(3H,d,J=4.3Hz),7.29-7.27(2H,m),7.02(4H,dd,J=8.2,12.7Hz),3.84(1H,dd,J =6.8,8.6Hz),3.37(1H,dd,J=8.6,13.9Hz),3.00(1H,dd,J=6.8,13.9Hz),2.29(3H,s). [ka]

[0092] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-phenyl-3-(p-tolyl)propanoate A stirred solution of 2-phenyl-3-(p-tolyl)propanoic acid (1.0 g, 4.2 mmol) in DCM (10 mL) containing DMF (200 μL) was treated dropwise with oxalyl chloride (518 μL, 5.9 mmol) under argon at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene (2×15 mL) to give the crude acid chloride. This was stirred with (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (710 mg, 5.1 mmol) in dry toluene (10 mL) at 100° C. under argon for 4 hours. The reaction mixture was concentrated in vacuo. The resulting residue was treated with DCM (60 mL) and water (40 mL) and basified to pH 10 with 1 M NaOH (aq). The organic fraction was separated, washed with brine, dried (MgSO), and concentrated in vacuo. The residue was purified on silica (12 g, 0-10% 2 M NH / MeOH in DCM) to give the title compound as a light brown oil (688 mg 45%). 1 H NMR(400MHz,CDCl3):δ 7.33-7.25(5H,m),7.03(4H,m),4.88(1H,m),3.78-3.72(1H,m),3.38(1H,m),3.18(1H,m)3.02- 2.88(3H,m),2.89,(3H,s),2.17(3H,s),2.07-1.91(4H,m),1.63-1.44(3H,m);LCMS(ESI)[M+H] + 364.2. [ka]

[0093] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methylbenzyl)-2-phenylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-phenyl-3-(p-tolyl)propanoate (688 mg, 1.9 mmol) in DMF (10 mL) was treated with paraformaldehyde (722 mg, 24.0 mmol) followed by 21% sodium ethoxide solution (20 μL, 0.054 mmol) and stirred for 24 h at 50±5° C. The reaction mixture was diluted with DCM (50 mL) and filtered through Celite. The filtrate was concentrated in vacuo, the residue was purified on silica (12 g 0–10% 2M NH / MeOH in DCM), and the resulting residue was further purified by HPLC, Kinetix Axia C18 RP column (long) using 10–60% CHCN in HO [0.1% HCOOH] over a 10 min gradient at 18 mL / min (UV=200 nm) to give the title compound as a white solid (260 mg, 35%). 1 H NMR(400MHz,CDCl3):δ 7.38-7.33(2H,m),7.31-7.27(1H,m),7.20(2H,d,J=7.3Hz,),7.01-6.97(2H,m),6.87-6.83(2H,m),5.14(1H,t,J=5.0Hz),4.04(2H,q,J =11.0Hz),3.49-3.34(5H,m),2.62-2.55(2H,m),2.52(3H,s),2.29-2.27(3H,m),1.87-1.69(4H,m),1.63-1.46(2H,m);LCMS(ESI)[M+H] + 394.3. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 29A and 29B, respectively.

[0094] Example 19: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate [ka] Methyl 3-(3-chlorophenyl)-2-phenylpropanoate 1 M Sodium bis(trimethylsilyl)amide in THF (20 mL, 20 mmol) was added dropwise to a stirred solution of methyl phenyl acetate (3.00 g, 20.0 mmol) and 3-chlorobenzyl chloride (3.16 g, 19.6 mmol) in dry THF (40 mL) under argon at −78° C., maintaining the temperature below −65° C. The reaction mixture was stirred for 1 h and then allowed to warm to room temperature over 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with EtOAc, washed with water, and then washed with brine. The organic fraction was dried (NaSO) and concentrated in vacuo to give the crude product as a yellow oil (5.48 g, 100%), which was used crude without purification. 1 H NMR(400MHz,CDCl3):δ 7.32-7.26(6H,m),7.16-7.14(2H,m),7.13-7.10(1H,m),3.82(1H,dd,J=6.7,9 .2Hz),3.61(3H,s),3.39(1H,dd,J=13.6,9.6Hz),2.99(1H,dd,J=13.6,6.8Hz). [ka]

[0095] 3-(3-chlorophenyl)-2-phenylpropanoic acid Methyl 3-(3-chlorophenyl)-2-phenylpropanoate (5.48 g, 20 mmol) in a mixture of THF (70 mL) and MeOH (7 mL) was treated with 2 M NaOH (aq) (28.5 mL, 57 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water and washed with EtOAc. The aqueous fraction was acidified to pH 1.0 with 1 M HCl and extracted with EtOAc. The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude product as a yellow oil that crystallized on standing (3.82 g 73%). Used without purification. 1 H NMR(400MHz,CDCl3):δ 7.34-7.27(5H,m),7.16-7.11(3H,m),7.00-6.96(1H,m),3.84(1H,dd,J=7.0,8.5Hz),3.38(1H,dd,J=8.5,13.9Hz),3.01(1H,dd,J=7.0,13.9Hz). [ka]

[0096] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(3-chlorophenyl)-2-phenylpropanoate A stirred solution of 3-(3-chlorophenyl)-2-phenylpropanoic acid (2.0 g, 7.7 mmol) in DCM (20 mL) containing DMF (300 μL) was treated dropwise with oxalyl chloride (955 μL, 5.9 mmol) under argon at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene (2×15 mL) to give the crude acid chloride. The resulting residue was stirred with (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (1.31 g, 9.3 mmol) in dry toluene (10 mL) at 100° C. under argon for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was treated with DCM (60 mL) and water (40 mL) and basified to pH 10 with 1 M NaOH (aq). The organic fraction was separated, washed with brine, dried (MgSO), and concentrated in vacuo. The residue was purified on silica (40 g, 0-10% 2 M NH / MeOH in DCM) to give the title compound as a light brown oil (1.06 g, 36%). 1 H NMR(400MHz,CDCl3):δ 7.33-7.26(5H,m),7.16-7.15(3H,m),7.03-7.00(1H,m),4.91(1H,t,J=5.4Hz),3.75(1H,dd,J=6.5,9.0Hz),3.48 (2H,s),3.03-2.91(2H,m),2.19(3H,s),2.07-1.94(3H,m),1.83-1.42(4H,m),1.36-1.28(1H,m);LCMS(ESI)[M+H] + 384.1 / 386.1. [ka]

[0097] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorobenzyl)-3-hydroxy-2-phenylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-(3-chlorophenyl)-2-phenylpropanoate (1.10 g, 2.9 mmol) in DMF (15 mL) was treated with paraformaldehyde (1.10 g, 36.0 mmol), followed by 21% sodium ethoxide solution (30 μL, 0.006 mmol) and stirred at 100 ± 5 °C for 24 h. The reaction mixture was diluted with DCM (50 mL) and filtered through Celite. The filtrate was concentrated in vacuo, and the residue was purified on silica (24 g, 0-10% 2M NH3 / MeOH in DCM). The product was further purified by HPLC, Kinetix Axia C18 RP column (long) using 10–60% CH3CN in HO [0.1% HCOOH] over a 10 min gradient at 18 mL / min (UV = 200 nm) to give the product as a white solid (554 mg, 50%). 1 H NMR(400MHz,CDCl3):δ 7.38-7.27(3H,m),7.16-7.06(4H,m),6.91(1H,t,J=1.7Hz),6.79(1H,d,J=7.6Hz),5.16(1H,t,J=5.0Hz),4.10(1H,d,J=10.6Hz),3.98(1H,d, LCMS(ESI)[M+H] + 414.2. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 30A and 30B, respectively.

[0098] Example 20: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate [ka] 2-(3-chlorophenyl)propanoic acid Methyl 2-(3-chlorophenyl)propanoate (590 mg, 2.97 mmol) in THF (12 mL) and MeOH (1 mL) at room temperature was treated with 2 N NaOH (aq) (4.2 mL, 8.41 mmol) and stirred overnight. The reaction mixture was concentrated in vacuo, and the resulting aqueous layer was acidified to pH 1 with 1 N HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified on silica (40 g 0-30% EtOAc in cyclohexane) to give the title compound as a pale yellow oil (229 mg, 42%). 1 H NMR (400MHz, CDCl3): δ 7.34-7.15(4H,m),3.72(1H,q,J=7.3Hz),1.51(3H,d,J=7.3Hz). [ka]

[0099] 2-(3-chlorophenyl)propanoyl chloride A stirred solution of 2-(3-chlorophenyl)propanoic acid (229 mg, 1.24 mmol) in DCM (3 mL) containing DMF (55 μL) was treated dropwise with oxalyl chloride (150 μL, 1.77 mmol) at 0° C. under argon. The resulting mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo to give the crude title compound, which was used immediately without purification. [ka]

[0100] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)propanoate The crude 2-(3-chlorophenyl)propanoyl chloride was stirred in dry toluene (3 mL) with tropine (214 mg, 1.51 mmol) at 100° C. under argon for 3 h. The reaction mixture was concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified on silica (40 g 0-10% 2N NH3MeOH in DCM) to give the title compound as a yellow oil (272 mg, 71%). LCMS (ESI) [M+H] + 308.2. [ka]

[0101] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)-3-hydroxy-2-methylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(3-chlorophenyl)propanoate (337 mg, 1.09 mmol) in DMF (2.5 mL) was treated with paraformaldehyde (49 mg, 1.64 mmol), followed by 21% sodium ethoxide solution (4.3 μL, 0.055 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The combined aqueous fractions were then basified to pH 13 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo. The resulting residue was purified on silica (40 g, 0–10% 2N NH3MeOH in DCM) to give the title compound as an off-white solid (193 mg, 52%). 1H NMR(400MHz,CDCl3):δ 7.34-7.26(3H,m),7.23-7.17(1H,m),5.06(1H,t,J=5.4Hz),4.07(1H,d,J=11. 3Hz),4.64(1H,d,J=11.3Hz),3.06-3.00(1H,m),2.99-2.93(1H,m),2.57(1H,br s),2.21(3H,m),2.16-2.03(2H,m),1.93-1.82(1H,m),1.80-1.69(1H,m),1.67( 3H,s),1.66-1.56(2H,m),1.51-1.44(1H,m),1.27-1.17(1H,m);LCMS(ESI)[M+H] + 338.12. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 31A and 31B, respectively.

[0102] Example 21: Synthesis scheme of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-methoxybenzyl)-2-phenylpropanoate [ka] 2-(4-chlorophenyl)propanoic acid Methyl 2-(4-chlorophenyl)propanoate (547 mg, 2.75 mmol) in THF (12 mL) and MeOH (1 mL) at room temperature was treated with 2 N NaOH (aq) (3.9 mL, 7.79 mmol) and stirred for 8 h. The reaction mixture was concentrated in vacuo, and the resulting aqueous layer was acidified to pH 1 with 1 N HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo. The residue was purified on silica (40 g 0-30% EtOAc in cyclohexane) to give the title compound as an off-white solid (137 mg, 27%). 1 H NMR (400MHz, CDCl3): δ 7.35-7.16(4H,m),3.71(1H,q,J=9.4Hz),1.49(3H,d,J=9.6Hz). [ka]

[0103] 2-(4-chlorophenyl)propanoyl chloride A stirred solution of 2-(4-chlorophenyl)propanoic acid (265 mg, 1.44 mmol) in DCM (4 mL) containing DMF (70 μL) was treated dropwise with oxalyl chloride (180 μL, 2.05 mmol) at 0° C. under argon. The resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated in vacuo to give the crude title compound, which was used immediately without purification. [ka]

[0104] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-chlorophenyl)propanoate The crude 2-(4-chlorophenyl)propanoyl chloride was stirred with tropine (247 mg, 1.75 mmol) in dry toluene (4 mL) at 100° C. under argon overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and extracted with 1N HCl. The combined aqueous fractions were then basified to pH 13 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a brown oil, which was used crude in the next reaction (230 mg, 52%). LCMS (ESI) [M+H] + 308.1. [ka]

[0105] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-chlorophenyl)-3-hydroxy-2-methylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-chlorophenyl)propanoate (230 mg, 0.75 mmol) in DMF (2 mL) was treated with paraformaldehyde (34 mg, 1.12 mmol), followed by 21% sodium ethoxide solution (3 μL, 0.037 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Additional paraformaldehyde (34 mg, 1.12 mmol) was added, followed by 21% sodium ethoxide solution (3 μL, 0.037 mmol), and stirring was continued at room temperature for 1 hour. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The combined aqueous fractions were then basified to pH 13 with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified on silica (40 g, 0-10% 2N NH3MeOH in DCM) to give the title compound as an off-white solid (118 mg, 47%). 1 H NMR(400MHz,CDCl3):δ 7.36-7.31(2H,m),7.28-7.22(2H,m),5.06(1H,t,J=5.5Hz),4.05(1H,d,J=11. 1Hz),3.62(1H,d,J=11.1Hz),3.06-3.00(1H,m),2.99-2.92(1H,m),2.52(1H,br s),2.21(3H,s),2.16-2.01(2H,m),1.93-1.82(1H,m),1.80(1H,m),1.67(3H, s),1.65-1.56(2H,m),1.49-1.42(1H,m),1.25-1.15(1H,m);LCMS(ESI).[M+H] + 338.1. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 32A and 32B, respectively.

[0106] Example 22: Synthesis scheme for (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(benzyloxy)phenyl)propanoate [ka] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(benzyloxy)phenyl)propanoate To a solution of 2-(4-(benzyloxy)phenyl)propanoyl chloride (1.61 g, 5.86 mmol) in toluene (20 mL) was added tropine (750 mg, 5.33 mmol) and the reaction was stirred at 90° C. for 3 hours, then at 50° C. for 16 hours. The reaction was diluted with 1N HCl, extracted with EtOAc, and the organics were discarded. The combined aqueous fractions were basified with 1N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the title compound (750 mg, 37%). 1 H NMR(400MHz,CDCl3)δ 7.47-7.29(5H,m),7.23-7.19(2H,m),6.97-6.90(2H,m),5.06(2H,s),4.94(1H,t,J=5.3Hz),3.62(1H,q,7.1Hz),3.06-3.00(1H,m ),2.98-2.93(1H,m),2.22(3H,s),2.12-1.98(3H,m),1.92-1.57(4H,m),1.48(3H,d,J=7.2Hz),1.43-1.35(1H,m).LCMS(ESI)[M+H] + 380.2,R t =0.97min (Method 2). [ka]

[0107] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(benzyloxy)phenyl)-3-hydroxy-2-methylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(benzyloxy)phenyl)propanoate (750 mg, 1.98 mmol) in DMF (8 mL) was treated with paraformaldehyde (89 mg, 2.96 mmol), followed by 21% sodium ethoxide solution (37 μL, 0.10 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and extracted with 1 N HCl. The combined aqueous fractions were basified with 1 N NaOH and extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified on silica (12 g, 0-10% MeOH in DCM) to give the title compound (685 mg, 85%). 1 H NMR(400MHz,CDCl3)δ 7.45-7.29(5H,m),7.25-7.20(2H,m),6.99-6.92(2H,m),5.06(2H,s),5.04(1H,t,J=5.5Hz),4. 09(1H,d,J=11.1Hz),3.59(1H,d,J=11.2Hz),3.04-2.99(1H,m),2.94-2.89(1H,m),2.50(1H,br s),2.20(3H,s),2.14-1.99(2H,m),1.90-1.78(1H,m),1.74-1.58(6H,m),1.49-1.41(1H,m),1.25-1.14(1H,m).LCMS(ESI)[M+H] + 410.2 R t =0.87min(Method 2). [ka]

[0108] (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-(4-hydroxyphenyl)-2-methylpropanoate (1R,3r,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(4-(benzyloxy)phenyl)-3-hydroxy-2-methylpropanoate (685 mg, 1.67 mmol) in EtOAc (10 mL) and MeOH (3 mL) was treated with palladium on carbon (10% wt, 150 mg) and stirred at room temperature under hydrogen for 16 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified on silica (12 g, 0-10% MeOH in DCM) to give the title compound as a white solid (278 mg, 52%). 1 H NMR (400 MHz, CDCl): δ 7.18-7.12(2H,m),6.77-6.71(2H,m),5.03(1H,t,J=5.1Hz),4.10(1H,d,J=11. 4Hz),3.57(1H,d,J=11.4Hz),3.11-3.05(1H,m),3.01-2.92(1H,m),2.27(3H,s) ,2.17(1H,dt,J=15.2,4.1Hz),2.08(1H,dt,J=15.3,4.3Hz),1.92-1.78(1H,m) ,1.67-1.54(6H,m),1.41(1H,d,J=15.3Hz),1.18-1.07(1H,m);LCMS(ESI)[M+H] + 320.3. The title compound 1 H NMR and 13 The C NMR spectra are shown in Figures 33A and 33B, respectively.

[0109] Example 23: Synthesis scheme for 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine [ka] 2-Nitrobenzoyl Chloride To a solution of 2-nitrobenzoic acid (5 g, 29.9 mmol) in DCM (140 mL) was added 1 drop of DMF, followed by the addition of oxalyl chloride (3.7 mL, 41.9 mmol), resulting in effervescence. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was concentrated in vacuo to give the title compound as a pale yellow oil (5.55 g, quantitative). The material was used without purification.1 H NMR (400MHz, CDCl3): δ 8.13-8.07(1H,m),7.84-7.68(3H,m). [ka]

[0110] N-(2-chloropyridin-3-yl)-2-nitrobenzamide To a solution of 2-nitrobenzoyl chloride (5.55 g, 29.9 mmol) in THF (120 mL) was added pyridine (14.5 mL, 0.18 mol) and 3-amino-2-chloropyridine (4.23 g, 32.9 mmol), causing the formation of a precipitate. The reaction was stirred at room temperature for 2 hours, then diluted with 10% aqueous citric acid and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the product as a tan solid (8.6 g, quantitative). The material was used without purification. 1 H NMR(400MHz,d6-DMSO)δ 10.61(1H,s),8.31(1H,dd,J=4.3,1.5Hz),8.25-8.16(2H,m),7.94-7.87(1H,m),7.84-7.75(2H,m),7.54(1H,dd,J=8.3,4.3Hz). [ka]

[0111] 2-Amino-N-(2-chloropyridin-3-yl)benzamide To a solution of N-(2-chloropyridin-3-yl)-2-nitrobenzamide (8.3 g, 29.9 mmol) in ethanol (100 mL) was added water (20 mL), iron (2.67 g, 47.8 mmol), and ammonium chloride (16 g, 0.3 mol). The mixture was heated at reflux for 40 minutes, then diluted with water and filtered. The filtrate was extracted with ethyl acetate, and the combined organic fractions were washed with brine, dried (MgSO), and concentrated in vacuo to give the title product as a light brown solid (7.4 g, quantitative). The material was used without purification.1 H NMR(400MHz,d6-DMSO)δ 9.93(1H,s),8.29(1H,dd,J=4.7,1.8Hz),8.05(1H,dd,J=7.9,1.8Hz),7.73(1H,dd,J=8.0,1.5Hz),7.48(1H,dd,J=7.8 ,4.7Hz),7.24(1H,ddd,J=8.4,7.1,1.5Hz),6.78(1H,dd,J=8.3,0.9Hz),6.61(1H,ddd,J=8.1,7.2,1.1Hz),6.48(2H,br s). [ka]

[0112] 5,11-Dihydro-6H-benzo[e]pyrido[3,2-b][1,4]diazepin-6-one 2-Amino-N-(2-chloropyridin-3-yl)benzamide (3.5 g, 14.1 mmol) was heated at 210 °C for 5 minutes. Upon reaching 200 °C, the reaction mixture turned black and foaming was observed. The reaction mixture was cooled to room temperature, and the solid residue was washed with saturated aqueous NaHCO3 and then with DCM to give the title product as a gray solid (2.89 g, 96%). The material was used without purification. 1 H NMR(400MHz,d6-DMSO):δ 9.94(1H,s),8.63(1H,s),7.90(1H,dd,J=4.84,1.6Hz),7.72(1H,dd,J=7.9,1.6Hz),7.41 -7.29(2H,m),7.13(1H,dd,J=8.3,0.8Hz),6.97(1H,dd,J=7.8,4.8Hz),6.95-6.89(1H,m). [ka]

[0113] 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine A mixture of 5,11-dihydro-6H-benzo[e]pyrido[3,2-b][1,4]diazepin-6-one (500 mg, 2.37 mmol) and phosphorus pentachloride in chlorobenzene (12 mL) was heated at 100° C. for 4 hours. The reaction mixture was cooled to approximately 4° C., isohexane (10 mL) was added, and the solid was filtered off. The solid was washed with more isohexane (10 mL) and dried in vacuo to give the product as a yellow solid (520 mg, 95%). The material was used without purification. 1 H NMR (400MHz, CDCl3): δ 9.96(1H,s),7.72-7.59(3H,m),7.41(1H,td,J=8.0,1.3Hz),7.16-7.04(3H,m).

[0114] Using 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine obtained in Example 23, pirenzepine of formula (II) of the present invention can be prepared according to the following reaction scheme. [ka] wherein R can be hexyl.

[0115] Example 24 Human muscarinic receptor assay I. Assay Protocols M1-M5 M1 Cell membrane homogenates (45 μg protein) were incubated for 60 minutes at 22°C with 2 nM [H]pirenzepine in a buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl, and 1 mM EDTA, in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μM atropine. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and then counted for radioactivity using a scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). Results were expressed as percent inhibition relative to control radioligand-specific binding. The standard reference compound was pirenzepine, which was tested at several concentrations in each experiment to obtain a competition curve from which its K i and IC 50 Calculate.

[0116] M2 Cell membrane homogenates (60 μg protein) were incubated for 60 minutes at 22°C with 2 nM [H]AF-DX384 in a buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, 5 mM MgCl, and 1 mM EDTA, in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μM atropine. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). Filters were dried and then counted for radioactivity using a scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). Results were expressed as percent inhibition relative to control radioligand-specific binding. The standard reference compound was methoctramine, which was tested at several concentrations in each experiment to obtain a competition curve from which its K i and IC 50 Calculate.

[0117] M3 Cell membrane homogenates (8 μg protein) were incubated for 60 min at 22°C with 0.2 nM [3H]4-DAMP in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μM atropine. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). Filters were dried and radioactivity was counted in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). Results were expressed as percent inhibition relative to control radioligand-specific binding. The standard reference compound was 4-DAMP, which was tested at several concentrations in each experiment to obtain a competition curve from which its K i and IC 50 Calculate.

[0118] M4 Cell membrane homogenates (16 μg protein) were incubated for 60 minutes at 22°C with 0.2 nM [H]4-DAMP in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μM atropine. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and then counted for radioactivity using a scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). Results were expressed as percent inhibition relative to control radioligand-specific binding. The standard reference compound was 4-DAMP, which was tested at several concentrations in each experiment to obtain a competition curve and then its K i and IC50 Calculate.

[0119] M5 Cell membrane homogenates (15 μg protein) were incubated for 60 minutes at 22°C with 0.3 nM [H]4-DAMP in a buffer containing 10 mM Tris-HCl (pH 7.4) and 2 mM EDTA in the absence or presence of test compounds. Nonspecific binding was determined in the presence of 1 μM atropine. After incubation, samples were rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and then counted for radioactivity using a scintillation cocktail (Microscint 0, Packard) in a scintillation counter (Topcount, Packard). Results were expressed as percent inhibition relative to control radioligand-specific binding. The standard reference compound was 4-DAMP, which was tested at several concentrations in each experiment to obtain a competition curve and then its K i and IC 50 Calculate.

[0120] II. Binding affinity M1~M5 The results of the human muscarinic receptor assay for some compounds of the invention are shown in the table below.

[0121] [Table 3]

[0122] Results showing greater than 50% inhibition or stimulation are considered to represent significant results for the test compound.

[0123] The compounds of the present invention and their pharmaceutically acceptable salts can be combined with one or more pharmaceutical carriers to form various types of formulations for delivery. For example, topical formulations can be used, which can include ophthalmologically acceptable preservatives, surfactants, thickeners, buffers, sodium chloride, and water to form aqueous, ophthalmologically compatible solutions and suspensions. Suitable topical formulations are described in review articles, such as "Recent Advances in Topical Ocular Drug Delivery" by VK Yellepeddi and S. Palakurthi (J. Ocul. Pharmacol. Ther. 2016, 32(2):67-82), which is incorporated herein by reference in its entirety. Systemic formulations (e.g., tablets taken orally) and formulations for intraocular injection are also contemplated. (Pharmaceutically Acceptable Carriers) Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in the field of pharmaceutical formulations (which is incorporated herein by reference in its entirety).

[0124] The specific type of formulation selected will depend on various factors, including the compound or salt thereof used, the frequency of administration, the location of the condition being treated, the selected route of administration, and standard pharmaceutical practice. Topical, ophthalmologically compatible aqueous solutions, suspensions, ointments, and gels are preferred dosage forms for treating ocular disorders of the anterior segment of the eye (cornea, iris, trabecular meshwork); or, if the compound can be formulated to be topically deliverable and penetrate tissues in the anterior segment of the eye, for treating ocular disorders of the posterior segment of the eye. The compound according to Formula (I) will typically be included in these formulations in an amount of about 0.01 to about 10.0 weight percent. Preferred concentrations for topical administration range from about 0.1 to about 5.0 weight percent. Thus, for topical administration, these formulations are delivered to the ocular surface one to six times daily, according to the routine judgment of a skilled clinician. Systemic administration, for example, in tablet form, is particularly useful for treating ocular disorders of the posterior segment of the eye, e.g., the retina.

[0125] The compounds of the present invention are preferably incorporated into ophthalmologically compatible formulations for delivery to the eye. The compounds may be combined with ophthalmologically acceptable preservatives, surfactants, thickeners, penetration enhancers, buffers, sodium chloride, and water to form aqueous, sterile ophthalmic suspensions or solutions. Ophthalmic solution formulations can be prepared by dissolving the compounds in a physiologically acceptable isotonic aqueous buffer. Additionally, ophthalmic solutions may contain an ophthalmologically acceptable surfactant to aid in dissolution of the compounds. Furthermore, ophthalmic solutions may contain agents that increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyvinylpyrrolidone, to improve retention of the formulation in the conjunctival sac. Gelling agents, including, but not limited to, gellan and xanthan gum, can also be used. To prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in a suitable vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations can be prepared according to published recipes for similar ophthalmic formulations by suspending the compound in a hydrophilic base prepared from a combination of, for example, Carbopol 974; preservatives and tonicity agents may also be incorporated.

[0126] The pharmaceutical composition may include one or more buffering agents or pH adjusters to provide improved pH control. In certain embodiments for topical use, the pharmaceutical composition of the present invention has a pH of 5.0 to 8.0, 5.0 to 7.0, 6.0 to 8.0, or 6.0 to 7.0. In one embodiment, the pH of the pharmaceutical composition of the present invention is about 6.3 to about 7.3. In a specific embodiment, the aqueous pharmaceutical composition of the present invention has a near-neutral pH of about 6.8.

[0127] Other contemplated excipients that can be used in the pharmaceutical compositions of the invention include, for example, antimicrobial agents, antioxidants, antistatic agents, lipids such as phospholipids or fatty acids, steroids such as cholesterol, protein excipients such as serum albumin (human serum albumin), recombinant human albumin, gelatin, casein, and salt-forming counterions such as sodium. These and additional known pharmaceutical excipients and / or additives suitable for use in the formulations of the invention can be found, for example, in "The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: The Science and Practice of Pharmacy, 21 st edition, Gennaro, Ed., Lippincott Williams & Wilkins (2005), and are known in the art.

[0128] In another aspect, the present invention provides (1) a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier. In one embodiment, the composition comprises a therapeutically effective amount, preferably about 0.01 to about 10.0 weight percent, more preferably about 0.01 to about 5 weight / volume percent, or about 0.1 to 5.0 weight percent, of (a) the compound and / or (b) the pharmaceutically acceptable salt. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For purposes of the present invention, solvates and hydrates are generally considered compositions unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be made up into a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional formulation procedures such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as auxiliary substances such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffers.

[0129] In another embodiment of the invention, the pharmaceutical composition is a tablet or gelatin capsule comprising the active ingredient together with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; in tablets, further c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavoring agents, and sweetening agents.

[0130] Tablets may be film coated or enteric coated according to methods known in the art.

[0131] The pharmaceutical compositions of the present invention may contain additional therapeutic agents in addition to the compounds of the present invention. The additional therapeutic agents may include, for example, other compounds and antibodies useful in treating ocular diseases.

[0132] The pharmaceutical compositions of the present invention can be administered to a patient. As used herein, the term "subject" or "patient" refers to human and non-human mammals, including, but not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows. Preferably, the subject or patient is a human.

[0133] Various delivery methods for administration of the pharmaceutical compositions are contemplated and may include, for example, topical, intravitreal, oral, IV, intracameral, and other methods known to those skilled in the art.

[0134] In one embodiment, administration will typically be by syringe.Therefore, the present invention provides a delivery device (e.g., syringe) containing the pharmaceutical composition of the present invention (e.g., pre-filled syringe).The patient receives an effective amount of the compound according to formula (I) as the main active ingredient.

[0135] In yet another embodiment, an intraocular insert or film is used to deliver the compounds of the present invention. In one such embodiment, the compound of Formula (I) is formulated in a polymeric intraocular insert comprising one or more mucoadhesive polymers that are biocompatible with the ocular surface and the ocular tear film. In certain embodiments, upon insertion of the polymeric intraocular insert into the cul-de-sac of the eye, the tear film thickness can increase for at least 30 minutes after insertion. The one or more mucoadhesive polymers can be selected from the group consisting of hyaluronic acid (acid or salt form), hydroxypropyl methylcellulose (HPMC), methylcellulose, tamarind seed polysaccharide (TSP), guar, hydroxypropyl guar (HP guar), scleroglucan poloxamer, poly(galacturonic) acid, sodium alginate, pectin, xanthan gum, xyloglucan gum, chitosan, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidine, carbomer, polyacrylic acid, and combinations thereof. In one embodiment of the present disclosure, the one or more mucoadhesive polymers may be HP guar, hyaluronic acid, and sodium hyaluronate.

[0136] The present invention further provides a method of delivering a compound according to formula (I) to a patient, comprising administering to the patient one or more times daily a pharmaceutical composition of the invention.

[0137] As used herein, all percentages are percentages by weight unless otherwise specified. Unless otherwise specified, the terms "a" and "an" shall mean "one," "at least one," or "one or more." Unless the context requires otherwise, singular terms used herein shall include pluralities and plural terms shall include the singular. For clarity, the contents of the patents, patent applications, and references cited throughout this specification are hereby incorporated by reference in their entireties.

[0138] Formulation Examples The following examples are included to illustrate embodiments of the invention. Those of skill in the art will recognize that changes can be made to the specific embodiments described herein and still obtain similar results without departing from the spirit and scope of the invention.

[0139] [Table 4]

[0140] The present invention and its embodiments have been described in detail. However, it is not intended that the scope of the present invention be limited to the particular embodiments of the processes, manufacture, compositions, compounds, means, methods, and / or steps described herein. Various modifications, substitutions, and variations can be made to the disclosed materials without departing from the spirit and / or essential characteristics of the invention. Accordingly, those skilled in the art will readily recognize from this disclosure that subsequent modifications, substitutions, and / or variations that perform substantially the same function or achieve substantially the same results as the embodiments described herein may be utilized in accordance with such related embodiments of the invention. Therefore, the following claims are intended to include within their scope such modifications, substitutions, and variations to the processes, manufacture, compositions, compounds, means, methods, and / or steps disclosed herein. The claims should not be read as limited to the described order or elements unless stated to that effect. It is to be understood that various changes in form and detail can be made without departing from the scope of the appended claims.

Claims

1. 1. An ophthalmic pharmaceutical composition for treating a mammalian subject having or at risk of having an ophthalmic disorder associated with modulation of muscarinic receptors, the composition being ophthalmologically compatible and comprising: (1) A compound and / or a pharmaceutically acceptable salt thereof (the compound is 【Chemistry 1】 (2) One or more pharmaceutically acceptable carriers 1. An ophthalmic pharmaceutical composition comprising:

2. 2. The ophthalmic pharmaceutical composition of claim 1, comprising a therapeutically effective amount of the compound and / or a pharmaceutically acceptable salt thereof.

3. 3. The ophthalmic pharmaceutical composition of claim 2, comprising about 0.01 to about 10.0 weight percent of the compound and / or its pharmaceutically acceptable salt.

4. 3. The ophthalmic pharmaceutical composition of claim 2, comprising about 0.01 percent weight / volume to about 5 percent weight / volume of the compound and / or a pharmaceutically acceptable salt thereof; or about 0.1 to 5.0 percent by weight of the compound and / or a pharmaceutically acceptable salt thereof.

5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, which is used to administer to the subject an effective amount of the compound according to any one of claims 1 to 4 and / or a pharmaceutically acceptable salt thereof.

6. 1. Use of a compound and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a mammalian subject having or at risk of having an eye disease associated with modulation of a muscarinic receptor, wherein said compound comprises: 【Chemistry 2】 ,use.

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